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ISSN 0021-2571 (print) · 2384-8553 (online) | Coden: AISSAW 55 (No. 3) | 203-309 (2019)

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ISSN 0021-2571 (print), 2384-8553 (online)Coden: AISSAW 55 (No. 3)

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Reg. Stampa - Tribunale di Roma, n. 482 del 29 ottobre 1985 (cartaceo); n. 121 del 16 maggio 2014 (online)

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AnnAlidell’Istituto Superiore di SanitàA science journAl for public heAlth

Ann Ist Super Sanità 2019 | Vol. 55, No. 3

President of the Istituto Superiore di SanitàSilvio Brusaferro

Responsible DirectorPaola De Castro

Editor-in-chiefEnrico Alleva Istituto Superiore di Sanità

Assistant EditorFederica Napolitani CheyneIstituto Superiore di Sanità

Scientific CommitteeEnrico Alleva, Luca Busani, Pietro Comba, Paola De Castro, Paola Fattibene, Alessandro Giuliani, Giovanni Rezza, Emanuele Scafato, Stefano Vella Istituto Superiore di Sanità

Editorial OfficeAnnarita Barbaro, Maria Cristina Barbaro, Alessandra Fuglieni, Federica Napolitani Cheyne, Laura RadiciottiIstituto Superiore di Sanità

Editorial Advisory BoardDino Amadori Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy Jacqueline N. Crawley Laboratory of Behavioral Neuroscience, NIMH, NIH, Bethesda, USAJean-François Delfraissy Agence Nationale de Recherches sur le sida et les hépatites virales, Paris, FranceChris Beyrer Johns Hopkins Bloomberg School of Public Health, Baltimore, USATony Fletcher London School of Hygiene & Tropical Medicine, London, UKSui Huang Institute for Systems Biology, Seattle, USA Ana Marušic Dept of Research in Biomedicine and Health, University of Split School of Medicine, Croatia Stefania Maggi CNR Aging Branch Institute of Neuroscience, Padova, Italy Francesco M. Marincola Infectious Disease and Immunogenetics Section, NIH, Bethesda, USAJuana Martín de las Mulas González-Albo Dpto de Anatomía y Anatomía Patológica Comparada, Facultad de Veterinaria, UCO, Córdoba, SpainPatrick Smeesters Université Catholique de Louvain, Louvain-La-Neuve, BelgiumDavid Vlahov School of Nursing, University of California, San Francisco, CA, USABernard Zalc (Boris) Centre de Recherche de l’Institut du Cerveau et de la Moelle epiniere, UPMC, Paris, France

Graphic design of the cover: Massimo Delle Femmine, Istituto Superiore di Sanità

The photograph on the cover is an optical microscope image of Alternaria alternata (at a 100x magnification)by Anna Maria Coccia, Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy

AnnAlidell’Istituto Superiore di SanitàA science journAl for public heAlth



Contents

Vol. 55, No. 3 2019

AnnAlidell’Istituto Superiore di Sanità

letter

203 The microbial safety of edible insects: a matter of processingGuglielmo Bonaccorsi, Enrico Simoncini, Donella Gestri, Mariella Talini, Sara Tesi, Fabio Rastelli, Giovanni Nardone and Chiara Lorini

OriginAl Articles And reviews

205 A combination of infrared spectroscopy and morphological analysis allows successfully identifying rare crystals and atypical urinary stones Aniello Primiano, Silvia Persichilli, Pietro Manuel Ferraro, Angelo Minucci, Giovanni Gambaro, Andrea Urbani and Jacopo Gervasoni

209 Factors predicting health science students’ willingness to be vaccinated against seasonal flu during the next campaignVincenza Gianfredi, Giulia Dallagiacoma, Sandro Provenzano and Omar Enzo Santangelo

217 Estimated burden of Chlamydia trachomatis female infection and consequent severe pelvic inflammatory disease, Italy, 2005-2016Michela Sabbatucci, Maria Cristina Salfa, Vincenza Regine, Patrizio Pezzotti and Barbara Suligoi

224 Design and hygiene issues in sports facilities. A pilot study which investigates fitness centres by using a multidisciplinary toolMarco Gola, Lisa Gaviraghi, Lorenzo Mario Capasso, Alessandro Cuda, Daniela D’Alessandro, Caterina Bertolini, Simona Riboli and Stefano Capolongo

233 Polypharmacy in the general population of a Northern Italian area: analysis of administrative dataFrancesca Valent

240 Training in pediatric palliative care in Italy: still much to doFranca Benini, Chiara Cauzzo, Sabrina Congedi, Liviana Da Dalt, Paola Cogo, Lilia Biscaglia and Luca Giacomelli

Brief nOtes

246 Integrated gastroenterology and rheumatology ambulatory: an innovative approach for enteropathic spondyloarthritis early diagnosisRoberto Lorenzetti, Palma Scolieri, Alessandra Guarini, Francesca De Marinis, Angelo Zullo, Cesare Hassan and Vincenzo Bruzzese on behalf of the Italian Society of Gastro-Rheumatology

MOnOgrAphic sectiOn

Health systems sustainability for rare diseasesEdited by Rita Maria Ferrelli, Bernardino Fantini and Domenica Taruscio

249 PrefaceRita Maria Ferrelli, Bernardino Fantini and Domenica Taruscio

251 Value based healthcare for rare diseases: efficiency, efficacy, equityBernardino Fantini and Concetta Maria Vaccaro

258 Primary prevention as an essential factor ensuring sustainability of health systems: the example of congenital anomaliesDomenica Taruscio, Eva Bermejo-Sánchez, Paolo Salerno and Alberto Mantovani

265 Health systems sustainability in the framework of rare diseases actions. Actions on educational programmes and training for professionals and patientsEmilia Severin, Marta De Santis, Rita Maria Ferrelli and Domenica Taruscio

270 Health systems for rare diseases: financial sustainabilityGeorgi Iskrov, Rumen Stefanov and Rita Maria Ferrelli

276 Integrated care for healthcare sustainability for patients living with rare diseasesRaquel Castro and Marta De Santis

283 Patient empowerment of people living with rare diseases. Its contribution to sustainable and resilient healthcare systems Marta De Santis, Clara Hervas, Ariane Weinman, Giulia Bosi and Valentina Bottarelli

292 Resilience in rare disease networksEdmund Jessop

296 Policies and actions to tackle rare diseases at European levelAntoni Montserrat and Domenica Taruscio

305 Book Reviews, Notes and Comments Edited by Federica Napolitani Cheyne

307 Publications from International Organizations on Public Health Edited by Anna Maria Rossi


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Dear Editor,the world population is constantly increasing, and it is widely accepted that, by 2050,

the world will host 9 billion people [1]. Feeding this growing population with more demanding consumers will necessarily require an increase in food production. This will inevitably put more pressure on the planet’s already limited resources.

Several studies suggest that the consumption of edible insects (entomophagy) may be a viable alternative or supplement to conventional protein sources [2-6]. However, in-sects, like many food products, are rich in nutrients and moisture, providing a favorable environment for microbial survival and growth, as already highlighted by several studies [2, 7-11].

Since, as of January 2018, arthropods are considered Novel Food in the European Union (Regulation (EU) 2015/2283), more research data about edible insects are neces-sary, waiting for a future market.

For this reason, samples of edible arthropods, already marketed as souvenir, were pur-chased online from an Italian insect-rearing agricultural holding and analyzed to verify their microbial safety.

Since at present there are no specific microbiological reference criteria for insects, results (Table 1, available online as Supplementary Material) were compared with those reported in the literature both for fresh and processed edible insects.

The total viable aerobic counts and the Enterobacteriaceae counts found in our study were generally lower than those reported for fresh edible insects, while the spore-forming bacteria counts were similar. On the other hand, comparing the results with literature data on processed edible insects, they were higher except for spore-forming bacteria, probably highlighting an inadequate processing or storage.

The bacterial flora found in the analyzed edible insects consists of known food con-taminants, with different risks for human health according to the species and probably the method of insect production [9]. The main aspect in food perspective is not so much the microflora composition of live animals, as the possibility to safely store and preserve derived products. Prevention, detection, identification, and reduction of microbial con-taminants are crucial for a successful and safe insect production. In order to respond to these control needs, the Food and Agricultural Organization (FAO) proposed the adoption, throughout the insect supply chain, of the Hazard Analysis Critical Control Points (HACCP) system [12]. Indeed, HACCP is recognized worldwide as a system for quality assurance, identifying, evaluating and controlling physical, chemical and biologi-cal hazards throughout the production process.

In conclusion, edible insects represent a new and sustainable protein source for hu-mans and have huge potential to meet the challenge of food security in the near future, while limiting the environmental impact of human activities related to food production. In this context, however, scientific data on potential foodborne hazards in edible insects are lacking; literature reveals weakness of evidence and scarcity of data. Although our study is set as an exploratory study based exclusively on a single agricultural holding’s samples, with all the limits of representativeness that derive from it, it confirms that insects can represent a compatible environment with the growth/survival of bacteria if inadequate processing measures are taken. To avoid these issues, insect use for food production should consider existing data derived from countries where insect consump-tion is usual. Assuming demand for edible insects as human food will increase, then new approaches for smart breeding, sustainable rearing, harvest and post-harvest processing

Ann Ist Super Sanità 2019 | Vol. 55, No. 3: 203-204DOI: 10.4415/ANN_19_03_01

letter

The microbial safety of edible insects: a matter of processing

Key words • entomophagy • edible insects • food safety • microbial community • insect processing

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will be crucial. Finally, it is inevitable that existing legislation will need to be significantly modified by adopting sanitary regulations and quality standards on nutritional composi-tions and on contaminants as well as a new approach to products’ labelling will be man-datory; the renewed European Novel Food Regulation is only the beginning.

Guglielmo Bonaccorsi1, Enrico Simoncini2*, Donella Gestri3, Mariella Talini3, Sara Tesi4, Fabio Rastelli5, Giovanni Nardone5 and Chiara Lorini1

1 Dipartimento di Scienze della Salute, Università degli Studi di Firenze, Florence, Italy2 Scuola di Specializzazione in Igiene e Medicina Preventiva, Università degli Studi di

Firenze, Florence, Italy3 Laboratorio di Sanità Pubblica, Azienda USL Toscana Centro, Florence, Italy

4 Corso di Laurea in Tecniche della Prevenzione nell’Ambiente e nei Luoghi di Lavoro, Università degli Studi di Firenze, Florence, Italy

5 Dipartimento della Prevenzione, Azienda USL Toscana Centro, Pistoia, Italy

*Corresponding author: [email protected] of interest statement: none

Financial support: none

REFERENCES

1. Alexandratos N, Bruinsma J. World agriculture towards 2030/2050. Land use policy. 2012;20(4):375. doi: 10.1016/S0264-8377(03)00047-4

2. van Huis A. Edible insects contributing to food security? Agric Food Secur. 2015;4(1):1-9. doi: 10.1186/s40066-015-0041-5

3. Belluco S, Losasso C, Maggioletti M, Alonzi CC, Paoletti MG, Ricci A. Edible insects in a food safety and nutritional perspective: A critical review. Compr Rev Food Sci Food Saf. 2013;12(3):296-313. doi: 10.1111/1541-4337.12014

4. Mlcek J, Rop O, Borkovcova M, Bednarova M. A comprehensive look at the possibilities of edible insects as food in Europe – A Review. Polish J Food Nutr Sci. 2014;64(3):147-57. doi: 10.2478/v10222-012-0099-8

5. Payne CLR, Dobermann D, Forkes A, House J, Josephs J, McBride A, et al. Insects as food and feed: European perspectives on recent research and future priorities. J Insects as Food Feed. 2016;2(4):269-76. doi: 10.3920/JIFF2016.0011

6. Schlüter O, Rumpold B, Holzhauser T, Roth A, Vogel RF, Quasigroch W, et al. Safety as-pects of the production of foods and food ingredients from insects. Mol Nutr Food Res. 2017;61(6):1-14. doi: 10.1002/mnfr.201600520

7. Garofalo C, Osimani A, Milanovic V, Taccari M, Cardinali F, Aquilanti L, et al. The micro-biota of marketed processed edible insects as revealed by high-throughput sequencing. Food Microbiol. 2017;62:15-22. doi: 10.1016/j.fm.2016.09.012

8. Klunder HC, Wolkers-Rooijackers J, Korpela JM, Nout MJR. Microbiological aspects of pro-cessing and storage of edible insects. Food Control. 2012;26(2):628-31. doi: 10.1016/j.food-cont.2012.02.013

9. ANSES Risk Assessment (France). Opinion of the French Agency for Food, Environmental and Occupational Health & Safety. Opin French Agency Food, Environ Occup Heal Saf. 2015;2(2009):27-31.

10. EFSA Scientific Committee. Risk profile related to production and consumption of insects as food and feed. EFSA J. 2015;13(10):4257. doi: 10.2903/j.efsa.2015.4257

11. Stoops J, Crauwels S, Waud M, Claes J, Lievens B, Van Campenhout L. Microbial commu-nity assessment of mealworm larvae (Tenebrio molitor) and grasshoppers (Locusta migratoria migratorioides) sold for human consumption. Food Microbiol. 2016;53:122-7. doi: 10.1016/j.fm.2015.09.010

12. Food and Agriculture Organization of the United Nations. Edible insects. Future pros-pects for food and feed security. Rome: FAO; 2013. Vol. 171. p. 1-201. doi: 10.1017/CBO9781107415324.004

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Key words• urolithiasis• infrared spectroscopy• morphocostitutional

analysis• rare stones

A combination of infrared spectroscopy and morphological analysis allows successfully identifying rare crystals and atypical urinary stones Aniello Primiano1,2, Silvia Persichilli1,2, Pietro Manuel Ferraro2,3, Angelo Minucci2, Giovanni Gambaro4, Andrea Urbani1,2 and Jacopo Gervasoni1,2

1Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Rome, Italy 2Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy 3Istituto di Medicina Interna e Geriatria, Università Cattolica del Sacro Cuore, Rome, Italy 4UOC di Nefrologia e Dialisi, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy


AbstractBackground. The combination of infrared spectroscopy and morphological analysis sig-nificantly improves the urinary stone analysis. In addition to common urinary stones, it is not unusual to encounter spurious or factitious stones that, if not appropriately identified, can lead to errors in the diagnosis. In this study, we show the importance of Infrared Spectroscopy and the morphological analysis, for determining the presence of drugs crystals or atypical components in the calculi.Methods. 1041 urinary stones were analyzed by morphocostitutional analysis, in addi-tion the rare stones were analyzed by chemical spot test analysis. Results. Among 1041 calculi analyzed, 1018 had a known composition, 23 samples were stones with rare composition or fake urinary stones. Conclusions. Infrared spectroscopy (FT-IR), allows to identify, theoretically, any sub-stance, including drug-containing calculi or calculi with unusual composition and iden-tify false stones. This is mandatory to treat patients affected by urolithiasis with a per-sonalized clinical approach.

INTRODUCTIONUrolithiasis is caused by the deposition of crystals in

the urinary tract; these formations start when the urine becomes supersaturated for a given salt. The presence in urine of promoters or inhibitors of crystallization may trigger the formation, growth, and aggregation of crystals. The crystals’ aggregation can produce kidney stones of different composition. The most common kidney stones are composed of calcium oxalate mono-hydrate (COM, whewellite), calcium oxalate dihydrate (COD, weddellite), carbonate apatite (CA, dahllite), ammonium urate, magnesium ammonium phosphate (PAM, struvite), calcium hydrogen phosphate dihy-drate (brushite), uric acid (AU0 anhydrous form and AU2 dihydrate form, uricite) and its salts and cystine. Spurious or factitious stones represent a very low per-centage [1].

Nowadays different methodologies are available for the analysis of renal stones that include wet chemistry tests, X-ray crystallography, infrared spectroscopy (FT-

IR) and stereomicroscopic study. Even if the guide-lines on urolithiasis of the European Association of Urology [2] underline the obsolescence of wet chem-istry and recommend the use of FT-IR, this technique is still widespread. FT-IR analysis allows more accu-rate results [3, 4] in the composition and discrimina-tion of real from fake urinary stones. This technique, combined with morphological analysis (stereo micro-scope), is known as morphocostitutional analysis and allows a more accurate urinary stone stratification [5]. Furthermore, this technique can recognize both amorphous substances and drug-containing calculi, that represent a low percentage (2-3.5% as described in other articles) [1-6] but anyway deserve attention, because if not recognized they will never be appropri-ate treated.

In this study, we summarized the composition of uri-nary stones obtained by morphocostitutional analysis (stereomicroscopic combined with FT-IR analysis) and focused the attention on rare and fake stones in order

Address for correspondence: Jacopo Gervasoni, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Istituto di Biochimica e Biochimica Clinica, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy. E-mail: [email protected].

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to demonstrate the clinical importance of the spurious stones identification. Furthermore, the rare stones were also analyzed by spot test analysis.

MATERIALS AND METHODSamples

We analyzed 1041 consecutive urinary stones from the Divisions of Nephrology and Urology of Agostino Gemelli University Hospital Foundation, collected by 705 males and 336 females (age range 19-75), after uro-logical surgery or spontaneous expulsion. Shape, colour, size and weight were registered for each stone at the time of delivery. The stones submitted to analysis were washed with deionized water and dried at room temper-ature for 24 h. All the samples have been characterized by both stereo microscopic analysis and FT-IR method as described below.

Stereo microscopic analysisMorphological analysis was conducted in accordance

with our previous published method [7]. The sample analyzed by stereo-microscope was observed at differ-ent magnifications (from 7.5× up to 50×). The first step concerned the study of the surface of the stones; then they were sectioned and the components of the core, middle layer and outer layer were identified separately.

FT-IR analysisThe stones were powdered in a mortar and were

mixed with an inert powdered support (dried potas-sium bromide) in a proportion of 0.5 to 2% in agate mortar. This mixture was transferred into an appropri-ate die and pressed at 10 t/cm2 to form a transparent pellet 13 mm of diameter. The pellet, assembled in a holder, was placed in the IR beam of the spectrome-ter. The spectral region investigated was from 4000 to 400 cm-1; 32 scans were averaged with a 4 cm-1 resolu-tion for each spectrum. A background spectrum was collected before every analysis, for the sample blank. Once more a background spectrum was measured to provide a relative scale for the absorption intensity. Background spectra were performed at air or pure KBr pellet. Spectra were recorded by means of a Perkin El-mer Spectrum One [8]. Then spectra were computer-matched with the Euclidean search application, a tool of SPECTRA NICODOM IR Library (obtained from Nicodoms.r.o., Hlavni 2727 CZ-14100 Praha 4, Czech Republic, EU) that compares the unknown spectrum with reference spectra contained in the library be-tween 4000 and 400 cm-1. A report is then generated for the various stone components. The results of the automatic comparison for a spectrum identification were provided as a list of the best-fitting spectra with their score. The score value can range from 0.000 to 1.000. Score 1.000 indicates a perfect likeness between the unknown spectrum and the reference one. In each case, a visual inspection of the spectra was performed to check the results [9].

Chemical spot testSpot test analysis for the qualitative tests of urinary

calculi composition was performed according to kit in-

structions (Urinary Calculi Analysis kit, DiaSys, Diag-nostic System GmbH, Holzheim, Germany). The assay consists of the addition of chemical reagents labeled R1 to R15 dropwise to the finely pulverized sample and placed into a vessel with 50 mL of distilled water. Then the appearance of certain colors, precipitates, or air bubbles would indicate positive results for one of the ions and cystine

This method allows detecting the presence of cystine and the following ions usually present in urinary calculi: carbonate, calcium, oxalate, ammonium, phosphate, magnesium, and urate.

RESULTSAmong 1041 calculi analyzed, 1018 (97.8%) had a

common composition and in this group the most fre-quent substance was calcium oxalate as reported in lit-erature [5].

The other remaining 23 (2.2%) samples were stones with rare composition or fake urinary stones.

As shown in Table 1, the spurious stones were com-posed principally of proteins (9/23; 39%). We have re-corded also three drug stones (3/23; 13%) of atazanavir (Figure 1) in patients infected with human immuno-deficiency virus (HIV) in treatment with this protease inhibitor [8] and one stone (1/23; 4%) of N-acetylsulfa-methoxazole, the acetyl derivatives of sulphamethoxa-zole, that is associated with crystalluria and rarely re-sponsible of urolithiasis [6].

Furthermore, we found two silicate urinary stones (2/23; 9%) and a peculiar case of false urolithiasis in a patient treated with synthetic absorbable suture that developed a polyglactine false stone (1/23; 4%).

We found a stone of aragonite (1/23; 4%) with not understood etiology.

Finally, we also detected six fake stones (6/23; 26%).As reported in Table 2, we analyzed the rare stones

also by chemical method. The results obtained showed the total disagreement of chemical analysis, as previ-ously reported [9].

Table 1Composition and frequency of 23 spurious stones

Spurious stone

Composition Number %

N-acetylsulfamethoxazole 1 4.3

Atazanavir 3 13.0

Proteins 9 39.1

Alpha-quartz 2 8.7

Aragonite 1 4.3

Calcite 2 8.7

Bread 1 4.3

Tripalmitine 1 4.3

Wax-paraffin 1 4.3

Albite 1 4.3

Polyglactine 1 4.3

Infrared spectroscopy and morphologIcal analysIs for IdentIfyIng rare crystals and atypIcal urInary stones

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DISCUSSIONMorphocostitutional analysis of urinary stone allows

a more accurate urinary stone stratification in order to recognize both amorphous substances and drug-con-taining calculi.

In this study, we found 2.2% of stones with rare com-position or samples resulted fake urinary stones. The results obtained by chemical analysis stress again the inaccuracy of this method, indeed the chemical analysis is not able to detect the rare stones and in addition it frequently gives wrong results that can induce the clini-cians to incorrect diagnosis (Table 2).

The identification of protein stones can be a marker of several pathologies, while the demonstration of a fac-titious stone may alert the clinicians to the possibility of

a pseudo-medical complaint and influence patient man-agement. The main clinical contexts for the growth of this kind of stone are pyelonephritis, glomerular kidney diseases, hematuria or crystal-induced bleeding, end-stage renal failure and long-term treatment with some antiseptic or antiviral drugs [5-11].

It is mandatory also to underline the possibility to identify drug stones, the knowledge of their composi-tion can be very useful for clinician, because recurrenc-es could be prevented by just discontinuing these drugs [12]. Moreover, the chemical analysis could not detect the drug-containing calculi and an incorrect biochemi-cal composition could lead to a mistake in the medical treatment. Patients who habitually use magnesium tri-silicate antacids can develop silicate urinary stone.

Figure 1Infrared spectroscopy (FT-IR) spectrum of atazanivir.

Table 2FT-IR vs chemical spot test analysis

Components detected

FT-IR analysis (n) Chemical spot test Comparison

Atazanivir (3) Oxalate Disagreement

N-acetylsulfamethoxazole (1) Ammonia / Magnesium Disagreement

Proteins (9) Oxalate / Calcium / Ammonia Disagreement

Alpha-quartz (2) ND Disagreement

Calcite (2) Carbonate Agreement

Aragonite (1) Ammonia Disagreement

Polyglactine (1) ND Disagreement

Tripalmitine (1) ND Disagreement

Wax-paraffin (1) ND Disagreement

Albite (1) Oxalate Disagreement

Bread (1) Oxalate Disagreement

Total (23)

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A particular case of false urolithiasis was found in a patient treated with synthetic absorbable suture, in fact prolonged contact with salt solutions such as those found in the urinary tracts may result in a false calculus formation of polyglactine.

The 26% of spurious stones were caused by incorrect sample collection or Munchausen’s syndrome psycho-pathology (albite, wax-paraffin, crumb of bread, tri-palmitine) except for calcite stones that are not always factitious [13, 14].

With the chemical analysis, the identification of this substances was not possible and only thanks to the in-troduction of the new analytical approach that com-bines infrared spectroscopy and morphological study of kidney stones it is now possible to find substances con-sidered rare, particular calculi, crystals of unexpected material and identify false stones.

CONCLUSIONThe use of a reliable technique is of great importance

in the management of urolithiasis expecially to identify-ing rare crystals and atypical urinary stones not identifi-able by chemical analysis.

Authors’ statementsNo potential conflicts of interest relevant to this arti-

cle were reported. The research did not receive specific funding, but was performed as part of the employment of the all authors. The data used to support the findings of this study have not been made available because of our Company policy.

Received on 23 February 2019.Accepted 28 May 2019.

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Key words• influenza vaccines• health science students• mandatory vaccination• cross-sectional study

Factors predicting health science students’ willingness to be vaccinated against seasonal flu during the next campaignVincenza Gianfredi1, Giulia Dallagiacoma2, Sandro Provenzano3 and Omar Enzo Santangelo3

1Scuola di Specializzazione in Igiene e Medicina Preventiva, Dipartimento di Medicina Sperimentale, Università degli Studi di Perugia, Perugia, Italy 2Scuola di Specializzazione in Igiene e Medicina Preventiva, Dipartimento di Sanità Pubblica, Medicina Sperimentale e Forense, Università degli Studi di Pavia, Pavia, Italy 3Dipartimento Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza, “G. D’Alessandro”, Università degli Studi di Palermo, Palermo, Italy


Abstract Introduction. Influenza is an infectious disease with a high burden, for which a safe and efficacy vaccine is available. However, vaccination coverage is generally low, also among Health Care Workers (HCW). Health Professions students are comparable to HCW in terms of workplace exposure. Aim. The study aim was to identify predictive factors of flu vaccination acceptance among Italian students of Health Professions. Methods. A cross-sectional study was performed using a validated, on-line, anonymous questionnaire. Data were analyzed performing both univariable and multivariable logis-tic analysis.Results. The results showed a statistically significant association between intention to vaccinate next year and: geographical distribution, considering themselves at higher risk due to their profession, having been vaccinated last year, having recommended the vac-cination last year, and being willing to recommend it next year and being favorable to mandatory vaccination. In conclusion, identifying an effective vaccination strategy and including students in flu vaccination campaigns might have positive effect on vaccination acceptance.

INTRODUCTIONInfluenza is an infectious disease with a very high

burden, both in young and adult people (81.8 DALYs per 100 000 population, according to The European Centre for Disease Control and Prevention, ECDC) [1]. In particular, data from the “Burden of Communi-cable Disease in Europe” project show, for influenza, a low individual but high population burden. The Center for Disease Control and Prevention (CDC) in Atlanta estimated that in the United States, during the 2017-2018 season, influenza affected about 48.8 million people, 22.7 million people requested health care as-sistance, 959 000 people were hospitalized and 79 400 died [2]. This complex disease management is clearly associated with high costs for the health system, and for

people themselves. In Australia, estimated costs related to health care were around $ 115 million in 2008. In Italy, according to the study conducted by Lai and col-laborators, the total cost of the nine influenza seasons from 1999 to 2008 was around 15 billion euro. The sea-sonal average was over 1.3 billion euro [3].

Despite the availability of safe and effective vaccines to prevent seasonal influenza infection, a significant proportion of eligible population remains unvaccinat-ed. In Italy, the flu vaccination is included in the Na-tional Immunization Plan (NIP) and is offered free of charge to certain groups of people that are at a higher risk either for age, professional exposure or for health conditions [4]. In particular, a Ministerial document was issued to identify all professionals who could be

Address for correspondence: Vincenza Gianfredi, Scuola di Specializzazione in Igiene e Medicina Preventiva, Dipartimento di Medicina Sperimentale, Università degli Studi di Perugia, Piazzale L. Severi 1, 06123 Perugia, Italy. E-mail: [email protected].

Vincenza Gianfredi, Giulia Dallagiacoma, Sandro Provenzano and Omar Enzo Santangelo

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exposed to biological agents or who could be a source of infection for others [5]. Obviously, Health Care Workers (HCWs) are included in this group of at-risk professionals. Starting from 2009, the World Health Organization’s Strategic Advisory Group of Experts has identified HCWs as a priority target group for flu vaccination [6]. Indeed, HCWs are routinely exposed to infected patients during their worktime, and, at the same time, they might also be carriers of infection for other patients, co-workers, friends and relatives. There are several preventive measures that can be adopted to minimize spreading infections, such as washing hands and covering mouth and nose when coughing or sneez-ing, but vaccination remains the most effective measure both for self protection and to protect others. In par-ticular, to significantly reduce morbidity, complications and mortality related to influenza, a high vaccination coverage must be achieved in target population groups: 75% of the target population is considered as the mini-mum rate, while 95% is the optimal rate of immuni-zation. Nevertheless, flu vaccination coverage in Italy is around 15% among the general population, while in people older than 65 years it is 53% and among HCWs it is approximately 15% [7, 8].

A growing body of evidences had identified patients and health care workers’ characteristics associated with flu vaccination refusal, and in this study we focused on university students of Health Professions. In fact, work-places such as health care facilities, are populated not only by professionals but also by students who attend different wards as part of their clinical training.

The aim of this study was to identify predictive factors of flu vaccination acceptance among Italian students of Health Professions.

MATERIALS AND METHODSStudy design

The “Vaccine and vaccine hesitancy” working group of the Committee of Medical Residents of the Italian Society of Hygiene and Preventive Medicine promoted a multi-centre, cross-sectional study administering a validated questionnaire available in literature [9]. The target population consisted of university students of Health Professions degree courses, without any restric-tions in terms of age or year of study. The administra-tion took place in 14 Italian Universities, considering the origin of the working group members who volun-tarily decided to participate. In each University a mem-ber of the research group was in charge of presenting the study and its aims, and of enrolling the students. The enrolment and explanation of the study took place during a lecture (from October 2017 to September 2018). After explaining the modality to participate, a Quick Response (QR) code, redirecting to the online questionnaire, was provided to the students.

All subjects were enrolled anonymously and on a vol-untary basis; informed consent was obtained from all participants. The 21-items on-line questionnaire was created using Google forms ® and all data was depos-ited in an electronic database protected by password, known only to the data manager. Ethical approval was given by the local Ethical Committee of the University

of Perugia (Comitato Universitario di Bioetica), Refer-ence Number 2017-20R.

Sample sizeThe population of reference for our study consisted

of Health Professions students enrolled in 14 Italian Universities. For practical reasons, we assumed the number of new students admitted every year in each Health Professions degree course to remain constant. To calculate the population of reference, the number of new students admitted in every degree programme during the last academic year was multiplied by the duration of that programme in years, and the resulting number of students was 49 643. We then proceeded to calculate the sample size, using the EpiInfo software with a confidence level of 95% and a margin of error of 5%. Not knowing the proportion of vaccine-hesitant students beforehand, since this was one of the aims of the study itself, the expected proportion was set at 50%. This allowed us not only to be more conservative, but also to maximise the required sample size. The result-ing sample size consisted of 328 students, but we dou-bled it to be more conservative. Therefore, we set 764 questionnaires as the minimum number in order for the study to be valid and its results to be accepted.

Statistical analysisThe variable “age” was dichotomized in ≤23 years

and >23 years and the answers of the Degree course variable were aggregated into three categories accord-ing to the students’ field of study: Medicine, Nursing and Other (which includes all the other students of the health professions who completed the questionnaire). According to the geographical area of university, the an-swers were categorized into: “South and Islands” (Bari, Messina, Naples, Palermo or Salerno), “Centre” (An-cona, L’Aquila, Perugia, Rome or Siena) and “North” (Parma, Pavia, Turin or Udine). The answers to the question “Do you think your level of knowledge about vaccine-preventable diseases and related vaccinations is” were aggregated into two answers, “Good/excellent” and “Insufficient/sufficient/fair”. The absolute and rela-tive frequencies were calculated for all qualitative vari-ables; Pearson’s Chi-square test (χ2) was used to analyze categorical variables. A multivariable logistic regression model was used. The dependent variable selected was “For the next season, do you think you are vaccinat-ing against the flu? Yes”. Each independent variable in the model is adjusted for all the other independent variables. Results are expressed as adjusted Odds Ratio (aOR) with 95% Confidence Intervals (95% CI). The level of significance chosen for statistical analysis was 0.05. The data was analyzed using statistical software STATA® version 14.

RESULTSA total of 3137 questionnaires were collected; how-

ever, 6 questionnaires were excluded because incor-rectly completed. The final sample therefore consisted of 3131 students of Health Professions with an aver-age age of 23.41 years (standard deviation 3.69). 1219 of the student sample was enrolled in medical school

HealtH science students’ willingness to be vaccinated against seasonal flu

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(59.89% male and 40.11% female), 1035 in nursing (74.98% male and 25.02% female) and the remain-ing 877 in other health professions (71.38% male and 28.62% female). Table 1 shows the sample description.

Table 2 shows the results of the bivariate analysis; in this section only the statistically significant results are reported. Regarding the question “For the next season, are you planning on vaccinating against the flu?” 32.71% of those aged >23 said that they will get vaccinated against seasonal influenza, compared to 38.21% of those aged ≤23 years; higher percentages of positive answers were found among students enrolled in the Medicine degree course, compared to nursing students or to other degree courses (39.54% vs 36.23% vs 26.91%); higher percentages of positive answers were also found among students of northern Italian Universities, compared to students of central Italian Universities, southern Italian Universities and Sicily (39.01% vs 10.35% vs 35.80%). 40.85% of the sample that believes to have a good or excellent level of knowledge about vaccine-preventable diseases will get vaccinated against seasonal influenza next year, compared to 30.42% of the sample that be-lieves to have a low level (insufficient/sufficient/fair) of knowledge about vaccine-preventable diseases. 32.35% of those who have never had a vaccine-preventable dis-ease in the last 5 years, compared to 38.10% of those who had it “at least once” think that they will get vacci-nated next year; 34.91% of those who considered them-selves to have a higher risk of contracting infectious dis-eases, compared to 27.41% of those who did not believe it, reported that they will get vaccinated next year. For the question: “Did you get vaccinated against seasonal flu last year?” 96.56% of those who answered “yes” will get the vaccine against seasonal flu next year as well. 44.98% of the subjects that recommended, according to the ministerial indications, vaccination against seasonal flu to patients, family members or general population during the last flu season will also get vaccinated dur-ing the next flu season, as opposed to 23.35% of those who did not recommend the vaccination last year. In the same way, 47.94% of the people that, according to the ministerial indications, will recommend vaccina-

tion against seasonal flu to patients, family members or general population during the next season, will get vaccinated compared to 11.54% of those will be vacci-nated but will not recommend the vaccination. 59.22% of those who recommended the vaccination to health workers during the last flu season, compared to 31.50% who did not recommend it, reported that they will get vaccinated next year. 47.44% of those who either partici-pated or collaborated in the organization of vaccination campaigns for health professionals during their intern-ships will get vaccinated against seasonal flu, compared to 34.59% of the sample that has neither participated nor collaborated in the organization of the campaigns. 39.44% of those who have received at least once any requests for clarification on vaccinations, compared to 29.62% of those who have never had any requests for clarification, reported that they will get vaccinated next year. 37.20% of those that are favorable to the possible introduction of mandatory vaccinations for school en-rollment said that they will get vaccinated during the next flu season, compared to 11.20% of those that are either contrary or indifferent to this policy. 38.92% of those that are favorable to the possible introduction of mandatory vaccination for health workers said that they will get vaccinated, compared to 6.37% of those that are either contrary or indifferent to it.

Table 3 shows the adjusted odds ratios (aOR). A multivariable logistic regression model was used. The dependent variable used this model was the following “For the next season, are you planning on vaccinating against the flu? Yes”. The statistically significant inde-pendent variables associated to this statement are: “Geographical area”: “Central Italy” and “Northern It-aly” (Central Italy aOR 0.62, North aOR 1.27), “Have you ever had a vaccine-preventable disease in the last 5 years? At least once” (aOR 2.46), “Given your future profession and your state of health, do you consider yourself a subject with a higher risk of contracting in-fectious diseases? Yes” (aOR 1.36), “Did you get vac-cinated against seasonal flu last year? Yes” (aOR 69.69), “During the last flu season, did you recommend the vaccination to patients, family members or general pop-

Table 1Description of the sample. Based on 3131 observations

Variables Male N (%) Female N (%) Total N (%)

Degree Course Medicine and Surgery 730 (59.89) 489 (40.11) 1219 (38.94)

Nursing 776 (74.98) 259 (25.02) 1035 (33.05)

Others* 626 (71.38) 251 (28.62) 877 (28.01)

Did you get vaccinated against seasonal flu last year?

Yes 1908 (68.58) 874 (31.42) 2782 (88.85)

No 224 (64.18) 125 (35.82) 349 (11.15)

During the next season, do you plan on recommending the flu vaccination to patients, family members or general population?

Yes, according toMinisterial recommendation

1125 (70.14) 479 (29.86) 1604 (51.23)

Yes, according to clinical evaluation

372 (64.81) 202 (35.19) 574 (18.34)

No 635 (66.63) 318 (33.37) 953 (30.43)

Age (mean ± SE) 23.24 ± 0.08 23.77 ± 0.12 23.41 ± 3.69

*Other students of health professions.


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Table 2Bivariate associations. Used Pearson’s Chi-square test

“For the next season, are you planning on vaccinating against the flu?”

Variables No (%) Yes (%) p-value

Gender Female 1381 (64.77) 751 (35.23) 0.588

Male 657 (65.77) 342 (34.23)

Age >23 years old 773 (61.79) 478 (38.21) 0.002

≤23 years old 1265 (67.29) 615 (32.71)

Degree Course Medicine and Surgery 737 (60.46) 482 (39.54) <0.001

Nursing 660 (63.77) 375 (36.23)

Other 641 (73.09) 236 (26.91)

Geographical area South and Sicily 633 (64.20) 353 (35.80) <0.001

Centre 639 (71.88) 250 (28.12)

North 766 (60.99) 490 (39.01)

You think your level of knowledge about vaccine-preventable diseases and related vaccinations is

Good/excellent 798 (59.15) 551 (40.85) <0.001

Insufficient/sufficient/fair

1240 (69.58) 542 (30.42)

Have you ever had a vaccine-preventable disease in the last 5 years?

Never 1123 (67.65) 537 (32.35) 0.001

At least once 827 (61.90) 509 (38.10)

Given your future profession and your state of health, do you consider yourself a subject with a higher risk of contracting infectious diseases?

No 609 (72.59) 230 (27.41) <0.001

I don’t know 239 (69.48) 105 (30.52)

Yes 1190 (61.09) 1093 (34.91)

Did you get vaccinated against seasonal flu last year? No 2026 (72.83) 756 (27.17) <0.001

Yes 12 (3.44) 337 (96.56)

During the last flu season did you recommend the vaccination to patients, family members or general population?

No 1067 (76.65) 325 (23.35) <0.001

Yes, based on my clinical evaluation

280 (57.97) 203 (42.03)

Yes, according to the ministerial indications

691 (55.02) 565 (44.98)

During the next season, do you plan on recommending the flu vaccination to patients, family members or general population?

No 843 (88.46) 110 (11.54) <0.001

Yes, based on my clinical evaluation

360 (62.72) 214 (37.28)

Yes, according to the ministerial indications

835 (52.06) 769 (47.94)

During the last flu vaccination campaign, did you recommend the flu vaccination to any health workers?

No 1881 (68.50) 865 (31.50) <0.001

Yes 157 (40.78) 228 (59.22)

Have you ever participated directly or collaborated in the organization of the vaccination campaigns for health professionals during your internship?

Yes 41 (52.56) 37 (47.44) 0.019

No 1997 (65.41) 1056 (34.59)

Have you ever received any requests for clarification on the topic of vaccinations (composition, contraindications, precautions, ...)?

Yes 1021 (60.56) 665 (39.44) <0.001

No 1017 (70.38) 428 (29.62)

What is your opinion about the introduction of mandatory vaccinations for school access?

Contrary 111 (88.80) 14 (11.20) <0.001

Indifferent 156 (84.32) 29 (15.68)

Favorable 1771 (62.78) 1050 (37.22)

How would you evaluate the possible introduction of mandatory vaccinations for health workers?

Contrary 147 (93.63) 10 (6.37) <0.001

Indifferent 221 (92.08) 19 (7.92)

Favorable 1670 (61.08) 1064 (38.92)


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Table 3Multivariable logistic regression. Adjusted odds ratio are presented. Each independent variable is adjusted for all the other inde-pendent variables. Based on 2996 observations

Dependent variable: “For the next season, are you planning on vaccinating against the flu? Yes”

Independent variable aOR 95% CI p-value

Gender Female 1

Male 1.01 0.82-1.23 0.982

AgeAs the unit increases 0.99 0.97-1.02 0.749

Degree Course Medicine and Surgery 1

Nursing 1.15 0.92-1.46 0.224

Other 1.05 0.81-1.36 0.706

Geographical area South and Sicily 1

Center 0.62 0.48-0.80 <0.001

North 1.27 1.01-1.61 0.044

You think your level of knowledge about vaccine-preventable diseases and related vaccinations is

Good / excellent 1

Insufficient/sufficient/fair 0.96 0.79-1.17 0.671

Have you ever had a vaccine-preventable disease in the last 5 years?

Never 1

At least once 1.46 1.21-1.76 <0.001

Given your future profession and your state of health, do you consider yourself a subject with a higher risk of contracting infectious diseases?

No 1

I don’t know 1.35 0.96-1.90 0.089

Yes 1.36 1.08-1.70 0.008

Did you get vaccinated against seasonal flu last year? No 1

Yes 69.69 37.57-129.28 <0.001

During the last flu season did you recommend vaccination to patients, family members, general population?

No 1

Yes, based on my clinical evaluation 0.90 0.64-1.26 0.530

Yes, according to the ministerial indications 0.74 0.57-0.97 0.027

During the next season, do you plan to recommend flu vaccination to patients, family members, general population?

No 1

Yes, based on my clinical evaluation 4.01 2.81-5.74 <0.001

Yes, according to the ministerial indications 7.02 5.12-9-62 <0.001

During the last flu vaccination campaign did you recommend the flu vaccination to health workers?

No 1

Yes 1.31 0.97-1.78 0.080

Have you ever participated directly or collaborated in the organization of the vaccination campaign for health professionals during your internship?

Yes 1

No 0.90 0.50-1.62 0.721

Have you ever received requests for clarification on vaccinations (composition, contraindication, precautions, ...)?

Yes 1

No 0.94 0.76-1.16 0.566

What is your opinion about the introduction of mandatory vaccination for school access?

Contrary 1

Indifferent 0.83 0.31-2.20 0.708

Favorable 0.77 0.34-1.76 0.536

How would you evaluate the possible introduction of mandatory vaccination for health workers?

Contrary 1

Indifferent 1.01 0.35-2.96 0.985

Favorable 7.17 2.91-17.69 <0.001


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ulation? Yes, according to the ministerial indications” (aOR 0.74), “During the next season, do you plan on recommending the flu vaccination to patients, family members or general population? Yes, based on my clini-cal evaluation” (aOR 4.01) and “Yes, according to the ministerial indications” (aOR 7.02), “How would you evaluate the possible introduction of mandatory vacci-nation for healthcare workers? Favorable” (aOR 7.17). Each independent variable is adjusted for all the other independent variables in Table 3.

DISCUSSIONInfluenza infection can be mild (in more than 50% of

the cases) or severe [10], depending on several factors such as seasonal flu virus strain, whether that specific strain was included in the vaccine, immune system con-ditions, age and co-morbidities [11]. Moreover, accord-ing to a WHO estimation, between 5% and 15% of the total population may be affected by flu every year [11]. Flu vaccination is currently the main measure to reduce the burden of influenza. According to the CDC, in the United States, influenza vaccination was able not only to prevent 5.3 million cases of influenza in the period 2016-2017, but it also decreased by 2.6 million the med-ical visits due to flu and avoided 85 000 influenza-relat-ed hospitalizations [12]. A recent systematic review and meta-analysis estimated that the increased occupational risk of pandemic influenza infection among HCWs is approximately 6% [13]. Nonetheless, there are several factors affecting vaccination uptake among HCWs [14]. Most of them are country and context specific, as con-firmed by an ECDC study [15]. According to a previous Italian study, one of the factors impacting on flu vac-cination uptake among HCWs was whether they would consider themselves at a higher risk of infection [16]. This data was also confirmed in our sample, where con-sidering themselves as a high risk group due to the future profession, was statistically associated to an increased vaccination uptake during the next flu season, both in bivariate (p-value <0.001) and multivariable analysis (aOR = 1.36, 95% CI = 1.08-1.70; p-value = 0.008). At the same time, the social network and peers’ influence have a considerable impact on flu vaccination uptake among HCWs [17]. In particular, our study confirmed that having recommended the flu vaccination the previ-ous year and planning on recommending it during the next season to patients, family members or the general population, was statistically associated with an increased vaccination uptake. Moreover, we found a border-line significant association between having recommended the flu vaccination to HCWs and flu vaccination accep-tance (p-value = 0.08). Also the social pressure may play an important role [18]. Indeed, the vast majority of our sample agreed with the introduction of the mandatory vaccination law and 87.3% of our sample also agreed with the hypothetical introduction of mandatory vacci-nation for HCWs. Moreover, being in favor of manda-tory vaccination was also associated with flu vaccination acceptance (aOR= 7.17, 95% CI = 2.91-17.69; p-value <0.001). A detailed analysis of the factors associated to being favorable to the mandatory vaccination, will be reported in a companion paper. Recently, Frederick

et al. demonstrated the effectiveness of mandatory flu vaccination policies both to protect HCWs and to im-prove vaccination coverage. The Authors compared the total number of HCWs days off due to symptomatic flu and the vaccination coverage in 3 hospital where vac-cination was mandatory and in 4 hospital where it was not. After the introduction of mandatory flu vaccination for HCWs, in the 3 American hospitals of the study, HCWs’ absenteeism was significantly reduced and flu vaccination uptake was higher [19]. Absenteeism due to sick leave plays a major impact on the Healthcare System, not only in terms of disease-related deaths and complications requiring hospital care, but also in terms of economic burden and loss of productivity. As a matter of fact, workers taking days off due to influenza lead to a shortage of staff that could cause not only a disrup-tion of the normal functioning of the facility but also a reduction in hospital elective admissions or outpa-tient visits. It has been estimated that, in the European Union, seasonal influenza contributes to an economic burden of € 6-14 billion years annually, considering both the direct and indirect costs related to it [20]. This bur-den could be significantly reduced through an appro-priate vaccination programme, whose benefits in terms of public health and monetary savings would definitely overweight the costs associated with its implementation [21]. Study by Colombo et al. showed that, regarding in-fluenza vaccination for HCWs, the benefit-cost ratio to the Local Health Unit is € 4.2, meaning that for every € 1 invested there is a return of € 4.2 [22]. However, other policies should be adopted along with mandatory vac-cination, in order to increase HCWs uptake [23]. Ac-cording to the systematic review conducted by Schmid et al., other factors can predict flu vaccination uptake, such as general attitudes on vaccination, having being previously vaccinated, having a personal history of influ-enza infection and specific vaccination knowledge [18]. In our analysis, both having had a vaccine-preventable disease in the last 5 years and having been vaccinated against flu the previous year were shown to positively affect vaccination uptake. Furthermore, a recent review found a strict association between HCWs vaccination and attitude of HCWs towards recommending the vac-cination to their patients [24]. However, it is important to highlight that having good skills in communication and an updated knowledge on this issue are essential for an efficient counselling session with hesitant patients [15, 24, 25]. Moreover, having a positive attitude toward vaccinations (considered as having collaborated in vacci-nation campaigns and being willing to provide clarifica-tions on the topic of vaccinations) was also associated to an increased vaccination uptake according to the bivari-ate analysis; however, the multivariable analysis did not confirm these data. This was probably due to the fact that only a small number of students had the possibil-ity to take part in these activities during their univer-sity years. At the same time, even if more than half of our sample reported an insufficient/sufficient/fair level of knowledge, this was not statistically significant in the multivariable analysis.

The wide variation in vaccination coverage among HCWs might also be affected by the high variability


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of professional profiles included in this group. Previ-ous systematic reviews found a flu vaccination coverage among HCWs ranging between 9-53%, for the follow-ing professional profiles: dental students, nurses, ancil-lary workers and physicians [26-29]. However, even if statistical significant differences were found in our sam-ple in the bivariate analysis, these were not confirmed by the multivariable analysis.

To the best of our knowledge, this is the first study aimed at assessing the factors associated with flu vacci-nation acceptance among Health Professions students. This was a cross sectional study and for this reason it was not possible to establish any causal relationship between variables. However, we used a validated ques-tionnaire, and even if an information bias may not be completely excluded, we tried to reduce it. Further-more, we also controlled for potential social desirabil-ity bias, through an anonymous on-line administration. Nevertheless, this study has some important strengths, because the questionnaire was on-line and with manda-tory answers, so there were no missing data. Moreover, the on-line administration was very inexpensive, easy to fill and allowed to reach a high number of students. Indeed, another important strength is the large sample size achieved. Nevertheless, the information was self-reported and recall bias cannot be excluded. Lastly, the questionnaire was based on multiple-choice items that probably limited the understanding of such a complex phenomenon, but they facilitated the analysis.

CONCLUSIONIn conclusion, even if university students are not

health professionals yet, they spend part of their time in healthcare facilities for their clinical training, and they will be the health care workers of the future. For these reasons, it is extremely important to invest in their education and to directly involve them in vaccination campaigns. Including students as a target group for flu vaccination campaigns might have a positive effect in increasing flu vaccination acceptance, because it would allow a stronger relationship between peers, it would improve awareness in considering themselves as a high-risk group, and it would increase their knowledge thanks to active training on the field. Engaging healthcare stu-dents in flu vaccination campaigns may also help them to care more both for themselves and for their patients. Moreover, identifying an effective vaccination strategy for HCWs can positively affect vaccination coverage and help achieve herd immunity, considering HCWs as a strategic target group.

Conflict of interest statementThere are no potential conflicts of interest or any fi-

nancial or personal relationships with other people or organizations that could inappropriately bias conduct and findings of this study.

Received on 17 March 2019.Accepted on 28 May 2019.

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Key words• Chlamydia trachomatis• sentinel surveillance• hospitalisation• pelvic inflammatory

disease• disability-adjusted life

years (DALYs)

Estimated burden of Chlamydia trachomatis female infection and consequent severe pelvic inflammatory disease, Italy, 2005-2016Michela Sabbatucci1,2, Maria Cristina Salfa1, Vincenza Regine1, Patrizio Pezzotti1 and Barbara Suligoi1

1Dipartimento Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy 2European Programme for Public Health Microbiology (EUPHEM) Training, Stockholm, Sweden


AbstractChlamydia trachomatis (Ct) is the leading sexually transmitted infection (STI) across Eu-rope. In Italy, Ct prevalence is low in general population, but predominance of asymp-tomatic infections, passive voluntary reporting, variable diagnostic criteria and coding practices can lead to considerable underestimation, preventing assessment of real bur-den of disease and health intervention. We analysed data on female genital Ct infection registered in STI sentinel surveillance systems in Italy from 2005 through 2016 and found 3305 women. Among them, those aged 20-24 years had the highest disability-adjusted life years (DALYs) estimation equal to 106.77 DALYs per 100 000-stratum specific pop-ulation. Through the study period, incidence rate (IR) for female Ct infection increased significantly from 2.9 to 7.1 per 100 000 resident population. Besides, we analysed data on pelvic inflammatory disease (PID) reported from the National Hospital Information system (NHIS) in the same period. We found 287 women hospitalised with concurrent PID and Ct infection. We recommend targeted screening programmes in women aged 20-24, definition of nationwide active surveillance system, standardisation of diagnostic criteria and ICD-9CM coding practices.

INTRODUCTION Genital infection caused by Chlamydia trachomatis

(Ct) is the most commonly reported sexually trans-mitted infection (STI) across Europe [1]. In 2012, the World Health Organization (WHO) estimated 131 mil-lion new annual infections among people aged 15-49 years [2].

Ct infection is curable by antibiotic treatment and long-term protective immunity is not induced [3]. As-ymptomatic Ct genital infection is estimated in about 70% of women [2], therefore it is often undiagnosed or untreated, favouring a silent spread of infection. Other-wise, short-term acute symptoms of cervicitis arise. In-fection can ascend to the upper reproductive tract and cause long-term sequelae as chronic pelvic pain, pelvic inflammatory disease (PID), tubal factor infertility (TFI) and ectopic pregnancy [2]. Recently, a systematic literature review conducted by the European Centre for Disease Prevention and Control (ECDC) estimated a 4-19% risk of developing PID after Ct infection. The

risk for chronic pelvic pain after PID was estimated around 18-75%. Infertility was associated to 16% of the women with PID in reproductive age [4].

European (EU) population-based analyses reported that prevalence of female Ct infection ranged between 1.7% and 17% [5, 6]. In 2004, the burden of Ct infec-tion and associated sequelae estimated in terms of dis-ability-adjusted life years (DALYs) metric ranked third (0.2 million DALYs including both sexes) in the WHO EU Region behind tuberculosis and HIV/AIDS (1.7 and 1.2 million DALYs, respectively) [7].

In Italy, Ct infection notification is not mandatory, national epidemiological data in the general popula-tion are not available, and neither national guidelines on who should be tested nor Ct screening programmes exist. Different sources of epidemiological data have been used to describe the dynamics of Ct infection in Italy, including: a) the STI Sentinel Surveillance System (SSS) based on a network of clinics (SSS-STIClin) [8]; b) the STI-SSS based on a network of microbiology lab-

Address for correspondence: Michela Sabbatucci, Dipartimento Malattie Infettive, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: [email protected].

Michela Sabbatucci, Maria Cristina Salfa, Vincenza Regine et al.

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oratories (SSS-STILab) [8]; c) local studies conducted among specific population groups (e.g., young women, pregnant women) [9-17]. Singly, these data-sources do not provide nationwide estimate on the number of Ct infections and associated sequelae. So far, lack of na-tional burden on Ct genital infection has not allowed drawing specific health promotion policies or educa-tional programmes for primary prevention.

The objective of the present study is to analyse the trend of Ct genital infection among women (outpa-tients or hospitalised cases) in Italy. The above data-sources are evaluated together for the first time to provide estimates on the national burden of female Ct genital infection and its sequelae in terms of DALYs.

MATERIALS AND METHODS Study design

We performed a retrospective ecological study by analysing three data-sources (SSS-STIClin, SSS-STI-Lab, and the National Hospital Information System – NHIS) to describe temporal trends of female Ct genital infection reported in Italy in the period 2005-2016 and to calculate its burden by DALYs metrics. We estimated the number of women who experienced severe Ct-asso-ciated sequela as those hospitalised with PID caused by Ct genital infection. As PID can have several causes, as a proxy, we identified the women hospitalised with PID and concurrent Ct infection. Due to country-specific issues on disease coding and consequent possible un-derestimation of data, we included Ct diagnosis at any body site among those hospitalised. For both Ct and PID cases, we considered women aged 15-70 years.

Data-sources and case definitions• SSS-STIClin: the network is composed of 12 public

STI clinics located in 11 cities (Gorizia, Trento, Bres-cia with two clinics, Milan, Turin, Genoa, Bologna, Florence, Rome, Bari, Cagliari) distributed in 10 out of 21 Italian regions and autonomous provinces. These specialised clinics provide diagnosis, treatment and care to symptomatic STI patients. Since 1991, this system collects anonymous individual socio-demographic, behavioural and clinical information on people with a confirmed STI. Only the first STI episode is reported. Since 2008, the diagnosis of Ct infection has been performed on endo-cervical swab and/or the first void urine by nucleic acid amplifica-tion test (NAAT). Previously, immune-enzymatic or immunofluorescence methods and swab samples were used. For the present analysis, we included women with Ct-related genital symptoms and labora-tory-confirmed diagnosis of Ct registered in the SSS-STIClin from 2005 through 2016.

• SSS-STILab: the network is composed of 13 public microbiology laboratories located in 13 cities (Trieste, Pordenone, Trento, Legnano, Turin, Ivrea, Fano, Pe-rugia, Rome, Galatina, Lecce, Catanzaro, Cosenza) distributed in nine out of 21 Italian regions and au-tonomous provinces. Since 2009, these laboratories collect anonymous individual sociodemographic, be-havioural and clinical data on people (symptomatic and non-symptomatic) who undergo testing for Ct

and/or Neisseriae gonohorroeae and/or Trichomonas vag-inalis. For the diagnosis of Ct infection, laboratories perform NAAT on samples from endo-cervical swab and/or the first void urine. We considered women tested for Ct, regardless of the presence of Ct-related genital symptoms.

• NHIS: it has 100% national coverage including hos-pitalised cases and day-surgery interventions of symp-tomatic people admitted to hospital. Demographic and clinical data are reported in digital medical re-cords and include up to five reasons for admission, which were used in the algorithms described below. For the present analysis, we defined a woman with Ct and PID by using two algorithms (one for Ct-positive women and one for PID cases). We based these al-gorithms on two sets of the International Classifica-tion of Diseases – 9th revision – Clinical Modifica-tion (ICD-9CM) codes specific for Ct infection or PID (13 and 32 codes, respectively; available online as Supplementary Material 1). Both algorithms were developed with the technical advice of gynaecologists qualified in Ct infection, and based on international literature. All data were anonymised.We obtained approval from the Ministry of Health

(MoH) to manage and analyse data.

Incidence rates The incidence rate (IR) of Ct infection was obtained

by dividing the number of women diagnosed with Ct infection reported in the SSS-STIClin by the number of women resident in the cities where the clinics are located.

We stratified the rough IR by four age groups (i.e. 15-24, 25-34, 35-44 and 45-70) and we calculated age-standardised IR in respect to the general Italian popula-tion. To estimate DALYs metrics, we used age groups by 4-year interval, according to the BCoDE model re-quirements (e.g. 15-19, 20-24, 25-29, and so on until 65-69).

The hospitalisation rates of women diagnosed with PID (hospPID rate) and of women diagnosed with con-current PID and Ct infection (hospPIDCt rate) were obtained by dividing the number of women hospitalised with PID and that of women hospitalised with concur-rent PID and Ct, respectively, by the number of women aged 15-70 years resident in Italy in the reference period.

Data were stored and managed according to the Ital-ian privacy rules. Neither informed consent, nor ethical committee clearance were required for this retrospec-tive study.

We performed descriptive statistical analysis using STATA version 12. Pearson – and Fisher exact tests were used to assess significance (p <0.05 level) in the trend analysis. We described the geographical distribu-tion of cases in Northern, Central and Southern (in-cluding islands) areas according to ISTAT criteria [18].

DALYs estimateWe estimated the burden of Ct infection in Italy in

terms of DALYs with 95% uncertainty intervals (UI) by using the ECDC-funded Burden of Communicable Diseases in Europe (BCoDE) toolkit [19, 20]. DALYs

Chlamydia traChomatis, Italy, 2005-2016

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metric included the number of years of life lost due to disability (YLD) and the number of years of life lost due to premature death (YLLs). We estimated the number of women diagnosed with Ct in the period 2009-2016 by multiplying the number (equal to 21 135 688) of Italian women aged 15-70 years in 2012 (central year in the reference period) with the Ct infection prevalence (2.6%) obtained from the SSS-STILab (data from the national AIDS unit – COA, unpublished data) between 2009 and 2016. Then, we calculated the number of symptomatic cases by multiplying our estimated num-ber of women diagnosed with Ct with the BCoDE tran-sition probability (equal to 20%, the percentage of Ct cases that develop symptomatic infection according to the BCoDE toolkit [19, 20]). We estimated the median annual number of symptomatic women by age group in Italy based on the age distribution of symptomatic women observed summing up data from the SSS-STI-Lab and the SSS-STIClin. We ran the BCoDE model by performing 10 000 iterations and null time discount rate. We presented results as median values and 95% UI, per year and per 100 000 stratum specific popula-tion (age group or Ct acute infection or Ct-associated sequelae), in terms of aggregated (i.e. DALY) and dis-aggregated (i.e. YLDs and YLLs) analysis.

RESULTSFrom 2005 through 2016, the SSS-STIClin reported

1301 symptomatic women diagnosed with genital Ct (Figure 1A), Almost half (45.9%) of them were aged 15-24 years (median age 25 years, interquartile range (IQR) 22-30 years) and over two thirds (70.1%) were Italian (data not showed). Based on these data, the number of women diagnosed with Ct doubled in the 12-years considered, from 76 cases in 2005 to 188 cas-es in 2016 (Figure 1A), accounting for 6.1% and 11.7% of women reported by the network with an STI, respec-tively. IR of female Ct infection increased significantly from 2.9 per 100 000 residents in 2005 to 7.1 per 100 000 residents in 2016 (p <0.0001). In particular, we showed a sharp increase starting from 2009 (IR 2.8 per 100 000 residents) to 2016 (IR 7.1 per 100 000 residents) (p <0.0001) (Figure 1A). Overall, the rough IR was 45.4 per 100 000 resident women. The stan-dardised IR was 34.0 per 100 000 female population distributed among the four age-groups as follows: 14.9, 11.2, 2.3 and 5.6 among the age-groups 15-24, 25-34, 35-44, and 45-70 years, per 100 000 female popula-tion, respectively.

From 2009 through 2016, the SSS-STILab reported 2275 women diagnosed with genital Ct (63.6% were symptomatic, data not showed). Their median age was 27 years (IQR 22-34 years) and most of them (81.3%) were Italian. Prevalence of female Ct infection re-mained stable from 2.4% in 2009 to 2.6% in 2016, with a peak in 2014 (3.2%; p <0.05; data not showed).

In the period 2005-2016, we identified 329 880 (0.78%) women hospitalised with PID with or without Ct infection among those reported in NHIS. Among them, 287 (0.087%) were reported with ICD-9CM codes (available online as Supplementary material 1) identifying Ct infection (Figure 1A). The median age of

women affected by PID and Ct was 32 years (IQR 23-38 years). The majority (72.5%) had Italian nationality (available online as Supplementary Material 2).

Based on the results obtained from the BCoDE tool-kit, the annual DALYs per 100 000 stratum specific population stratified by age group (Figure 1B) shows the burden of Ct infection affecting mostly the women aged 20-24 years (106.77 DALYs per 100 000 stratum specific population).

In particular, the number of Ct women was estimated in 111 575 cases per year (Table 1). The median annual burden of Ct acute infection was estimated at 23.99 DALYs (95% UI: 21.28-26.92) per year corresponding to 0.08 DALYs per 100 000 stratum specific popula-tion (95% UI: 0.07-0.09). Regarding acute infection, DALYs were due entirely to YLDs (Table 1).

Overall, we estimated that over 99% of the nation-al burden of Ct infection resulted from sequelae and amounted to 5978.85 DALYs per year corresponding to 19.10 DALYs per 100 000 stratum specific population (95% UI: 9.84-34.22; Table 1).

As for the Ct-associated PID cases, we observed a de-creasing temporal trend from 27 average cases in 2005-2006 to 17 average cases in 2015-2016, although not significant in terms of hospPIDCt rate (0.093 in 2005 and 0.069 in 2016 per 100 000 residents; p >0.05). Figure 2A shows the Ct-associated PID cases stratified by year of notification and Italian and non-Italian na-tionality. Figure 2B shows that the highest hospPIDCt rate (0.24 per 100 000 residents) was among the wom-en aged 15-24 years. During the 12-year period, most (41.8%) of the hospitalised foreign women diagnosed with concurrent PID and Ct were between 25 and 34 years old, while the majority of the Italian women (33.2%) were admitted to hospital with PID and Ct later in lifetime, at between 35 and 44 years old (Figure 2B). Mainly, hospitalised women diagnosed with con-current PID and Ct were reported and resided in North Italy (66.6% and 63.8%, respectively) and had median hospital stay of five days (available online as Supple-mentary material 2). Almost half of them (43.6%) were admitted to the hospital under emergency conditions: 23.7% had a scheduled admission, 18.1% had a doctor’s proposal and 1.4% were transferred from other public or private institutes; 13.2% had non-specified type of provenance (data not showed).

Based on the results obtained from the BCoDE tool-kit, PID resulted as the main sequela of Ct infection, together with chronic pelvic pain syndrome (Table 1). Overall, the annual burden of Ct-associated sequelae was estimated at 5954.85 DALYs (95% UI: 3057.00-10 686.03). It was almost completely (99.8%) due to YLD and corresponded to 19.03 DALYs per 100 000 stratum specific population (95% UI: 9.77-34.14; Table 1).

DISCUSSION Here we described cases due to Ct genital infection

reported in Italy from 2005 through 2016 in SSS-STI-Clin and from 2009 through 2016 in SSS-STILab, and we estimated the national burden of female Ct infec-tion in terms of DALYs metrics. Besides, we calculated the incidence of a severe sequela as Ct-associated PID


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requiring hospitalisation registered in NHIS between 2005 and 2016. Although female Ct genital infections (adding up both SSS-STIClin and SSS-STILab data) significantly increased by 26% between 2009 and 2016, in this period the number of hospitalised women with PID and Ct infection has halved, even if not significant-ly. These diverse temporal trends might be explained by a range of events: I) rise in the number of Ct symptom-atic cases; II) improved sensitivity in their notification among STI clinics, mostly due to increased sensitivity of NAAT testing after 2008; III) potential increase in test-ing rates; IV) earlier detection of genital Ct infection allowing timely treatment and prevention of sequelae [21]; V) shift in PID care from inpatient to outpatient settings based on comparable reproductive outcomes

among women with mild-to-moderate PID to contain costs [22, 23]; VI) lack of standardised diagnostic cri-teria to define PID cases in hospital medical records leading to low accuracy in ICD-9CM coding and un-derestimation of Ct-associated PID cases. An overall decline in the hospitalisation rates for PID was reported also in other countries [1, 24].

The reliability of the information obtained from our data-sources, the national coverage of NHIS, the stable collection of data over time and the high diagnostic standards for Ct infection adopted in the clinics and microbiology laboratories participating in the sentinel systems make this study worthy. Underestimation of cases with Ct genital infection limited our analysis. In fact, Ct infection is not reported mandatorily in Italy,

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Table 1Annual estimated burden of Chlamydia trachomatis female infection and associated sequelae, Italy, 2009-2016 (time discounting was not applied). We obtained data from the Burden of Communicable Diseases in Europe (BCoDE) toolkit funded by the European Centre for Disease Prevention and Control (ECDC)

Cases per Year DALY per case

per 100 000 Stratum specific population

YLD YLL DALY YLD YLL DALY

Acute total 111 575.01 23.99 0 23.99 2.15E-04 0.08 0 0.08

Sequelae

Pelvic inflammatory disease 60 234.11 395.30 0 395.30 3.54E-03 1.26 0 1.26

Tubal infertility 122.47 14.93 0 14.93 1.34E-04 0.05 0 0.05

Ectopic pregnancy 428.81a 10.61 8.79 19.40 1.74E-04 0.03 0.03 0.06

Chronic pelvic pain syndrome 27 919.23 5523.73 0 5523.73 0.05 17.65 0 17.65

Tubo-ovarian abscess 481.87 1.49 0 1.49 1.34E-05 4.77E-03 0 4.77E-03

Sequelae Total 5 946.07 8.79 5 954.85 0.05 19.00 0.03 19.03

All health outcomes Total 5 970.06 8.79 5 978.85 0.05 19.07 0.03 19.10

aIncluded 0.16 death. Abbreviations: DALYs, disability-adjusted life years; YLD, years lived with disability; YLL, years of life lost due to premature death. The toolkit is freely downloadable from https://ecdc.europa.eu/en/publications-data/toolkit-application-calculate-dalys. Results are expressed in median values.

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the SSS-STILab collected data by those laboratories participating in the network only and the SSS-STIClin reported symptomatic patients who attended these public clinics. We have no track of those tested at other public clinics and laboratories, or at private health care facilities. Besides, frequent absence of symptoms and/or lack of awareness to be infected by Ct lead to under-ascertainment of cases from the community. In addi-tion, women diagnosed with PID approaching health care in Italy receive syndromic management and are not hospitalised. In case of persistence of symptoms only, after 48h they might be hospitalised with diagnosis of possible PID due to polymicrobial genital infection (without laboratory confirmation). Regional differences in ICD-9CM coding accuracy and ability for Ct diag-nosis might explain different proportions of hospital-ised cases in diverse Italian areas.

Taking into account that 9-15% of women diagnosed with PID are hospitalised [4] and based on the num-ber of hospitalised PID cases observed in our 12-year analysis, about 2-3 million women with PID due to all causes were expected in Italy during 2005-2016. Con-sidering that 4%-19% of PID cases are estimated to be associated with Ct infection [4], in the reference period about 88 000-700 000 PID cases due to Ct infection (up to about 60 000 cases per year) were expected. We found correspondence between this estimate on the number of PID cases caused by Ct and the results obtained with the BCoDE toolkit. Of them, based on the above-mentioned 9-15% PID hospitalization rate, 8000-100 000 women with PID due to Ct infection should have been hospitalised in the period 2005-2016. We identified 287 hospitalised women diagnosed with concurrent PID and Ct infection. This result suggests that in Italy under-reporting might play a relevant role in this discrepancy and at the same time that Ct-asso-ciated PID cases are hospitalised rarely and treated at home mostly, anyway increasing the rates of antibiotic consumption needed for the therapy, if not the costs of hospitalization.

Moreover, we showed that Ct infection affected mostly young women aged 15-24 years, and that the contribution of young non-Italian women in the spread of Ct infection is considerable (about one-third among the 15-24 age group), confirming data reported by the SSS-STILab [8, 17].

Under ascertainment, changes in testing practices and case definitions together with voluntary reporting suggested the need for improving and standardising the clinic-diagnostic path and data collection for Ct genital infections and associated sequelae. National prevention strategy for STI has been absent since 2012 [25]. As of January 14, 2019, as little as 68 dedicated public health-care services for Ct diagnosis and case management ex-ist throughout the country (over 60 million residents) [26]. A small number compared to other EU countries with similar population [25]. The diagnostic test for Ct is offered free of charge in some clinics only. Currently, sexual health and STI prevention are optional part of

school education and specific Ct prevention campaigns have never be delivered.

CONCLUSIONS We recommend the establishment of nationwide ac-

tive surveillance system of laboratory-confirmed cases of Ct genital infection to monitoring the type of diag-nostic tests used and evaluating assay-dependant differ-ences of Ct incidence and prevalence in diverse settings and geographical areas through the country. Quality and focused epidemiological studies could better char-acterise risky sexual behaviours of the population most at risk to address targeted educational programmes for primary prevention. Promotion of condom use at the community level should be implemented. Overall, our national estimate for female Ct infection exceeded twice the EU burden (19.10 DALYs and 8.52 DALYs per 100 000 stratum specific population, respectively) [27], evidencing urgent need to starting preventive pro-grammes to diagnose early and treat properly Ct infec-tion, thus avoiding sequelae. Indeed, one single offer of Ct screening may reduce the incidence of PID at 1 year by 36% [4]. Our results pointed to young women between 20 and 24 years old as the population with the highest DALYs. Age targeted screening programmes with educational interventions would allow timely treat-ment by capturing adolescents usually reluctant to seek medical care, also identifying those asymptomatic who otherwise would not have been tested.

Authors’ contributions MS wrote the manuscript, selected the specific ICD-

9 codes identifying Ct and PID cases and analysed data from NHIS; MCS managed and analysed data from the SSS; VR extracted data of the medical records from NHIS and supervised the statistical analysis; PP provided the 12-year medical records collected by the Ministry of Health, and supervised data extraction from NHIS and the statistical analysis; BS conceived and su-pervised the study project; all the authors contributed to the manuscript draft and revision.

AcknowledgementsThe authors are grateful to S. Guaschino and F. De

Seta for useful discussions on the algorithm identifying Ct and PID cases from NHIS and to all the clinical cen-tres and laboratories participating in the SSS-STIClin and the SSS-STILab. Special thanks to A. Cassini and S. Vuzem for their assistance with the BCoDE toolkit and to A. Andreasen for manuscript English revision.

Funding No funding was needed for the work described.

Conflicts of interest statementNone declared.

Received on 15 March 2019.Accepted on 19 June 2019.


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Key words• design and management

strategies• fitness centres• evaluation tool• indoor environment• multidisciplinary

approach

Design and hygiene issues in sports facilities. A pilot study which investigates fitness centres by using a multidisciplinary toolMarco Gola1, Lisa Gaviraghi1, Lorenzo Mario Capasso2, Alessandro Cuda2, Daniela D’Alessandro3, Caterina Bertolini2, Simona Riboli2 and Stefano Capolongo1

1Dipartimento di Architettura, Ingegneria delle Costruzioni e Ambiente Costruito (ABC), Politecnico di Milano, Milan, Italy 2Dipartimento di Sanità Pubblica, Medicina Sperimentale e Forense, Università degli Studi di Pavia, Pavia, Italy 3Dipartimento di Ingegneria Civile Edile e Ambientale (DICEA), Sapienza Università di Roma, Rome, Italy


AbstractIntroduction. Awareness of the benefits of the physical activity on health by the general public has increased the number of people who is practicing it in the recent years. The gyms are the primary place – as the main indoor environment – for practicing physical activity.Methods. A multidisciplinary tool was used primarily to investigate and analyse the gen-eral aspects of fitness centres then an assessment tool was created to evaluate a specific aspect such as the location, dimension, maintenance, etc. from the design, hygiene and safety points of view. Each section of the tool consisted of a series of questionnaires where the facility managers and the researches must have answered.Discussion. The tool was tested on various cases by analysing the critical issues which affects the quality of spaces and end users’ health.Conclusions. The critical points observed from the tool that has an impact on the design of the gyms will help to shape future of these facilities. Several design and management strategies were also highlighted to improve the hygiene and health issues of fitness centres.

INTRODUCTIONIn the most developed countries, according to recent

studies, people spend more than 90% of their life in indoors including leisure time [1-3] in enclosed dwell-ings and workplaces making the indoor environments a major determinant of health [4-5]. The attention by the Scientific Community therefore was focused on how the environmental factors, especially the indoors, have influenced the human health, and wellness, in particu-lar the indoor air quality [6]; in fact, the Italian Ministry of the Environment (1991), has defined the “indoor air” as the air that is present in confined non-industrial life and working spaces (homes, offices, hospitals, schools, etc.) [7].

The healthiness of confined spaces is influenced by many factors, such as pollutants due to the presence of people, human activities, air conditioning systems, and building materials [8]. Indoor pollution is defined as

the presence of different chemical, physical and biologi-cal pollutants in the air. Protracted exposure to one or more of these pollutants due to frequent and prolonged stays in confined environments may result in health is-sues ranging from respiratory and allergic disorders to the neoplasms [9].

In the 2000s, wellness and health were associated with the idea of fitness which was subsequently identified with an attainment and maintenance of physical fitness with constant and targeted physical activity followed by a series of healthy habits and behaviours. Avoiding ex-cesses and unbalanced lifestyles would make it possible to lower the risks of contracting illnesses, and foster the maintenance of a good state of health and wellbeing [10]. The growing interest on health and illness pre-vention through exercise and physical activity further involved public administrations, which, in synergy with medical communities, to promote and underscore the

Address for correspondence: Marco Gola, Dipartimento di Architettura, Ingegneria delle Costruzioni e Ambiente Costruito (ABC), Politecnico di Milano, Via Giovanni Ponzio 31, 20133 Milan, Italy. Email: [email protected].

Hygienic and design issues in gyms

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importance of the habits and behaviours listed above as the key sources of health and wellbeing.

According to the results of ISTAT survey (2006), the confined environments mostly used for physical exer-cise are gyms, where the activities can be grouped un-der the name of exercises, aerobics, fitness, etc. [11]. A sports facility is a place that can be considered as multifunctional, from the point of view of operation and consequently also from a legal one. In fact, it is first and foremost a place of sports activity [12], as well as a workplace both in the management phase and in the realization of the facility itself [13].

Gyms, indoor swimming pools, and some velodromes are defined as confined sports environments. As far as gyms are concerned, nowadays they are environments largely frequented by both athletes, for training and competitive activities, and by the general public, for recreational and/or rehabilitation purposes. To date, these structures are not regulated in their construction and management by a clear and organic national legisla-tion, and despite the attempt of some regions to fill the existing regulatory void, a primary point of reference is missing. An exception is represented by school gyms, for which reference is still made to the now dated general regulations for school buildings [14], and some specific regional regulations for the prevention of health risks within sports buildings. The regulations analysed refer to the Italian regions Basilicata, Calabria, Liguria, Marche, Tuscany, and Umbria [15]. All these norms state project designs related to specific requirements for the opening and operation of centres for physical exercise.

A clear and updated regulatory system is a key fac-tor in ensuring public health protection in general, and especially when dealing with indoor environments [16]. Since gyms are confined places where, due to a large number of people and the type of activity performed therein, numerous indoor pollutants can accumulate, it is very important that these environments meet require-ments that allow users to carry out a physical activity without compromising their health and safety [17]. In general, scientific literature points out that in the de-sign, implementation, and subsequent management phases, all the physical components that define climate in a confined environment (microclimate) and may di-rectly affect the conditions of thermal well-being have to be assessed, then athletic performance and more generally the state of health [13]. As the international regulations on sporting locations indicate, for all the rooms where natural ventilation can be guaranteed the general requirements apply, while as far as the thermo-hygrometric, renewal and air quality parameters are concerned, each country, and specifically also each re-gion, can provide restrictions.

The aim of this investigation is to perform a pilot study to assess a multidisciplinary tool, designed to evaluate the efficiency of gyms as a health promoter. METHODSDevelopment of the tool

In order to assess the quality of gyms, a multidisci-plinary team, starting from previous studies concerning the topic and regulations on sports facilities, developed

a tool to understand the state of these sports facilities, and, if present, the health risks associated with indoor pollutants [18, 19].

The tool is divided into eight different sections. Each section includes questions with multiple answers or val-ues. In order to make the instrument simple, clear and comprehensible for completion by technicians and fa-cility managers, questions have been organized by topic with many graphical references.

Each section is described below.• General information – The first section of the tool

investigates general information regarding the facil-ity, with the aim to understand its location, age, size and the number of users and employees involved. The interest of this section is to understand whether the sport facilities’ proximity or distance from city cen-tres affects their size. It could be expected that being closer to the city centres, being an area that is demo-graphically denser, would correspond to an increase in the number of users who frequent these structures. The section also verifies whether the space is located inside a building where other activities are carried out or if the building is dedicated exclusively to fitness.

• Gym location – In this second section the purpose of the questions is to analyse the distribution of fit-ness spaces among the floors within the building (one or more floors), for the reasons described below. In the case of underground, semi-basement or ground floor spaces there may be several health hazards like humidity, due to the accumulation of moisture from various sources (i.e., rising damp, seepage or conden-sation), and low illumination and/or lack of natural ventilation. The resolution of all these aspects is es-sential to ensure adequate drying and removal of dan-gerous airborne contaminants like cigarette smoke and radon [20]. Exposure to radon, a radioactive noble gas, carcinogenic if inhaled (Group I accord-ing to the IARC – International Agency for Research on Cancer – classification) and recognized as the sec-ond cause of lung cancer, is higher in basements and semi-basement, and hyperventilation in gyms could increase exposure risk. If the gym is located next to the ground, the tool investigates whether a radon gas concentration measurement has ever been carried out within the premises, in order to check if the facil-ity’s management is aware of the presence of this risk, and, above all, if there are systems for its removal.

• Gym spaces – The third section of the question-naire investigates the activities performed within the structure to understand the relationship between the size of the facility or the maximum number of users, and the number and type of functions and services provided by the structure. It is expected that as the facility surface area increases, as a consequence of the increasing number of users, there will be a greater number of functions than in smaller facilities or with a limited user base. In general, there are basic func-tions common to all facilities, like a foyer, an area with equipment, at least one locker room, and at least one room for group classes [21].

• Functional design – This section investigates the layout of the premises and the type of pathways

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that users and employees follow to move within the structure, to enter, exit or move from one function to another. The objective is to verify the affinities and differences between the two types of paths, and to understand if there are intersections that should be avoided. Another purpose is to verify if there are over-lapping flows that should be differentiated, like ac-cessing and leaving the gym space. This configuration is not recommended as it increases the potential risk of carrying dust and dirt from the outdoors into the gym space [22]. In addition to the pathways, the ac-cessibility of the facility by disabled users is verified. The questions in this part are intended to highlight if a structure is not accessible to some or all disabled users, the reasons for the impediments and whether they can be resolved by installing special machines for overcoming architectural barriers, or if more sig-nificant modifications are needed that may require structural changes.

• Finishing – The following section investigates both the interior finishing materials, as well as, although indirectly, their hygienic implications in terms of clean-ability. The purpose of the section is therefore to understand whether the materials used for cov-ering the ceilings, floors and, if necessary, walls are suitable, or, because of their characteristics, are more prone to absorb moisture or to facilitate accumula-tions of dust and allergens [23-24]. These consider-ations are also extended to furniture and equipment for physical activity.

• Dimensions – The section investigates the dimen-sions of the activity rooms, both in terms of net sur-face and net height [25]. This is to understand if the relationship between the surface area of the room and the maximum number of users participating in fitness activities is acceptable, and whether the height of the premises is adequate in relation to the size and number of expected users. Temperature and humid-ity values of the air within these spaces are also re-quired, if monitored. The purpose is not only to verify whether these values are constantly monitored, but also their compliance with the requirements of sports regulations [12].

• Ventilation and air conditioning systems – The section verifies whether spaces are adequately venti-lated and if there are projections in the rooms that can potentially accumulate dust and allergens [26-27]. It also checks if the spaces are properly lit. The section aims at verifying whether the temperature and humidity values of the air are measured on a regular basis, indicating awareness of the risks associ-ated with the presence of high values, especially in the case of dampness. Finally, the last two questions assess in detail whether ventilation by opening win-dows is sufficient to ensure good air exchange [28].

• Cleaning procedures – The last section concerns management aspects connected to cleansing proce-dures of activities rooms and equipment. In particular, the tool investigates if cleanliness is sufficient for the size of facilities and, above all, if the cleaning prod-ucts employed are appropriate and prevent the release of volatile organic compounds responsible for poor

quality air conditions [29]. In addition, it asks how frequently filters for forced air recycling are replaced. In fact uncleaned or unsubstituted filters might be-come bacteria and mould reservoirs, which are then released into the environment with negative effects on people [30]. Lastly, the tool inquired if the formation of mould colonies and the deterioration or alteration of finishing materials have ever been detected. A pilot application of the tool was carried out in the

city of Milan on different case studies (gyms and fitness centres), in order to check questions’ consistency and ease of compiling. The criterion applied for the selec-tion of gyms consisted in achieving a sample of build-ings, as much as possible various and heterogeneous, which encompasses both small and large structures, in the city centre and in the suburbs, belonging to fitness chains and private providers, recently open or placed in historic or older buildings. The selection criteria ap-plied for the enrolment included first of all the location, in order to ensure a picture of the supplies all over the city. Secondly, it distinguished private structures and fit-ness chains in order to get a proportional sample. The research of the centres was done through online data-banks.

Once identified, 40 fitness centres were contacted. In addition to explaining the survey and its purposes, they were asked to collaborate answering anonymously to the questionnaire.

Only 18 structures showed their availability, 3 of them were excluded because they were part of the same fitness group. The pilot study was then conducted on 15 structures, as reported in Figure 1.

Two were the modalities for filling the questionnaire, depending on whether the structure granted or not the opportunity to make an on-site visit. In this former case, the questionnaire was filled in loco by the evaluator with the help of the manager or a member of the staff; in the latter, it was forwarded by email and then printed and completed by the manager himself who then sent it back to the evaluator. In this case, the researchers were available to support the manager for any doubt regard-ing the compilation, in order to avoid errors.

Data obtained from the questionnaire were inserted in an Excel database, in order to highlight structural and environmental characteristics of these facilities and to offer design indications useful for both designers and managers.

RESULTS and DISCUSSIONAlmost all the investigated structures are recently

constructed (as Figure 2 shows). In fact, analysing the year of construction or inauguration of the buildings, only 3 of them (20%) became operational before 2000, one of which was located in the central urban area and two in metropolitan satellite areas. Seven gyms (46.7%) opened between 2000 and 2009, four of them were lo-cated in metropolitan satellite areas, two in semi-central areas and one in urban peripheral area; the remaining 5 gyms (33.3%) became operational between 2010 and 2014; two of them were placed in central urban areas, two in semi-central areas and one in an urban periph-eral area.


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In terms of sizing, the structures are divided into three categories according to the total area: small-sized gyms (<500 sqm); medium-sized gyms (between 500 sqm and 1500 sqm) and large-sized gyms (>1500 sqm). Among the analysed structures, 20% have an area of fewer than 500 sqm, 40% between 500 and 1500 sqm, whereas 40% over 1500 sqm, which usually correspond to big fitness centres.

In the study sample, only 4 (26.7%) of the analysed structures are for gym use only. The remaining 11 (73.3%) are located in buildings with other functions:

offices, private residences (53.0%), commercial activi-ties (13.3%), and tertiary services (6.7%).

Thirteen gyms (86.7%) have part of their spaces in the basement. In relation to the risk of the presence of Radon gas inside the activities’ rooms, the owners of these 13 structures were asked if they were aware of the ground attachment modalities of the building. Indeed, the most effective ways for removing this threat from the structure is to provide a crawl space, or, al-ternatively, a cavity, so that air recirculation can help reduce concentrations in closed environments. These

CENTRAL URBAN AREA

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Figure 1Map of the structures contacted and analysed for a survey. The sample is various and covers the whole territory of Milan.

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Figure 2Distribution of the analysed gyms by age and area.


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solutions are easier to find in recent constructions. Re-garding the investigated gyms only 3 (23.1%) knew they had crawl spaces, 2 (15.4%) were not able to answer and 8 (61.5%) declared they didn’t have any mean of radon reduction. Overall, it emerges that most of the centres have never measured radon levels.

The survey shows that in structures sized less than 500 sqm many functions are lacking and changing rooms for customers and employees are unified. By contrast, gyms with a floor area ranging from 500 and 1500 sqm pres-ent a larger number of spaces and services, even though only structures larger than 1500 sqm are equipped with modern and cutting-edge services such as swimming pool, spa, solarium, food services, etc. [10].

Dimensional profile strongly influences also the layout organization and users’ routes, as reported in Figure 3.

In smaller sports centres both the categories of people who use these spaces follow the same path, which is a basic path, not further simplified, that leads from the en-trance to the changing room and then to the gyms. The

organization of the routes grows together with the size of the structure: the paths are distinguished by the type of locals they link, and by the people who walk them down (customers or employees). During the on-site vis-its, it was possible to notice that, with l regard to the routes, there is a critical issue linked to the input and output flows in the structure. In fact, in many structures, people who go into the changing rooms before doing physical activity walk the same path of those who leave from fitness practice. Such a situation is not recom-mended because it potentially increases the risk of car-rying dust and pollutants from the outdoor environment into the spaces for physical activity [22]. In general, it would be better to keep different routes or, alternatively, to organize the changing room as a filter zone between the entrance and the area where all the fitness activities are performed, and where it is possible to benefit from all the services that the structure provides.

The sample also shows that in 2 (13.3%) gyms dis-abled users may not be able to access the structure. Out

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Figure 3Customers-employees routes in the analysed structures divided by size.


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of the 86.7% of structures accessible to disabled users (13 gyms), in 26.7% (4 gyms) the access is limited to some areas.

In terms of design, the section related to materials used for making the finishing of the gyms has the aim of verifying they are not dangerous for customers and em-ployees’ health. Building products can indeed worsen living conditions by directly releasing polluting or dan-gerous substances, by absorbing and then releasing sub-stances from other sources or by favouring the build up of dirt and the growth of microorganisms, which may increase the risks of incurring in one or more building-related diseases. With respect to finishing, materials that can cause these effects are glues, cladding for pav-ing and revetment, carpet, varnishes, dyes, panels, false ceilings, and furniture. In almost all the analysed centres it was possible to notice that the materials were suit-able, as Table 1 shows. Particularly the cladding, often realized in plastic laminate for both flooring and walls, proved to be in good state, smooth and easily cleanable. The sole exceptions are two cases where it was found the presence of exposed brick and wooden ceiling. Both these materials, being very porous, are more likely to accumulate microorganisms because of the imbibition, which favours their proliferation [31]. It is possible to prevent indoor air pollution caused by building prod-ucts with a wise choice of materials, methods of laying and installation and finishing processes.

With respect to dimensional aspects, the tool inspects the relationship between the size of activities rooms and the number of users. No difference between the size of

specific areas and the number of clients expected to use them has emerged from the comparison of case studies.

In parallel with the maximum number of users each room can hold, air temperature and humidity values in those rooms were also asked. As per existing prescrip-tions, the air temperature inside the activities room must vary between a minimum of 16 °C and a maxi-mum of 20 °C with humidity values not lower to 50%. In fact, higher values of air temperature and humidity may favour the proliferation of germs, bacteria, and mi-croorganisms which, scattering in the air, may lead to inadequate conditions of the spaces. The values record-ed from the sample are for most out of the standard.

With respect to ventilation systems, it emerges that, in most cases (14/15), the whole building, or only a part, is equipped with implants projecting from the ceiling, which increases the probability of dirt and determines a worsening of indoor air quality [32]. The designer should, therefore, prefer lighting fittings integrated with the ceiling and ventilation systems on top of the false ceiling. Regarding the air exchange implant, almost all the structures are equipped with a forced air system.

This is positive because in this way the exchange is mechanically controlled by the specific equipment which enables the manager to set different values ac-cording to the needs.

The regular monitoring of air humidity and the tem-perature inside the gyms is another aspect investigated by the survey, which asked if these values are regularly measured. Confirming data emerged in the previous section, the temperature is monitored more often than humidity (respectively 85% and 35%) and structures seem to be indeed very little interested in keeping its value within certain standards. Once again, the man-ager is responsible for the constant monitoring of air temperature and humidity in order to intervene if these values rise or fall excessively.

Eventually, the last two questions of the section con-nected to ventilation system asked if in the spaces for activities there is some form of air turnover – even through windows opening – and if so, how long they are kept open. While the feedback was positive in the 55% of the cases (in total 8) for the first query, not even a structure was able to answer to the second question, impeding to define if the windows opening is sufficient for ensuring an appropriate air exchange.

Anyway, it is always good to flank the forced air re-cycling with a natural air turnover but being careful to respect the established time limits to avoid an excessive fall of relative humidity and temperature and the for-mation of airflows disturbing the users in the activities spaces.

The cleaning is strictly related to the size of the fitness centre: while smaller ones do the cleaning only two or three times a week, in the larger ones the cleaning staff is always present inside the activities spaces and cleans continuously during the daily opening (as long as the size of the structure increases the cleaning modality be-comes extensive and more careful).

In almost all the cases, the cleaning activity is per-formed by a specialized external agency and, for what concerns the equipment used, this can be done either

Table 1 Finishing materials analysis in case studies detected

Ceiling Number (%)

Cement 2 (13.3)

Drywall false ceiling 1 (6.7)

Modular false ceiling 6 (40.0)

Plaster 5 (33.3)

Wood 1 (6.7)

Total 15 (100.0)

Floor Number (%)

Ceramic 1 (6.7)

Laminate 7 (46.7)

Parquet 7 (46.7)

Total 15 (100.0)

Wall Number (%)

Plaster, exposed brick 1 (6.7)

Mural paint 2 (13.3)

Washable paint 9 (60.0)

Glass 3 (20.0)

Total 15 (100.0)


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by the cleaning staff, the structure’s personnel and the customers themselves. This is another important datum because reveals constant hygiene of tools which should not be underestimated considering that these ones sometimes have parts which can easily absorb sweat and humidity creating an ideal environment for micro-organisms [31].

The maintenance of the ventilation system is another relevant issue. Just like finishing materials and equip-ment inserts, the filters of the ventilation system can turn into germs and allergens reservoirs and, if they are not regularly clean or substituted, they can make the ventilation system a source of biological risk [33]. Thus, it is really important to undertake routine maintenance of the system and to replace the filters. The survey highlights that in the majority of gyms (55%) the filters are cleaned or substituted monthly but, in other cases (15%), the structures declared that they replaced them only once in a year, or even that they’ve never changed them. Naturally, it depends on the dimensions of the gym and the number of hours of the functioning of the implant itself.

The last section dealt with hygienic and sanitary matters. In fact, it was asked if moulds were ever been found in the implants, or if finishing materials have ever shown signs of alteration or decline. While for questions regarding moulds negative answers predominated, posi-tive answers prevailed about material alterations (60%). In both cases, the problem is connected with standing water, which penetrates finishing materials or furniture, creating a favourable environment for microorganism potentially dangerous for human health [34, 35]. Thus, it is up to the designer to realize a waterproof system of ground attachment and an efficient implant suitable for rainwater disposal. On the other hand, it is the duty

of the manager to make sure that the implants in the structure work synergistically in order to ensure a cor-rect air recycling and to keep optimal environmental and thermo-hygrometric conditions.

CONCLUSIONSThe multidisciplinary tool allowed us to verify poten-

tial critical issues related to the collection of informa-tion needed for carrying out a complete and exhaustive investigation, to be potentially extended to wider con-texts. The time for filling the questionnaire is reason-able (roughly 60 minutes). The questions seem to be appropriate, but the answering modality showed some difficulties, which can be overcome using closed-ended questions. The questionnaires sent by email and filled by the managers of the structures were not complete, thus it was necessary to verify ex-post all the questions on site.

A potential limit can be deducted from the tool itself, which needs to be filled by a competent evaluator or, at least, by someone instructed about its use and sup-ported by the manager of the structure.

The main deficiencies are observed in the section related to spaces’ sizing in contrast to the scheme re-ported in the questionnaire. In this respect, a question regarding the volume of the environment and the layout of the room will be included in case it does not corre-spond to the scheme references.

Planned modifications include a clearer definition of the number of users, which has to refer to the mean number of people who attended the gym in the previ-ous 6 months. This will make it easier to quantify the air volume needed. In the light of the survey we car-ried out and the results we obtained, it was possible to make some considerations and draw indications useful

Table 2Design and management strategies for gyms and fitness centres

Design / maintenance strategies Avoided side effects References

Proper sealing and protection of groundwork structures The rise of radon gas and humidity Signorelli et al., 2016 [9]

Appropriate functional layout The overlap of customers and employees’ routes

Braniš and Šafránek, 2011 [22]

Internal finishing materials smooth, easily cleanable and free from gaps

Settlement and growth of microorganisms

Buonanno et al., 2012 [36]

Suitable mechanical air ventilation system Air pollution and thermal discomfort De Antonellis et al., 2016 [37]

Openings for natural lighting and ventilation Air pollution, thermal discomfort, growth of microorganisms

Popov VI et al., 2016 [38]

Furniture and ventilation system components not protruding from the walls and the ceiling

Settlement and growth of dirt, dust, bacteria and allergens

Braniš et al., 2009 [39]

Appropriate sizing of activities rooms,avoiding rooms with excessively high ceiling

Formation of convective motions of the air

De Antonellis et al., 2016 [37]

Structure equipped for ensuring accessibility to disable people, if only to a minimum number of rooms, and participation to selected typology of courses.

Accessibility forbidden for disable users Brandizzi and Carbone, 2004 [21]

Monitoring air temperature and humidity Microclimate discomfort Sacks and Shendell, 2014 [40]

Programming cleaning measures and maintenance of force air recycling systems

Settlement/growth of bacteria and microorganism and air pollution

Bouzgarou et al., 2013 [26]

Cleaning locals and equipment with specific products which limit the dispersal of polluting agents in the air

Air pollution inside the environments Alves et al., 2014 [29]


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for the designer who needs to plan this kind of struc-ture, as summarized in Table 2. Furthermore, the results achieved show how poor indoor air quality is often not due to an incorrect design or a careless choice of mate-rials and furniture, but to inadequate maintenance and management of the structure operated by the manager. For this reason, it was possible to obtain some man-agement indications useful for keeping locals in good conditions of indoor comfort.

In conclusion, the tool has shown to be very useful on at least two aspects: on one hand as a mean for under-standing designer trends (and typologies of structures) on the territory, and on the other as a tool for the sur-veillance of the quality of health promotion spaces.

Authors’ contributionAll authors contributed equally in the preparation of

this manuscript.

Conflicts of interest statementThe authors declare that there is no conflict of inter-

est regarding the publication of this paper.

Data availability statementThe data used to support the findings of this study are

included in the article.

Received on 4 November 2018.Accepted on 27 June 2019.

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Key words• polypharmacy• drug prescriptions• administrative databases• cohort study• Italy

Polypharmacy in the general population of a Northern Italian area: analysis of administrative dataFrancesca Valent

SOC Istituto di Igiene ed Epidemiologia Clinica, Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy


AbstractIntroduction. The aim of this study was to estimate the prevalence and assess patient-re-lated determinants of polypharmacy in the general population of the Italian area around Udine.Materials and methods. A retrospective cohort study was conducted using administra-tive databases: drug prescriptions, hospital discharges, ambulatory care prescriptions, ex-emptions from medical charges. Various definitions of polypharmacy were adopted (co-prescription of multiple medications, use of multiple medications for overlapping time periods). The role of patient’s characteristics on polypharmacy was assessed through regression analyses.Results. In 2017, 63.7% of the general population received at least one drug prescrip-tion. 25 218 persons were co-prescribed ≥ 5 medications at least once. The prevalence of co-prescriptions among persons ≥ 65 years was 31.7%. 20 793 persons used ≥ 60 DDDs of ≥ 5 medications. The prevalence of all these phenomena was much higher in the el-derly than in children and adults. The number of comorbidities significantly affected all types of polypharmacy.Conclusions. In this area, the prevalence of polypharmacy is high, particularly among the elderly. Age and comorbidities significantly affect the risk. Further research will aim at evaluating the health effects and appropriateness of polyphamacy.

INTRODUCTIONAs a consequence of multimorbidity, which is com-

mon among older persons and whose frequency is ex-pected to rise because of population ageing [1, 2], the use of multiple medicines is widespread. For example, a prevalence survey in 17 European countries reported that from 26.3 to 39.9% of the population ≥ 65 years of age responded that they take at least five different drugs on a typical day, including prescribed medication, over-the-counter medications, and dietary supplements [3].

The use of multiple medications by a patient, known as polypharmacy, may be necessary in many cases; nonethe-less, it is associated with both adverse outcomes on the patients [4], economic costs for society [5, 6], and, in the primary care setting, increased medication errors [7].

Despite the relevance of this phenomenon for all the above-mentioned issues, a recent systematic review highlighted that there is no uniform definition of poly-pharmacy [8]: the analysis of more than 100 articles re-vealed that there were a total of 138 definitions, 80.4% of which were numerical only and an additional 10.7%

also specified either a duration of therapy or healthcare setting, the remaining being descriptive definitions. The most common definition, used by almost half of the ar-ticles, was numerical (five or more medications daily) [8]. Among descriptive definitions, some addressed co-prescribing or simultaneous use [8].

A study conducted in Rome from health administra-tive databases confirmed that polypharmacy is a rele-vant issue in Italy, related to age and comorbidities; the study also showed that prevalence estimates changed using different algorithms [9].

The objective of this research was to estimate the prevalence and to assess patient-related determinants of polypharmacy in the Northeastern Italian area served by the Azienda Sanitaria Universitaria Integrata di Udine (ASUIUD), 251 838 inhabitants as of January 1, 2017, using the administrative health databases of ASUIUD.

METHODSThis retrospective cohort study was based on the

health administrative data of ASUIUD. In particular,

Address for correspondence: Francesca Valent, SOC Istituto di Igiene ed Epidemiologia Clinica, Azienda Sanitaria Universitaria Integrata di Udine, Via Colugna 50, 33100 Udine, Italy. E-mail: [email protected].

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the drug prescription database, the hospital discharge database, the ambulatory care prescriptions database, and the database of exemptions from medical charges, which includes patients who receive free medications or outpatient care because of certified chronic conditions defined by the Italian Ministry of Health and which may help identifying patients with a certain disease since each disease or group of diseases is associated with a specific national code [10, 11]. The databases are completely anonymous, nonetheless, they can be linked with each other at the individual patient level through a stochastic key which is univocally attributed to each subject. In-hospital medications were not in-cluded in this analysis since medications administered during hospital stay are not recorded electronically at the individual level.

All the analyses were referred to the year 2017. Dif-ferent definitions of polypharmacy were adopted: 1) prescriptions of ≥ 5 different medications (i.e., different 7-digit Anatomical Therapeutic Chemical (ATC) codes [12]) on exactly the same date (i.e., “co-prescriptions”); 2) use of ≥ 5 different medications for ≥ 60 defined daily doses (DDDs) in the year; and 3) use of ≥ 5 different medications with > 30, >60, and > 90 overlapping days of theoretical medication coverage in the year, where medication coverage was estimated adding the pre-scribed DDDs to the date of medication retrieval from the pharmacy. The analyses were stratified by sex and age category (0-14 years, pediatric; 15-64, adult; 65-79, younger elderly; ≥ 80, older elderly).

To assess the influence of comorbidities on polyphar-macy, the number of different types of comorbidity per patient was assessed, applying algorithms developed by the Italian Local Health Agency of Brescia [13] to the health administrative data of ASUIUD (hospital dis-charge records, medication prescriptions, ambulatory care prescriptions, and exemptions from medical charg-es). Comorbidity types identified by the algorithms in-clude chronic lung diseases, chronic heart failure, other cardiovascular diseases (including hypertension), diabe-tes mellitus, disorders of lipid metabolism, HIV, chronic kidney disease, rare diseases, cancer, digestive system diseases, autoimmune, endocrine diseases, neurological diseases, transplanted organs. The number of different comorbidities was assessed among patients with medi-cation co-prescriptions. Among all patients with at least one drug prescription in 2017, the association between number of comorbidities and the likelihood of co-pre-scriptions of ≥ 5 drugs was assessed through multivari-ate logistic regression adjusting for the potentially con-founding effect of patient’s sex and age category. The association was assessed trough the odds ratio (OR) with 95% confidence intervals (95% CI).

In addition, the association between the number of comorbidities and both a) the number of different med-ication used for ≥ 60 DDDs in the year, among subjects using ≥ 60 DDDs of at least one medication, and b) the number of days of overlapping coverage among subjects with ≥ 5 medications with at least one day of overlap, were assessed through two linear regression models, also adjusting for the potentially confounding effect of patient’s sex and age category. The associations were ex-

pressed by the beta coefficients; results with p-value < 0.05 were considered statistically significant.

Finally, to investigate other characteristics of the pop-ulation potentially associated with polyphamacy, we as-sessed the proportion of subjects exempt from medical charges due to low family income (evaluated through an indicator of equivalent economic situation called ISEE) among those fulfilling the 3 above-listed defini-tions of polypharmacy.

All the analyses of the present study were conducted using SAS v9.4 (SAS Institute Inc. Cary, NC, USA).

Compliance with ethical standardsSince this analysis was based on anonymous admin-

istrative data, patient informed consent could not be obtained and Ethical Committee approval was not re-quired in Italy.

RESULTSIn 2017, 3 105 481 prescriptions were retrieved from

the prescription database. Of all subjects living in the ASUIUD area, 160 465 (63.7%) received ≥ 1 medica-tion prescription in 2017: 55.8% were females; 8.5% were children, 54.5% adults, 25.0% younger elderly, and 10.9% older elderly. In the year of study, 25 218 patients received ≥ 1 co-prescription of ≥ 5 different medications (10.0% of the population), for a total of 82 044 episodes of co-prescription of ≥ 5 medications (polypharmacy definition 1). As shown in Table 1, the prevalence of co-prescriptions is much higher in the elderly than among adults. Overall, the proportion of population ≥ 65 years of age who were co-prescribed ≥ 5 medications at least one in 2017 was 31.7%. The monthly distribution of the number of co-prescriptions of ≥ 5 medications by age category did not show any specific pattern (Figure 1). The 5 most commonly groups of medications found in such co-prescriptions (not necessarily in the same co-prescription) by age group are shown in Table 2. The ob-served different co-prescription patterns were 66 206, with frequency ranging from 1 to 119 cases (available as Supplementary materials). Of the 5 most common co-prescription patterns, all but one included one drug for peptic ulcer and gastro-esophageal reflux disease, one antithrombotic agent, and three medications acting on the cardiovascular system, as follows:

- A02BC02 + B01AC06 + C07AB07 + C09AA05 + C10AA05 (N=119)

- A02BC02 + B01AC06 + C07AB02 + C09AA05 + C10AA05 (N=76)

- A02BC02 + B01AC06 + C03CA01 + C07AB07 + C09AA05 (N=30)

- B01AC06 + C07AB07 + C09AA05 + C10AA05 + C10AX09 (N=25)

- A02BC02 + B01AC06 + C08CA01 + C09AA05 + C10AA05 (N=24)

In 2017, 20 793 patients (8.2%) used ≥ 60 DDDs of ≥ 5 medications (polypharmacy definition 2): 1 in the age group 0-14 (0.003%), 3407 in the age group 15-64 (2.2%), 10 752 in the group 65-79 (24.1%), and 6633 in the group ≥ 80 (34.3%). The median number of comor-bidities for patients with co-prescriptions of ≥ 5 medi-cations was 0 among children (interquartile range 0-2)

PolyPharmacy in northern italy

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and 3 in all other age groups (interquartile range 2-4). The number of overlapping days covered with ≥ 5 dif-

ferent medications (polypharmacy definition 3) is illus-trated in Table 3. More than 5% of the whole population had ≥ 5 medications overlapping for > 90 days in a year. The prevalence of such an important overlap was much higher in the elderly groups. The prevalence of overlaps of ≥ 5 medications was slightly more frequent among males (Table 4).

Of all subjects living in the ASUIUD area, those

with at least one chronic condition were 2.5% in the age group 0-14, 28.3% in the age group 15-64, 80.8% in the age group 65-79, and 99.3% among persons ≥ 80 years of age. Among children, there was no one with ≥ 5 comorbidities; on the other hand, the coexistence of 5 or more long-term conditions was found in 0.3% of the population 15-64, in 3.7% of those 65-79, and in 5.0% of those ≥ 80 years of age. Table 5 shows the association of the number of comorbidities with the various forms of polytherapy. Among subjects with at

Table 1Prevalence of co-prescriptions of ≥ 5 medications in the population of the Azienda Sanitaria Universitaria Integrata di Udine, Italy, 2017

Sex Age category N of patients with co-prescriptions

Population Prevalence (%) Total N of co-prescriptions

F 0-14 6 15 222 0.04 6

F 15-64 2369 79 510 2.98 5926

F 65-79 6047 24 276 24.91 18 825

F ≥ 80 5080 12 804 39.68 17 097

M 0-14 6 15 693 0.04 6

M 15-64 2551 77 454 3.29 7891

M 65-79 6281 20 334 30.89 22 288

M ≥ 80 2878 6538 44.02 10 005

Total 25 218 25 1831 10.01 82 044

Figure 1Number of co-prescriptions of ≥ 5 medications by month and age category, Azienda Sanitaria Universitaria Integrata di Udine, Italy, 2017.

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least one prescription in 2017, the likelihood of being co-prescribed ≥ 5 medications increased by more than 3 times for each additional comorbidity. Among subjects with prescriptions of ≥ 60 DDDs of at least one drug in the year, adjusting for the confounding effect of sex and age, a patient is likely to be prescribed ≥ 60 DDDs of one additional medication for each additional comor-bidity. Also, each additional comorbidity increases the average coverage with ≥ 5 medications simultaneously by 27 days.

Among all subjects with co-prescriptions of ≥ 5 medications (polypharmacy definition 1), no one was exempted from medical charges due to low income in the age group 0-14, 1.6% had such an exemption in the group 15-65, 0.1% in the group 65-79, and < 0.1% in the group ≥ 80 years of age. Among those using ≥ 5 different medications for ≥ 60 DDDs in the year (poly-pharmacy definition 2), no one had exemptions due to low family income in the age group 0-14, 1.2% had such an exemption in the group 15-64, 0.1% in the group

Table 2The five most common groups of medications found in co-prescriptions of ≥ 5 medications by age category, Azienda Sanitaria Universitaria Integrata di Udine, Italy, 2017

Age category

4-digitATC code

Medication group

N of co-prescriptions

% of all co-prescriptions

0-14a R03A adrenergics, inhalants 10 83.3

H02A corticosteroids of systemic use 9 75.0

R03B drugs for obstructive airway diseases, inhalants, other than adrenergics

9 75.0

J01C penicillins 6 50.0

15-64 C10A lipid modifying agents 8580 62.1

B01A antithrombotic agents 8165 59.1

A02B drugs for peptic ulcer and gastro-esophageal reflux disease

7919 57.3

C07A beta blocking agents 6025 43.6

A10B blood glucose lowering drugs, excl. insulins

4264 30.9

65-79 B01A antithrombotic agents 27 611 67.2%

C10A lipid modifying agents 24 550 59.7%


23 074 56.1%

C07A beta blocking agents 18 528 45.1%

A10B blood glucose lowering drugs, excl. insulins

12 784 31.1%

≥ 80 B01A antithrombotic agents 19 106 70.5%


16 565 61.1%

C07A beta blocking agents 11 872 43.8%

C10A lipid modifying agents 10 730 39.6%

C03C high-ceiling diuretics 8809 32.5%

aonly the first 4 medication groups are shown since several others were equally frequent

Table 3Overlapping days covered with ≥ 5 different medications in the population of the Azienda Sanitaria Universitaria Integrata di Udine, Italy, 2017

Overlap(days)

N Prevalence (%)

00-14 15-64 65-79 ≥ 80 Total 00-14 15-64 65-79 ≥ 80 Total

≤ 30 91 6444 7320 3680 17535 0.29 4.11 16.41 19.03 6.96

31-60 7 1680 3198 2070 6955 0.02 1.07 7.17 10.70 2.76

61-90 2 955 2291 1504 4752 0.01 0.61 5.14 7.78 1.89

> 90 10 2384 7091 4244 13729 0.03 1.52 15.90 21.94 5.45


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65-79 and 0.1% in the group ≥ 80 years of age. Among patients with an overlap of ≥ 5 medications lasting > 30 days (from polypharmacy definition 3), the proportion of those with exemption from medical charges due to low family income was 0 among children, 1.4% among subjects 15-64, 0.1% among both subjects 65-79 and subjects ≥ 80 years of age.

DISCUSSIONThis research illustrated various prescriptive issues

related to polypharmacy in the general population of a Northern Italian area using health administrative data-bases. These results are not affected by sampling error, selection bias, or recall bias. In fact, the data cover the entire population and are collected for administrative purposes in an objective way.

This research showed that polypharmacy is by far more common among the elderly, especially those ≥ 80 years of age, than among adults, irrespective of the definition of polypharmacy. Not only are 31.7% of the elderly co-prescribed ≥ 5 medications at least one in a year, but more than 15% of younger elderly and more than 20% of older elderly have an overlapping use of ≥ 5 medications for more than 90 days in a year.

As expected, the medications that were most fre-quently involved in polypharmacy differed depending on the age group. Among children, medications were inhalants for obstructive airway disease, antibiotics and systemic corticosteroids; among adults and elderly patients, drugs for peptic ulcer and gastro-esophageal

reflux disease, antithrombotic agents, antihypertensive medications, and lipid modifying agents were the most frequently co-prescribed.

In Italy, only few studies had previously been con-ducted on polypharmacy in the outpatient setting among the general population. One of those studies was conducted in the Italian Region Friuli Venezia Gi-ulia [14], which includes our study area. That study, an-alyzing polypharmacy in the hospital, general practice, and long term care facility settings, showed a very high prevalence of polypharmacy in the elderly population, as high as 57.7% of patients being co-prescribed 5-9 drugs and 9.7% being prescribed 10 or more. However, such estimates were based on a one-week point-prev-alence survey which might have not been representa-tive of the general prescription habits either because of random error or because of systematic error due to the possible existence of seasonal variations, of bias in the selection participating GPs, or of bias in the selection of the surveyed patients.

Another study was conducted [15] in the Emilia-Romagna Region, based on the analysis of outpatient drug prescriptions. The proportion of elderly patients exposed to overlapping treatment with ≥ 5 medications for ≥ 1 day was 39.4%. The most frequent groups of drugs involved in polypharmacy in that study were the same that characterized polypharmacy in the elderly population of the area of Udine.

The European data based on data from the large Survey of Health, Ageing and Retirement in Europe

Table 4Prevalence of overlapping days covered with ≥ 5 different medications in the population of the Azienda Sanitaria Universitaria Integrata di Udine, Italy, 2017, by sex

Overlap(days)

Females (% of population) Males (% of population)

0-14 15-64 65-79 ≥ 80 Total 0-14 15-64 65-79 ≥ 80 Total

≤ 30 0.18 4.72 17.84 19.80 8.08 0.41 3.48 14.70 17.51 5.74

31-60 0.03 1.06 7.05 10.36 2.95 0.02 1.08 7.31 11.36 2.56

61-90 0.01 0.51 4.65 7.44 1.88 0.01 0.71 5.71 8.44 1.89

> 90 0.03 1.08 12.01 19.32 4.75 0.03 1.97 20.53 27.07 6.23

Table 5Association between number of comorbidities and likelihood of co-prescription of ≥ 5 medications among all subjects with at least one drug prescription, number of different medications with ≥ 60 DDDs prescribed in one year among users of ≥ 60 DDDs of at least one medication, and number of overlapping days of coverage with ≥ 5 medications in one year among users of ≥ 5 medi-cations for at least one overlapping day in the Azienda Sanitaria Universitaria Integrata di Udine, Italy, 2017

Co-prescription of ≥ 5 medications

N of medications with ≥ 60 DDDs

N of overlapping days of coverage

with ≥ 5 medications

Variable OR 95CI Beta coefficient p-value Beta coefficient

p-value

Sex (F vs M) 0.75 0.73-0.78 -0.4144 < 0.0001 -21.38 < 0.0001

Age (0-14 vs 15-64) 0.07 0.04-0.13 0.1258 0.0579 16.25 0.0579

Age (65-79 vs 15-64) 2.70 2.29-2.82 0.6837 < 0.0001 10.71 0.0107

Age (≥ 80 vs 15-64) 5.44 5.18-5.72 1.1888 < 0.0001 18.35 < 0.0001

N of comorbidities (continuous) 3.44 3.39-3.50 1.1184 < 0.0001 27.42 < 0.0001

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(SHARE) project, Wave 6, found a prevalence of “use of at least 5 different drugs on a typical day” among participants ≥ 65 years ranging from 26.3 to 39.9% [3]. In particular, in Italy the prevalence was 32.9% (95% CI: 32.3-33.5%), increasing with age category from 26.4% in subjects 65-74 to 45.1% in those ≥ 85 years, and slightly higher in males (33.2%) than in females (32.5%). Number of chronic diseases was also associ-ated with polypharmacy, as was in the present study.

Due to the absence of social and lifestyle information on the health administrative data of the ASUIUD, the association of those factors on the prevalence of poly-therapy could not be assessed, as done in the European survey [3]. Among subjects with polypharmacy in the area of Udine, only a very small proportion had obtained an exemption from medical charges because of low fami-ly income: from little more than 1% in the population 15-64 years of age to less than 1% in the other age groups. However, these data should not be interpreted as a lack of association between low income and polypharmacy. In fact, not all economically disadvantaged citizens apply for such an exemption, especially if they are already enti-tled to exemptions because of chronic conditions or civil invalidity [10, 11]. On the other hand, the present study confirmed that prevalence of polypharmacy increases with increasing age and number of comorbidities, as shown also by Fano et al. [9], exposing patients who are fragile per se to the additional health risks from polyphar-macy adverse effects and inappropriate prescribing [14]. These results indicate a situation which deserves inter-ventions to address polypharmacy.

In addition, to better define the impact of polyphar-macy on the population health of ASUIUD, a new co-hort analysis of administrative data could be conducted to compare health outcomes of patients with and with-out polypharmacy or with different levels of polyphar-macy, taking into account demographic factors and co-morbidity level.

This study has some limitations, mainly due to the ad-ministrative nature of data. First, in the analyses of the long term use of multiple medications the DDDs were used to estimate duration, however the DDDs may not accurately reflect the actual prescribed doses [16], thus durations might have been misestimated in some cases. Then, as in all studies where the medication is not di-rectly administered by the researcher, there is no guar-antee that the drug has been assumed, or assumed as prescribed, by the individual. In addition, intake of over-the-counter medications could not be considered (now including frequently used medications such as treat-ments for gastroesophageal reflux disease), suggesting

that the actual prevalence and severity of polypharmacy might be even greater than our estimates. Further, no information was available on socioeconomic character-istics of subjects other than exemptions from medical charges released because of low family income, thus leaving potential associations between social factors and polypharmacy unexplored. Finally, there are cases where co-prescribing multiple medications is appropri-ate, but this analysis did not assess appropriateness. The information on all the co-prescription patterns was available, but with over 80 000 co-prescription episodes in 2017, the observed different co-prescription patterns were more than 65 000 and an individual evaluation of each one was unfeasible.

Since the vast majority of the elderly population and almost 30% of the adult population in our area is affected by long-term conditions, with 5% of the population ≥ 80 having 5 or more comorbidities, polypharmacy may be the obvious consequence of the justified attempt to con-trol chronic and often multiple diseases. Nonetheless, polypharmacy may be more harmful than beneficial for some patients, due to the possibility of drug-drug inter-actions [17], that may even result in toxicity or treatment failure [18, 19]. In addition, most clinical trials are con-ducted and most clinical guidelines are developed as if patients have a single condition; clinical recommenda-tions generally do not consider the possible cumulative impact that multiple guidelines may have on a single pa-tient [20]. Clinical guidelines taking into account multi-morbidity and polypharmacy, then, are needed [21].

Despite not being able to assess appropriateness and the potential for drug-drug interactions, this study de-scribed the high prevalence of polypharmacy in the gen-eral population of ASUIUD, including children, high-lighted classes of medications that are more commonly involved in co-prescribing, and identified that the elder-ly and patients affect by multimorbidity are particularly exposed to this phenomenon and the related health risks. Further research which will help clarify the actual impact of polypharmacy on health outcomes is feasible and will be conducted in this area. Information of GPs on this issue should also be kept as a priority.

Funding None.

Conflict of interest statementNone declared.

Received on 8 March 2019.Accepted on 27 June 2019.

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Key words• education• pediatric palliative care• end-of-life• postgraduate

Training in pediatric palliative care in Italy: still much to doFranca Benini1, Chiara Cauzzo1, Sabrina Congedi1, Liviana Da Dalt2, Paola Cogo3, Lilia Biscaglia4 and Luca Giacomelli5,6

1Cure Palliative Pediatriche, Terapia del Dolore, Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova, Padua, Italy 2Dipartimento di Pediatria di Urgenza, Dipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova, Padua, Italy 3Dipartimento di Medicina, Sezione di Pediatria, Università degli Studi di Udine, Udine, Italy 4Cooperazione Odontoiatrica Internazionale (COI NGO), Turin, Italy 5Polistudium SRL, Milan, Italy 6Dipartimento di Scienze Chirurgiche e Diagnostica Integrata, Università degli Studi di Genova, Genoa, Italy


AbstractAim. This survey investigated the availability of training programs in pediatric palliative care (PPC) for Italian postgraduates specializing in pediatric medicine.Methods. Two questionnaires were developed: (i) a questionnaire addressed to the Di-rectors of Italian postgraduate pediatric medicine programs (n = 37); and (ii) a survey to the postgraduate students in pediatric medicine at the University Hospitals of Padua and Udine (n = 127).Results. 14 directors participated (response rate: 37.8%). In 85.7% of cases (n = 12), lectures on PPC were offered, for a supposed maximum of 90 minutes/year. 116 students responded (response rate: 91%): they stated that, approximately 40 min/year of training on PPC was provided. In total, 37% of responders stated they attended a PPC Service during their training. The majority of responders (68.1%, n = 79) did not feel ready to care for a pediatric patient with life-limiting disease. Conclusions. Although PPC is well-recognized as part of a pediatrician’s training, it receives poor attention.

INTRODUCTIONThe number of children diagnosed with life-limiting

(LL) and life-threatening diseases is unfortunately high: it has been estimated that 10 per 10 000 children aged 0-19 years suffer from a LL disease, with an an-nual mortality rate of 1 per 10 000 children aged 1-17 years, and these figures are increasing [1, 2]. Guaran-teeing an acceptable quality of life for children with LL diseases is a healthcare priority, and this goal can be achieved with an adequate control of symptoms to be pursued through specific medical competencies, a multidisciplinary approach, proper communication and organizational skills. However, the majority of children with LL diseases present many uncontrolled symptoms; moreover, communication, spiritual and social aspects are frequently not comprised into the care program and often delegated to the patient’s family, overall resulting in a reduction in the quality of care [3-5].

Pediatric palliative care (PPC) is the discipline that

can respond to spiritual, emotional and relational needs taking care of the child’s body, mind and soul, and supporting, at the same time, his/her family [6]. The goal of PPC is to ensure the best quality of life possible for both children affected with a LL disease and their relatives, evaluating all their needs and assess-ing the risk-benefit balance of each act, procedure and choice, without jeopardizing the efficacy and safety of proposed interventions. Of note, PPC is not the only end-of-life (EOL) care: according to the current model, curative, palliative and bereavement care should coex-ist for each patient, and one aspect may prevail on the others according to the different phases of the disease course [7]. Despite its importance, PPC is still scantly diffused, and a lot of children with LL diseases have no access to PPC services: for instance, in Italy no more than 5% of children eligible to PPC have actual access to a dedicated service [8].

In order to widen the diffusion of PPC and serve chil-

Address for correspondence: Franca Benini, Cure Palliative Pediatriche, Terapia del Dolore, Dipartimento di Salute della Donna e del Bambino, Uni-versità degli Studi di Padova, Via Giustiniani 3, 35128 Padua, Italy. E-mail: [email protected].

Training in PPC in iTaly

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dren with the best possible level of care, proper train-ing should be mandatory; however, in Italy, training of healthcare professionals in PPC is incomplete and in-adequate thus representing an important barrier to the full implementation of PPC all over the country [9-12]. To our knowledge, detailed information on the PPC training and its diffusion in Italy is not available.

This survey aimed to determine the availability of training programs in PPC and EOL care for Italian postgraduates specializing in Pediatric Medicine and how the knowledge and skills offered as part of their training is structured.

METHODSDesign

A cross-sectional national survey on the attitudes of Italian postgraduate students specializing in pediatrics based on the knowledge and skills in PPC and EOL was conducted from June to August 2017.

In particular, two questionnaires were developed: (i) a questionnaire was sent to the directors of Italian post-graduate pediatric medicine programs; and (ii) an on-line survey was sent to all the postgraduate students in pediatric medicine at the University Hospitals of Padua and Udine.

The two questionnaires were developed by experts in PPC and professional methodologists in line of a previ-ous similar effort [13]. Pilot versions of the question-naires were administered to a director of Italian post-graduate pediatric medicine program and to a group of postgraduate students. Feedback was taken into account and critically included in the final versions of both questionnaires by the development committee.

The two questionnairesThe questionnaire for the Pediatric Residency Pro-

grams’ Directors consisted of 30 questions and was aimed at collecting data and opinions on the organi-zation of training programs regarding pediatric pain therapy and PPC. The second questionnaire consisted of 75 items divided into five categories, and was aimed at collecting social and demographic features (age, sex, year of degree and residency), evaluating the pe-diatric residents’ impressions concerning information received during their training and assessing the actual knowledge of these topics using appropriate questions. Both questionnaires combined dichotomous, multiple choice, demographic and Likert response scale ques-tions with free-text questions. Approximately 20 min-utes were necessary to complete each survey.

The survey was conducted using the Google Forms web-based program survey. A link to the survey was sent out to the participants by email together with brief explanation of the aims of the survey. Two reminders were sent to non-responders, and completion of the questionnaire was considered as consent to participate in the study.

Data analysisData were analyzed by descriptive statistics using the

SAS 9.4 (SAS Institute Inc., Cary, NC, USA) for Win-dows.

RESULTS Questionnaire n. 1

A total of 14 directors of Italian postgraduate pediat-ric medicine programs out of the 37 who were contact-ed participated in the study, with an overall response rate of 37.8%. Overall, 92.9% (n = 13) rated pain man-agement as “very important” clinical skills. In 85.7% of cases (n = 12), topic lectures dealing with PPC were offered during postgraduate training programs. More-over, 85.7% (n = 12) offered specific training program in pain management, and 78.6% (n = 11) offered spe-cific training in PPC.

The duration of these lessons ranged between 50 and 90 minutes/year. Resident training in PPC was of-fered in six different schools (42.9%) but was manda-tory only in two cases of PPC-dedicated services. In the other structures, the training period took place at the Pediatric Onco-Hematology Service. In three (21.1%) schools, it was possible to devote the final year of spe-cialization entirely to PPC.

Questionnaire n. 2• Baseline characteristics

In total, 116 postgraduate students in pediatric medi-cine completed the survey, with an overall response rate of 91% (116/127). The mean age of the responders was 29 years (standard deviation: 5 years), and 81.9% of them (n = 95) were females. More than one-third of the participants (37.1%, n = 43) attended a period in a PPC service during their residency.

• Level of trainingAccording to the results of this second questionnaire,

approximately 40 minutes of training on palliative care (in general), EOL and PPC care was provided in each academic year; only 16.5% (n = 19) of the participants received basic PPC training, and 20.7% (n = 24) of re-sponders did not receive any basic training regarding the above-mentioned fields. Only 15.3% (n = 15) of the responders declared to have received > 6 hours in PPC training during the entire postgraduate course.

Overall, 91.4% (n = 106) of responders indicated PPC as an essential competence for a pediatrician who must actively participate in the care of patients with LL diseases. Only 5.2% of pediatric residents (n = 6) did not agree with this.

• Attendance to a PPC serviceIn total, 37% of responders (n = 43) revealed they

attended a PPC service during their postgraduate training program, in most cases for a period of 16-60 days (Figure 1). In 87.9% (n = 102) of cases, they were involved in the management of a child with complex needs. In total, 12.3% of postgraduate residents (n = 14) dealt with the communication of incurable disease at firsthand, four of them with the supervision of a se-nior physician; 16.4% (n = 19) of the residents inter-viewed declared they carried out the communication of a child’s death to his/her family, but only in two cases after adequate training.

More than half of participants (58.6%; n = 68) moni-tored at least one child at EOL care, more frequently in

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ICU and Onco-Hematology Service and mostly during the last 2 years of residency, with experience of EOL that increased with the experience and year of post-graduate course (Figure 2).

Regarding management of children’ EOL care, re-spiratory symptoms and pain control were indicated as the most disturbing ones, and pharmacologic treatment with strong opioids and benzodiazepines was consid-ered the most appropriate therapy by approximately half of the responders (52.8%, n = 56).

• Level of knowledgeAlmost all of postgraduate students (96.6%, n = 112)

correctly defined PPC as “the care addressed to children with life-limiting and chronic illnesses, who need high levels of care, regardless of the expected survival time”. In 65.5% of the cases (n = 76), PPC was correctly defined as a care that should start when the diagnosis of incurability

is made. Between 90% and 100% of participants denied that PPC necessarily entails the suspension of treat-ments, that PPC exclusively regards the onco-hemato-logic field, that the symptoms’ control is the only aim of care and that the child’s home is the only adequate place to deliver CPC.

Figure 3 shows the percentage of correct answers to the above-mentioned questions: an increase over time, but still suboptimal, rate of correct answers was shown.

In total, 91 postgraduate students (78.4%) properly indicated categories of diseases eligible to PPC and in 12 cases (10.3%) it was stated how the eligibility of a patient to CPC, independently to the specific illness, is highly related to the complexity of care required.

Overall, 33.6% of the responders (n = 39) was aware of local PPC services, while 4.3% (n = 5) had a knowl-edge of the organizational procedures to dispose for a body of a dead child.

Figure 1 Attendance to a pediatric palliative care (PPC) service.

Figure 2Experience with monitoring of a child at his/her death. All number are expressed as percentages of the total number of responders (n = 116).


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• Self-evaluationThe majority of responders (68.1%, n = 79) did not

feel ready to care for pediatric patient with a LL dis-ease, 73.2% (n = 85) of the postgraduates interviewed perceived that they did not feel ready to manage a child’s EOL care and 63.7% (n = 74) of the respondents considered their skills in PPC and EOL management to be “weak” or “very weak”.

Among the 37 postgraduate residents (31.9%) who declared they felt ready to manage a child with a LL illness, 81.1% (n = 30/37) received specific training in PPC and 75.7% (28/37) received specific training in EOL care. On the other hand, 70.2% (26/37) aimed at improving his/her knowledge of PPC, and in particu-lar of bioethical and spiritual issues. Almost all of the respondents (94.8%, n = 109) declared “important” or “very important” to acquire specific knowledge and competence in EOL management during their post-graduate training. A training period in CPC service was associated with increased self-perception of expertise, with more attitude in managing findings of EOL (data not shown).

Three educational approaches were considered as most useful: direct observation of older residents or senior doctors caring for a pediatric patient with a LL disease (judged useful by 85.3% of responders, n = 99); discussion of clinical cases discussion within small mul-tidisciplinary groups (70.7%, n = 82); communication training with standardized patients/families and/or role play (69.8%, n = 81).

DISCUSSIONOnly scant information exists on the actual imple-

mentation of PPC training. Our survey investigated this issue from two different perspectives, namely pediatric program directors and postgraduate students, with the aim to provide a picture, although limited, of the cur-

rent status of PPC training in Italy. However, we must point out that only a limited number of responders were collected for each questionnaire, and therefore our data cannot be considered immediately and fully representa-tive of the Italian scenario.

First, the value of PPC as both a clinical competency and as a component of pediatric residency education was well recognized by program directors and postgraduate students, in line with previous studies and with current recommendations that indicate dissemination of PPC as a major unmet clinical need [6, 12, 13]. Although the importance of PPC training was well recognized, only a very limited number of hours was dedicated to PPC and EOL care during the pre- and post-graduate academic course, with only a minority of students (15%) receiving > 6 hours of training and less than 40% of them attend-ing a dedicated PPC service during their residency pe-riod. Remarkably, program directors and postgraduate students were not consistent in estimating the number of training hours dedicated to these issues. Moreover, a substantial number of the residents judged their train-ing as inadequate and they did not feel ready to manage either a child with a LL disease or the EOL care of a pediatric patient. However, even if time devoted to CPC training resulted inadequate, a progressive increase in both knowledge and competence from the first to the last year of residency is reported. This finding also sug-gests an individual effort in the acquisition of more ex-pertise in the field, representing the first step towards focused didactic opportunities.

The poor attention dedicated to PPC and EOL care training reported in Italy, according to the results of our survey, was not totally unexpected, since a low level of medical professionals’ training in PPC was already documented in countries other than Italy, partly due to poor dissemination of PPC service, economical and or-ganizational issues, and lack of both formally defined

Figure 3Proportion of correct answers given by the responders.

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classes and senior physicians with a dedicated expertise and [12, 14-16]. Moreover, very little attention is paid to ethical reflection and teamwork skills acquisition [17]. On these bases, a mandatory PPC educational program has been proposed for all medical students [18, 19], and accordingly, standardized training pro-tocols are increasingly being offered in some countries [20-24]. These programs include training in specific is-sues, such as communication skills and managing EOL symptoms, and are based on unconventional teach-ing methods (e.g. bedside training, “train-the-trainer” model, discussion-based seminar, role play) [23, 24]. Remarkably, in our survey, these approaches have been identified as those potentially most effective, and we therefore feel that the definition of standardized PPC training protocols based on those methods may be con-sidered by relevant bodies. Moreover, the presence of a PPC service can improve not only the management of a child with a LL illness, but also residents’ training, in line with previous evidence [25].

CONCLUSIONIn Italy, the access to PPC for children with LL ill-

nesses is still limited and many barriers limit develop-ment of an adequate network of CPC services. Among these, one of the greatest critical issue is the lack of healthcare workers who are trained in CPC.

Data collected by our surveys suggest that although PPC is well-recognized as primary competencies in a pediatrician’s training a poor attention is actually paid to these skills. Therefore, it appears necessary to devel-op curricula for medical students and design tailored programs addressed to pediatric residents and aimed to the acquisition of knowledge and skills about the man-agement of children with LL illnesses and their families, including also communication methods and principles of bioethics.

AcknowledgmentsEditorial assistance was provided by Aashni Shah

(Polistudium srl, Milan, Italy) and was supported by internal funds.

Authors’ contributionStudy design: FB, CG, SG; data analysis: CG, LG;

data interpretation: all; manuscript drafting: CG, SG, LG; manuscript revision: all; approval to submit: all.

Conflict of interest statementThe authors have no conflicts of interest directly rel-

evant to this study.

Received on 9 May 2019.Accepted on 4 July 2019.

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2. Goldman A. ABC of palliative care. Special prob-lems of children. BMJ. 1998;316:49-54. doi: 10.1136/bmj.316.7124.49

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6. World Health Organization. Cancer pain relief and pal-liative care in children. Geneva: WHO; 1998. Available from: www.who.int/cancer/palliative/definition/en/

7. Michelson KN. Pediatric end-of-life issues and palliative care. Clin Pediatr Emerg Med. 2007;8(3):212-9. doi: 10.1016/j.cpem.2007.06.006

8. Commissione della Società Italiana di Cure Palliative. Conferenza di consenso. Le cure palliative pediatriche: dalla diagnosi di inguaribilità al lutto. SICP; 2016. p. 1-23. Available from: www.fedcp.org/news-menu/906-le-cure-palliative-pediatriche-dalla-diagnosi-di-inguaribilita-al-lutto.html.

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glia U, Verona ACP. Cure palliative pediatriche: perché occuparsene. Quad ACP. 2011;18(5):216-20.

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Key words• inflammatory bowel

disease• enterophatic

spondyloarthritis• management• diagnosis

Integrated gastroenterology and rheumatology ambulatory: an innovative approach for enteropathic spondyloarthritis early diagnosisRoberto Lorenzetti, Palma Scolieri, Alessandra Guarini, Francesca De Marinis, Angelo Zullo, Cesare Hassan and Vincenzo Bruzzese on behalf of the Italian Society of Gastro-Rheumatology

Medicina Interna, Gastroenterologia e Reumatologia, Ospedale Nuovo Regina Margherita, Rome, Italy


INTRODUCTIONPatients with inflammatory bowel disease (IBD) may

develop different extra-intestinal manifestations [1]. Among these, Spondyloarthritis (SpA) is the most fre-quently reported, with an incidence rate of 17-39% [2, 3]. Early diagnosis of SpA is crucial to perform a tight disease control with an impact on its natural history, particularly for preventing permanent disabilities [4]. However, diagnosis of SpA may be delayed in a sub-stantial number of IBD patients for different reasons. Indeed, the disease may be asymptomatic in the early phase, the immunosuppressive/sulfasalazine treatment may mask non-specific rheumatic symptoms, or the gastroenterologist (and the patient) may underestimate inflammatory back pain. On the other hand, an IBD may develop in patients with SpA, although the inci-dence is near 1 case per year of follow-up [5]. Simi-larly, early diagnosis may be difficult, particularly when are present only vague intestinal symptoms that the rheumatologist (and the patient) may overlook or an immunosuppressive treatment is already performed. It is counterintuitive that an early diagnosis could reduce the intestinal disease progression, potentially prevent-ing complications or surgical interventions.

In the current clinical practice, diagnosis and man-

agement of patients with coexisting IBD and SpA – de-fined as Enteropathic Spondyloarthritis (ESpA) – are usually carried on by a single specialist, which is the gastroenterologist or rheumatologist, according to the initial disease diagnosed. In such a scenario, a holistic patient management is prevented given that one of dis-ease is beyond the direct field of specialist expertise. To overcome such a limitation, we pioneered an integrat-ed “GastroReumatology” ambulatory in our Hospital, on behalf of Italian Society of Gastro-Rheumatology (SIGR).

METHODSIn such dedicated ambulatory, a gastroenterologist

and a rheumatologist with a long-lasting expertise in IBD and SpA, respectively, simultaneously visit those patients referred for a suspected ESpA. In detail, pa-tients were selected based on the presence of some clinical indicators – defined “red flags” (Figure 1) – sug-gestive of SpA and/or IBD, in agreement with Italian Expert Panel on the management of coexisting SpA and IBD [6]. In detail, a dedicated help-line was created where two experienced IBD nurses (AG and FDM), specifically trained for both IBD and rheumatic red flags, performed a brief interview of patients referred by

Address for correspondence: Roberto Lorenzetti, Medicina Interna, Gastroenterologia e Reumatologia, Ospedale Nuovo Regina Margherita, Via Emilio Morosini 30, 00153 Rome, Italy. E-mail: [email protected].

AbstractPatients with inflammatory bowel disease (IBD) may develop rheumatic diseases, par-ticularly enterophatic spondyloarthritis (ESpA). Similarly, an IBD may develop in patients with SpA. Management of these patients in a dedicated ambulatory could be advanta-geous. We pioneered an integrated “GastroReumatology” ambulatory where a gastroen-terologist and a rheumatologist with a long-lasting expertise in IBD and spondyloarthritis, respectively, simultaneously visit those patients referred for a suspected ESpA. A total of 101 different patients with suspected or known IBD and/or a rheumatic disease were vis-ited. A new diagnosis of ESpA was eventually achieved in 13 (12.9%) patients, and further 12 patients with an already known ESpA were referred for an appropriate management. No cases of IBD in those patients with an established rheumatic disease were observed. Early diagnosis of ESpA is possible in a “GastroReumatology” ambulatory.

InnovatIve approach for enteropathIc spondyloarthrItIs early dIagnosIs

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their General Practitioners, and selected those with at least 1 suggestive symptom deserving an integrated vis-it. The nurses fixed the visit even for those patients with a doubtful red flag in order to avoid diagnosis missing.

RESULTSFrom January 2015 to December 2018, 132 visit ses-

sions were performed, and a total of 101 different new patients were evaluated in this integrated ambulatory. Patients performing a control visit were excluded from this computation. According to standard diagnostic cri-teria for IBD and rheumatic diseases, 5 patients’ groups were identified, as summarized in Table 1. As shown, a new diagnosis of ESpA was overall performed in 13 (12.9%) cases, including 4 patients presenting “red flags” for both IBD and SpA (Group 1) and other 9 patients with known IBD with only vague rheumatic symptoms who were eventually diagnosed with a SpA by the rheumatologist (Group 2). In addition, further 12 patients with an already known ESpA where referred by other physicians to be followed in our integrated “GastroReumatology” ambulatory (Group 3). In 15 pa-

tients with known SpA (Group 4), no cases of IBD were found. Moreover, in 26 patients without known IBD or SpA, but with musculoskeletal and intestinal symptoms (Group 5), no diagnosis of ESpA was performed. A joined therapeutic approach was started, and the ap-propriate follow-up was scheduled for all these patients. Of note, in our series, ESpA diagnosis was promptly performed in 1 patient of Group 1 who complained of chronic abdominal pain and peripheral joints pain for which she underwent a number of previous gastroenter-ology and rheumatology separate visits in other Hospi-tals during the last 3 years without achieving a definite diagnosis.

DISCUSSIONDiagnosis and management of patients with ESpA

is generally performed by a single specialist, that is a gastroenterologist or rheumatologist, according to the initial disease diagnosed. However, by following such an approach, the final diagnosis of coexisting IBD and SpA is difficult and, not rarely, postponed. Indeed, a recent Italian study found that ESpA diagnosis in IBD patients was delayed by a mean of 5.2 year [7]. It is expected that an early diagnosis of ESpA could be im-plemented when a patient is referred to a dedicated ambulatory, instead of being separately – and some-times repeatedly – referred to different specialists. The probability of response to anti-TNF-α treatment is re-duced when this rheumatic disease is not diagnosed in an early phase, with an increased risk of permanent in-ability [8]. In our series, a new diagnosis of ESpA was performed in 9 (21%) out of 44 IBD patients, as well as in all 4 patients presenting with “red flag” for both IBD and rheumatic disease. In another Italian, large series of IBD patients, the ESpA was diagnosed in 9% of cases [7]. Therefore, presence of the so-called “red flags” for a rheumatic disease in IBD patients seems to be helpful in identifying ESpA. On the contrary, no cases of IBD were eventually diagnosed in those with a known rheumatic disease complaining of abdominal symptoms, most likely due to the small sample size. Indeed, in a recent systematic review and meta-anal-ysis, the prevalence of clinically apparent IBD among

Table 1Results of “GastroReumatology” ambulatory activity

Group Setting IBD SpA

1 With “red flags”’ for IBD and SpA(N = 4)

2 Crohn’s disease2 Ulcerative Colitis

2 Peripheral spondyloarthritis 2 Axial spondyloarthritis

2 With IBD evaluated for SpA(N = 44)


5 Peripheral spondyloarthritis 1 Enthesitis; 3 Axial spondyloarthritis

3 With known ESpA(N = 12)


1 Psoriatic spondyloarthritis; 7 Peripheral spondyloarthritis2 Axial spondyloarthritis; 2 Ankilosing spondyloarthritis

4 With SpA evaluated for IBD(N =15)

15 no IBD 5 Psoriatic spondyloarthritis; 5 Peripheral spondyloarthritis4 Axial spondyloarthritis; 1 Enthesitis.

5 Without known IBD or SpA with musculoskeletal and intestinal symptoms (N = 26)

26 no IBD 14 Fibromyalgia; 12 Orthopedic disorders

Figure 1Clinical indicators (red flags) suggestive of Spondyloarthritis (SpA) or Inflammatory bowel disease (IBD).

Roberto Lorenzetti, Palma Scolieri, Alessandra Guarini et al.

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individuals with SpA has been estimated to be approxi-mately 7% [9]. Based on this estimation, only 1 case was expected in our sample size. However, no patient in the group 4 presented with elevated faecal calpro-tectin values or showed endoscopic pictures suggestive of IBD. The presence of intestinal symptoms in these patients could depend, at least in part, on the use of non-steroidal anti-inflammatory drugs (NSAIDs) due to SpA symptoms.

There were some patients with at least one red flag in whom nor IBD nor rheumatic disease were diagnosed. This would suggest that the presence of these signs are sensible, but not specific. Indeed, some symptoms (per-sistent fever, anaemia, weight loss, chronic diarrhoea) included in the “red flags” for IBD are shared with other clinical conditions. Moreover, in order to exclude a missed diagnosis, even those patients with doubtful “red flags” were scheduled for the integrated visit.

The peculiarity of our Ambulatory consists not merely in offering a combined gastroenterological and rheuma-tologic visit, but that these clinical evaluations were per-formed by specialists particularly dedicated to IBD and SpA, respectively. Our preliminary data would suggest that diffusion of such an integrated “GastroRheumatol-ogy” ambulatory could be implemented, particularly in those hospitals where IBD patients are followed. In-

deed, the contemporary presence of a dedicated rheu-matologist could be advantageous for an early ESpA diagnosis, with a prompt and shared management of these patients. Moreover, the combined management of patients with already known ESpA (Group 3) has re-sulted very useful in choosing the proper drug treatment expected to be effective for both conditions, in agree-ment with guidelines from Italian Expert Panel [6]. In detail, therapy was accordingly changed in 33% of pa-tients in the Group 3. In the Group 2, the combined management allowed a prompt diagnosis of peripheral and/or axial articular involvement using the clinical and instrumental gold standards for diagnosis.

In conclusion, our data would suggest that in a dedi-cated “GastroRheumatology” ambulatory an early diag-nosis of ESpA is possible, so that a better prevention of disease-related disabilities is expected. Last, but not the least, a more appropriate utilization of resources and a better perceived quality of care by these patients are also expected.

Conflict of interest statementNone.

Received on 19 April 2019.Accepted on 4 June 2019.

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1. Mantzaris GJ, Viazis N, Polymeros D, Papamichael K, Bamias G, Koutroubakis IE. Clinical profiles of moderate and severe Crohn’s disease patients and use of anti-tumor necrosis factor agents: Greek expert consensus guide-lines. Ann Gastroenterol 2015;28(4):417-25.

2. Turkcapar N, Toruner M, Soykan I, Aydintug OT, Ce-tinkaya H, Duzgun N, et al. The prevalence of extrain-testinal manifestations and HLA association in pa-tients with inflammatory bowel disease. Rheumatol Int. 2006;26(7):663-8. doi: 10.1007/s00296-005-0044-9

3. Salvarani C, Fries W. Clinical features and epidemiology of spondyloarthritides associated with inflammatory bow-el disease. World J Gastroenterol. 2009;15(20):2449-55.

4. Smolen JS, Breedveld FC, Burmester GR, Dougados M, FitzGerald O, Gladman DD, et al. Treating spondylo-arthritis, including ankylosing spondylitis and psoriatic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2014;73(1):6-16.

5. Essers I, Ramiro S, Stolwijk C, Blaauw M, Landewé R, van der Heijde D, et al. Characteristics associated with

presence and development of extra-articular manifasta-tions in ankylosing spondylitis: 12-year results from OA-SIS. Rheumatology. 2015;54(4):633-40.

6. Olivieri l, Cantini F, Castiglione F, Felice C, Gion-chetti P, Orlando A, et al. Italian Expert Panel on the management of patients with coexisting spondyloarthri-tis and inflammatory bowel disease. Autoimmun Rev. 2014;13(8):822-30. doi: 10.1016/j.autrev.2014.04.003

7. Conigliaro P, Chimenti MS, Ascolani M, Triggianese P, Novelli L, Onali S, et al. Impact of a multidisciplinary approach in enteropathic spondyloarthritis patients. Autoimmun Rev. 2016;15(2):184-90. doi: 10.1016/j.au-trev.2015.11.002

8. Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis. 2004;63(5):535-43.

9. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and me-ta-analysis. Ann Rheum Dis. 2015;74(1):65-73.

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heAlth systeMs sustAinABility fOr rAre diseAsesEdited by Rita Maria Ferrelli, Bernardino Fantini and Domenica Taruscio

PrefaceRita Maria Ferrelli1, Bernardino Fantini2 and Domenica Taruscio3

1Servizio Formazione, Istituto Superiore di Sanità, Rome, Italy 2Faculté de Médecine, Université de Genève, Genéve, Switzerland 3Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy


A disease or disorder is defined as rare in Europe when it affects less than 1 person in 2000. There are more than 6000 rare diseases. 80% of rare diseases are of genetic origin, whereas 20% are multifactorial and are often chronic and life-threatening. In spite of the limited number of people that can be affected by a single rare disease, the total number of patients living with a rare disease is high: on the whole, rare diseases may affect 30 million European Union citizens. This epidemiologic pattern deserves to be tackled at the European level. The European Commission has been financing several initiatives and Joint Actions with the purpose of providing a better support at European, na-tional and local levels. Among them, the Joint Action RD-ACTION (www.rd-action.eu) aimed at ensuring an integrated European approach to the challenges faced by the Rare Disease (RD) community and at promoting, catalysing and triggering multi-stakeholder debates which are necessary both at European level, to build shared strategies, and at national level, to support the integration of EU policies on rare diseases across Member States.

RD-ACTION was co-funded by the EU Health Programme 2014-2020. It started in 2015 and ended in June 2018. RD-ACTION brought together 64 part-ners – academia, Ministries of Health, health institutes, medical universities and patients’ organisations – from 40 countries, including all 28 EU Member States. The strength of RD-ACTION lies in its multi-stakeholder integrated approach and its pan-European and well structured coverage that included, but that was not limited to the European patient organisation for rare diseases (EURORDIS – Rare Diseases Europe).

Among the activities carried out by the Joint Action, the National Centre for Rare Diseases (Centro Nazi-onale Malattie Rare, CNMR) at the Italian National Institute of Health (Istituto Superiore di Sanità, ISS) was entitled to develop a specific task to identify mech-anisms influencing sustainability, equity and resilience of health systems for rare diseases. This monograph aims at collecting issues debated during the progress of CNMR task. All of them represent crucial factors

raised by the study of rare diseases in the light of im-proving the organization and sustainability of services for patients living with rare diseases.

Fantini and Vaccaro review the literature available on value based health care and relate it to RD. Start-ing from the critics of an purely economic definition of value and healthcare evaluation, efficacy and efficiency, they include the equity dimension in the definition of value-based healthcare and underline the need of radi-cally re-examining how to organise the delivery of pre-vention, and healthcare services, in the framework of a new culture of health and well-being, to empower and give voice to vulnerable groups.

Taruscio and coll. focus on primary prevention as an essential factor ensuring sustainability of health sys-tems for rare diseases. They emphasize an integrated “One Health” approach, linking knowledge and action, as a requirement to get effective primary prevention. The role of surveillance of health events and potential health-damaging factors, science-based risk analysis, citizens’ empowerment and education of health profes-sionals is crucial in primary prevention.

Severin and coll. stress the role of education in build-ing sustainable health system and allowing better health and well-being for people with rare diseases. They sus-tain that by giving knowledge, training competences and promoting active participation and responsibil-ity through education, a new dialogue between policy-makers, stakeholders, professionals and rare disease pa-tients community will provide public health responses to special healthcare needs of people with rare diseases.

Iskrov and coll. face the financial sustainability issue, highlighting the role of health promotion, disease pre-vention, primary and integrated care, patient-centred care for achieving effective, appropriate and sustainable healthcare. Moreover, they remember that a proactive health workforce planning and forecasting make health systems resilient to future shocks.

Castro and De Santis are concerned with the integra-tion mechanisms that are an essential condition for ensuring continuity of care and sustainability. They re-port on the system levers for the effective design and

Address for correspondence: Rita Maria Ferrelli, Servizio Formazione, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: [email protected].

Rita Maria Ferrelli, Bernardino Fantini and Domenica Taruscio

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implementation of integrated care frameworks, namely: political support and commitment, governance, stake-holder engagement, organisational change, leadership, collaboration and trust, workforce education and train-ing, patient empowerment, financing and incentives, ICT infrastructure and solutions, monitoring and evalu-ation system.

According to De Santis and coll., patient empow-erment is recognised as key enabler in creating sus-tainability as addressing challenges faced by modern healthcare systems in terms of effectiveness, access and resilience. In the field of rare diseases, empowerment strategies have greater value due to low prevalence, lack of expertise, poor quality of life. The Authors report av-enues to patient empowerment, namely: health literacy and capacity-building; shared decision-making; support to self-management.

Jessop considers the question of resilience and long-term sustainability that has been raised by the devel-opment of the European Reference Networks. The author refers to five “characteristics” for a resilience in-dex adaptable to networks: awareness, diverseness, self regulation, integration, adaptation. Nevertheless, rare diseases networks should also examine their macrocul-

ture of artefacts, espoused values and unarticulated as-sumptions through which network members coordinate network activities.

Montserrat and Taruscio review the main areas for pol-icy actions: development and implementation of Euro-pean Reference Networks, as a main strategy for shar-ing of knowledge, clinical expertise and foster research; integration of high-quality patient registries, biobanks, and bioinformatics support, as key infrastructure tools addressing research and healthcare needs; the imple-mentation of National Plans or National Strategies on RD in EU Member States by sharing experiences, capacity building and linking national efforts through a common strategy at a European level; actions driven by the recommendations for primary prevention of con-genital anomalies (the main RD group with multifacto-rial aetiology); policy provisions to foster research and development of orphan drugs.

In conclusion, all of the authors enriched the debate around the sustainability of health systems for rare dis-eases and pinpoint the factors that are particularly rel-evant to match equity and an appropriate and sustain-able use of resources to respond to the healthcare needs of people living with rare diseases.

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Value based healthcare for rare diseases: efficiency, efficacy, equityBernardino Fantini1 and Concetta Maria Vaccaro2

1Faculté de Médecine, Université de Genève, Genève, Switzerland 2Fondazione Censis, Area Welfare e Salute, Rome, Italy


INTRODUCTIONThe expression “value-based healthcare” was first in-

troduced in 2006 by Michael E. Porter in a book pub-lished in collaboration with Elizabeth Olmsted Teisberg [1]. It should not be surprising that this proposal came from an academic known for his theories on econom-ics and particularly business strategies and competi-tion. Rising health care costs are a major global chal-lenge and health systems should also be evaluated from an economic and financial point of view. A number of factors contribute to the financial crisis of the health systems, including ageing populations and the per-manently increasing costs of medical technology and pharmaceutical products. However, an underlying and misunderstood source of healthcare’s escalating costs has been the inability of healthcare provider organisa-tions (such as large hospitals and sanitary structures) to properly measure and manage the true costs and value of healthcare.

In this book Porter apply to health systems a con-cept of business management proposed in his 1985 best-seller Competitive advantage: creating and sustaining superior performance and known as “global value chain” (GVCs), that is the full range of activities that are re-quired to bring a product from its conception, through its design, its sourced raw materials and intermediate inputs, its marketing, its distribution and its support to the final consumer. In the health care marketplace the “final consumer” is the patient and according to Porter, “value-based care” seems to carry the promise to signifi-

cantly reduce overall costs spent on healthcare, linking the prices of diagnostic analyses, drugs and treatments to their actual value to patients: «The way to transform health care is to realign competition with value for pa-tients. Value in health care is the health outcome per dollar of cost expended» (1, p. 20).

In a very influential and seminal paper published in July 2009 in the NEJM on Value Based Healthcare, Porter define value improvement as «better patient outcomes relative to the costs of achieving them. The single most powerful step to improve health outcomes is to just start measuring them at the level of patients with a given medical condition – such as breast cancer or knee or hip arthritis – or in delivering primary and preventative care for patient segments such as healthy adults» [2]. In the conclusions of the paper Porter rises the «big question» if it is possible to move «beyond a re-active and piecemeal approach to a true national health care strategy centred on value», suggesting that the only real solution is «to align everyone in the system around a common goal: doing what’s right for patients».

Two questions emerge from this conclusion: 1. What is a value «right for patients»? 2. Can this concept of value and the relative strategies be applied not only to acute and chronic diseases, such as cancer or diabetes, but also to rare diseases?

MATERIALS AND METHODSThe paper reviews the main literature available on the

of value based health care and relates it to rare diseases.

Address for correspondence: Bernardino Fantini, Faculté de Médecine, Université de Genève, Rue Michel Servet 1, 1211 Genève 4, Switzerland. E-mail: [email protected].

Key words• healthcare• rare diseases• equity• vulnerability• resilience

AbstractThe paper reviews the literature available on value based health care and relates it to rare diseases. Starting from the economic definition of value and healthcare evaluation, efficacy and efficiency, it includes the equity dimension to define value-based healthcare. It embraces also the cultural framework associated to the concepts of health and disease, normal and pathological, right or wrong for the patient. The paper highlights that a pre-vention and recovery view and global evaluation of costs/benefits ratio for rare diseases make difficult and limited the applicability of the value-based approach to rare diseases. Since epidemiology of rare diseases identified a series of difficulties in applying value-based public health strategies to rare diseases, the paper underlines the necessity of new culture of health and well-being, radically re-examining how to organise the delivery of prevention, and healthcare services, and finding alternative ways of empowering and giv-ing voice to vulnerable and marginalised groups.

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The questions focus on the value “right for patients” and if this concept of value and the relative strategies be applied to rare diseases.

RESULTSThe last quoted passage of Porter’s paper bring us di-

rectly to the very origins of medical thought and medi-cal practice and to the theoretical and moral basis of medicine and health policies.

Starting from classical times, from the origins of the western medical thought, medicine has acquired a double status: it is a special form of knowledge and a knowledge-based social practice. The Greeks had a single expression for designating this double nature, iat-ricke technè, translated in Latin with Ars medica and in modern language as Medical Art. Medicine is not only a scientific discipline and its activities must be evalu-ated with two different sets of criteria, based respective-ly on knowledge and in value, looking at what is ‘true’ but also at what it is “good”. Therefore, criteria of truth must be accompanied by criteria of value. The physi-cian does not have as sole basis for his or her decision a “criterion of truth” (the rules used to judge the accuracy of statements and actions) but also a “criterion of value” (the moral appropriateness and utility for the patient).

For this reason medicine is an “applied science”, which links together knowledge, ethical and practical principles [3]. As a science it requires an epistemology, a theory of knowledge; as an ‘applied’ practice it requires a theory of congruence between actions, possible results and their value. In clinical medicine, therefore, each medical act must be scientifically grounded but also have a value, primarily for the patient. This remains the basis of the patient-physician individual relationship.

In philosophical and linguistic terms, the concept of “value” has been applied to two different domains. At the general level, there is a difference between moral value and the value of objects or processes. Moral val-ues are those that have to do with the conduct of per-sons, usually leading to praise or blame and to an ethi-cal evaluation. The value of objects or processes, on the other hand, is linked to that is economically good for the society and for the individual person. Ethical values and economic values have therefore different domains of application.

In healthcare, however, especially in the case of rare diseases, these two aspects are necessarily linked. An intervention in these field has always an economic val-ue, for the individual and for the society, but cannot be evaluated without taking into account ethical prin-ciples, in primis equality and the right to health.

Patient oriented healthcareAccording to Michael Porter, the central focus of a

value-oriented healthcare system must be on increas-ing value for patients. This corresponds to a profound change that has occurred in the last decades in the rela-tionships between doctors and patients. In fact, one of the most important change in the health system of the last decades is related to patient and his or her health attitudes and behaviours, a cultural change which in-cludes also the evolution of the role of the physician,

traditional holder of a power based on exclusive medical knowledge. In Italy, from a Censis survey conducted in 2018, it emerges that the majority of Italians considers that the relationships between doctor and patient must be based on collaboration in decisions regarding thera-pies (Figure 1) [4].

The spread of health information, through the new and traditional media, represented a great driver for the transformation of health demand and the physician, who is the expert by definition, begins to waver in front of an increasingly informed patient, who less and less ac-cepts the asymmetric dimension of the care relationship. In this sense, direct access to health information, above all through a powerful information tool like the Inter-net, has increased disinter-mediated behaviours of the patient, for example in the choice of health services, or in the exchange of health information among peers [5].

The new patient figure (informed, aware, autono-mous, empowered), becomes the protagonist of indi-vidual paths of health promotion and protection.

But how to evaluate the value for the patient of the health care delivery?

In the economist’s view the evaluation is limited to the economic value, cost effectiveness playing an almost exclusive part in current decisions about the funding of health practices, institutions, and technologies: «Achiev-ing high value for patients must become the overarch-ing goal of health care delivery, with value defined as the health outcomes achieved per dollar spent» [6]. In this context, the “value” in value-based healthcare is derived from measuring health outcomes against the cost of de-livering the outcomes. However, the risk is to adopt a purely payer-centred perspective, where “value” means delivering cheap but mediocre services, an advantage for payers, not patients. The focus is on minimising the costs of each intervention and limiting services rather than on maximising value over the entire care cycle. «Lowering Costs and Improving Outcomes» becomes an «Health Imperative», which aims at identifying «a number of factors driving expenditure growth including scientific

Doctor and patient work together to make decisions

Doctor decides on patient's health and care

Doctor provides information on illness and therapies and decisions are taken by patient

58,0% 19,6%

22,4%

Figure 1The new set-up of the doctor-patient relationship (val. %). Source: Censis, 2018.

Value based healthcare for rare diseases

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uncertainty, perverse economic and practice incentives, system fragmentation, lack of patient involvement, and under-investment in population health». [7]

In the present organisation of the healthcare system, competition seems to be the key word, but competition takes place on discrete services, procedures, tests and interventions rather than on the full care cycle: «Nobody takes an overall care-cycle perspective, including steps to avoid the need for interventions (prevention) and on-going management of medical conditions to forestall re-currence (disease management). The current structure maintains ways of organising medicine that have long been obsolete. The adverse consequences for patient value are enormous» [1, p. 5]. Value in health care in therefore determined in addressing the patient’s health condition over the full cycle of care, from prevention and monitoring to treatment and ongoing management.

This evaluation includes equality of health outcomes, equality of resource use, and allocation of resources in proportion to the severity of the individual’s ill health. Adopting a value-based objective will have profound implications for allocation of resources throughout the healthcare system.

DISCUSSIONFrom the individual patient to public health

With the development of public health, which deals not with individuals but with populations, another ques-tion arises: the traditional synthesis between truth and value is still valid for public health and health promotion?

Classically, the mission of public health has been stated as “the fulfilment of society’s programs in assuring condi-tions in which people can be healthy” [8]. Starting from the Health Reforms in the 19th century, public health agencies have used a large combination of scientific and technological tools (basic science, clinical research, epi-demiology, statistics, behavioural research, health care institutions and services, economics, and legislations) to understand and control the causes of health threats, ac-quiring the right tools to systematically prevent, mitigate, or suppress these causes in entire populations.

But how to attribute a value to the results of a public health programme, the activities of an institution, the quality of a preventive or health promotion intervention?

In 1972 Archibald Leman Cochrane exposed in a lec-ture the results of his analysis of the activities of the Na-tional Health Service in UK. His lecture (and the short book that resulted from it) was entitled Effectiveness and Efficiency, and the two words became the guideposts of health care in many countries [9]. Effectiveness means the adequateness to accomplish a purpose and produc-ing the intended or expected results. Efficiency means performing or functioning in the best possible manner with the least waste of time, effort and especially mon-ey. Treatments and health practices must be measured and evaluated by their outcomes and their costs. Co-chrane’s lecture led directly to the ascent of evidence-based medicine and indirectly to health reforms based on the pursuit of efficient and effective outcomes in value-based models.

However, the lecture’s and book’s title left out a third essential word, that Cochrane considered of the same

importance than the first two: equity. Cochrane sug-gested in fact three criteria for establishing priorities in care and prevention: Efficiency, Efficacy, Equity. If the first two “Es” deal with economic value, the third has a fundamental ethical aspect and moral value.

Too often, the economic values remain dominant and the third dimension, “Equity”, is neglected. Equity is a concept which derive directly from the fundamental Right to Health included in the Constitution of the WHO: «The enjoyment of the highest attainable stan-dard of health is one of the fundamental rights of ev-ery human being …» (Preamble). The objective of the World Health Organization has been defined as « the attainment by all peoples of the highest possible level of health» (Art. 1) [10]. Accordingly, any policy and ac-tivity which impairs an equal enjoyment of the right to health and produces discrimination in access to health care is ruled off. Equity as a consequence is a funda-mental value in health care and public health.

A further step in the definition of value in health care and public health has the increasing consciousness of the importance of the social determinants of health, starting with the Commission created by WHO and chaired by Sir Michael Marmot. The final report of the Commis-sion, Closing the gap in one generation, underlines the need to take into considerations and the different levels of the factors which can modify the health status of an indi-vidual or a population [11]. As a matter of fact, complex interactions exist between age, sex, and constitutional factors, with individual lifestyle factors, social and com-munity networks, and finally general socio-economic, cultural and environmental conditions [12]. Socio-eco-nomic and political context, governance, cultural values, living and working conditions, besides behaviours and biological factors determines the distribution of health and well-being, as well as health inequities.

In Italy, several surveys carried out in the last years by Censis, related to representative samples of about 1000 Italian adults, show some important changes in their health attitudes, opinions and behaviours. First of all, the increasing relevance attributed by Italians to lifestyles and environmental conditions as determinants of health on which it is possible to act [13].

A new perspective is taking on a growing weight, with a more informed and empowered patient, becoming the protagonist of promoting one’s health and new lifestyle habits and health-oriented behaviours.

A rich literature on social determinants of health emphasises the negative consequences on health expe-rienced by citizens who are in situations of social dis-advantage, because of greater exposure to risk factors, more consistent vulnerability to illness and disability, lower life expectancy. The importance of personal re-sources is evident also by considering a simple indicator as the declared state of health of the ISTAT survey on the health condition of the Italians [14]. The percent-age of people (within groups of the same age) who de-clare themselves to be healthy increases as the level of education (as proxy of social status) increases, as well as, on the other hand, the share of those with at least two chronic diseases increases when the level of educa-tion decreases


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Culture matters …Values are embodied in medical knowledge and

health practices and the personal experience of health and well-being is fundamentally determined by the cultural contexts that contribute to make its meaning. These frameworks and beliefs inform also the actions of policy-makers and health care practitioners as well as the people they care for.

In 2014 a Lancet Commission has suggested a cultur-ally informed approach to health and well-being, indi-cating that «the systematic neglect of culture in health and health care is the single biggest battier to the ad-vancement of the highest standard of health worldwide» [15]. Culture, as defined by UNESCO, is not a rigid set of abstracts ideas and concepts, but a set of «distinctive spiritual, material, intellectual and emotional features of society of a social group … [which] encompasses, in addition to art and literature, life styles, ways of living together, value systems, traditions and beliefs» [16].

Culture, in its dynamic and diversity, sets the frame-work for attribute meaning to events and objects, and is something all members of families, communities and populations share. It frames the sense of reality, deter-mines the parameters within which decisions are taken and actions performed, giving a sense of purpose and direction to life. Organisations, institutions, and profes-sional groups also develop they own culture, which pro-duces diverse schemas of thought and practices.

The concepts of health and disease, and the rela-tive beliefs are part of a cultural framework. Values are embodied in medical knowledge and health practices and they constitute a set of shared values, which de-fines what is normal and what is pathological [17], what is right or wrong for the patient. Viewing health and care in purely clinical terms leaves health systems ill-equipped to understand the psychological, social and cultural determinants of illness and health. Far from a purely medical discourse, the culture of care, health and well-being is built upon a foundation of shared values and beliefs, that must be taken into account.

Health is not the absence of illness, but a search for well-being in the diverse conditions of life and accord-ing to the diverse individual constitutions. Moving from the traditional concepts based on the disease to a more large concept of health linked with the global well-be-ing and the realisation of each individual’s life project shits the accent of health care and public health policy towards people’s subjectively defined experiences and perceived needs. In such a way health becomes an ob-jective that should be pursued and promoted through individual and community commitment.

This is particularly true for rare diseases, where the pathological condition is always present, but this does not preclude a search for well-being and the accom-plishment of the individual’s life project. This cultural change in health establishes the framework for measur-ing the value of a specific health care measure or public health policy.

Rare diseases and value-based public health The traditional public health approach has been ex-

tremely successful in the developed world, with effec-

tive responses to sudden health crises (e.g., infectious outbreaks), persistent health problems (e.g. chronic or non-communicable diseases), or in controlling envi-ronmental risk factors (pollution, accidents, nutrition, water, natural disasters). However, this traditional ap-proach to healthcare seems to have a limited applicabil-ity to rare diseases, because the diseases are extremely diverse and the patients are few and scattered across populations.

The applicability to rare diseases of the value-based approach, based primarily on prevention and recovery and on global evaluation of costs/benefits ratio seems therefore limited. Rare diseases are in fact character-ised by a large number and broad diversity of disorders. This diversity implies a preventive and therapeutical approach based on individuality. There are very few commons traits between the diverse disorders and the category of ‘Rare Diseases’ is an artificial grouping with-out clear ways to group together diverse diseases. The unique link between them seems to be the genetical or gestational basis of most of them. As a consequence, public health approaches may not seem suitable for rare diseases, because the primary measures of suc-cess relate to the prevention of large numbers of cases, measurable health betterments, and the avoidance of premature deaths.

Rare diseases constitute a fundamental paradox be-cause if on one side diversity and individuality seem to place rare disease outside the real of public health, on the other side the reasons to apply a public health ap-proach to rare diseases are compelling. Rare diseases are a major public health problem and a priority be-cause persons with rare diseases form a sub-population of large dimensions. At the social level, the diagnosis of a rare disease can severely affect the lives of patients, their families and caregivers, with a substantial eco-nomic impact for the individuals and the communities in general. The consequences of this paradox is that the sustainability of health systems for rare diseases share additional challenged to those faced by health systems that are stressed by the current financial crisis.

Rare diseases are serious chronic diseases, usually be-ginning in childhood and may be life-threatening. As a consequence, they represent for the healthcare system challenges fundamentally different from those of more common diseases. Rarity significantly complicates the tasks, because of the small number of patients, the dif-ficulties in reaching widely dispersed patients, the lack of validated and standardised procedures for care and rehabilitation, and limited clinical expertise and expert centres. For many rare diseases, basic knowledge on the specific cause of the disease, its pathophysiology, the natural course of the disease and the relative epide-miological data is scarce, sometimes totally unavailable. This significantly delays or overrides both diagnose, care giving and prevention. Case definitions for classifi-cation are usually lacking and as a consequence screen-ing strategies and surveillance lack efficiency [18]. The knowledge on rare diseases epidemiology has luckily increases considerably in the last decades [19] and the resulting literature clearly identify a list of difficulties in applying value-based public health strategies to them:


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1. scope and capacity of most registries and databases are limited to the pure medical and clinical discourses; 2. knowledge of most rare diseases is insufficient (“or-phan diseases”); 3. longitudinal data collections are scarce; 4. outcomes of treatment and care are diverse and difficult to quantify; 5. diagnosis are difficult and often delayed; 6. the development of therapeutics and treatments is often fragmented and slow; 7. specialised and coordinated medical care are scarse and expensive, because of its complexity and multidimensionality; 8. standards of care for treatment and rehabilitation are not evidence based because health research is necessar-ily done at small scale.

Furthermore, in the case of rare diseases, if the quan-titative evaluation of the costs is a relatively easy task, much more difficult is to establish the quantity and especially the quality of the outcomes. The model of “value-based healthcare” is mainly suited for managing chronic diseases or conditions like cancer, diabetes, obe-sity, high blood pressure, chronic obstructive pulmonary disease (COPD), or heart diseases. Value-based care models focus on helping patients recover from illnesses and injuries more quickly and at a minimum cost.

Can this approach still be valid for a large but sparse population of individuals affected by disabling, life-threatening, and largely unpreventable diseases? How to evaluated a health outcome in a patient with a rare disease?

A positive answer to these question requires the pro-posal of a lager view of values, reaffirming that even in the case of rare diseases the main aim of stakeholders, policy makers and institutions in charge of national strategies is to quantify the burden of pathological condition and available resources for sustainable and resilient health system, taking into account the three “Es” proposed by Cochrane, the principles of Efficien-cy, Efficacy and Equity. But this requires a new culture of health and well-being and the need to radically re-examine how to organise the delivery of prevention, wellness, screening, and routine health maintenance services, finding alternative ways of empowering and giving voice to vulnerable and marginalised groups.

Changing values: vulnerability and resilienceOne of the main results of the cultural change in

health demand is related to a new patient, who is in-formed, aware, autonomous, and empowered. The pa-tient’s empowerment is particularly important because can translate into a real growth of health awareness and culture, with positive results in terms of prevention de-velopment, increase of ability to recognise symptoms and diseases, enhancement of compliance and effective management of the health conditions. More specifi-cally, the patient’s empowerment can represent a value especially in rare diseases. As in any serious chronic dis-eases, the patient’s role becomes strategic, because a rare disease is a life-long condition, with a great impact on life possibilities and on daily life activities. Patients, caregivers and families are protagonists in managing the disease and individual and family commitment and resources are strategic for coping with its difficulties. The outcome of cultural changes on health, in terms

of patient’s awareness and accountability, is one of the most important aspects that can impact not only on health behaviours but also on care systems and public health objectives.

For this reason, in recognising the patient’s strategic role, the necessity and the value of his participation in the decisions for the care that concern him and in the management of his chronic conditions, we must also take into account an equally central aspect, health in-equalities. Their reduction is an ethical imperative, but also a fundamental value for the enhancement of the patient’s role in the management of rare diseases. Diverse value systems and health views can either pro-mote or limit the equal distribution of health resources. Vulnerable groups face very often barriers to integration and participation.

Vulnerability is at the same time a common every-day term and a rigorous scientific concept. It underlines physical and mental fragility, incapacities to work, to socialise and to realise own life project, to construct and maintain social networks. Vulnerability quite often leads to marginalisation and stigmatisation, to social in-equalities and health insecurity. Vulnerable populations and groups often do not become involved in well-being studies, also because they are reluctant to do so, partic-ularly when they feel alienated or marginalised. This can unintentionally reinforce health inequalities and deny certain groups a voice in the decision-making processes that affect their lives. As for the whole society, often the most vulnerable are the most silent.

If vulnerability has a negative acceptation and a pas-sive sense, another word and concept implies an active attitude in coping with difficulties and bad health con-ditions: resilience.

Resilience is usually defined as an individual’s ability to successfully adapt to life tasks in the face of social disadvantage or highly adverse conditions. Resilience is the ability of an individual or a system to ‘bounce back’ from a negative experience, to continue to function in changing situations or adverse conditions and events, re-establishing and eventually developing personal ef-ficiency and social integration. This implies three dif-ferent modalities, connected with increasing difficulty of the adverse situations: to absorb its consequences, to adapt to them, and to trasforme the adversity in the possibility of new developments.

Resilience is not a permanent character trait but a process of building a structured system with gradual discovery of personal abilities and the development of proper coping techniques, that allow to effectively overcome negative conditions or crises. More generally, resilience cans be defined as the ability to maintain nor-mative behaviours and realise aimed tasks at the various stages of life, even when the starting conditions of the personal life can be handicapped by a rare disease.

Resilience can be linked to individual persons, but it is also a fundamental property of social groups, fami-lies, associations, professional teams, and also institu-tions. Resilience must be developed by all the actors of the health care for rare diseases 99: patients and their families, physicians and caregivers, institutions, asso-ciations, institutions, industries, international organ-


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isation, NGOs. Evidence suggests that efforts of this type have empowered patients with rare diseases and their organisations as they seek and obtain wider social recognition, more participation in research, and better health care [20].

Fostering individual and community resilience in face of rare disease conditions is the main aim of a value-based healthcare. There are several factors that can develop and sustain a person’s or a group’s resilience and most of them are value-based: the ability to make realistic plans and being capable of taking the steps nec-essary to follow them, a positive self-concept and con-fidence in one’s strengths and abilities, communication and problem-solving skills, and the ability to develop and control strong emotions and feelings. Value-based public health can help patients to improve their health, reduce the incidence and the effect of the disease and pathological condition, and live healthier lives [21]. Well-being can be reached even in presence of infirmity or handicap. An individual with a rare disease should enjoy the highest attainable standard of health.

The challenge it to re-evaluate what one takes for granted in healthcare and public health and rethink the spontaneous assumptions about what is health and what will make a person healthier. There are many diverse and interrelated cultural practices that can en-hance resilience and values. In the field of rare disease more ambitious objectives are possible within a value-based paradigm: reduce the impact of disease on pa-tient, they relatives and caregivers, and on community; improve the management of associated health condi-tions; produce a smooth transition between paediatric and adult care; improve the quality of life and life ex-pectancy; enhance the participation of patients in their communities, workplaces, cultural life, and society in general; develop of cultural activities and acquiring more social recognition.

Genomics, epigenomics and rare diseasesWith the complete sequence of the human genome

we are now in a unique position in the history of medi-cine to define the genetic basis of human diseases pre-cisely, with optimal sensitivity and specificity. The pre-cise molecular characterisation of human disease will allow us to understand the basis for disease determin-ism, susceptibility and environmental influence. The re-cent development of genome-wide analysis seems to be able to offer an explanation for the different phenotypic manifestations of the same disease, to obtain disease prognosis with greater accuracy and to establish new methods and tools for prevention. The aim becomes now to refine and, ideally, personalise disease treatment for optimal therapeutic efficacy. Rare diseases look as unique, individual diseases and the idea of “individual or personalised therapy” seems to be the most promis-ing approach, especially with the development of new personalised biotech products for treating rare diseases.

The new field of epigenetics shown how social con-texts and determinants can influence genetic makeup. Epigenetics, defined as the science that studies “the set of modifications to our genetic material that change the ways genes are switched on and off” [22], focuses

not merely on gene expression, but also on how diverse factors in our natural and social environments affect what genes are expressed and the ways in which they are expressed. Environmental factors have a profound effect on gene expression, and in the classic “rainbow” model of the social determinants of health proposed in 1993 by Dahlgreen and Whitehead [23], the central core with the age, sex and constitutional factors is not only a set of causal factors for determining upward the individual lifestyle and the general population health conditions, but also the result of a downward causation, which change the ways in which the constitutional fac-tors are expressed along the whole life course.

These scientific developments can produce a para-digmatic change in the concept of health and in public health strategies, thanks to the possibility to personalise prevention, healthcare and promotion of health. Togeth-er with the three “Es” proposed by Cochrane (Effec-tiveness, Efficiency, and Equity) the new paradigm in a value-based medicine and health will be based on 4 “Ps”: Preventive, Predictive, Participatory, and Personalised.

CONCLUSIONSA value-based public health strategy for rare diseases

should concentrate on a few objective, clearly defined by a scientific and ethical analysis, which is in general al-ready available in the scientific literature, epidemiologi-cal inquires and policy reports. These objectives include the definition of the population impact through epide-miological research adequate for low-prevalence diseas-es and the evaluation of the costs associated with these diseases, such as medical costs, lifetime productivity loss, financial impact on caregivers, and impact on the employability of patients. Particularly important are the objectives of documenting progression of health status and associated quality of life, evaluate health outcomes (in the largest sense of the term), evaluate and compare health care practices, identifying evidence-based find-ings on best practices and standards of care, create net-works to share research, knowledge and values.

In order to attain these objectives new research strat-egies based on values are needed, integrating the com-plexities and individuality of lived experiences into an expanded evidence base on on health vulnerabilities that includes assessments of subjectively defined needs, thanks to a narrative and qualitative research and a cul-ture-centred approach.

FundingThis work was supported by the Health Programme

of European Union, in the framework of the Joint Ac-tion for Rare Diseases, Project n. 677024 “Promoting Implementation of Recommendations on Policy, Infor-mation and Data for Rare Diseases – RD-ACTION”.

Conflict of interest statementThe authors declared no potential conflicts of interest

with respect to the research, authorship, and/or publi-cation of this article.

Submitted on invitation.Accepted on 24 April 2019.


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Primary prevention as an essential factor ensuring sustainability of health systems: the example of congenital anomaliesDomenica Taruscio1, Eva Bermejo-Sánchez2, Paolo Salerno1 and Alberto Mantovani3

1Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy

2Instituto de Investigación de Enfermedades Raras (IIER), ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas), Centro de Investigación sobre Anomalías Congénitas (CIAC). CIBERER (U724). Instituto de Salud Carlos III, Madrid, Spain 3Dipartimento di Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, Rome, Italy


INTRODUCTIONPrimary prevention in public health and in the field of rare diseases

Since Hyppocrates, public health care means that, be-sides treating disease when it occurs, science and actions should reduce the occurrence of diseases. This is specifi-cally called “prevention”. Primary prevention includes the actions aimed at avoiding the onset of the disease. This means intervening before health effects occur, through measures modifying risk factors, their distribution or the way they reach the individual, for instance by banning substances or conditions known to be associated with one or more disease or adverse health status. Primary prevention, thus, results on eradicating, eliminating or minimizing the impact of disease and disability on the population, through interventions that are applied before there is any evidence of disease or injury, by controlling causative risk factors; the main focus are disease risk fac-tors, in order to reduce the disease incidence.

Reducing disease incidence means a healthier soci-ety, while reduced disease burden means improved life

quality and working capacity, reduction of avoidable disabilities and mortality, and lower costs for diagnosis and treatments, among other advantages, for the indi-vidual as well as for the society. Thus, strengthening and implementing primary prevention with the support of scientific evidence makes the healthcare system more efficient and sustainable, while providing significant benefits to society as a whole, apart from the individual tangible and intagible advantages.

The different and relevant disciplines and actors in-volved in primary prevention often tend to think and operate in silos [1], concentrating on specific determi-nants such as lifestyles or living environment. Indeed, the actual problems call for an integration and cross-fer-tilization among different expertise fields. For instance, communities with low socio-economic status are more prone to live in more polluted settings, with insufficient availability of green areas or healthy food purchases. Therefore, it is also important to gather accurate data that can be analysed wisely to avoid confounding and to properly assess possible interactions of different vari-

Address for correspondence: Domenica Taruscio, Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Email: [email protected].

Key words• primary prevention• sustainability• resilience• health promotion• birth defects

AbstractProtection of early development contributes to health of next generations. Congenital anomalies (and other adverse reproductive outcomes) are an important public health is-sue and early indicator of public health risks, as early development is influenced by many risk factors (e.g., nutrition, lifestyles, pollution, infections, medications, etc). Effective primary prevention requires an integrated “One Health” approach, linking knowledge and action. This requires surveillance of health events and potential health-damaging fac-tors, science-based risk analysis, citizens’ empowerment and education of health profes-sionals. From the policy standpoint, joint budgeting mechanisms are needed to sustain with equity intersectoral actions (involving policy domains of health, social affairs, edu-cation, agriculture and environment). States should devote resources to strengthen reg-istries and systematic data collection for surveillance of congenital anomalies, to better inform national prevention strategies. Investing in primary prevention based on scientific evidence is essential to support sustainable and resilient health systems and sustainable development of the society.

Primary Prevention for sustainable health

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ables and linked factors. These accurate analyses will have an impact on the identification of risk factors and the delineation of primary prevention measures.

It is important to note that, although primary preven-tion makes the health systems more sustainable, and despite its recognized major role among public health actions, paradoxically it does not attract a correspond-ing fraction of resources devoted to health by policy makers. For instance, countries from the European Union (EU) overall allocate less than 3% of healthcare expenditure, and as low as 1% in some countries, to pri-mary prevention actions [2].

The reduction of risk factors for poor health out-comes may involve actions beyond the specific domain of healthcare systems. The capacity to fulfill the primary requirements (food security, housings), the quality and safety of living environment (air, water, food), the social environment (education, income, lifestyles), the deci-sions of policy makers (in what refers to resources de-voted to health services), are all determinants involved in increasing or reducing threats for health. In prin-ciple, policies should consider their potential impact on health and undergo “health-proofing”, as recently implemented in Ireland and a few other EU Countries.

The 2013 Annual Growth Survey [3] recognised that “in the context of the demographic challenges and the pressure on age-related expenditure, reforms of health-care systems should be undertaken to ensure cost-effec-tiveness and sustainability, assessing the performance of these systems against the twin aim of a more efficient use of public resources and access to high quality health-care”. The assessment of healthcare policies should be more prevention-oriented. Effective prevention is evalu-ated on the basis of “diseases avoided”. This means that fit-to-purpose sets of performance indicators and out-come measurements should be developed accordingly to better plan future programs and strategies.

When extending the considerations on primary pre-vention to rare diseases, congenital anomalies (CA) rep-resent a proper field of reflection and action. Many rare diseases are congenital because they result from altera-tion of prenatal development. This means that their man-ifestations are present at birth or can be even evident before the delivery. In fact, prenatal diagnosis is possible for many of them. CA, also known as birth defects, are defined by the World Health Organization (www.who.int/topics/congenital_anomalies/en/) as structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth or later in life. Indeed, CA represent an important fraction of rare dis-eases and, at the same time, most CA can be considered rare diseases, based on their frequency [4]. They repre-sent a significant health burden, leading to an overall in-creased morbidity and to a considerable risk for prema-ture death among affected people, as well as for lifelong disabilities and dependence in many surviving cases [4]. CA’s presence since birth or earlier implies that they, and their consequences, must be faced from that early point in life, Due to the critical role of non-genetic factors in their etiology, CA are the main group of rare diseases in which primary prevention measures have a known benefi-cial impact. Indeed, since 2013 the European Union has

endorsed a body of evidence-based Recommendations for primary prevention of CA [5]. These recommendations may be relevant to other adverse pregnancy outcomes as well (prematurity, stillbirths, developmental delays and related disabilities), and even they can have an impact on parents’ health (since for instance modifying lifestyles or adopting better protection in the workplace will also benefit them), as non-genetic risk factors are frequently shared. The Recommendations [5] discussed the differ-ent institutional and societal levels relevant for develop-ing and implementing primary prevention strategies.


primary prevention of rare diseases, with a special fo-cus on CA. Several medical databases and additional information resources were utilised and included gov-ernment documents, reports from international bodies such as the World Health Organisation, and academic studies. The key search terms were primary preven-tion, congenital anomalies and rare diseases, from 2000 through January 2018. Articles of interest were reviewed to determine which were relevant and sub-jected to analysis. Selected papers were later used to extrapolate the most relevant messages about primary prevention of on CA.

RESULTSThe reviwe showed that the importance of CA on

public health is clear: Christianson et al. [6] estimated that overall 7.9 million children are born each year with serious CA of genetic or partially genetic (multifacto-rial, gene-environment) origin, and additional hundred thousand more are born with serious CA of post-con-ception origin. In general, and depending on the popu-lation considered, it is estimated that approximately 3-6% of newborn infants worldwide are affected by seri-ous CA [7-9]. Moreover, according to the 2015 Global Burden of Disease study, CA led to 8.5% (7.7-9.5%) of deaths under the age of 5 years in 2015 [10], and at least 3.3 million children under 5 years of age die from CA each year [9]. CA represented the most important cause of death below 5 years of age in countries with low and very low under-5 mortality [11]; in addition, Oza et al [12] observed that the proportion of deaths from CAs was relatively stable across their study period (data for 2000-2013 in 194 countries), showing the smallest relative decrease in risk compared to other causes (e.g., infections); some authors have estimated that mortality due to CA for the under-5 age group is likely to be a four-fold underestimate [13]. Beyond mortality, an esti-mated 3.2 million of those who survive may be disabled for life [9]; disability-adjusted life-years (DALY) rates due to CA have increased lately [14]; the years lived with disability (YLD) have increased for CA [15]. Ter-minations of pregnancy for CA were almost three times more frequent than infant deaths and stillbirths with CA combined [16], and this affects the Global Burden of Disease figures and their interpretation.

These eloquent figures, matched with their intrauter-ine origin and the major role of non-genetic factors, en-hance the interest of their study within the field of rare

Domenica Taruscio, Eva Bermejo-Sánchez, Paolo Salerno and Alberto Mantovani

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diseases, and make them priority targets for research [17] and prevention. Primary prevention of CA is fea-sible because scientific evidence points to several risk factors (e.g., obesity, infectious and toxic agents) and protective factors (e.g., folic acid supplementation and glycemic control in diabetic women) [18].

The bullet points below summarize the main fields pertinent to primary prevention of CA, encompassing both health systems and policies in relevant fields: • Actions to mitigate low socio-economic status and poor

education might have an impressive impact on a num-ber of critical determinants, such as lifestyles (tobac-co smoking and alcohol drinking during pregnancy, among others), and unbalanced diet associated with the increased risk of overweight/obesity, which, in its turn, is a significant risk factor for CA.

• Lifestyles can partly be tackled by specific policies, whose effectiveness should be evaluated in the con-text of specific countries. It is critical to reduce the consumption of energy-dense foods and drinks, to-bacco and alcohol: a combination of policy actions and individual empowerment, starting from school, seems a suitable general approach. For instance, in Italy, smoking in public places, including the work-place, has been forbidden by law in 2003: the law, matched with publicly-supported anti-smoking adver-tising, has been received by society with a favourable attitude and has contributed to reduce the number of smokers and especially the environmental exposure to passive smoking. Indeed, as already pointed out, exposure to tobacco smoking is a risk factor for CA and other adverse pregnancy outcomes.

• Low socio-economic status and poor education are associated with a reduced access to correct informa-tion about health-protecting and health-promoting behaviours, such as the periconceptional supplemen-tation with folic acid, and other preconception care measures.

• The schooling system can play a major role in reducing health inequalities due to different socio-economic status and promoting health awareness and empow-erment. The promotion of health literacy programmes since primary school can support the adoption of a healthy lifestyle from childhood; a timely empower-ment during school age toward correct lifestyles and behaviors may significantly reduce the risk factors for CA in the next generation.

• Actions to control and reduce the exposure to pollut-ants in living environment, workplace and foods: the cur-rent EU regulations on hazardous chemicals (e.g., the REACH regulation [19]) put emphasis on the identi-fication and management of developmental toxicants. The EU food safety is possibly the domain where pre-vention and control of pollutants is most developed: however, emphasis needs to be put on the identifica-tion of emerging risks [20]. In particular, food safety systems should exploit the available knowledge to im-prove prevention of long-term risks along the whole food chain, such as those related to endocrine dis-rupting substances [21]. Full implementation of the EU regulations, currently the world’s most advanced ones, calls for a balance between scientific evidence,

a reasonable use of the precautionary principle and the necessary involvement of the industrial and agro-food sectors.

• Pollution is not evenly distributed throughout the EU population: a number of areas are highly exposed to releases from toxic industrial activities and/or chemi-cal waste from different sources (e.g., petrochemicals or persistent and bioaccumulative –“legacy” – con-taminants). In communities with higher exposure to these hazardous chemicals in living environment, CA (together with other adverse reproductive outcomes) represent an important public health issue [22]. As shown, for instance, in Italy by Sentieri, a Istituto Superiore di Sanità-led project. CA are also a sensi-tive sentinel for environmental quality [23], due to the relatively short latency time and the high suscep-tibility of the intrauterine life to major toxicological modes of action, such as endocrine disruption.

• The majority of the EU population aged between 18 and 65 years spends over half of their lives at the work-place. Workplace represents a diversified environment where exposures through multiple physical, chemical and biological agents can occur: to date women at fertile age are involved in every job role in the EU. But importantly, also men can be exposed to these hazards in the workplace, therefore their gametes will form and mature in an environment that can have an impact on the risk for gene mutations as well as on fertility. Effective prevention and health monitoring interventions in the workplace should be achieved through the co-operative involvement of employers, workers, occupational health professionals and legis-lators. Health and societal policies should recognize the basic right for a workplace environment that min-imizes the health risks for workers as well as for their offspring.

• Chronic diseases such as diabetes, infectious diseases such as rubella and the emerging Zika viruses, as well as the inappropriate use of certain drugs, such as the antiepileptic drugs with known teratogenic efects, among others, are recognized risk facts for CA. Such risk factors can be significantly mitigated by function-ing and accessible healthcare services. Hence, actions of top relevance for the protection of the generation(s) to come include the care for maternal chronic diseases (e.g., diabetes, epilepsy), the deliverance of vaccina-tion programmes (e.g., toward rubella) and the en-forcement of pharmacovigilance programmes. These measures are supported by teratology information ser-vices where the different actors involved in primary prevention (health care professionals and lay people) can solve their questions on the different risks and possible measures. Such policies could also receive a significant support by fostering the consistent in-volvement of pharmacists and nurses.

• Pre-conception care is surely the most effective way to put in practice all the known measures for primary prevention of CA, adapting them to the specific char-acteristics of each couple. Therefore, policies should put special focus on the establishment of services spe-cifically devoted to this approach by which risk fac-tors can be identified, the most appropriate measures


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can be adopted accordingly, the most convenient in-formation can be provided (adapted to the specific characteristics of each couple of parents to be) by health care workers or specialists, and some preven-tive measures can be put in practice.

• Pregnancy planning is another pivotal issue, that should be promoted by all means.

• The inadequate access to health services may be a spe-cial concern for low-status population groups and/or groups considered as “marginal” (immigrants, gypsies and other social-cultural groups, isolated communi-ties). The primary prevention of CA in such popula-tion groups may require, therefore, specific attention and ad hoc actions.

• Health systems include data collection and surveil-lance: CA and rare disease registries of adequate quality can provide a valuable support to prevention strategies, e.g., by allowing ad hoc studies in order to assess potential risk factors (maternal diseases, drug treatment, occupation, etc.) or preventive actions, e.g., the diffusion of periconceptional folic acid sup-plementation at the right timing and dosing.

• Also, considering that the frequency of every single CA is rather low, data sharing and networking are very important for the research of any aspect related to CA, but specifically on preventive measures [24].

DISCUSSIONIn 2015, countries under the umbrella of United Na-

tions adopted the 2030 Agenda for Sustainable De-velopment and its 17 Sustainable Development Goals [25]. Governments, businesses and civil society togeth-er with the United Nations are mobilizing efforts to achieve the Sustainable Development Agenda by 2030. Universal, inclusive and indivisible, the Agenda calls for action by all countries to improve the lives of people everywhere. In particular Goal 3 “Ensure healthy lives and promote well-being for all at all ages” specifically states “Ensuring healthy lives and promoting the well-being for all at all ages is essential to sustainable de-velopment. Major progress has been made. However, many more efforts are needed to fully eradicate a wide range of diseases and address many different persistent and emerging health issues.”

Primary prevention, therefore, clearly pertains to the domain of sustainability. Health system sustainabil-ity means that today’s efforts to protect and promote health will not reduce resources so to jeopardize the future efforts to provide an equitable and functioning health system to the next generation(s). Hence, owing to primary prevention, the health system will be more sustainable for the society. A science-based primary pre-vention will reduce both burdens of premature deaths and of chronic disabilities (measureble as DALY) re-lated to CA. This is important also in an ageing society: following the paradygm of “Developmental Origins of Health and Diseases”, an effective primary prevention in the early lifestages (starting from intrauterine life, and even preconceptionally) can improve the quality of life of the increasing aged population, and reduce the societal costs for long-term treatment and care of chronic, often invalidating conditions [26].

Data suggest that local and national public health in-terventions are highly cost-saving. Cuts to public health budgets in high income countries therefore represent a false economy, and are likely to generate billions of eu-ros of additional costs to health services and the wider economy [27].

Sustainable development in the field of health is the goal of meeting the needs of the present without compromising the ability of future generations to cover their own needs. In the fields of food safety and envi-ronmental health, for instance, the phasing-out and re-placement of hazardous chemicals (such as mutagens, teratogens, endocrine disruptors) are actions that can reduce the burden of disease for generations to come, by enforcing a safer living environment today. Disease prevention must start with improved nutrition and re-duced exposure to environmental chemicals during de-velopment [26]. Also, sustainable food safety implies the efforts towards the comprehensive knowledge and management of key factors related to to food and diet for protecting and promoting next generation’s health; such efforts will contribute to the effectiveness of the overall sustainability policies [28].

Besides sustainability, prevention may also involve the concept of resilience at different levels.

Resilience means to adapt the system to changes in order to keep it functioning. The system must be able to adapt itself effectively to changing environments and identify and apply innovative solutions to tackle signifi-cant challenges – shortages of expertise/resources in spe-cific areas, unexpected surges in demand with limited resources. In other words, the system needs to build and maintain resilience. Emerging risks, presenting either as new hazards or as new aspects of recognized hazards, call for resilient responses: one example in CA field is the recently recognized teratogen Zika virus [29]. Emerging risks make evident the need for the health system to be able to understand changes and to adapt/modify its re-sponses accordingly. The World Health Organization has considered Zika virus as a case study for emerging risk challenge. European countries can learn from the expe-rience of other regions on how to communicate about Zika and apply these lessons to the European context, as the possible scenarios of Zika outbreaks can show sig-nificant differences in terms of size, and composition of the population at risk, cultural and socioeconomic real-ity and preparedness and response capacity.

To this respect, health promotion is important. It is the process of empowering people to increase control over their health and its determinants through health literacy efforts and multi-sectorial action to increase healthy be-haviors. This can be addressed to the community-at-large or to populations at increased risk of negative health outcomes. Disease prevention and health promotion share many goals, and there is considerable overlap between functions. In fact, it is useful to characterize disease pre-vention services as those primarily concentrated within the health system domain, while health promotion ser-vices depend on intersectorial actions and/or are con-cerned with the social determinants of health.

Primary prevention actions should be targeted based on scientific evidence. This statement should not hide


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the many uncertainties still existing. A few examples of gaps of knowledge that increase the burden of un-certainties on primary prevention actions regarding CA can be mentioned: in the field of health interventions, the benefit-to-risk assessment of flour fortification with fo-lic acid; in the field of chemical safety, the possible role of developmental exposures to pollutants in the obesity/diabetes epidemics; in the field of response to emerging risks, the role of climate changes on emerging infectious agents (such as Zika virus) and the associated terato-genic risks; in the field of safe use of medications, the as-sessment of possible risks derived from the use of herbal drugs and other widespread “alternative” medicines, in relation to pregnancy; in the field of safe food, undertak-ing actions to identify and characterise emerging risks .

On one hand, the recognized presence of significant gaps of knowledge cannot, by any means, hamper the enforcement of evidence-based actions here and now.

On the other hand, and importantly, prevention needs research and innovation. An uncertainty is a gap of knowledge that can impair the assessment of the ben-efits introduced by a certain action. Therefore, uncer-tainties have to be identified and characterized, in order to plan and launch relevant research activities. Recently, it has been stated that for better sustainability and use-fulness, it is crucial to refocus and streamline surveil-lance activities, avoiding a “recreational” data collection, in order to turn the statistically significant results into clinically relevant data. Also, it has been recommended to perform a “triple surveillance” [30]: surveillance of causes, of disease occurrence, and of health outcomes. Such integral surveillance can be a really effective tool for primary prevention of CA.

RECOMMENDATIONS AND CONCLUSIONSCA, which include an important fraction of rare

diseases, are liable to risk reduction by means of sci-ence-based primary prevention. In order to achieve an effective primary prevention, the following general rec-ommendations have to be taken into account: • the professional education and training of all health

professionals (not limited to physicians) should pro-vide an adequate room to primary prevention from both the qualitative and quantitative standpoint; this should include epidemiology, social medicine, envi-ronmental health, food safety and nutrition, as these themes can be relevant to the work of the majority of health professionals.

• EU Member States should consider the “health-proofing” of all their policies. As pointed out in the above paragraphs, side to the health system, primary prevention involves several other legislative, interven-tion and scientific domains.

• Health is a fundamental human right; at the same time, it can be considered that the “investment” on primary prevention generates both tangible and in-tangible benefits. It has been said that “early child-hood development is a smart investment” and “the earlier the investment the greater the return” [31]: investing in primary prevention is obviously the earli-est possible investment. Nobel Laureate Economist James Heckman’s research makes the economic case

for early childhood investments starting before birth.In conclusion, the considerations on CA as an ex-

ample for primary prevention in the rare diseases field identify the following highlights:1. investing in primary prevention based on scientific evidence is one essential factor supporting sustainabil-ity of health systems;2. primary prevention is a pillar of sustainable develop-ment of the society; protection of the early develop-ment will enable healthier next generation(s) reaching full adulthood and ageing;3. in regard of many risk factors (e.g. nutrition, life-styles, pollution, infections, medications), CA (together with other adverse reproductive outcomes) represent both an important public health issue per se as well as an early indicator of public health risks;4. effective primary prevention requires an integrated “One Health” approach, linking knowledge and action pertaining to human health as well as to physical and social living environments. From the policy standpoint, joint budgeting mechanisms can be envisaged to sus-tain intersectorial actions, involving the policy domains of health as well as others, e.g., social affairs, education, agriculture, and/or environment; 5. EU Member States (and any country, in fact): should devote resources to strengthen registries, and other tools for systematic data collection and surveillance on CA, so as to better inform national prevention strategies.6. pillars of primary prevention include science-based risk analysis and surveillance of potential health-dam-aging factors, citizen’s empowerment and education of health professionals; 7. characterization of uncertainties that weaken scien-tific evidence should target research programmes aimed at supporting the scientific basis of primary prevention;8. EU Member States should consider the health and equity aspects [32, 33] in all their policies (short, mid and long term). Moreover, The DG SANTE Scientific Committees recommend more dialogue between risk assessors and socio-economists [34].

In summary, primary prevention for CA as well as for other rare diseases, must be considered (better earlier than later) as a pillar of sustainability of health systems and a duty of policy makers with respect to society, which expects that the system provides a better quality of life to all, leaving no one behind.

FundingThis research was supported by the Health Pro-

gramme of European Union, in the framework of the Joint Action for Rare Diseases, Project n. 677024 “Promoting Implementation of Recommendations on Policy, Information and Data for Rare Diseases – RD-ACTION”.





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33. Ferrelli RM, Gentile AE, De Santis M, Taruscio D. Sustainable public health systems for rare disease. Ann Ist Super Sanità. 2017;53(2):170-5. doi: 10.4415/ANN_17_02_16

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Health systems sustainability in the framework of rare diseases actions. Actions on educational programmes and training for professionals and patientsEmilia Severin1, Marta De Santis2, Rita Maria Ferrelli3 and Domenica Taruscio2

1Genetics Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 2Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy 3Servizio Formazione, Istituto Superiore di Sanità, Rome, Italy


INTRODUCTIONAccording to WHO, a good health system delivers

quality services to all people. Good healthcare services are those which deliver effective, safe, quality personal and non-personal health interventions to those who need them, when and where needed, with minimum waste of resources [1].

Nowadays, health care systems in both developed and emerging economies face the problem of insuf-ficient resources to meet the anticipated health care needs of all citizens. Ageing populations, longer life expectancy, increasing demand for services, new tech-nologies and new medicines all contribute to the finan-cial pressures. Doctors and patients are aware of these pressures [2, 3].

In the context of concerns about rising health care costs and the lack of availability of necessary supplies required to maintain life, or a specific quality of life, rare diseases are drawing attention to the demand for special services, challenging whether patient expecta-tions are realistic, and whether current models of ser-vice delivery are sustainable [4, 5].

Research based on decades of experience in the de-veloping world has identified educational status (espe-cially of the mother) as a major predictor of health out-comes, and economic trends in the industrialized world have intensified the relationship between education and health [6].

MATERIAL AND METHODSTo collect evidence that education plays a key role

in building sustainable health care system for persons with RDs, an electronic literature search was conduct-ed using different medical databases and additional information resources (including government docu-ments, reports from international bodies such as the World Health Organisation, Eurordis or UNESCO and academic studies). The key search terms were educa-tion, health care system, sustainable development and healthcare professionals and rare diseases, from 2000 through January 2018. Studies reporting about educa-tion for healthcare professional who provide medical services to both children and adult patients with RDs or other diseases were included as well. Articles of interest were reviewed to determine which were relevant and subjected to analysis. Selected papers were later used to compare healthcare education between the patients with RDs and other disease groups to emphasize the need for specific and complex actions on educational programs and training in the field of RDs.

RESULTSThe facts – what is already known about rare diseases

Rare diseases (all together) represent an international public health issue and no one country, no one conti-nent alone can solve the problems posed by rare dis-eases [7].

Address for correspondence: Emilia Severin, Genetics Department, Carol Davila University of Medicine and Pharmacy, 24 Kiseleff Avenue, Bucharest 011346, Romania. E-mail: [email protected].

Key words• education • health care system• rare disease• sustainable development

Abstract Rare disease community is one of the largest patient populations in the world estimated to be 350 million of people. Collectively common, rare diseases pose a significant medical and economic burden for health systems worldwide. In this respect, rare diseases are con-sidered a priority of public health. The study is a review aimed to determine whether there is evidence that education plays a key role in building sustainable health system and will allow better health and well-being for people with rare diseases to be achieved. This review shows evidence that providing quality education through different ways and actions the lives of people suffering from a rare disease and their families can be improved.

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People with a rare disease (RDs) deserve equal access to care, treatment and rehabilitation as the other pa-tients while the kind of disease they are suffering from put them in a special relation with their normal legiti-mate aspirations and with the rest of the society. More-over, 50% of RDs affects children who have difficulties in attending school and integrate themselves into local activities of community [7].

Prices for RD healthcare services are rising at a rate that is unsustainable for most patients and their fami-lies due to chronic illnesses, development of expensive new medicine, high-tech medical equipment and pro-cedures for genetic diagnostic testing, patients expecta-tions for access to the latest technologies. Therefore, they need a healthcare system dedicated to their specif-ic needs and able to assure a coherent approach to their specific problems [8]. But the diagnosis and treatment protocols have to be balanced with resources conserva-tion and management [9].

The configuration of health services varies from coun-try to country but everywhere education and training of professionals are an important component of the sus-tainability of health system.

Within this context it should be ensured that sufficient health professionals are trained, competent, with the necessary knowledge and skills. Likewise, strong links need to be made in both directions between education providers and Centers of Expertise for rare diseases.

When dealing with rare diseases, medicine is sustain-able only if:• medical treatment is meant not only to improve the

length of the patients’ life but the quality of their life as well;

• the life quality improvement of the sick people does not hurt the quality of life of the healthy people;

• the adequate medical and social services provided in order to meet these needs presently remain available for the future generations [4]. For reaching these three targets one needs a pragmat-

ic farsighted visionary educational system with a holistic perspective. The four pillars of education [10], “learning to know, learning to do, learning to live together, learn-ing to be” should be applied to change the health knowl-edge, skills, awareness and health attitudes and behavior regarding sustainability in the health care system and the connection between health and the environment.

DISCUSSION“The great aim of education is not knowledge but action”

(Herbert Spencer)

We know rare diseases exist. But it’s not enough to know. We need to act based on that knowledge. There is a difference between what we know, learn and what we do. Education should bridge the gap between knowl-edge and behavior informing, training and motivating people (professionals, parents, caregivers, communi-ties) to translate the health knowledge into actions. Therefore education can serve as a powerful tool in transforming rare diseases care. Worldwide education is an important mechanism for enhancing the health and well-being of individuals because it reduces the need

for health care, the associated costs of dependence, lost earnings and human suffering [11]. According to Eichler et al., 2009 [12] on the health system level, the additional costs of limited HL range from 3 to 5% of the total health care cost per year and on the patient level, the additional expenditures per year per person with limited HL compared to persons with adequate HL range from US $ 143 to 7798.

Having in mind these challenges, education policy-makers and stakeholders have to rethink the strategy in the age of precision medicine characterized by chang-ing of the paradigm of health care from being reactive to being proactive [13]. Patient is a person, not just a diagnosis. In addition, conventional medicine could not to solve all problems of persons with RDs. A new strat-egy directed to holistic and integrated care is the hope and future for RDs. The strategy will determine where they focus their attention over the long term: to develop healthier habits, incentivize healthier consumption and develop an environment and infrastructure that facili-tate population health [14]. Educational actions should be implemented in a way that planning, delivering and monitoring Rare Disease issues become core work of the health system. A sustainable health system pro-motes, maintains and improves the health of population.

We have chosen the following actions on formal and non-formal education for a sustainable health care sys-tem in the framework of RDs hoping to have a real im-pact on RD patients life.

Integration of an education package on rare diseases in the curriculum of the medical degree course for professional development – students are the future for RD patients and their families

Being rare and complex, RDs should be approached holistically. Therefore a collaborative and multidisci-plinary health and social care team should be involved in the management of patients with RDs. At the mo-ment, the number of healthcare experts in rare diseases is low. Special undergraduate and postgraduate educa-tion and training programs should be developed and supported in the field of rare diseases.

Coping with rare disease from a medical care point of view requires professional creativity as well as the capac-ity to integrate new concepts and therapies within the old state of knowledge. This could be achieved only if the training of the medical students include more than updated information, the necessary ingredients for the development of an individual professional personality characterized by scientific and moral convictions, based on which a dynamic and proactive behavior in coping with the rare diseases challenges could be built. That would require appropriate curriculum, pedagogy, tools of assessment as well as the adequate overall structures [15]. Medical students should be encouraged to par-ticipate in programmes designed for RDs. In addition, universities and education providers should create op-portunities for medical students to learn about RDs and understand patients experience, keep them in contact with RD Centres of Expertise and provide them links to patient organizations (Eurordis, Nord) and reference portal/knowledge databases (Orphanet).

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Continuing Medical Education and training programmes for all healthcare professionals, allied health professionals and industry professionals

Learning is an ongoing process and by offering con-tinuing education and training, universities and other accredited medical centers are committed to provide best resources and training for all healthcare profes-sionals who are encouraged to take advantage of these opportunities. Continuing education programmes on RDs for health professionals support an educated and informed health workforce to provide the best health services to populations worldwide and to achieve the best possible health for all [16]. A variety of courses and training modules (live or online events) on RDs topics is offered for physicians, nurses, dentists and other health-care professionals aiming to improve medical practice and implement holistic patient care. In addition, CME facilitates lifelong learning and is a fundamental factor in the maintenance of certification.

Integration of healthcare sustainability concept in medical schools and universities – from basic to higher education

To respond the needs for a sustainable health system one has to put a special accent on the formative rather than on the informative dimension of knowledge trans-ferred to the future experts to be involved in the rare diseases field. That will allow the experts to adapt them-selves to the rather fast progress of the science in this field. “Promoting health, promoting sustainable develop-ment emerges as a metaphor used by WHO, UNESCO and UNICEF for launching a new initiative “Make every school a Health Promoting School”. This makes schools a unique setting for preventive interventions, and school years an important period to establish healthy behav-iours that will contribute to a lifetime of health promo-tion. However, challenges remain. Global mortality and morbidity estimates in children and adolescents suggest that school age children have significant needs for health promotion, prevention and health care services [1]. This concept is also applicable for RDs: approximately 50% of people affected by rare diseases are children and 30% of them will not leave to see their 5th birthday.

Involvement in rare diseases research activities Rare diseases are a priority area of research funding

for the European Union. Research activities, extending from bench research, clinical research to translational research, have the potential to develop attitudes to-wards science and potential science-based career. The future experts, while in school, must be integrated in the scientific research effort in the field of rare diseases. This could be done either by including them in different research programs or by inviting researchers to regular-ly inform the students on the priorities in their fields, as well on the obstacles they have met and on the ongoing achievements. Not only the professionals but the entire society must build upon the present scientific discover-ies and respond adaptively to the new scientific ones, while assuring an intrinsic technologic dynamism able to maintain the viability and resilience of the present health systems’ best practices and performances within an ever changing societal environment.

Practical clinical training in centers of expertise (CEs)

CEs provide education and training to healthcare professionals from all disciplines, including paramedi-cal specialists and non-healthcare professionals (such as school teachers, personal/homecare facilitators) when-ever possible [17].

The medical students must be kept in permanent contact with the activities of the centers of expertise and diagnosis, thus developing their practical expertise. There are rare diseases of course, but there are indi-vidual patients, as well. One should develop appropriate expertise from both points of view.

Academic training providing with general scientific knowledge is extremely important, but equally impor-tant are the good practice guidelines, case studies and the understanding of the specific problems the prac-titioners in the RD concrete centers of diagnosis and treatment are coping with.

Development of the capacity to interact with patients and their families through education

Beside the medical training, the development of the social sensitivity and of the capacity to interact with the patients and their families would be crucial. In many cases the medical experts are able to deal with the chal-lenges of the diseases but not equally able to deal with patients and their families, in order to put in place an early warning system which would allow for a medical in-tervention in an optimal time or for the necessary coop-eration between the health system officials, the patients, the patients’ families and the whole society within which the patients must be treated, hosted and integrated. The school should train the all healthcare providers (primary, nursing or specialty care) for all health and social care services (preventive, curative, rehabilitative or palliative) from these points of view as well.

IT skills and knowledge acquired through professional training

There could not be put in place a national health sys-tem for rare diseases without a solid international and transnational medical, scientific, social and financial co-operation [18]. In today’s fast-changing health care envi-ronment, communication and collaboration can develop tailored and adaptable solutions that work, especially due to the complexity of rare diseases. Moving patients from home to one health care setting or to another can have negative effects on the health of patient and the well-being of family caregiver. Educational programmes develop the ability of healthcare professionals to change routine, adapt and evolve in order to manage rapid changes in the healthcare practice. The programmes in-clude knowledge and skills related to information and communications technology (ICT) as well. In 21st cen-tury technology has changed the healthcare – informa-tion is moving and patients stay home but not “alone”. Therefore healthcare providers should be familiar with medical technology dealing with the storage, retrieval, sharing, and use of health care information, data, and knowledge for communication and decision making.

Whether or not health professionals go on working

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together in partnership, through social media, such as LinkedIn, Facebook, Twitter or other social network-ing websites, they are connected to each other and can share personal experience and collaborate online on dif-ficult rare disease cases.

Sharing and developing best practice in medical education and training

Best practices must be known and disseminated. Shar-ing examples of best practice in rare disease cases which worked well, can help medical schools and universities which educate students and train doctors to dive up healthcare standards. Free and easy access to the sci-entific and technology progress must be allowed among professionals. A strong health information infrastructure, when coupled with an effective health communication system, can improve health systems in drastic ways. For instance, European Reference Networks for rare diseases (RD ERNs) are foreseen by the Cross-Border Health-care Directive to share knowledge, facilitate the mobility of expertise, and allow Member States to provide highly specialised services of high quality for patients where this would have been impossible without European network-ing, such as in the case of rare diseases [19].

For the success of educational programs dedicated to healthcare professionals working in the field of RDs ad-ditional supporting actions are needed such as:

Informing and educating the large and diverse public – raise necessary awareness, understanding and action among general population. In the field of rare diseases it is im-portant to know but also to explain. Public awareness is crucial. The rare diseases cannot be cured or cannot be cured completely only in hospitals and at home. The people suffering of rare diseases must leave and receive appropriate treatment in society without scaring it or being rejected by it. A special public information and education to make RDs more visible it is therefore necessary. It is not only for the non-governmental or-ganizations, social activists and administrative institu-tions to provide such public awareness. The physicians themselves must be prepared for being social activists and providing public awareness. Such abilities must be trained in the university alongside with the medical training. Public health campaign is required to dissemi-nate the health education among the general popula-tion. It is known that the local and international me-dia play a vital role as the link between health workers and the general public - “it has been observed that the greater the media emphasis on a given social theme or topic, the greater the public concern about the topic” [20]. Health authorities educate and entrust the me-dia with essential health care information about people living with a rare disease, which is then relayed to the public in readily accessible formats through a variety of media channels [21]. Mass media campaigns have generally aimed primarily to change knowledge, aware-ness and attitudes, contributing to the goal of changing behaviour [22]. For instance, Rare Disease Day annual campaigns make the patients’ voices heard and increase visibility of RDs at international level. At national level, RONARD (Romanian Alliance for RD) created an ef-fective dissemination strategy for raising awareness, un-

derstanding and action in the general public. RONARD launched since 2011 an annual one-week school for medical journalists in the hope that three effects might occur: the learning of correct health information and knowledge, the changing of health attitudes and values, and the establishment of new health behavior. Medical journalists are an action and advocacy group in the posi-tion to influence and change the public health opinion.

For rural communities populated by people with limited health education via radio and television can be used as health communication tools. The programs should be planned to help them to stay healthy and to empower them to manage their health [20]. For in-stance, RONARD created NoRo Radio, a private radio station which disseminates scientific and health infor-mation of general / particular public interest on rare diseases and promotes the social integration on people with rare diseases as well. Printed media and Internet can be also used as health communication tools.

Education for general social support in the community. Rare diseases are chronic diseases which need long-term care and tend to require high-cost care. A sustainable health care system requires constant and sometimes massive financial funding. This implies the governmen-tal budgetary contribution and private charity. Both must be mobilized. Moreover, the public contribution is to be facilitated by public understanding and accep-tance. In other words, the society should accept that the public budgets must include financial provisions in support of the rare diseases treatment. The universities must prepare their experts in order to act as successful fund raisers as well, and to act within the society and in direct contact with the governmental competent bodies for getting and assuring sustainable financial resources in response to the rare diseases ongoing necessities.

Patient empowerment and engagement through education. There are different views on patient empowerment. But speaking about rare diseases as chronic conditions, in order to achieve good results, the patients need to be involved in the health care solutions [23]. There is evi-dence that good control of a disease is seen to be de-pendent on the quality of information the patient has received. Thus education must be tailored to the indi-vidual and provided in the context of patient’s life [24]. Through education process patients acquire knowledge, skills, and self-confidence in controlling one’s life and claiming one’s rights. However, there is another view which regards patient empowerment. Rare disease pa-tients are often the leading “experts” in their diseases – sometimes, for very rare diseases, they turn out to be the sole experts. Their knowledge and experience are valuable assets that are, thanks to empowerment, a driving force to shape rare disease related issues [25].

CONCLUSIONSOur review provides a starting point and an evidence

base to plan and deliver future educational programs for healthcare professionals, patients living with a rare disease, parents, caregivers, communities. Giving knowledge, training competences and promote active participation and responsibility through education, a new dialogue between policy-makers, stakeholders,

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professionals and rare disease patients community will provide public health responses to special healthcare needs of people with rare diseases.

Authors’ contributionAll authors were co-leaders in the conceptualization

of the study, data analysis and interpretation, manu-script preparation and revision. All authors read and approved the submitted version of the manuscript.


of European Union, in the framework of the Joint Ac-tion for Rare Diseases, Project n 677024 “Promoting Implementation of Recommendations on Policy, Infor-mation and Data for Rare Diseases – RD-ACTION”.




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Health systems for rare diseases: financial sustainabilityGeorgi Iskrov1,2, Rumen Stefanov1,2 and Rita Maria Ferrelli3

1Department of Social Medicine and Public Health, Faculty of Public Health, Medical University of Plovdiv, Plovdiv, Bulgaria 2Institute of Rare Disease, Plovdiv, Bulgaria 3Servizio Formazione, Istituto Superiore di Sanità, Rome, Italy


INTRODUCTIONHealth systems deliver preventive, diagnostic, cura-

tive and palliative health care services to people in order to improve their health. Health systems in the Euro-pean Union (EU) Member States are varied, reflecting different societal choices. Over the last decade, Euro-pean health systems have faced consistent, common challenges: increasing cost of health care, population ageing associated with a rise of chronic diseases and multi-morbidity leading to growing demand for health care, shortages and uneven distribution of health pro-fessionals, health inequalities and inequities in access to health care. Moreover, in recent years, the economic crisis has limited the financial resources available and thus aggravated Member States’ difficulties in ensuring their health systems’ sustainability. In turn, this jeop-ardises Member States’ ability to provide universal ac-cess to good quality health care. Health systems need to be resilient: they must be able to adapt effectively to changing environments, tackling significant challenges with limited resources [1].

This is particularly true for rare diseases [2, 3]. These

conditions are a threat to the health of EU citizens in-sofar as they are life-threatening or chronically debili-tating disorders with a low prevalence and a high level of complexity. Rare diseases are defined as conditions affecting no more than 5 per 10 000 persons in the EU. Despite their rarity, there are so many different types of rare diseases that millions of people are affected. It is estimated that between 5000 and 8000 distinct rare dis-eases exist today, affecting between 6% and 8% of the population in the course of their lives. In other words, the total number of people affected by rare diseases in the EU is between 27 and 36 million. Most of them suffer from less frequently occurring diseases affecting one in 100 000 people or less. These patients are par-ticularly isolated and vulnerable [4].

Distribution of public spending on health depends on a variety of factors, from disease burden and sys-tem priorities to organisational aspects and costs [5, 6]. Nowadays, virtually all health care systems face serious sustainability challenges. In the case of rare disease, pri-ority setting involves complex value-laden choices that are often ethically controversial. This controversy arises,

Address for correspondence: Georgi Iskrov, Department of Social Medicine and Public Health, Faculty of Public Health, Medical University of Plov-div, 15A Vassil Aprilov Blvd., 4002 Plovdiv, Bulgaria. E-mail: [email protected].

Key words• health system

sustainability• health policy• rare diseases• priority setting• European reference

networks

AbstractIntroduction. Distribution of public spending on health depends on a variety of factors, from disease burden and system priorities to organisational aspects and costs. Nowadays, virtually all health care systems face serious sustainability challenges. This is particularly true for rare diseases, where priority setting involves complex and often controversial value-laden choices.Method. The theoretical framework underlying the approach of this work is based upon the State of Health in the EU, a two-year initiative undertaken by the European Com-mission and developed in cooperation with the Organisation for Economic Co-operation and Development and the European Observatory on Health Systems and Policies. Results. The 2017 report identified five cross-cutting sustainability issues: health promo-tion and disease prevention, primary care, integrated care, health workforce planning and forecasting, person-centred health data.Implications and recommendations. Rare diseases have been one of the priorities of the Community’s programmes for research and development. The EU has stimulated a series of actions in the field of rare diseases. These project activities could set up the practical cooperation and come up with the knowledge to translate and to work on the identified five key challenges of EU Member States health systems’ sustainability and resilience.

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in part, because it involves conflicting moral obligations – beneficence versus distributive justice – which results in different levels of funding and opposing interests of a number of involved stakeholders [7]. Nevertheless, EU health policy is built on principles and overarching val-ues of universality, access to good quality care, equity and solidarity. These are of paramount importance for patients with rare diseases. Because of their low prev-alence, their specificity and the high total number of people affected, rare diseases call for a global approach based on special and combined efforts to prevent sig-nificant morbidity or avoidable premature mortality, and to improve the quality of life and socioeconomic potential of affected persons [2-4, 8].

METHODThe theoretical framework underlying the approach

of this work is based upon the State of Health in the EU, a two-year initiative undertaken by the Europe-an Commission that provides policy makers, interest groups and health practitioners with factual, compara-tive data and insights into health and health systems in EU countries [9, 10]. The cycle is developed in coop-eration with the Organisation for Economic Co-opera-tion and Development and the European Observatory on Health Systems and Policies. It is also aligned to the policy objectives set out in the 2014 Commission Com-munication on effective, accessible and resilient health systems [1].

RESULTSThe 2017 State of Health in the EU report provides

an in-depth analysis of EU Member States’ health sys-tems. It looks at the health of the population and im-portant risk factors, as well as at the effectiveness, ac-cessibility and resilience of health systems in each EU member state.

Five cross-cutting conclusions come forward [10].

Health promotion and disease prevention pave the way for a more effective and efficient health system

Prevention is the key to avoid ill health and achieve a high level of mental and physical well-being effectively and efficiently. However, only a small fraction of health care budgets, political attention and stakeholder en-gagement are dedicated to prevention. Guided by the UN Sustainable Development Goal for 2030 to reduce by one third premature mortality from non-communi-cable diseases, the Commission is working closely with Member States to focus on prevention and social deter-minants of health [10].

A strong primary care guides patients through the health system and helps avoid wasteful spending

Strong primary care can contribute to strengthening the overall health system’s performance by providing affordable and accessible care, coordinating care for patients so that they are given the most appropriate services in the right setting, and reducing avoidable hospital admissions. Efficient primary care is the key to integration and continuity between and across levels of

care, which is essential for patients, particularly those with complex needs [10].

Integrated care tackles a labyrinth of scattered health services to the benefit of the patient

The rising burden of chronic disease and multi-mor-bidity requires countries to confront the fragmentation of health services and shift towards integration: linking or coordinating providers along the continuum of care and putting the patient at the centre. Integrated care models are expected to contribute for better effective-ness, accessibility and resilience of health systems. This new challenge demonstrates also the importance of the right skill mix and training and of being able to share information effectively [10].

Proactive health workforce planning and forecasting make health systems resilient to future shocks

To strengthen prevention, primary care and inte-grated service delivery, health systems need a workforce of sufficient capacity and with the right skills and flex-ibility to meet the changing demands of health care. Yet many countries are confronted with critical health workforce problems such as supply, distribution and a traditionally oriented skill mix. Reforms in initial educa-tion and training programmes and investment in con-tinuous professional development are needed to foster new and appropriate skill sets [10].

The patient is at the centre of the next generation of better health data for policy and practice

More holistic, person-centred health data would have an enormous potential for improving the quality of care and the performance of health systems across the EU. Data capturing patient experiences and outcomes could markedly enrich knowledge on all topics. Genera-tion of better information will provide a set of tools to more effectively treat patients with increasingly com-plex conditions and multiple morbidities, and deliver the outcomes that patients value the most [10].

IMPLICATIONS AND RECOMMENDATIONSThe 2017 State of Health in the EU report concludes

that only by rethinking health systems it can be ensured that they remain fit-for-purpose and provide patient-centred care [10]. Sustainability and resilience of health systems for rare diseases could be achieved by tackling the challenges identified and making the right health policy choices [2, 3]. Rare diseases have been one of the priorities of the Community’s programmes for research and development [4]. In order to improve the coordina-tion and coherence of national, regional and local initia-tives addressing rare diseases, the EU has stimulated a series of actions in the field of rare diseases. These proj-ect activities could set up in fact the practical coopera-tion and come up with the knowledge to translate and to work on the identified five key challenges of EU Mem-ber States health systems’ sustainability and resilience.

Switching the focus to prevention and the social determinants of health

Health promotion and disease prevention pave the

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way for a more effective and efficient health system. Aside from the unbalanced investments in prevention, social inequalities need to be tackled [10]. In this con-text, the EUROCAT Project provided essential epide-miologic information on congenital anomalies in Eu-rope. The project evaluated the effectiveness of primary prevention and assessed the impact of developments in prenatal screening. The outcomes of the project activ-ity could act as an information and resource centre for the population, health professionals and managers re-garding clusters or exposures or risk factors of concern, as well as could provide a ready collaborative network and infrastructure for research related to the causes and prevention of congenital anomalies and the treatment and care of affected children [11-14]. The BURQOL-RD Project has addressed the social determinants of health in rare diseases in Europe. The project gener-ated a methodological framework to measure the socio-economic burden of and health-related quality of life in rare diseases. It performed a pilot study and its out-comes could help refining and packing tools for con-tinuous and extensive focus on the social impact of rare diseases [15-17].

Guiding patients through the health system with strong primary care

Strong primary care efficiently guides patients through the health system and helps avoid wasteful spending [10]. In the context of rare diseases, newborn screening is a cost-effective approach that results in improvements in expectancy and quality of life for af-fected infants. This is of paramount importance in the primary care for rare diseases, as it could eliminate the need for an otherwise expensive diagnostic odyssey, by substantially decreasing extra referrals and psychologi-cal stress for patients and caregivers [18]. In 2009, the Commission launched a tender on evaluation of popu-lation newborn screening practices for rare disorders in the Member States. This project activity reported on the practices of neonatal screening for rare disorders in all Member States, estimated the number of infants screened and the number of disorders included in the newborn screening and described the reasons for the se-lection of these disorders. It successfully identified types of medical management and follow-up implemented in the Member States and established a network of ex-perts analysing the information and formulating a final opinion containing recommendations on best practices and recommending a core panel of newborn screening conditions. These outcomes could help Member States in medical management and follow-up of rare disease patients, fostering primary care and avoiding unneces-sary referrals [19-21].

Integrating care for a sustainable and effective service

Integrated care ensures that a patient receives joined-up care. It avoids the situation, where care is frag-mented and patients have to search their way through a maze of care facilities. Health systems in the European Union aim to provide high-quality, cost-effective care [10]. This is particularly difficult however, in cases of

low-prevalence and complex rare disease. In this con-text, the EU established 24 European reference net-works in 2017 that involve more than 900 highly-spe-cialised healthcare units from over 300 hospitals in 26 Member States. These networks are working on a range of thematic issues, including bone disorders, childhood cancer and immunodeficiency. The European Refer-ence Networks are virtual networks aiming to facilitate discussion on complex or rare diseases and conditions that require highly specialised treatment and concen-trated knowledge and resources. In the context of sus-tainability and resilience of health systems, European reference networks could help applying EU criteria to tackle rare diseases requiring specialised care, as well as ensuring the availability of treatment facilities where necessary [22-24].

Creating a health workforce resilient to future challenges

Proactive health workforce planning and forecast-ing make health systems resilient to future evolutions. Health authorities need to prepare their workforce for upcoming changes: an ageing population and multi-morbidity, the need for sound recruitment policies, new skills and technical innovation [10]. In the context of rare diseases, promotion and communication on the management of rare diseases by disseminating trust-worthy guidelines globally is a key issue. The RARE-Bestpractices Project created a platform to improve the management of rare disease patients. The project built a comprehensive public database of trustworthy guide-lines, ranging from diagnostic tests and treatments to the organisation of care, to help professionals, patients, policy makers with the best and most up to date infor-mation. It also produced mechanisms to identify and prioritise rare disease clinical research needs in order to optimise, as well as to redefine the clinical research agenda taking into consideration both patients’ and cli-nicians’ interests. These outcomes are very important and could help setting up training activities targeted at key stakeholders to spread expertise and knowledge in the field of guidelines [25-27]. Orphanet, the portal for rare diseases and orphan drugs, could also greatly con-tribute for achieving these goals [28-30].

Addressing an important knowledge gap with better, patient-centred data

Patients should be at the centre of the next genera-tion of better health data for policy and practice. The digital transformation of health and care helps cap-ture real-world outcomes and experiences that matter to patients, with great potential for strengthening the effectiveness of health systems [10]. In this context, support for registries and databases for rare diseases is crucial. The EPIRARE Project defined the state of the art of existing registries with reference to their legal ba-sis, organisational and IT measures used, type of data collected, compliance with the rules on personal data protection, quality assurance, operational and finan-cial support. The project agreed on a minimum data set for all rare diseases and defined criteria for quality assessment of data, data sources and procedures in the


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registries. These outcomes could help determining the scope, operation and governance model of rare disease registry platforms, balancing the interests of relevant stakeholders and ensuring long-term sustainability [31-33].

Further observations in relation to the sustainabil-ity of health systems for rare diseases relate to the availability of resources for health systems: while so-cial and demographic pressures increase demand for health care, and technological and scientific advances continue to increase costs, in Europe, the financial crisis posed major threats to healthcare sustainability. Governments’ response to the crisis was cutting public health-care budgets, and transferring healthcare costs to individuals and families through out-of-pocket pay-ments. As a result, not only equity was jeopardized, suffering the least wealthy from the greatest health effects, but also austerity policies affected economic growth much more adversely than previously believed. Moreover, while little research has been done about the health consequences of the crisis, groups concerned with biomedicine, pharmaceuticals, and medical tech-nologies are driving the process for setting health re-search priorities, and government ministries of science have coordinated them nationally with little input from Ministries of Health. Considering the complexity of policy-making and the process of resource allocation for healthcare, the WHO identified whole-of-govern-ment and whole-of-society approaches as a set of tools to manage the complex policy process and identified the following features for comparing good governance practices [34]:• Forward looking: long-term view based on statistical

trends and informed predictions of the probable im-pact of the policy;

• Innovative: questioning established methods and en-couraging new ideas;

• Informed by evidence: using the best available evi-dence from a range of sources;

• Inclusive: taking account of the impact of the policy on the needs of everyone directly or indirectly af-fected;

• Joined-up: horizontal and vertical integration;• Adaptive: learning from experience of what works

and what does not;• Evaluative: including systematic evaluation;• Accountable: being democratically legitimized, trans-

parent and responsive to the demands of citizens.According to Aluttis and coll. [35], organizational

structure, resources, partnership, workforce, knowledge development, leadership and governance and country specific play a relevant role in public health. The same factors are crucial for health systems sustainability for rare diseases as well. The organizational structure shapes the infrastructural ability of the system to con-tribute to the goals to healthcare systems for rare dis-eases. Allocation and provision of human and financial resources to healthcare systems for rare diseases; col-laboration among organizations for effective practice; qualified human resources with adequate skills and knowledge; all of them are fundamental for healthcare. Knowledge development is the base providing informa-

tion on the health status and supporting evidence-based health policy and interventions at all levels; leadership and governance represent the ability and willingness of governments to improve public health, since they de-velop and implement effective health policies and ex-pressing qualities in strategic thinking. Therefore, all of them represent key elements and mechanisms for the sustainability of the health systems for rare diseases.

In relation to the financial sustainability, government have the responsibility of allocating resources to the dif-ferent public sectors. Following the financial crisis that hit Europe, budgets for healthcare decreased, inequali-ties in health increased. According to the International organization Oxfam, several countries have success-fully reduced economic inequality by means of cracking down on financial secrecy and tax dodging; redistribu-tive transfers; and strengthening of social protection schemes; investment in universal access to healthcare and education; progressive taxation; strengthening wage floors and worker rights [36].

Oxfam calls on governments to use their tax revenue to provide universal healthcare, education and social protection for citizens. Moreover, it has recommended policies in multiple contexts to strengthen the political representation of citizens to achieve greater equity, un-derlining the importance of citizens’ active participation in the mechanisms of resilience. These policies include:- a global goal to end extreme economic inequality in every country. This should be a major element of the post-2015 framework, including consistent monitoring in every country of the share of wealth going to the rich-est one percent;- stronger regulation of markets to promote sustain-able and equitable growth; and- curbing the power of the rich to influence political processes and policies that best suit their interests.In order to address fiscal pressure in future, internation-al and national policy-makers should aim to:- develop better information systems, in order to get timely and relevant data to monitor health effects of economic shock;- strengthen health financing policy design: public spending on health is more explicitly linked to popula-tion health needs; the public revenue base is not overly reliant on employment; and tax subsidies do not foster inequalities in paying for and accessing health services; - invest in measures to promote efficiency; - foster governance and leadership at international and national levels.

CONCLUSIONSWe used the five identified axes of public health chal-

lenges in the 2017 State of Health in the EU report to start a broad debate on the issue of sustainability of health care systems for rare diseases. Our analysis is suggesting a number of possible ways by which the outcomes of successful EU-funded projects could help addressing and achieving sustainability and resilience of health systems for rare diseases.

AcknowledgmentsThis work was carried out in the framework of the

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Joint Action “677024/RD-ACTION”, which has re-ceived funding from the European Union’s Health Pro-gramme (2014-2020).

The content of this article represents the views of the authors only and is their sole responsibility; it cannot be considered to reflect the views of the European Com-mission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the Euro-pean Union. The European Commission and the Agen-cy do not accept any responsibility for use that may be made of the information it contains.

Authors’ contribution statementGI, RS and RMF contributed to the design and im-

plementation of the research, to the analysis of the re-sults and to the writing of the manuscript.

Conflict of interest statementNone of the authors has any kind of conflict of inter-

est to declare.


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Integrated care for healthcare sustainability for patients living with rare diseasesMarta De Santis

Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy


INTRODUCTIONThe world has changed over the last 30 years: urban-

ization, ageing and globalized lifestyle changes com-bine to make chronic and non-communicable diseases – including depression, diabetes, cardiovascular disease and cancers – and injuries increasingly important causes of morbidity and mortality. The growing prevalence of chronic diseases and population aging – are placing a heavy burden on health systems, individuals, families, businesses and governments. The World Health Orga-nization (WHO) estimates that an increase of 10% of chronic diseases is associated with a reduction of 0.5% of annual economic growth [1]. On other hand, in the light of scientific and technical developments, people live for longer. The children born with complex con-ditions are now living to adulthood, while those with learning disabilities and other groups have lifelong needs. All these people need continuous care and sup-port, and the right systems and resource to enable that. In addition, the renewed socio-economic, cultural and epidemiological conditions have undermined health systems, highlighting the weaknesses of the traditional way of understanding and organizing the health system. In fact, although health systems are also a reflection of a globalizing consumer culture, however do not provide an adequate response to need and demand, and that they are driven by interests and goals that are discon-nected from people’s expectations. In fact, the tradi-tional approaches to care focus on individual diseases

and are based on a relationship between an individual health/social care service-user and a single health/social care professional. Then, current health systems amplify the potential for care fragmentation between different professionals and care organisations.

Thus, the increasingly complex and multidimensional care request, combined with the presence of increas-ingly aware and demanding patients, accentuates the need for new strategies to rationalize resources, orga-nizational methods and use of services, which preserve economic sustainability by acting on waste and on in-efficiencies. In this scenario, the identification of inte-gration mechanisms reveals an essential condition for ensuring continuity of care.


integration of heal services and relates it to rare diseas-es. Several medical databases and additional informa-tion resources were utilised and included government documents, reports from international bodies such as the World Health Organisation, EURORDIS and aca-demic studies. The key search terms were integration of care and rare diseases, from 2000 through January 2018. Articles of interest were reviewed to determine which were relevant and subjected to analysis. Selected papers were later used to extrapolate the most relevant messages about integration of healthcare services for rare diseases.

Address for correspondence: Marta De Santis, Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00162 Rome, Italy. E-mail: [email protected].

Key words• integrated care• rare diseases• organizational change• patient empowerment

AbstractThe increasingly complex and multidimensional care request, combined with the pres-ence of increasingly aware and demanding patients, accentuates the need for new strate-gies to preserve health systems economic sustainability. Therefore, integration mecha-nisms reveal an essential condition for ensuring continuity of care. The paper reviews the main literature available on the integration of heal services and relates it to rare diseases. The literature identifies several system levers for the effective design and implementation of integrated care frameworks, namely: political support and commitment, governance, stakeholder engagement, organisational change, leadership, collaboration and trust, workforce education and training, patient empowerment, financing and incentives, ICT infrastructure and solutions, monitoring and evaluation system.

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RESULTSThe importance of integration is emphasized by the

WHO global strategy on people-centred and integrated health services. The strategy calls for shifting the way health services are funded, managed and delivered, and proposes five interdependent strategic directions that need to be adopted for health services to become more people-centred and integrated (Figure 1). The five inter-dependent strategic directions include: 1. empowering and engaging people; 2. strengthening governance and accountability;3. reorienting the model of care;4. coordinating services;5. creating an enabling environment.

Our review highlighted that there is no unifying definition or common conceptual understanding of integrated care, which is most likely a result of “the polymorphous nature of integrated care itself” [2]. The concept of integrated care is strongly shaped by per-spectives and expectations of various users in the health system, making a unified definition difficult.

“Integrated care” is a term that reflects a concern to improve patient experience and achieve greater ef-ficiency and value from health delivery systems. The aim is to address fragmentation in patient services, and enable better coordinated and more continuous care. In effect, the perspectives that construct the concept are likely to be shaped by views and expectations of various stakeholders in the health system. The literature reviewed offers a range of examples of how integrated care might be adopted in practice.

The rarity and complexity of rare diseases highly con-dition the availability of knowledge about their impact on patients’ and families’ life expectancy, daily life and autonomy. Indeed, patients affected by a particular rare disease are few and spread geographically. It is there-fore clear that RD have special requirements which dis-tinguish them from other complex or chronic diseases. They are not only complex but also frequently unpre-dictable, requiring often stays in hospital, specialist care

and access to professional and medical knowledge not always available or may not even exist. The knowledge on the impact of rare diseases on patients’ functionality remains a challenge within the national systems, which often entails an inadequate recognition and inappro-priate compensation for disabilities, exacerbating the social and economic vulnerability of people living with a rare disease and of their families. Several studies, con-ducted by patient’s organisations, have demonstrated the serious impact of rare diseases. Results of the first European-wide survey on the everyday impact of rare diseases – “Juggling care and daily life: the balancing act of the rare disease community” [3], conducted by EURORDIS survey initiative, Rare Barometer Voices and involving 3000 patients and carers [4, 5] – put into evidence the serious impact of rare diseases and the need for integrated care.

DISCUSSIONThe WHO global strategy on people-centred and in-

tegrated health services identified five strategic direc-tions.

Put together, the five strategic directions represent an interconnected set of actions that seeks to trans-form health systems to provide services that are more people-centred and integrated. However, for each spe-cific context, the exact mix of strategies that will be used needs to be designed and developed, taking into account local contexts, values and preferences. The benefits of a people-centred and integrated approach are well documented: increased delivery efficiency, de-creased costs, improved equity in uptake of service, bet-ter health literacy and self-care, increased satisfaction with care, improved relationships between patients and their care providers, and an improved ability to respond to health-care crises [6]. Recognizing that health sys-tems are highly context-specific, it is clear that there is no a single model of people-centred and integrated health, instead several strategic directions to better co-ordinate care around people’s needs. In view of litera-ture reviews, it’s clear that establishing integrated care is a multifaceted and long-term process, due also to the difficulties in showcasing the causality between the de-livery of integrated care and outcomes.

There are many reasons for this. Firstly, in the con-text of integrated care it is not possible to effectively separate multicomponent strategies that are needed to achieve results. Secondly, the criteria for assessing the success of integrated care models are not necessarily specific or measurable. Lastly, there are few opportuni-ties for making comparisons with alternative models or control cases. However, there does appear to be some guidance on the first steps required to make change happen; specifically, development of a common vision should be based on a clear articulation of the popula-tion’s needs in local communities, which then can de-velop into a shared strategy for change. The identifica-tion of population needs, therefore, should be a starting point in developing any integrated care strategy. It is clear that even these first steps for integrated care re-quire careful planning and that the process of change needs strong leadership and good management support

Empowering and engaging people

Strengtheninggovernanceand accountability

Reorienting the model of care

Coordinatingservices

Creating anenabiling

environment

Figure 1Five interdependent strategic directions to support people-centred and integrated health services (Reproduced with kind permission from WHO – WHO Global Strategy on People-cen-tred and Integrated Health Services; 2015 [6]).

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[7]. In other words, it’s required a paradigm shift in policy action and a genuine commitment to engaging with communities in the attainment and protection of their health.

Since integrated care is strongly shaped by perspec-tives and expectations of various users in the health system, success of each solution is to depend on the context in which the integration is introduced, not just the initiative itself.

The conceptualization of integrated care is multidi-mensional and encompasses four key elements: a) the types of integration (e.g., functional, organisational, etc.); b) the breadth of integration (i.e., vertical or hori-zontal); c) the degree of integration; and d) the process of integration (i.e., structural, cultural, social) [2]. A re-cent review of the literature on integrated care revealed some 175 definitions and concepts [8]. The most com-mon definition of integration comes from the World Health Organization: “The organization and manage-ment of health services so that people get the care they need, when they need it, in ways that are user friendly, achieve the desired results and provide value for mon-ey”. This reinforces the fact that integration is a means to an end, not an end in itself.

WHO suggests a common set of principles, that pro-vide a unifying values framework [6]. The core prin-ciples of people-centred and integrated health services are: • Comprehensive – offering care that is comprehensive

and tailored to the evolving health needs and aspira-tions of people and populations, with a commitment to universal health coverage.

• Equitable – providing care that is accessible and avail-able to all.

• Sustainable – delivering care that is efficient, effective and contributes to sustainable development.

• Coordinated – ensuring that care is integrated around people’s needs and effectively coordinated across dif-ferent providers and settings.

• Continuous – providing care and services across the life course.

• Holistic – focusing on physical, socioeconomic, men-tal and emotional well-being.

• Preventive – tackling the social determinants of ill-health through action within and between sectors that promotes public health and health promotion.

• Empowering – supporting people to manage and take responsibility for their own health.

• Goal oriented – in terms of how people make health care decisions, assess outcomes and measure success.

• Respectful – of people’s dignity, social circumstances and cultural sensitivities.

• Collaborative – supporting relationship-building, team-based working and collaborative practice across primary, secondary and tertiary care, and with other sectors.

• Co-produced – through active partnerships with peo-ple and communities at an individual, organizational and policy-level.

• Endowed with rights and responsibilities – that all people should expect, exercise and respect.

• Governed through shared accountability – of care

providers to local people for the quality of care and health outcomes.

• Evidence-informed – so that policies and strategies are guided by the best available evidence and sup-ported over time through the assessment of measur-able objectives for improving quality and outcomes.

• Led by whole-systems thinking – that views the health system as a whole and tries to understand how its component parts interact with each other and how the system is influenced by factors beyond it.

• Ethical – by making sure that care optimizes the risk–benefit ratio in all interventions, respects the individual’s right to make autonomous and informed decisions, safeguards privacy, protects the most vul-nerable and ensures the fair distribution of resources. Contextualizing integrating care to the field of rare

diseases, it is important to underline that Rare diseases (RD) are heterogeneous in terms of prevalence, age of onset, clinical severity and outcome. However, they share various common features: they are often serious, chronic, progressive, degenerative and associated with co-morbidities. Rare diseases (RD) are heterogeneous in terms of prevalence, age of onset, clinical severity and outcome. However, they share various common features: they are often serious, chronic, progressive, degenerative and associated with co-morbidities. For most RD there isn’t a specific treatment available and existing treatments are not always able to minimize all the complex impairments generated by the disease. Even when RD are not associated with a disability, will in many cases influence the person’s health condition and impact on daily life in a disabling way [4].

To resolve this problem, some Member States are developing specific project to improve the knowledge and visibility of disabilities associated with RDs, and to provide tools to help the stakeholders. In France, for instance, Orphanet (the international database and portal on RDs and orphan drugs) is currently working on describing the functional consequences of each rare disease, having developed the Orphanet Functioning Thesaurus, derived and adapted from the International Classification of Functioning, Disability and Health – Children and Youth [9, 10]. According to surveys car-ried out by EURORDIS [4, 5]: • 65% of respondents have to visit different health, so-

cial and local services in a short period of time; • 67% feel that these services communicate badly be-

tween each other; • 7 in 10 find that organising care is time-consuming

and 6 in 10 find it hard to manage; • 7 in 10 do not feel well informed about their rights; • 7 in 10 reduce or stop their professional activity due

to the disease and the care burden. These everyday challenges result in significant loss of

income and financial difficulties, often compounded by the need to relocate to another home adapted to their health needs or situated closer to the health or social services. Moreover, people living with a rare disease feel that they face discrimination in leisure activities (32%), education (30%) and daily activities (29%). 32% of pa-tients also felt discriminated in the labour market, ei-ther when searching for a job (17%) or at their current


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job (15%) [11]. Then, in the particular context of rare diseases, including the challenges in regards to diagno-sis, feelings of exclusion and lack of treatment generate a considerable moral suffering and burn out situations are frequent among patients and family members.

Hence it is clear that, although providing holistic support to any given patient is certainly an added chal-lenge, the rare diseases are likely to benefit consider-ably from integrated care that bridges professions and knowledge bases. On the other hand, as early as 2008, the European Commission and Council recognized the need for coordination of care provided to people living with a rare disease, nationally and internationally, rec-ommending Member States to [12, 13]: • establish and implement plans or strategies for rare

disease in order to aim to ensure that patients with rare diseases have access to high-quality care, within the framework of their health and social systems;

• organise healthcare pathways for people living with a rare disease through the establishment of coop-eration with relevant experts, and exchange of pro-fessionals and expertise within the country or from abroad when necessary;

• encourage Centres of Expertise to be based on a mul-tidisciplinary approach to care when addressing rare diseases;

• gather national expertise on rare diseases and support the pooling of that expertise with European counter-parts in order to support: (a) the sharing of best prac-tices on diagnostic tools and medical care as well as education and social care in the field of rare diseases. EUROPLAN, the European Project for Rare Diseas-

es National Plans Development (www.europlanproject.eu) played a crucial role in these activities. This project promotes a “double level” approach: respectful of na-tional decisions but also intended to ensure a coher-ent and consistent progress in EU rare diseases care. In fact, trough EUROPLAN Recommendations [14] provided tools to Member States for developing a plan or strategy, linking it to a common framework at the European level. These recommendations and report of several national conferences [15] recommended taking into account the need for social inclusion, psychologi-cal and educational development for people living with rare, chronic and debilitating diseases. It’s been also recognized the instrumental role of social services to the empowerment, the wellbeing and health of people living with a rare disease. Several adopted national plans include specific measures to facilitate coordination be-tween health and social and support services. Various countries have already started to implement some of these approaches.

In 2016, the European Commission has reiterated and strengthened its position adopting “The Commis-sion Expert Group Recommendations to Support the Incorporation of Rare Diseases into Social Services and Policies”, and sustaining clearly the need to promote measures that facilitate multidisciplinary, holistic, con-tinuous, person-centred and participative care provi-sion to people living with rare diseases. In the holistic and person-centred approach, social services play a fun-damental role to achieve a high level of social protec-

tion, health protection, gender equality, and economic, social and territorial cohesion. In fact, they should help people to participate fully in all aspects of life and to maintain own independence, in order to increase qual-ity of life. To achieve these goals, social services should be closely interlinked with health services, educational services.

These documents, sided by other recent policy devel-opments at European and national levels, represent an important policy step into approaching rare diseases’ complex challenges in regards to holistic care provision [16].

Innovative approaches aiming at bridging the gap between health, social and community service and sup-port providers are currently being developed and test-ed in different European countries: standards of care, networks of expertise, case management services, one-stop-shop services, amongst others.

The EU-funded project INNOVCare has also de-veloped a factsheet with input from all stakeholders to highlight why integrated care is needed for rare dis-eases. This factsheet states that Integrated care ensures that people living with a rare disease and their carers: • overcome the care burden that they face and secure

the services and support that they require; • achieve a quality of life on an equal footing with other

citizens; • participate in society and in the job market to their

highest potential; • fully realize their fundamental human rights.

The challenge of providing holistic care to people liv-ing with a rare disease is huge and requires multidisci-plinary teams, involvement of all stakeholders as well as change of perspectives, of care provision concepts and of services. The organization of holistic care pathways at national level is essential to overcome this challenge. At national level, centers of expertise play an important role: are responsible for gathering and coordinating knowledge and care and – as such –- should promote the cooperation with other care providers, including social services and other local services. In France, 23 National Health Networks for Rare Diseases (Filière de Santé Maladies Rares) have been created by the Ministry of Health to coordinate actions between dif-ferent stakeholders involved in care provision to people living with rare diseases. The mission of these Networks consists of reducing the diagnosis and therapeutic wavering; facilitating the entry and orientation in the care pathway; implementing actions in the social field (in collaboration with the National Solidarity Fund for Autonomy), targeted at improving social care and al-location of disability compensatory benefits. Specific actions are defined according to needs of the diseases covered by the network and inter-networks actions are also developed, for instance, a working group has been set up to improve education, pathway at school and care taking at school [16].

An excellent example of integrated care is also found in Resource Centres for Rare diseases, which have re-cently gathered in the European Network of Resource Centres – RareResourceNet. RareResourceNet aims at accelerating the development and the implementation

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of holistic high quality care pathways for people living with a rare disease across Europe, contributing to raise standards of care and support.

Resource centres for rare diseases are a one-stop shop service, complementary to health and social care ser-vices, specifically designed for people living with a rare disease and their carers. They provide holistic services and support, while also creating a bridge between pa-tients and families and various stakeholders, services and professionals providing health care, social care, and social support – including rehabilitation, education and employment. They thus empower service provid-ers, professionals, patients and carers to overcome the challenges of rare diseases. Moreover, they advocate for the adoption of holistic and integrated care services and policies in European countries.

An example of a resource centre for rare diseases is the NoRo Pilot Reference Center for Rare Diseases, in Romania, set up in 2011, through a project implement-ed in partnership with Frambu Norway (www.frambu.no) and funded by Norway Grants. This offers a social service and a medical service, which provides holistic care based on a multidisciplinary and complementary approach and on the individual assessment of patients’ needs. The centre ensures continuity of care through a one-stop-shop style of service, specifically designed for people living with a rare disease, combining medical, social and educational service. The integration of social services through setting up one-stop-shop services has the potential to generate cost efficiency, effectiveness of the delivery and capacity to tackle complex and mul-tiple problems while also ensuring take-up and coverage [17].

Another resource that is being promoted as guaran-tee of integrated care is the “case manager”. To date, in most rare disease cases, the role of the case manager is assumed by patients or family members, without having sufficient information regarding care, the health and so-cial system and relevant contacts. This situation is very burdensome for people living with a rare disease and their families. Family members – often the main car-ers – frequently find themselves in burn out situations, unable to cope physically and psychologically with the situation. Therefore, professional case managers are crucial in relieving the care burden faced by people liv-ing with a rare disease and their families.

These professionals represent an element that can ensure that there is a better coordination in the care pathway of people living with a rare disease, function-ing as a link between the health and the social needs of the patient, particularly in very complex situations, due to the course of care and the need for the intervention of multiple structures and professionals. Case manag-ers have an instrumental role in supporting patients and families as well as professionals.

The EU-funded INNOVCare project (www.innov-care.eu) has developed and outline for the role of case manager, with the input of all stakeholders involved in care delivery and decision making on care for people living with a rare disease [18]. According to this outline, case managers should: • act as a single and stable point of contact;

• listen, inform, support and empower patients and families;

• asses and monitor patients’ and families’ needs; • provide holistic, patient-centred care planning & care

co-ordination; • act as a hub of information and knowledge; • inform, support and empower care professionals; • facilitate coordination between services/networks of

services; • help to prevent risks and to limit use of health ser-

vices, when these may not be needed; • develop working methods that support patient/fami-

lies empowerment. The INNOVCare project is also the testing use

of case managers in the context of rare diseases, and should bring to light more information on the impact of this type of service on care provision and on the quality of life of patients and families. Main goal of this project is collect data on unmet social needs of people living with a rare disease and their families in the EU, analyse existing social care pathways in a selection of Member States in order to facilitate the creation of a European network of resource centres to ensure exchange of good practices.

Another example can be found in The Netherlands, where case management for an individual with a rare disease is often divided into organisational and medi-cal components. For help regarding the organisational aspects of care as such, the “case manager” is a nurse-practitioner who is in close contact with the responsible clinician. For medical issues only, there is the so-called physician-manager, who coordinates the multidisci-plinary care and is the immediate contact for medical questions. This physician, having a broad overview of the disease and its health and psychosocial impact, can refer the patient to other professional care-givers within the network of expertise or outside of it for paramedical care or other types of services [16].

Lastly, European Reference Networks (ERNs) and their constituent healthcare providers are also key ac-tors in facilitating integrated care for rare diseases, in accordance with recommendations adopted by EU-CERD and by the Commission Expert Group on Rare Diseases. ERNs can support integrated care by for ex-ample follow a multi-disciplinary approach and func-tioning as a platform to share experiences and good practice. Centres of expertise, on their hand, can co-ordinate within the specialised healthcare sector mul-tidisciplinary competences/skills, including paramedical skills and social services. They also can provide educa-tion and training to non-healthcare professionals (such as school teachers, personal/homecare facilitators) as well as contribute to and provide accessible informa-tion adapted to the specific needs of patients and their families, of health and social professionals. Discussions on the roles of ERNs in supporting integrated care can also be found in the report of the Joint RD-Action and INNOVCare workshop on “Creating a Sustainable En-vironment for Holistic & Innovative Care for Rare Dis-eases & Complex Conditions” (April 2018). This work-shop also highlights several other important topics, case studies and good practices on integrated and holistic


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care for rare diseases, which are available for download online on the project website.

CONCLUSIONS Various methods are currently being used to promote

integrated care for rare diseases and there are yet sev-eral challenges to fully address this issue. However a review of experiences in implementing integrated care in Europe has identified elements of good practices deemed to be successful and which potentially could be transferable across Europe. Were identified several inter-related “building blocks” or “system levers” for the effective design and implementation of integrated care frameworks [19, 20]. These relate to: 1. Political support and commitment. System-wide transformative change can only happen when many pol-icy levers are aligned and activated towards shared goals. 2. Governance. Establishing strong governance mecha-nisms at both national and local level and among all ser-vice providers, care authorities and actors involved is an essential step in configuring integrated care models. 3. Stakeholder engagement. The broader the ambition, the more numerous and diverse are the stakeholders that should be engaged; effective communication strat-egies establish trust, confidence and good collaboration and involvement of all stakeholders. 4. Organisational change. The provision of integrated care and service redesign implies changes in the health-care structures, organisation of workflows, workforce development and resource allocation to provide more responsive care delivery. 5. Leadership. Effective national leadership and the emergence of local leaders are important factors in managing the complex process of transformation and implementation of integrated care solutions. 6. Collaboration and trust. The broad set of changes needed to deliver integrated care presents a significant challenge that can be partially overcame by the willing-ness to collaborate and put the interest of the overall care system above individual incentives. 7. Workforce education and training. The implementa-tion of integrated care solutions often requires the re-design of health and social care professionals’ roles and the creation of new roles to ensure continuity of care. 8. Patient focus/empowerment. The patient is a mem-ber of the “care team”: he or she must be involved in the decision-making processes, and care plans need to be tailored to patients’ individual needs. 9. Financing and incentives. Different funding models can support the transition to the time when the new integrated services are fully operational and the older ones are decommissioned. 10. ICT infrastructure and solutions. Integrated care re-quires the sharing of health information across diverse

providers to enable continuous collaboration and citi-zens’ active involvement. 11. Monitoring/evaluation system. The establishment of monitoring and performance evaluation systems is essential to provide evidence of the impact on quality of care, cost of care, access and citizen experience.

To date, the evidence base for the benefits of integrat-ed care on both patient outcomes and cost effective-ness is based yet on small-scale examples, although the scale of implementation is slowly growing. Better, more comparable and longer term data collection and report-ing will be crucial for building a more comprehensive evidence base.

Promoting integrated care and bridging the gaps be-tween health and social care for rare diseases is not only necessary but crucial to increase the life expectancy, quality of life and autonomy of people. For this reason, to guide future policies integrated assistance, it’s rec-ommended that: • information on ongoing pilot projects/case studies and

good practices is consolidated and widely dissemi-nated: the long term impact assessment of the pilot care provisions is essential to support robust evidence based decision making on integrated care, as the im-pact on quality of life and the return on investment are hardly short term outcomes; research on econom-ic evaluation of the integrated care, should consider the economic long term impact beyond the healthcare and service provision onto a society level: taking into account the consequences of the impact of integrated care provision on patients’ and carers’ health, wellbe-ing, autonomy and financial burden [16];

• the evaluation of impact uses a suitable comprehen-sive set of outcome indicators that take into account both the evaluation of impact of healthcare and social services’ interventions as well as the personal quality of life outcomes for patients, their families and carers;

• patients and families are directly engaged in the design and implementation of these innovative solutions.


of European Union, in the framework of the Joint Ac-tion for Rare Diseases, Project n. 677024 “Promoting Implementation of Recommendations on Policy, Infor-mation and Data for Rare Diseases – RD-ACTION”.




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2. RAND Europe. National Evaluation of the Department of Health’s Integrated Care Pilots. Cambridge: RAND Europe 2012. Available from: www.rand.org/content/dam/rand/pubs/technical_reports/2012/RAND_TR1164.pdf.

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3. EURORDIS-Rare Diseases Europe. Juggling care and daily life. The balancing act of the rare disease commu-nity; 2017. Available from: http://download.eurordis.org.s3.amazonaws.com/rbv/2017_05_09_Social%20sur-vey%20leaflet%20final.pdf.

4. EURORDIS. The voice of 12000 patients. Experiences and expectations of rare disease patients on diagnosis and care in Europe. Paris: EURORDIS; 2009. Available from: www.eurordis.org/IMG/pdf/voice_12000_patients/EURORDISCARE_FULLBOOKr.pdf.

5. EURORDIS. First rare barometer Voices survey on the impact of rare diseases on daily life; 2016. Available from: www.eurordis.org/sites/default/files/release-innovcare-survey-launch-finalv2.pdf.

6. World Health Organization. WHO global strategy on people-centred and integrated health services. Geneva: WHO; 2015. (WHO/HIS/SDS/2015.6). Available from: www.who.int/servicedeliverysafety/areas/people-centred-care/global-strategy/en/.

7. World Health Organization. Integrated care models: an overview. WHO; 2016. Available from: www.euro.who.int/__data/assets/pdf_file/0005/322475/Integrated-care-models-overview.pdf.

8. Armitage GD, Suter E, Oelke ND, Adair CE. Health sy-stems integration: state of the evidence. Int J Integr Care. 2009;9(2):none. Available from: http://www.ijic.org/in-dex.php/ijic/article/view/URN%3ANBN%3ANL%3AUI%3A10-1-100558. doi: http://doi.org/10.5334/ijic.316.

9. World Health Organization. International Classifica-tion of Functioning, Disability and Health. Children & Youth Version. Geneva: WHO; 2007. Available from: https://apps.who.int/iris/bitstream/handle/10665/ 43737/9789241547321_eng.pdf;jsessionid=EA38EC5DCD45F833C9B151B967EFBE6B?sequence=1.

10. Orphanet. Orphanet Functioning Thesaurus. Available from: https://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_Functioning_Thesaurus_EN.pdf.

11. FEDER – Federación Española de Enfermedades Raras. Estudio sobre situación de Necesidades Sociosanitarias de las personas con Enfermedades Raras en España (Estudio ENSERio) [Study on the situation of social-sanitary needs of people with rare diseases in Spain (ENSERio Study)]; 2009. Available from: https://enfermedades-raras.org/ima-ges/stories/documentos/Estudio_ENSERio.pdf.

12. European Commission. Communication from the Com-mission to the European Parliament, the Council, the Eu-ropean Economic and Social Committee and the Commit-tee of the Regions on “Rare Diseases: Europe’s challenges”.

COM (2008) 679 final. Available from: http://ec.europa.eu/health/ph_threats/non_com/docs/rare_com_en.pdf.

13. Council of the European Union. Council Recommen-dation of 8 June 2009 on an action in the field of rare diseases. (2009/C 151/02). Available from: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2009:151:0007:0010:EN:PDF.

14. EUROPLAN – European Project for Rare Diseases Na-tional Plans Development. Recommendations for the Development of National Plans for Rare Diseases; 2010. Available from: www.europlanproject.eu/Resources/docs/2008-2011_2.EUROPLANRecommendations.pdf.

15. EUROPLAN – European Project for Rare Diseases Natio-nal Plans Development. Main results of the 15th EURO-PLAN National Conferences. Final report; 2011. Availa-ble from: https://webgate.ec.europa.eu/chafea_pdb/assets/files/pdb/2007119/2007119_d09_00_oth_en_ps.pdf.

16. Castro R et al. Bridging the gap between health and so-cial care for rare diseases. Key issues and innovative solu-tions. In: Posada de la Paz M et al. (Eds.). Rare diseases epidemiology: update and overview. (Advances in Experi-mental Medicine and Biology, AEMB Book 1031). Sprin-ger International Publishing AG; 2017. Available from: https://doi.org/10.1007/978-3-319-67144-4_32.

17. European Commission – Directorate General for Em-ployment, Social Affairs and Inclusion. Call for Proposals VP/2014/008 on Social Policy Innovations Supporting Reforms in Social Services; 2014. Available from: http://ec.europa.eu/social/main.jsp?catId=629&langId=en&callId=408&furtherCalls=yes.

18. INNOVCare – Innovative Patient-Centred Approach for Social Care Provision to Complex Conditions. Case managers for rare diseases. Roles and training outlines; 2018. Available from: https://innovcare.eu/wp-content/uploads/2018/04/Outline-of-role-and-training-of-case-managers_print.pdf.

19. European Commission (by the Expert Group on Health Systems Performance Assessment). Tools and Methodo-logies to Assess Integrated Care in Europe; 2017. Availa-ble from: https://ec.europa.eu/health/sites/health/files/sy-stems_performance_assessment/docs/2017_blocks_en_0.pdf.

20. European Commission. The Commission Expert Group Recommendations to Support the Incorporation of Rare Diseases into Social Services and Policies; 2016. Availa-ble from: https://ec.europa.eu/health//sites/health/files/rare_diseases/docs/recommendations_socialservices_po-licies_en.pdf.

[Editor’s NoteThe name of the author Raquel Castro has been removed from the list of authors in this new version of the present paper (6 July 2020). Raquel Castro was involved in reviewing the text in the framework of the European RD-Action project, however she has not taken part in the final revision of the paper, therefore by common agreement between all the authors and as asked by the same Raquel Castro, her name should not appear in the by-line].

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Patient empowerment of people living with rare diseases. Its contribution to sustainable and resilient healthcare systems Marta De Santis1, Clara Hervas2, Ariane Weinman2, Giulia Bosi2 and Valentina Bottarelli2

1Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy 2EURORDIS – Rare Diseases Europe, Paris, France


INTRODUCTIONHistory and concept

The many origins and sources of inspiration of the no-tion of empowerment can be traced back to such varied domains as feminism, Freudian psychology, theology, the Black Power movement, and Gandhism. Another important influence to the empowerment “philosophy” appears to be the work of Paolo Freire and his concept of “popular education” developed in the 1960s, which became influential in development practices in Latin America in the 1970s, associated particularly with lit-eracy projects [1]. However, it is not until the 1970s, especially the 1976 publication of Black empowerment. Social work in oppressed communities by Barbara Solo-mon, that the term formally comes into use by social service providers and researchers. In the 1980s, empow-erment was seen, for the most part, as a radical project of social transformation, to enable otherwise excluded social groups to define and claim their rights collectively [2]. A notable example related specifically to the field of health and people living with a disease, is the self-empowerment movement of people living with AIDS during the 1980s, particularly the drafting of their 1983 “Denver Principles” where the idea that personal ex-periences should shape the AIDS response was first

voiced [3] and in which they made their seminal dec-laration stating: “We condemn attempts to label us as ‘victims’, a term which implies defeat, and we are only occasionally ‘patients’, a term which implies passivity, helplessness, and dependence upon the care of others. We are ‘People With AIDS’ ” [4]. It is therefore in the context of various social movements that the word ‘em-powerment’ begins to be used increasingly in research and intervention concerning groups experiencing mar-ginalisation, such as African Americans, women, gays and lesbians, and people with disabilities.

From this historic overview, it appears that empower-ment refers in essence to principles such as the abil-ity of individuals and groups to act in order to ensure their own well-being or their right to participate in any decision-making that concerns them. However, em-powerment is a complex concept that has been used in different ways. Gibson suggested that “Empowerment is […] easier understood by its absence: powerlessness, helplessness, hopelessness, alienation, victimisation, subordination, oppression, paternalism, loss of a sense of control over one’s life and dependency” [5]. In addi-tion, not only are we lacking an agreed upon definition of “empowerment”, but the word itself does not trans-late easily or equally. For example, in both German and

Address for correspondence: Valentina Bottarelli, EURORDIS – Rare Diseases Europe, Rue d’Egmont 11, 1000 Bruxelles, Belgium. E-mail: [email protected].

Key words• patient empowerment• rare diseases• patient engagement• healthcare systems• sustainability

AbstractThe notion of empowerment is linked to patients’ everyday life and is the base allowing for the patient engagement through which individuals and communities are able to ex-press their needs, are involved in decision-making, take action to meet those needs. In the field of rare diseases, empowerment strategies have greater value due to low preva-lence, lack of expertise, poor quality of life. Avenues to patient empowerment are: health literacy and capacity-building; shared decision-making; support to self-management. Pa-tient empowerment is recognised as key enabler in creating sustainability as addressing challenges faced by modern healthcare systems in terms of effectiveness, access and resilience. It is recommended to develop a comprehensive EU roadmap on patient em-powerment including specific recommendations, taking stock of good practices. This holistic approach should lead to a society where all actors are fulfilled human beings and unmet needs are addressed in compliance with fundamental human rights.

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French, the English expression “to empower” can be translated into two different verbs: ermächtigen/auto-riser (which suggests “power over”) on the one hand, and befähigen/rendre capable (“power to”) on the other [2]. There are other possibilities for a French transla-tion: the Quebec French dictionary uses the word autonomisation; the World Bank [6] uses the words “demarginalisation” and “integration”. Empowerment is also found in the literature as “renforcement des ca-pacités et participation” [6].

Another issue of definition is the distinction between empowerment being a process/approach or being a goal/outcome, although these two concepts are not nec-essarily disparate: The World Bank, for instance, defines “empowerment as the process of enhancing the capacity of individuals or groups to make choices and to trans-form those choices into desired actions, which both build individual and collective assets, and improve the efficiency and fairness of the organisational and institu-tional context which govern the use of these assets” [7].

In the field of healthcare, the term patient empower-ment gained prominence as part of a move away from paternalism towards more equitable and collabora-tive models of healthcare delivery, with the potential for improving cost-effectiveness of care, especially for people affected by long term conditions [8]. In this sense, empowerment is viewed as a process of “activat-ing” patients, who as a result of “rejecting the passivity of sick role behaviour and assuming responsibility for their care (…), are more knowledgeable about, satisfied with, and committed to their treatment regimens” [9]. The European Patients’ Forum explains this distinction between the individual (patient) level and the collec-tive (patient community) level as the difference be-tween gaining personal skills in the former, and creating mutual support groups, identifying issues through the sharing of information and creating a coalition with po-tential for advocacy in the latter [10]. Another impor-tant nuance highlighted in the EU-funded EMPATHiE project (“Empowering Patients in the Management of Chronic Diseases”) is the fact that “an empowered patient has control over the management of their con-dition in daily life” and they “develop self-confidence, self-esteem and coping skills to manage the physical, emotional and social impacts of illness in everyday life” (www.eu-patient.eu/contentassets/543c15ed8f8c40f692030a0a0d51b8e2/empathie_frep_en.pdf). Therefore, patient empowerment can go beyond solely changing the way one copes and manages healthcare strategies, but also enter the realm of everyday life.

The fact that patient empowerment as a process can occur at the individual level and at the collective level, as well as in the medical context and outside of it, means that patient empowerment can have an impact at: micro (patient) level, in terms of improved health, greater sat-isfaction with the treatment option and better quality of life and psychological state; at macro (community) level in terms of quality of health and social services and design of interventions responding better to needs; and at policy level in terms of policy prioritisation, design, and cost-effectiveness [10]. In view of these elements, four components can be considered as fundamental to

the process of patient empowerment: 1) understanding by the patient of his/her role; 2) acquisition by patients of sufficient knowledge to be able to engage with their healthcare provider; 3) patient skills; and 4) the pres-ence of a facilitating environment. In sum, although the term can have different meanings and interpretations, patient empowerment generally refers to the process that allows an individual or a community to gain the knowl-edge, skills, and attitude needed to make choices about their care.

In the field of rare diseases this process of empower-ment takes on an even greater value. First off, because, due to the low prevalence and the lack of expertise and adequate information, the patient is forced to become knowledgeable about his own disease state. Moreover, people living with a rare disease are often at high risk of experiencing poor quality of life, including increased levels of anxiety, depression, pain, fatigue and limited ability to participate in society. The results of the Rare-Barometer survey “Juggling day care and daily life” [11], developed in the framework of the InnovCare project (www.innovcare.eu), with over 3000 respondents, pro-vides detailed evidence of this reality. This has made it clear that, while each disease may have its own set of characteristics and health impacts, people living with a rare disease often share similar experiences and chal-lenges – including limited information, no treatment, lengthy times to diagnosis and isolation. In addition, it is often the very rarity of rare diseases that has left them largely disregarded by the research or medical commu-nity and policy makers.

To overcome these difficulties, empowerment, de-fined as an action-oriented notion with the focus on removal of formal or informal barriers, and on trans-formation of relations between communities and in-stitutions, becomes a necessity for people living with a rare disease. It becomes crucial to look at this group collectively, rather than at each rare disease indepen-dently, to identify the common problems and gather the actors (critical mass) for joint actions (collaborative work) towards the strengthening of the actors’ abilities and their recognition in the social field. This realisation has led to patient empowerment being effectively ap-plied in the rare diseases community over the last few decades. Empowerment strategies in the rare diseases community include improving access to information on the basis of indigenous knowledge, finding supportive groups, and establishing dialogues, and they have led to reduced social exclusion and health disparities, and built a sense of community [12]. These strategies occur at both the individual (patient) level as well as at the community level.

Firstly, it is important to highlight that individual em-powerment of people living with a rare disease has been mediated by the rapid growth of web-based health-re-lated information, notably by:• the possibility of establishing or joining online cross-

border communities for people with the same disease or the same problem, of which the platform of online patient communities RareConnect.org is a prominent example in terms of both disease and geographical coverage;

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• and by the availability of help lines and other sup-port services often offered by patients’ organisations. In particular, help lines, supported by the European Network of Help Lines for Rare Diseases (www.eurordis.org/content/help-line-services), play an es-sential role in providing the often lacking informa-tion that patients face, especially in the absence of disease-specific patient organisations. In addition, another key component of individual

empowerment is the ability to self-care, including the self-management of the condition. This ability of the patient to deal with all the elements of its condition, including symptoms, treatment, physical and psycho-social consequences, and lifestyle changes, requires the coordinated approach between physicians, patients, care-givers, and health care organisations. Self-manage-ment support allows the development of confidence, self-efficacy and skills to control daily life. In the case of people living with rare diseases, it is often the case that patients themselves and in particular, family members, act as primary carers. However, research reveals that self-management and the collective support required to achieve it is far from being an easy task [11].

Secondly, it is crucial to point out the key role of pa-tients’ organisations. “Rare disease patient organisations have been created as a result of experience gained by patients and their families from being so often exclud-ed from health care systems and thus having to take charge of their own disease themselves. The scientific community’s inadequate knowledge of rare diseases and the scarce attention given to them by national com-petent authorities and the pharmaceutical industry has led to the creation of associations of patients and par-ents. Rare disease patient associations aim at gathering, producing and disseminating the limited existing infor-mation on their disease and making patients and par-ents voices’ heard. Their actions have already ensured progress in healthcare and social assistance provided to patients and carers, development of treatments, and in raising public awareness of rare diseases” [11]. In this sense, patient organisations act at both the individual and collective levels of patient empowerment. In fact, the very nature of rare diseases patient organisations places “patient empowerment” at the core of their mis-sion. For EURORDIS-Rare Diseases Europe, the EU alliance of rare disease patient organisations, “patient empowerment” is one of the three key components of its tripartite mission and is centred on information shar-ing, community-building, networking opportunities for members and capacity-building for patients.

MATERIAL AND METHODThe document is the result of a review of literature

on topic, patient advocates’ testimonials, EU policy documents and legislation, results of surveys performed under the RareBarometer survey programme (www.eurordis.org/voices), as well as consultation with EU-RORDIS (www.eurordis.org) European Public Affairs Committee (EPAC). The brief, after shedding light on the concept of “patient empowerment” and its historic development, tries to define the way in which patient empowerment is implemented and to identify the link

between patient empowerment and equity, resilience and sustainability of healthcare systems.

RESULTSa) What is an empowered patient?

The Alma Ata Declaration issued by the World Health Organisation (WHO) as far back as 1978 stated that: “The people have the right and duty to participate indi-vidually and collectively in the planning and implemen-tation of their healthcare” [13]. In 2006, the Council of the European Union declared that patient involvement is a common operating principle in the health systems of the European Union [14]. However, today this is still not the patient’s experience on a daily basis. But, what is an empowered patient? And what is the distinction between an empowered and an engaged patient?

In health care, the rapid proliferation of health infor-mation on the Internet has resulted in more patients turning to the Internet, particularly social networks such as PatientsLikeMe (www.patientslikeme.com/), Con-nected Living (www.connectedliving.com/) or RareCon-nect, specifically for rare diseases) as their first source of health information. This rapid evolution of digital tech-nologies has shifted the focus to sharing and co-creation of knowledge. This has radically changed the way pa-tients interact with institutions, with the media and with other stakeholders in the reference context.

However, the information patients access indepen-dently will vary in quality. This wealth of information can be very powerful, but it can also be confusing, in particular if the individual patient is not able to use ef-fectively the information. In this respect, empowering patients means enabling them to make good use of their available knowledge by providing tools, techniques, and support that allow them to actively participate in the management of their health and life if they wish so. However, empowerment is not a simple process, nor is it necessarily linear, and it is not a process that can be imposed, only facilitated [10].

Moreover, it is not always easy to distinguish clearly between patient empowerment and patient involve-ment/engagement. Generally speaking, only once a patient is empowered, can a patient be engaged, the difference between the two being that the former (pa-tient empowerment) is the common base allowing for the latter (patient engagement). The concept of pa-tient involvement refers specifically to the rights and the benefits of patients to have a central position in the healthcare process, it goes beyond the availability of in-formation or health literacy: it is about the interaction between the patient and the healthcare provider and encompasses a wide range of different aspects.

Recently, the EU-funded EMPATHiE project devel-oped the following working definition of an empowered patient which combines both terms: “An empowered patient has control over the management of their condi-tion in daily life. They take action to improve the quality of their life and have the necessary knowledge, skills, attitudes and self-awareness to adjust their behaviour and to work in partnership with others where necessary, to achieve optimal well-being. Empowerment interven-tions aim to equip patients (and their informal caregiv-


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ers whenever appropriate) with the capacity to partici-pate in decisions related to their condition to the extent that they wish to do so; to become “co-managers” of their condition in partnership with health professionals; and to develop self-confidence, self-esteem and coping skills to manage the physical, emotional and social im-pacts of illness in everyday life” [10].

Additionally, and in line with the scheme illustrated by Christopher Rissell [15], the European Patients’ Forum (EPF) proposes a definition of empowerment that includes the significant role of patient organisa-tions in advocating for the patient perspective at policy level, this incorporating both the individual (patient) and the collective (patient community) dimension of empowerment.

Several countries have put patients at the centre of their healthcare policy [16]. The NHS in the UK, for example, has promoted the concept of patient involve-ment using the well-known slogan: “No decision about me without me” [17]. At the EU level, a remarkable example of the adoption of the latter principle is the 2015 Addendum to EUCERD Recommendations on European Reference Networks (ERNs) for Rare Dis-eases (31 January 2013) whereby “Patients and patient representatives should play an integral role in the de-cision and opinion making process in RD ERNs and be involved in structural and clinical network activi-ties. It is recommended that RD ERNs demonstrate meaningful patient involvement, patient-centredness and empowerment through recognition of the role of patients, as experts by experience and co-producers of knowledge, in RD ERN structural and clinical activities and therefore demonstrate meeting the legal require-ments in the Delegated Acts [18]”. This principle has been translated into the governance of the existing 24 ERNs and the involvement of ePAGs (European Pa-tient Advocacy Groups) in each ERN.

To sum up, empowerment is “a process through which individuals and communities are able to express their needs, present their concerns, devise strategies for involvement in decision-making, and take political, social, and cultural action to meet those needs [10]”. In particular, for rare disease patients, this translates in a process leading to collective intelligence to solve complex problems, it is continuous production and im-provement of information, knowledge expertise as well as well as support and solutions [19].

Empowerment of patients is a task which involves and encourages interaction of communities, health care professionals, policy-makers and all other civil society actors with respect to health and wellbeing of individuals. “Empowering patients means providing them with the opportunities and the environment to develop the skills, confidence and knowledge to move from being a passive recipient of care to being an active partner. Empowerment needs to take place simultane-ously both at the population and the individual level. It therefore requires a cultural change, involving a change in the balance of power to recognise chronic patients as experts in their own care by experience and also “co-managers” of their condition in partnership with health professionals” [20].

This change can be achieved by focusing on educa-tion and training for all stakeholders, patients, health professionals and institutions. Revitalising public health requires rethinking education of health professionals to produce a more flexible, multi-skilled workforce able to meet the growing challenges and to support patient empowerment and consumers with the adequate level of health literacy, and fostering communication, man-agement and leadership capacities at all levels. It will be thus possible to promote innovative and high-quality, truly patient-centred, sustainable health systems of the future.

b) How is a patient empowered?Taking control of one’s own health involves more than

just gaining a voice. For this reason, there are many ways in which patients can be empowered. The follow-ing are often identified as key ones:

Health literacy, education and capacity-building. – Although empowerment involves much more than becoming an educated/informed patient, the right in-formation and resources are fundamental tools for empowerment. The WHO [21] highlighted that lim-ited health literacy negatively affects health, reinforces health inequalities, especially among poorer popula-tions, and leads to higher healthcare system costs. Im-proving health literacy and education not only empow-ers patients but also contributes to the sustainability of healthcare systems.

Health literacy is a dynamic, interactive process whereby the information is critically analysed and ap-plied to influence or take action to change the com-munity. Patients need to know where to find reliable information from trustworthy sources. In this sense, the European Commission’s recent paper on Digital Health Literacy focused on the use of the Internet to search for health-related information. The EU eHealth Action Plan 2012-2020 – Innovative Healthcare for the 21st Century also looks at how greater access to ser-vices and information and the use of social media for health can strengthen patient-centred care and empow-erment [22].

Health literacy addresses the environmental, po-litical and social factors that determine health. Health education also encompasses capacity-building and aims to influence not only individual lifestyle decisions, but also raises awareness of the determinants of health, and encourages individual and collective actions which may lead to a modification of these determinants. Health education is achieved therefore, through methods that go beyond information diffusion and entail interaction, participation and critical analysis. Such health education leads to health literacy, leading to personal and social benefit by enabling effective community action, and contributing to the development of social capital [23].

Patient organisations often fulfil the task of ensuring education for patients and healthcare professionals by developing and often funding helplines, information and developing ad hoc trainings for patients so that they can become fully-fledged partners in decision-making and/or in the relations with other actors they


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come across in their healthcare pathway. In the field of rare diseases, trainings such as the EURORDIS Open Academy (www.eurordis.org/content/eurordis-open-academy#tabs-1) or the EUPATI programme, are extremely important to build patients capacities and to allow them to understand the scientific landscape, to discuss with researchers, medical staff and industry on equal foot, or to develop those personal skills that are essential for the interactions with other healthcare stakeholders.

Umbrella patient organisations that acting at the na-tional level also play a crucial role in capacity-building. By pooling patients across the country together and act-ing as a single voice, national patient organisations are able to contribute to empowerment at all three levels (micro, macro and policy). In particular, they are able to provide input for appropriate policy, research and health provision that responds to the needs of the con-stituent population. In addition, this collective national grouping facilitates the interaction with similar group-ings from other countries in order to exchange best practices and learn from the successes and challenges experienced in different contexts.

Shared decision-making and Integration of pa-tients’ views. – Shared decision making (SDM) has been defined as: “an approach where clinicians and pa-tients share the best available evidence when faced with the task of making decisions, and where patients are supported to consider options and to achieve informed preferences [24]”. In sum, shared decision-making is the process by which a clinician and a patient jointly make a health decision after discussing options, poten-tial benefits and harms, and considering the patient’s values and preferences. At its core, shared decision-making rests on accepting that individual self-determi-nation is a desirable goal and that clinicians need to support patients to achieve this goal, wherever feasible. Self-determination in the context of SDM does not mean that individuals are abandoned. SDM recognises the need to support autonomy by building good rela-tionships, respecting both individual competence and interdependence on others.

The key to understanding this concept is to recognise that in every medical or health decision, there are at least two sources of expertise for making a good choice. The clinician has had lengthy and extensive medical training; but only the patient knows his/her attitude to risk, how the illness is experienced in his/her particu-lar social circumstances, and his/her values and prefer-ences. Therefore, “the Patients as Partners concept (…) takes patient engagement even further by considering the patient as a full-fledged member of the healthcare team (…) Chronically ill patients develop experiential knowledge that can enhance their self-managed care and complement the scientific knowledge of health-care professionals. In other words, from a patient’s perspective, quality healthcare decisions are based on two complementary forms of knowledge: the scientific knowledge of health professionals and the patient’s own experiential knowledge” [25].

An example of success in pursuing the integration of

patients’ views is the recent creation of the European Patient Advocacy Groups (ePAGs, www.eurordis.org/content/epags), patient representatives ensuring that patients are fully represented in the governance of each and every European Reference Networks, promoting and encouraging a patient-centric approach in both de-livery of clinical care, service improvement and strate-gic development and decision-making, in line with the above-mentioned Addendum of the EUCERD Recom-mendation’s on ERNs.

In sum, the approach to healthcare where health pro-fessionals make all decisions with little or no input from the patient has evolved over the last decades towards a patient model whereby individual patients’ needs, values, and experiences are crucial for personalised and person-centred healthcare. Patient participation or engagement is recently receiving greater attention, as it be-comes increasingly evident that it can be an innovative and viable approach to ensuring appropriate care in the current environment strained by limited resources.

Support to self-care and self-management. – Self-care is increasingly viewed as a core component of the management of long-term conditions. The majority of care for chronic conditions is provided and coordinated by the people themselves, with the support of family members and carers, at home and in the community [26]. This also applies to people living with a rare dis-ease and their families.

Self-management is defined as the ability of the pa-tient to deal with all that a chronic illness entails, in-cluding symptoms, treatment, physical and social con-sequences, and lifestyle changes. For self-management to be effective, it needs to rely on the proactive engage-ment of physicians, patients, care-givers, and health care organisations. The coordinated approach between all those involved will enhance patient care and more ef-fectively treat patients with multiple chronic conditions. Self-management plays a crucial role for those patients who suffer from multiple chronic conditions or multi-symptomatic diseases, such as the majority of rare diseases. With effective self-management, the patient can monitor his or her condition and make whatever cognitive, behavioural, and emotional changes needed to maintain a satisfactory quality of life [27]. Many prevalent chronic conditions, including rare diseases, although unique in their own attributes and demands, share common challenges associated with their man-agement, that include dealing with symptoms and dis-ability; monitoring physical indicators; managing com-plex medication regimens; maintaining proper levels of nutrition, diet, and exercise; adjusting to the psycho-logical and social demands, including difficult lifestyle adjustments; and engaging in effective interactions with health care providers.

For people living with a rare disease, however, self-management (and the collective support required to achieve it) is far from being the reality. In the survey Juggling rare diseases and daily lives [11], one of the high-est needs expressed is the “request for services that help patients to maintain their autonomy and help self-man-agement of the disease, including rehabilitation services


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and therapies (48%), psychological support (47%), sup-port to adapt house to the needs (30%), medical devices (28%) and adapted transports (23%). Autonomy is par-ticularly at risk in cases in which the person needs help with their most basic and private needs or when the im-pairment affects his/her ability to communicate” [11].

Self-management support allows the development of confidence, self-efficacy and skills to control daily life, provided that is carried out according and in respecting each person’s individual needs and preferences. Self-management support, as a consequence, has a positive impact on the healthcare systems as it helps make best use of all available resources by improving adherence, reducing hospitalisation and emergency visits, and improving health outcomes [10].

Self-management programs such as the Arthritis Self-Management Program (ASMP) and the Diabetes Self-Management Program in the US demonstrated the fea-sibility of self-management intervention programmes, leading to positive health outcomes, many of which per-sist for years, with an added benefit of reduced health care costs [28, 29].

DISCUSSIONHow to empower rare disease patients in sustainable healthcare systems

From what is illustrated above it emerges clearly that achieving patient empowerment is a key enabler in the process of creating sustainable and equitable systems for all, thus addressing the challenges faced by modern healthcare systems (demographic shift, increased burden of chronic diseases, increasing costs of treatments and care, limited access to innovative care, intra-European difference, etc.). The European Patients’ Forum’s latest campaign highlight five elements of patient empower-ment (1. education, 2. expertise, 3. equality, 4. experience and 5. engagement) which demonstrate that patients are active people who can, if supported and according to their individual capabilities and situation, make a differ-ence for the sustainability of healthcare systems (www.eu-patient.eu/campaign/PatientsprescribE/).

This is recognised in the 2014 Communication from the European Commission on effective, accessible and resilient health systems where the impact of patient em-powerment on health systems is explained in terms of:

1) effectiveness: positive clinical outcomes, improved quality of life, better use of health services, which re-spond the needs of patients;

2) access: more transparency and understanding of the healthcare system by the patient can ensue in bet-ter access to healthcare; also, empowered patients can advocate for improved access;

3) resilience: information flow in the system has proved to improve the resilience of health systems [30].

In fact, an important element is that results of patient empowerment beginning at “micro level” then produces “macro effects”.

At the micro (individual) level, the first benefit expe-rienced by the patient is improved health (i.e. quantity and quality of life years gained): by empowering pa-tients it is be possible to achieve results in terms of more appropriate and effective use of healthcare resources,

lower use of drugs, less health inequalities among pop-ulation, less treatment errors and an increased use of preventive services. In addition, as highlighted in the EMPATHiE project, additional outcomes of patient empowerment include greater patient satisfaction, pro-fessional satisfaction, increased quality of life, improved clinical outcomes and better use of health services [31]. Patients who are empowered to make decisions about their health have greater satisfaction because the cho-sen treatment or screening option better reflects their personal preferences, needs and values and the cost-benefit relation that the patient and her/his family see as appropriate. In the long-term this leads to consid-erable advantages in terms of psychological state and quality of life, as well as in savings for health service costs. For the adult population this also translates into workplace productivity gains, experienced by patients, their family and their employers.

At the macro level, the empowerment of patients and their representatives has a positive impact on the qual-ity of health and social services. There is a political ac-knowledgement at EU level that patients should be “at the centre” of healthcare systems and that to achieve this, patients’ representative organisations should be part of healthcare-related policy and decision-making [32]. Collective patient empowerment, through the meaningful involvement of patient representatives and organisations in health policy, service design and evalu-ation with the aim to improve the system, will be the key to fostering patient empowerment in all EU health systems and will lead to public spending on healthcare that is more explicitly linked to population health needs.

At the highest (or policy) level, through their represen-tative organisations, patients can offer guidance to de-cision-makers on quality care that is also cost-effective, and can therefore contribute to the debate for re-shap-ing healthcare systems. Over the years, patient groups have been giving individual patients a stronger voice. They are also involved in disease education for patients and healthcare professionals by providing helplines, emotional support, information, access to treatment and generally fighting for patients’ rights. And they con-duct advocacy discussions about the healthcare system and play a crucial role to show real and concrete need of patients and citizens.

By their individual and collective actions, empowered patients have therefore a crucial role in promoting ac-tions that lead to reduction of inequalities by correcting social injustices affecting the patients themselves and by offering them back to society [19]. Patient empow-erment thus helps reduce the multiple vulnerabilities (physical, moral, social and economic) and proposes a new concept of collective and collaborative production of common goods, which needs collective and collabor-ative action, in order to make the best possible choices for all.

Therefore, patient empowerment addresses the serious unmet social needs of people living with a rare disease and their families which affect their dignity, autonomy and other fundamental human rights expressed in the Universal Declaration of Human Rights and in the UN Convention of the Rights of Persons with Disabilities.


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In this sense, “sustainable” is what ensures equity of access so as to fulfil the human rights of people whose needs are often seriously unmet, in order to make them empowered citizens. Only with dignified and fulfilled citizens a society can be said sustainable.

CONCLUSIONS Achieving patient empowerment is a key enabler in

the process of creating sustainable and equitable sys-tems for all. To help this process, a number of recom-mendations were made a few years ago through the EUROPLAN project (www.europlanproject.eu). Pa-tient empowerment was a specific area addressed in the Recommendations for National Plans and Strategies for Rare Diseases Conferences developed by EURO-PLAN [33] and in the 15 EUROPLAN National Con-ferences [34].

Based on the above and on other activities highlight-ed in this policy brief, including those carried out by EURORDIS and other patient groups, it appears that a number of potential initiatives strengthen patient em-powerment in the rare disease community and deserve being supported, notably:• Ensure an active role and effective engagement of

patients at all key decision-making points at the na-tional/regional/local level (“nothing about me without me”). Specifically, but not exhaustively: - Involve patients in Steering Committees or equiva-

lent bodies overseeing the implementation and/or the monitoring /evaluation of National Plans or Strategies for rare diseases;

- Include patients in the evaluation of the opportu-nity/costs of policy planning on RDs – basically any time “benefit” is to be assessed;

- Recognise the role of patients/patient representa-tives in hospitals, centres of expertise and other lo-cal decision-making bodies relevant for specific dis-eases or groups of diseases.

• Integrate patients in clinical trial design focusing on meaningful endpoints and patient outcomes.

• Promote patients’ training, educational and capacity building initiatives, so to allow patients to become fully-fledged partners in decision-making. On clini-cal trial design for example, training is extremely im-portant to allow patients to understand the scientific landscape and to discuss with researchers, medical staff and industry on equal foot.

• Support patient empowerment initiatives through public money in order to guarantee an effective con-tribution of patients as equal partners.

• Improve awareness-raising on the role of patients in the decision making process to improve public per-ception.

• Guarantee that the progress made in empowering patients and in rare disease policy in general be main-tained in spite of changes in government and volatile political backgrounds.

• Ensure that medical and paramedical staff receive adequate professional training to help them identify and treat rare diseases, but also to help them interact with patients in a context of shared decision-making.

• Promote the creation of telephone help lines that play

an essential role for the provision of general and spe-cific information on rare diseases, with the promo-tion of best practice exchanges and quality assurance initiatives.

• Develop or reinforce the role of “Case managers” who could address the specific range of needs of the rare disease patient and help them navigate the com-plex environment.

• Promote self-management initiatives adapted to peo-ple living with rare diseases, tailored to each disease or disease group, ideally designed in the context of European Reference Networks, to accompany dis-ease-specific ‘strategies of care’ or clinical guidelines.

• Adapt social services so that they cater to the needs of patients with RDs and promote the inclusion of rare disease specificities in national social policies – allow integration of people living with rare diseases in school, workplace and social life in general.There are currently a number of such initiatives that

qualify as promoting patient empowerment and thus promoting more sustainable healthcare systems, how-ever these are scattered and unevenly applied across the EU countries and regions.

It may therefore be argued that the ultimate recom-mendation could be to develop a roadmap or strategy at EU level on patient empowerment that includes the above specific recommendations and takes stock of ex-periences and best practices existing across the EU or beyond, encouraging their uptake in a comprehensive and systematic framework. Such a strategy would be applied to the appropriate level(s) of governance (Eu-ropean, national or local) to ensure that patient empow-erment becomes a reality and contributes to improved healthcare across Europe’s national systems.

In conclusion, such a strategy would be one where-by the attainment of the highest possible standards of health depends on a comprehensive, holistic approach which goes beyond the traditional curative care, involv-ing patients, communities, health providers and other stakeholders. This holistic approach should empower individuals and communities to take actions for their own health, foster equality in partnership for public health, promote intersectoral action to build healthy public policies and create sustainable health systems in the society, where all actors are fulfilled human beings and unmet needs are addressed in compliance with fun-damental human rights.

FundingThis research was supported by the Health Pro-

gramme of European Union, in the framework of the Joint Action for Rare Diseases, Project n. 677024 “Pro-moting Implementation of Recommendations on Policy, In-formation and Data for Rare Diseases — RD-ACTION”.





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11. EURORDIS Rare Barometer. Juggling care and daily life: the balancing act of the rare disease community. A Rare Barometer survey. 2017. Available from: http://downlo-ad2.eurordis.org.s3.amazonaws.com/rbv/2017_05_09_Social%20survey%20leaflet%20final.pdf.

12. Aymé S, Kole A, Grofth S. Empowerment of patients: lessons from the rare diseases community. The Lan-cet. 2008;371(9629):2048-51. doi: 10.1016/S0140-6736(08)60875-2

13. World Health Organization. Declaration of Alma Ata: International Conference on Primary Health Care, Alma Ata, USSR. 1978. Available from: www.who.int/publica-tions/almaata_declaration_en.pdf.

14. Council of the European Union. Council Conclusions on Common values and principles in European Union Health Systems. Official Journal of the European Union. 2006/C 146/01. Available from: http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2006:146:0001:0003:EN:PDF.

15. Rissel C. Empowerment: the holy grail of health promo-tion? Health Promotion International, Oxford University Press. 1994;9(1):39-48.

16. European Commission. Eurobarometer qualitative study. Patient involvement. Aggregate report; 2012. Available from: https://ec.europa.eu/health/sites/health/files/sy-stems_performance_assessment/docs/eurobaro_patient_involvement_2012_en.pdf.

17. Department of Health and Social Care. Equity and excellence: liberating the NHS. Policy Paper. 2010.

Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/213823/dh_117794.pdf.

18. European Commission. Rare Disease European Refe-rence Networks. Addendum to EUCERD Recommen-dations of January 2013. 2015. Available from: https://ec.europa.eu/health//sites/health/files/rare_diseases/docs/20150610_erns_eucerdaddendum_en.pdf.

19. Le Cam Y. L’empowerment des patients est-il un facteur de justice sociale? Présentation at Conférence Internatio-nale d’Ethique Clinique. Paris; 2014.

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21. World Health Organisation – Regional Office for Euro-pe. Health literacy. The solid facts. 2013. Available from: www.euro.who.int/__data/assets/pdf_file/0008/190655/e96854.pdf.

22. Bonsignore C, Brolis E, Ionescu A, Karusinova V, Mitko-va Z, Raps F, Renman V, Ricci Fedotova N (European Health Parliament). Patient empowerment and cen-tredness. 2017. Available from: www.healthparliament.eu/wp-content/uploads/2017/09/EHP-papers_Patients-empowerment.pdf.

23. World Health Organisation. Track 2: Health literacy and health behaviour. 2017. Available from: www.who.int/he-althpromotion/conferences/7gchp/track2/en/.

24. Elwyn G, Coulter A, Laitner S, Walker E, Watson P, Thomson R. Implementing shared decision making in the NHS. BMJ. 2010;341:c5146. doi: 10.1136/bmj.c5146

25. Pomey MP, Ghadiri DP, Karazivan P, Fernandez N, Clavel N. Patients as partners: a qualitative stu-dy of patients’ engagement in their healthcare. PloS ONE. 2015;10(4):e0122499. doi: 10.1371/journal.pone.0122499

26. Chronic Conditions Working Group. Living well with a chronic condition. Framework for self-management sup-port national framework and implementation plan for self-management support for chronic conditions: COPD, asthma, diabetes and cardiovascular disease. Ireland: He-alth Service Executive; 2017. Available from: www.lenus.ie/handle/10147/622639.

27. Barlow J, Wright C, Sheasby J, Turner A, Hainsworth J. Self-management approaches for people with chronic con-ditions: a review. Patient Educ Couns. 2002;48(2):177-87.

28. Lorig KR, Ritter P, Stewart AL, Sobel DS, Brown BW Je, Bandura A, Gonzalez VM, Laurent DD, Holman HR. Chronic disease self-management program: 2-year health status and health care utilization outcomes. Med Care. 2001;39(11):1217-23.

29. Lorig KR, Sobel DS, Ritter PL, Laurent D, Hobbs M. Effect of a self-management program on patients with chronic disease. Eff Clin Pract. 2001;4(6):256-62.

30. European Commission. Communication from the Com-mission on effective, accessible and resilient health sy-stems. COM(2014) 215 final. Available from: https://ec.europa.eu/health//sites/health/files/systems_perfor-mance_assessment/docs/com2014_215_final_en.pdf.

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692030a0a0d51b8e2/empathie_frep_en.pdf.32. European Patient Forum – EPF. EPF campaign on patient

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national plans for Rare Diseases. 2010. Available from: www.europlanproject.eu/Resources/docs/2008-2011_2.EUROPLANRecommendations.pdf.

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Resilience in rare disease networksEdmund Jessop

National Health Service – NHS England, London, United Kingdom


INTRODUCTIONA system or network may respond to change in three

ways – absorb, adapt or transform. For example, if a team member is off sick, the extra

workload may be absorbed by colleagues who see more patients or work longer hours. In a network, the net-work as a whole may absorb change in the same way: if a key member of staff at one centre is absent, the work (for example, laboratory specimens) could be sent other centres in the network.

If the change cannot be absorbed, it may be possible to adapt to the change. For example a rare disease cen-tre which faces a shortage of medical staff may adapt by changing its skill mix to increase the use of specialist nurses with extra qualifications.

The third possibility is to transform the organisation, system or network. Large scale transformation rarely happens because it is so difficult to do well. But for ex-ample a network based on seeing patients face to face may transform to a model of telemedicine; or a treat-ment network may transform to a teaching network to expand its depth and coverage. More fundamentally a medical network centred on hospitals may trans-form to a patient-based network while maintaining its goal of improving quality of life for people with rare disease.

The development of European Reference Networks has raised the question of the long-term sustainability in networks. One aspect of this problem is resilience, traditionally understood as the ability of a system to function during, and return to normal after, an external shock. This paper aimed to explore current thinking on network resilience in healthcare.

METHODThe bibliographic databases Medline and Embase

were searched on 13 December 2017 using the terms “resilience” or “resilient” or “resiliency” and “network” or “system” and “health” or “healthcare”. Abstracts were scrutinised for relevance and full-text papers retrieved. A narrative review was conducted.

RESULTSAfter de-duplication, 347 citations were retrieved. A

great majority of these papers focussed on psychologi-cal resilience in individuals not resilience in networks. After scrutiny of abstracts, 12 papers were retrieved for full text reading and narrative review.

DISCUSSIONResilience and surge capacity

The original concept of resilience was developed as the response to massive external change. Classic ex-amples include physical disruption (earthquake, flood, or terrorist action) or events such as SARS or Ebola. Massive economic shocks may have the same effect on health systems.

Therrien et al. [1] discuss the relationship between surge capacity and resilience. They describe four as-pects of surge capacity, known as the 4 ‘S’:• staff;• stuff (e.g. supplies and equipment);• structures (e.g. hospitals);• systems (e.g. processes for decision making).

A resilient system will have accessibility, diversity and redundancy in the first three categories, but also “ap-propriate models of decision making, communication and sense making, supported by organizational values such as self criticism, respect among employees, inno-vation, a sense of responsibility, and the application of rules and best practices”.

Therrien et al. [1] use their analysis of the H1N1 epi-demic in Canada to suggest three dimensions for plan-ners to consider. These three dimensions are related to the types of complexity (detailed and dynamic complex-ity), the temporal aspects of resilience (passive and proac-tive resilience) and the nature of order (favorable order and favorable disorder).

This framework specifically relates to resilience in crisis situations where surge capacity is required. The under-lying goal is returning the system to its state before the external shock. The next section considers the recently developed concept of “everyday resilience”.

Address for correspondence: Edmund Jessop, NHS England, Skipton House, 80 London Road, London SE1 6LH, United Kingdom. E-mail: [email protected].

Key words• resilience• networks• rare disease

AbstractA resilient system is one which continues to perform its function or goal during a period of change. The original concept was formed around return to the status quo after major external shocks. Recently the concept of “everyday resilience” has been proposed. Every-day resilience is the adaptive and learning response of systems to the daily disturbance of normal routines. For everyday resilience, human factors are as important as physical resources. Rare disease networks can use several strategies to build resilience.

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Everyday resilienceResilience has traditionally been conceived as the re-

sponse to the massive disruption of major events such as H1N1 or major economic crisis. Recent work has developed the concept of “everyday resilience”. Barasa et al. [2] provide a theoretical framework and Gilson et al. [3] give case studies from Kenya and South Africa.

Barasa et al. [2] challenge the simple concept that resilient systems return to their original state after an external shock. This implies that systems are linear and static. But in fact health systems are constantly chang-ing, in a myriad of small ways. They are adaptive com-plex systems. These systems consist, in Barasa’s typol-ogy, of both “hardware” (infrastructure, commodities, human resources, finance) and “software”. The software is both tangible (management knowledge and skills, and organizational systems and procedures) and intan-gible (software of values and norms, relationships and power). Barasa et. al feel that it is the software which promotes resilience. Thus “resilience becomes an active process within a dynamic health system that is con-stantly navigating challenges by becoming better”.

The case studies of Gilson et al. [3] illustrate these concepts. They studied a district in Kenya and two health districts in South Africa. Three common sets of issues were identified:• unstable and evolving governance structures;• resource challenges and frequent policy change;• instability at the service delivery front line.

Gilson et al comment that “challenging conditions that are the norm for those working in district health systems in low-income and middle-income countries. Health managers at these levels routinely face instabil-ity, such as changes in governance structures and fi-nancing mechanisms, payment and other resource pro-vision delays, and frequent, abruptly imposed policy directives. They commonly work with unstable authori-ty delegations, manage unpredictable staff and address changing patient and community expectations. These conditions are not the acute, external shocks more usu-ally discussed in relation to health system resilience” [3].

This case study focused on the role of managers in a hierarchical system, with sub-district, district and na-tional levels. Rare disease networks such as the Euro-pean Reference Networks have different governance structures and no clear managerial hierarchy. Neverthe-less, many health systems could agree that “challenging conditions are the norm”.

Network resilienceThere are very few published studies which examine

resilience of networks (as opposed to individual hospi-tals).

Sheaff et al. [4] provide case studies of four networks in the English National Health Service at a time or organisational change. They define network “macro-culture” as the complex of artefacts, espoused values and unarticulated assumptions through which network members coordinate network activities. These compo-nents of artefact, value and assumption are further ex-plained as follows:

1. Artefacts are of two kindsa) the network’s collective products or services – its

“core artefacts” – and the technologies and inputs used to produce them;

b) symbolic artefacts which physically represent (e.g., as logos, publications) the values described below.

2. Values, which are also of two kindsa) espoused, negotiable values concerning: what is-

sues, problems and tasks face the network; network members’ roles; rules of conduct; conventions (accept-ed approaches and solutions to problems); and special-ised language;

b) taken-for-granted, non-negotiable values: basic underlying assumptions, often so internalised as hardly to be consciously formulated, for instance defining the “moral economy” governing members’ behaviour.

Examples of artefacts from a network for coronary heart disease included:• a new sub-regional primary angioplasty service;• ensuring more equitable care for patients at the inter-

face between secondary and tertiary care;• adaptation of national standards, e.g. [national]

guidelines, to the local situation;• increasing uptake of cardiac rehabilitation.

Sheaff et al. found that artefacts adapt to change faster than values, and values adapt faster than assump-tions [4].

For a Europe-wide rare disease network, it seems likely that core artefacts will be products such as guide-lines or consensus conferences. The espoused values are likely to be set out in the constitution or governance documents of the network; and we may speculate that the basic underlying assumptions about behaviour and so on may come from a common socialization into the profession of medicine and its allied disciplines. But cultural differences between countries – for example as-sumptions about how politeness is enacted or gratitude is expressed – may affect the function of multinational networks.

Mathematical modelsMathematical models of networks, though often hard

to understand for non-specialists, may suggest features of networks worth exploring in the real world.

Gao et al. [5] built a mathematical model of “complex” networks, characterised as “systems are composed of nu-merous components linked via a complex set of weight-ed, often directed, interactions”. This model predicted that density, heterogeneity and symmetry are the three key structural factors affecting a system’s resilience.

It is not clear how well this model describes current rare disease networks. We do not yet have descriptions of properties such as density, heterogeneity and symme-try. The requirement for European Reference Networks to have members in at least eight member states guaran-tees some level of heterogeneity because of the different health systems in which the centres are located. Sym-metry implies that the networks should take care not to be dominated by one or two large centres. Density may come from an active network with plenty of interactions between all members of the network (as opposed to pairs or cliques which ignore the full membership).

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Human factorsMartineau [6] describes “people centred health sys-

tems” in a commentary on the Ebola crisis in West Af-rica. He calls for a focus on the people, relationships and local contexts that constitute health systems and the practices that produce crisis responses. He com-ments [6] as follows:

“Recognising that flexibility, for example, is impor-tant in how a health system responds to a major crisis must be complemented by understanding how people within a particular health system might actually become more flexible in their roles or actions, or its knock-on ef-fects on other important health system properties. The capacities of health workers to reprioritise their clinical activities, of people who are unwell to alter their care-seeking practices, or of previously non-health actors to take on new health roles vary hugely between and with-in health systems, and depend in particular on power and trust relationships between each actor”.

This focus on people, on social dynamics and on the building of relationships reminds us that rare disease networks are not an abstract entity. They are a gather-ing of people – a community. Attention must be paid to the building of that community through normal social interaction. Martineau states that “system strengthen-ing initiatives must embed explicit localized efforts to build mutual trust, respect and dignity between health actors and the communities they serve alongside initia-tives to improve the clinical quality of care”. Seen in this light, opportunities to meet face to face are important. Also events such as conference dinners are not optional extras but part of the process.

Olafsdottir et al. [7] provide an example of the need to involve communities. The 2008 economic crisis in Iceland developed over a matter of days, requiring se-vere cutbacks in public sector spend in all areas. In the health sector, the immediate response included closing down units (resulting in staff redundancies), changing 7-day wards to 5-day wards, and reducing overtime payments. For the first time in the history of Iceland, out-of-pocket payments for hospitalisation were intro-duced, which allowed for charges every time people had to be hospitalised, except in case of births.

Three months after the crisis the Minister, who had relied heavily on external consultants, announced fur-ther proposals [7]:

“[One proposal] was to convert one of the hospitals in the capital area into a geriatric institution. Services usually offered in this hospital were to be redistributed to other hospitals. Some of the specialised services were to be moved to the main hospital in the capital, others to be tendered out to the private sector. The operating theatres, however, were to be merged with the operat-ing theatre in a hospital outside the capital area (Su-durnes), where they were to be run as a new private entity led by health professionals”.

These proposals were however not adopted because of a change of government in February 2009 and the resultant change in political philosophy.

Olafsdottir et al. consider that the response to the economic crisis was weak because of poor transparency (documents and analyses supporting decisions were not

made public) and poor opportunities for participation by all stakeholders (over-reliance on external consul-tants) [7].

Evaluating and building resilience – Resilience IndexKruk et al. have proposed a Resilience Index [8]. Al-

though designed for national health systems, it is easily adaptable to networks. Five “characteristics” are pro-posed: aware, diverse, self regulating, integrated, adap-tive. Aims and measures are set out for each character-istic, with a total of 25 measures for systems to consider. For example a self regulating system will aim to isolate threat and maintain core functions, and to leverage outside capacity. The measures for this are memoran-dums of understanding with non-state providers and a database of service delivery alternatives for affected and non-affected populations; and collaboration agree-ments with regional and global actors.

In the field of rare disease, for example, production problems have created drug shortages which required engagement with regional and global actors such as Eu-ropean patient organisations and global pharma com-panies. More locally problems in the home care sup-plier markets have led to a requirement for databases of service delivery alternatives.

Thomas et al. [9] offer a simpler framework with a stronger emphasis on financial and economic aspects: this framework was from a case study of health systems in Ireland following the 2008 economic crisis. They pro-pose three categories, and some measures for each, as follows: • financial resilience (e.g. Protection of health funding

compared to economic decline);• adaptive resilience (e.g. Reduction in staffing with

no commensurate reduction in service, Protection of services – no loss of entitlements or rationing by volume);

• transformatory resilience (e.g. Clear specification of reforms, Evidence base for reforms).

CONCLUSIONSRare disease networks should build everyday resil-

ience by consciously developing their day-to-day inter-actions. They should also examine their macroculture of artefacts, espoused values and unarticulated assump-tions through which network members coordinate net-work activities. Mathematical models suggest the im-portance of density, symmetry and heterogeneity but it is important to remember the people-centred aspects of networks.

Networks can assess their resilience by using a Resil-ience Index.

AcknowledgementsI am grateful to Maurella Della Seta and her team for

literature search and library help.


of European Union, in the framework of the Joint Ac-tion for Rare Diseases, Project n. 677024 “Promoting

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Implementation of Recommendations on Policy, Infor-mation and Data for Rare Diseases – RD-ACTION”.

Conflict of interest statementThe author declared no potential conflicts of interest



REFERENCES

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2. Barasa EW, Cloete K, Gilson L. From bouncing back, to nurturing emergence: reframing the concept of resi-lience in health systems strengthening. Health Pol Plann. 2017;32:91-4. doi: 10.1093/heapol/czx118

3. Gilson L, Barasa E, Nxumalo N, et al. Everyday resilien-ce in district health systems: emerging insights from the front lines in Kenya and South Africa. BMJ Glob Health. 2017;2:e000224. doi:10.1136/bmjgh-2016-000224

4. Sheaff R, Benson L. Farber L, Schofield J, Mannion R, Reeves D. Network resilience in the face of health system reform. Soc Sci Med. 2010;70:779-86.

5. Gao J, Barzel B, Barabasi AL. Universal resilience pat-

terns in complex networks. Nature. 2016;530:307-12. doi: 10.1038/nature16948

6. Martineau FP. People-centred health systems: building more resilient health systems in the wake of the Ebola crisis. Int Health. 2016;8:307-9. doi: 10.1093/inthealth/ihw029

7. Olafsdottir AE, Allotey P, Reidpath DD. A health system in economic crises: a case study from Iceland. Scand Pub Health. 2013;41:198-205.

8. Kruk MEK et al. Building resilient health systems: a pro-posal for a resilience index. Br Med J. 2017;357:j2323. doi: 10.1136/bmj.j2323

9. Thomas S et al. A framework for assessing health system resilience in an economic crisis: Ireland as a test case. BMC Health Serv Res. 2013;13:450. Available from: www.biomedcentral.com/1472-6963/13/450

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Policies and actions to tackle rare diseases at European levelAntoni Montserrat1 and Domenica Taruscio2

1Comité National Maladies Rares, Luxembourg 2Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Rome, Italy


INTRODUCTION Rare diseases (RDs), including those of genetic origin,

are defined by the European Union as life-threatening or chronically debilitating conditions whose prevalence is so low (less than 5 per 10 000) that special, combined efforts are needed to address them in order to prevent significant morbidity or perinatal or early mortality or a considerable reduction in an individual’s quality of life or socio-economic potential. This definition first ap-peared in EU legislation in Regulation (EC) 141/2000 of 16 December 1999, on orphan medicinal products and was extended to the public health field by Commis-sion Communication on RDs: Europe’s challenges of 11 November 2008, and by Council Recommendation on an action in the field of RDs, of 9 June 2009. Around 6000 diseases are described in the Orphanet database (https://www.orpha.net), affecting between 6% and 8% of the European people. In other words, between 27 and 36 million persons in the European Union are af-fected, or will be affected in a moment of their life, by a rare disease. There is probably no other area of health care where collaboration between 28 different national approaches can be so efficient and effective.

POLICIES AND ACTIONSThe Directive 2011/24/EU on the application of

patients’ rights in cross-border healthcare clarifies pa-tients’ rights to access safe and good quality treatment

across EU. This Directive was the consequence of sev-eral decisions of the European Court of Justice related to the free circulation of patients as part of the EU fun-damental right of the free circulation of persons. The European Reference Networks (ERNs) are being set up under this 2011 Directive and the European Com-mission adopted, through legal means the criteria and conditions which the European Reference Networks (ERNs) and the healthcare providers must fulfil. A new era for cooperation in the field of health was unveiled on 9 March 2017 as the first 24 ERNs were launched. Each of the 24 ERNs addresses groups of rare dis-eases including bone disorders, endocrine conditions, hereditary metabolic disorders, connective tissue and musculoskeletal diseases, immunodeficiency, autoin-flammatory and autoimmune diseases; oncological and non-oncological haematological diseases. These net-works, each having a co-ordinator, involve more than 900 highly-specialised healthcare units from over 300 hospitals in 26 Member States.

The overarching objective of ERNs is that patients have an improved access to quality diagnosis, care and treatment. This should be achieved by facilitating the mobility of the knowledge; only if absolutely necessary the mobility of patients should be envisaged (https://ec.europa.eu/health/ern_en). Each ERN operates by sharing and generating data and knowledge, clinical guidelines and performing training and e-learning. The

Address for correspondence: Domenica Taruscio, Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: [email protected].

Key words• rare diseases• policies• public health• registries• research

Abstract Rare diseases (RDs) are defined by the European Union as life-threatening or chronical-ly debilitating conditions, with a prevalence lower than 5 per 10 000 inhabitants. Around 6000 diseases are described, affecting between 6% and 8% of the European population. Due to their severity, diffusion and multi-faceted aspects, RD are an area where collabo-ration in public health, health care and research provides a major integrated added value. Main areas for policy actions include: the development and implementation of European Reference Networks, as a main strategy for sharing of knowledge, clinical expertise and foster research; integration of high-quality patient registries, biobanks, and bioinformat-ics support, as key infrastructure tools addressing research and healthcare needs; the implementation of National Plans on RD in EU Member States by sharing experiences, capacity building and linking national efforts through a common strategy at a Euro-pean level; actions driven by the recommendations for primary prevention of congenital anomalies (the main RD group with multifactorial aetiology); policy provisions to foster research and development of orphan drugs.

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ERN initiative is mainly driven by EU countries. The Board of Member States is the formal body in charge of the approval and termination of networks and member-ships as provided in the Commission’s Implementing Decision [1]. The Board is comprised of representatives of the 28 EU countries and the EEA countries.

In this context, the 4th Conference on European Reference Networks, “ERNs in action” [2] organized by the European Commission took place on 21 and 22 November 2018 in Brussels with the involvement of the main ERNs stakeholders, including ERNs represen-tatives, policy makers, national authorities, scientific communities and patients associations. ERNs are an excellent example of pan-European collaboration, unit-ing many different stakeholder groups (e.g. patients, Health Care Providers, scientists, policy makers). The ERNs have access to a dedicated Clinical Patient Man-agement System (CPMS) [3] to provide virtual, cross-expert and cross-border consultations for real patients whose cases warrant the pooling of knowledge across the ERN community. The ERNs main challenges for the future are linked to the long-term sustainability and their integration in healthcare systems of the Countries.

The European Commission provides non-competi-tive funding opportunities and the 2018 Public Health Programme dedicates € 13.8 million to “Multiannual specific grant agreements for European Reference Networks” for the subsequent 3 years. The Networks expect also to receive the outcomes of applications to a Call launched via the Connecting Europe Facility (CEF), to support the ERNs in engaging with and us-ing the CPMS.

Cooperation at EU level makes a real difference to rare diseases patients and their families, as well as the health professionals helping them. No country alone has the knowledge and capacity to treat all types of rare, complex and low-prevalence conditions and diseases, but by cooperating and exchanging life-saving knowl-edge at European level through ERNs, patients across the EU will have access to the best expertise available.

One of the main obstacles to clinical research and treatment advancements in RDs is the difficulty in con-ducting clinical trials. Clinical trials in RDs have to deal with the geographic spread of patients but also with the high heterogeneity within the same disease. The ap-proval process of orphan drugs by regulatory agencies may also have to deal with limitations inherent to the small populations.

RD patient registries are powerful instruments that help and facilitate clinical research, planning of clinical trials, patient care as well as healthcare management. A pivotal aspect is the connection of registries with bio-banks and clinical bioinformatics for RD research, as developed by the European project RD-Connect [4]. In particular, registries constitute a key support to ERN activities. A rapid proliferation of RD registries has oc-curred during the last years, either disease-specific or targeting RD groups at national [5], European [6] or international level. The analysis performed within the EPIRARE project (www.epirare.eu) identified three main typologies of registries, on the basis of their main purpose: public health, clinical and genetic research,

and treatment registries [7]. Registries should maintain high-quality standards. Recommendations for quality implementation deal with such aspects as governance, Findable, Accessible, Interoperable and Reusable (FAIR) data, documentation, training, and auditing [8].

On these bases, the European Commission has pro-posed a common platform of RDs registries that will allow improving and increasing integrated uses. The European Commission Joint Research Centre (JRC) develops and maintains this European Platform on Rare Diseases Registration. Currently, the migration of two surveillance networks, the European Surveillance of Congenital Anomalies (EUROCAT) (www.eurocat-network.eu) and the Surveillance of Cerebral Palsy in Europe (SCPE) (www.scpenetwork.eu), has been fully achieved.

One main function of the EU RD Platform is to en-able interoperability for the 747 existing RD registries in Europe according to the Orphanet inventory [9]. The second function is to offer a sustainable solution for two large European surveillance networks: Europe-an Surveillance of Congenital Anomalies (EUROCAT) and Surveillance of Cerebral Palsy in Europe (SCPE). EUROCAT is European network of population-based registries for the epidemiological surveillance of con-genital anomalies. It covers about one third of the Euro-pean birth population. The Central Database contains about 800 000 cases with congenital anomalies among livebirths, stillbirths and terminations of pregnancy, re-ported using the same standardised classification and coding. These high quality data enables epidemiologi-cal surveillance of congenital anomalies, which includes estimating prevalence, prenatal diagnosis and perinatal mortality rates and the detection of teratogenic expo-sures among others.

Due to the rarity of the diseases, none of the 28 EU Member States have enough data to conduct epidemio-logical, clinical or pharmacological studies to advance knowledge in this field. The information that is avail-able is fragmented in these hundreds of registries across Europe, and until now there have been no uniform, ac-cepted standards to govern the collection and organ-isation of these data. Capitalizing on the earlier set of indicators and common data elements proosed by the project EPIRARE [10], the “Set of Common Data Ele-ments for Rare Diseases Registration” [11] is the first practical instrument released by the EU RD Platform aiming for an increased interoperability of the data reg-istries. It defines the minimum data elements to be reg-istered by all rare diseases registries across Europe, and provides instructions on how and in which format each data element should be registered.

The document describes the 16 data elements con-sidered to be essential to enable further research. They refer to patient’s personal data, diagnosis, disease his-tory and care pathway, as well as information to be pro-vided for research purposes. All existing and new data registries across Europe are recommended to use this standard as the basis for their data collection activities. The standard was produced by a Working Group coor-dinated by the JRC and composed of experts from EU projects working on common data sets: EUCERD Joint

Antoni Montserrat and Domenica Taruscio

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Action, EPIRARE and RD-Connect.European Commission JRC is planning to use the

European Rare Disease Registry Infrastructure (ER-DRI) in order to fine tune the tools even further to per-fectly fit all stakeholder’s needs. ERDRI is part of the European Platform on Rare Diseases Registration (EU RD Platform). By promoting interoperability between data sources, the EU RD Platform supports knowledge generation on rare diseases and helps reaching the nec-essary critical numbers to conduct epidemiological, clinical, translational, pharmacological and other stud-ies and research for advancing diagnosis and treatment for RD patients. The semantic interoperability is based on the collection of metadata on all data elements col-lected by participating registries. Additionally, Europe-an Directory of RD registries will be created containing the list of participating RD registries, descriptive infor-mation, specific rare disease addressed, scope, operat-ing institution, etc.

A list of the data elements collected by the registries according to these MDR (Central Metadata Reposi-tory) will be the core components of the European RD Registry Data Warehouse constituted by aggregated data and a Reporting data set (RDS) with a Subset of Common Data Set without patient identification. That will create added value for all stakeholders and a se-lected European RD data publicly access. The general benefits of EDRI ant the created interoperability could be the maximisation of the utility of participating regis-tries, enabling use of data across the registries, to pro-vide accelerated communication, enabling automated data (searching/finding), enabling studies and research, extended use and re-use of existing data for various pur-poses.

A very useful and promising tool to reinforce and com-plement the European Platform on Rare Diseases Reg-istration is the European Union Project RD-Connect (https://rd-connect.eu/). Patient registries, biobanks, and bioinformatics support are key infrastructure tools required for genomic research in rare disease; data shar-ing and linking of patients, samples, and analysis is also essential. The infrastructure developed by RD-Connect supports research in rare disease to find new genes, bio-markers, and therapeutic targets more quickly and ef-ficiently. Its ultimate goal will be to improve outcomes for rare disease patients via major improvements in diagnostics and therapeutics. The therapeutics market in rare disease has strong growth potential due to the high (and unmet) medical needs for most rare diseases. Genomic research and development will thus be highly relevant for many markets, including genetic testing, biomarkers, and therapeutics [12].

The Council Recommendation of June 2009 recom-mended that Member States adopt, by the end of 2013, a national plan or strategy for rare diseases [13]. 25 countries have adopted a national plan or strategy for rare diseases (NP/NS) compared to only 4 in 2008, and the focus has moved more from “adopting” to actually implementing and evaluating the success of these first (and sometimes second) national plans or strategies. In the critical preparatory phase, the EUROPLAN project [14] has been pivotal in order to share relevant experi-

ences within countries, promote capacity building and link national efforts through a common strategy at a European level. Therefore, EUROPLAN facilitated the implementation of National Plans in almost all EU and several non-EU Countries [15].

At Member State level, there is a great heterogeneity in the state of advancement of national policies, plans or strategies for rare diseases. Significant progress has been made towards this goal: 13 countries have time bound NP/NS which were still apparently active in July 2018: Austria, Croatia, Czech Republic, Estonia, France, Hungary, Ireland, Luxembourg, Netherlands, Portugal, Romania, Slovak Republic and Slovenia. 6 countries adopted time-bound NP/NS which had ex-pired by July of 2018 and appear to have been replaced/renewed: Bulgaria, Finland, Greece, Italy, Latvia and Lithuania. The following countries adopted NP/NS which appear to be “ongoing” (i.e. according to the data received, do not cover specific time periods): Belgium, Cyprus, Denmark, Germany, Spain, United Kingdom. Three EU MS appear not to have adopted a NP/NS: Poland, Malta and Sweden. Switzerland and Norway also now have a RD plan or strategy [16].

It is interesting to mention that in other zones of the World a lot of countries have adopted NP/NS following the European model. This is the case in: Brazil, Colom-bia, Peru, Argentina, Japan, Singapore, Taiwan, South Korea, India (on discussion), Russia, Ukraine, Kazakh-stan and others.

Another very relevant EU action, impossible to im-plement from a single Member State, is the revision of the International Classification of Diseases (ICD). The EU is cooperating closely with the World Health Orga-nization (WHO) in revising the existing International Classification of Diseases (ICD) to ensure better codi-fication and classification of RDs in the ICD 11th ver-sion [17], which should be adequately coded and trace-able in all health information systems contributing to their adequate recognition in national health care and reimbursement systems.

Until recently there was no systematic effort to es-tablish an inventory of rare disorders, except in the field of genetic defects where the Online Mendelian Inheri-tance in Man (OMIM) (www.omim.org) had started to document knowledge on genetic phenotypes as a proxy for genes, then on human genes when identified, as ear-ly as 1966 [18]. The compilation of an inventory of rare diseases, beyond genetic diseases, started in a system-atic way in 1996, in the context of the rare disease data-base and knowledge base, Orphanet, established jointly by the French National Institute of Health and Medi-cal Research (INSERM) and the French Ministry of Health [19] before being supported by the EUCERD Joint Action between the Member States of the Euro-pean Union [20]. As a pilot initiative Orphanet not only collected information on rare diseases published in the scientific literature, but also classified them, from 2007 onwards, with a poly-hierarchy approach, each clini-cal entity being assigned an Orpha number. This effort was supported by the European Commission which not only co-financed Orphanet from 2001 onwards still to-day, but also established, in January 2004, a Rare Dis-


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eases Task Force with the mandate to contribute im-prove the codification of rare diseases, amongst other public health objectives [21].

In November 2014 a Recommendation on Ways to Improve Codification for Rare Disease in Health In-formation Systems [22] was adopted by the EU Com-mission Expert Group on Rare Diseases. The document includes a recommendation to further promote Orpha codes within the development of ICD11 in order to al-low a seamless transition of rare disease classification from Orpha codes to ICD11 when the latter is released. The Expert Group recommends that Member States implement the Orpha codes system and that codifica-tion of rare diseases be addressed within Member State rare disease national plans.

An assessment of the number of rare clinical entities having a specific code in ICD 10 can be derived from the effort carried out by Orphanet to cross-reference Orpha codes with ICD 10 codes, starting from the Or-phanet list of rare clinical entities defined as a clinically unique, distinct entity, whatever the number and nature of the causes, and following the European definition for rarity, i.e. a prevalence equal of no more than 1 in 2000 in the general population of Europe (Figure 1). The cross-referencing is based on the 2010 online ver-sion of the ICD-10, but takes into account the official WHO updates endorsed in 2011 and 2012. In Janu-ary 2015, among the over 6954 clinical entities listed by Orphanet, 355 of them only have a unique specific code in ICD 10. Each entry in the health information systems (group, disorder, subtype) is given a unique and stable ORPHA number (the Orpha codes). Each en-try is given a preferred term and as many synonyms as necessary. In fact the situation is complex as one ICD code sometimes corresponds to one Orpha code, but also one ICD code can correspond to a group of rare entities or to a group of both rare and non-rare entities.

To increase rare disease representation in ICD-11, the objective is to expand the number of specific codes.

The Systematized Nomenclature of Medicine Clini-cal Terms (SNOMED CT) (www.snomed.org) is run by the International Health Terminology Standards Devel-opment Organisation and is available in over 50 coun-tries. It has been adopted as the standard terminology for the National Health Service in the UK and includes not only disease classification but also other medical terminology areas. Nearly 3000 rare diseases have a specific SNOMED CT code. The lack of data about rare diseases, due to the absence of codes for most rare diseases, deserves a special effort in epidemiology to make rare diseases more visible in the healthcare sys-tems, in parallel with the ongoing process to incorpo-rate codes for rare diseases in ICD and SNOMED-CT, as this process will not provide full results before several years [22].

The implementation of ORPHA codes [23] in nation-al health information systems is ongoing. In addition to the progression of this implementation in Germany and France, pilot experiences are being conducted in Hun-gary, Latvia and Norway. ORPHA codes are currently being used in centres of expertise in the Netherlands and Slovenia. ORPHA codes are also being implement-ed in patient registries in Portugal, UK and Spain. In Switzerland, the Hôpitaux Universitaires de Genève and CHUV implement ORPHA codes in digital pa-tient records since 2015. The use of ORPHA codes as a complement to already existing coding systems is being explored in most EU Member States [24], as recom-mended by the European Commission Expert Group on Rare Diseases.

In the meantime, the European Commission sup-ports the Orphanet approach to improve quality and traceability of RDs in health information systems by using “Orphacodes” on a voluntary basis at a national

ICD9 + ICD10 + OMIMICD9 + ICD10 + OtherICD10 + OMIMICD10 + OMIMICD10 + OMIM + SNOMED-CT + OtherICD10 + SNOMED-CTOMIMORPHA

Coding systems for coding Rare Diseasepatients in Europe (as of May 2017)

According to the RD-ACTION survey answers

Figure 1Overview of Rare Diseases coding terminologies in Europe.


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level. These Orphacodes refers to the Orphanet classifi-cation of diseases and it is a stable and evidence-based nomenclature based on published expert classifications.

The European Joint Programme – Rare Diseases (EJP-RD) [25] is an instrument from the European Commission allowing high-level strategic organization and performance of research activities in an organized and transversal manner. It is operated by Programme Owners (typically ministries) and Programme Manag-ers (Research Funding and Research Performing or-ganizations) in conjunction with other relevant stake-holders (e.g. patients’ organisations, regulatory bodies and the private sector). The 2018 Work Programme of the EU Horizon 2020 Programme included a very important call, to establish an EJP in the field of rare disease research with an EC budget of € 55 million for 5 years (2019-2023). In preparation for this call, an ex-pert drafting committee was assembled in late 2016, to outline the contents of an EJP for RD. The basic goal was to support translational research in the rare disease arena, from bench to bedside and back again: in other words, to develop a sustainable ecosystem allow-ing a virtuous circle between rare disease care, research and medical innovation. The proposal was further de-veloped during the course of 2017 and 2018, and the drafting group expanded to a vast consortium of 85 partners, led by the French INSERM. The proposal was submitted in April 2018 and approved in July, with an anticipated start date of January 2019. The total bud-get of the entire EJP is expected to exceed € 110 mil-lion (€ 55 million directly from the EC, supplemented with substantial national and in-kind contributions). 33 countries will participate in total, from 25 EU Members States, 8 Associated Countries, and one Third Country (Canada). The main goals of the EJP RD are: to im-prove the integration, the efficacy, the production and the social impact of research on RD through the de-velopment, demonstration and promotion of Europe/ worldwide sharing of research and clinical data, materi-als, processes, knowledge and know-how; to implement and further develop an efficient model of financial support for all types of research on RD (fundamental, clinical, epidemiological, social, economic, health ser-vice) coupled with accelerated exploitation of research results for benefit of patients. EJP-RD is an inclusive effort, building on existing resources, experiences and networks including eRare, Orphanet, RD-Connect, EURORDIS, ERNs, and research infrastructures like ELIXIR (www.elixir-europe.org), BBMRI (www.bbmri-eric.eu), EATRIS (https://eatris.eu/), ECRIN (www.ecrin.org), INFRAFRONTIER (www.infrafrontier.eu), amongst many others.

Primary prevention and health promotion are also relevant to RD policies. At least 20% of RD have a multifactorial basis. In particular, congenital anomalies (CA) are the paradigm example of RD liable to primary prevention actions, since most of them have a multi-factorial (gene-environment) etiology. However, the in-sufficient attention to an integrated preventive strategy has led to the prevalence of CA remaining relatively stable in recent decades. On 2012 two European proj-ects, EUROCAT and EUROPLAN, have joined efforts

to provide the first science-based and comprehensive set of recommendations for the primary prevention of CA in the European Union. The resulting EUROCAT-EUROPLAN “Recommendations on Policies to Be Considered for the Primary Prevention of Congenital Anomalies in National Plans and Strategies on Rare Diseases” [26] were endorsed by European Union in 2013. The recommendations exploit interdisciplinary expertise encompassing drugs, diet, lifestyles, maternal health status, and the environment; evidence-based ac-tions are pointed out aimed at reducing risk factors and at increasing protective factors and behaviors at both individual and population level. The recommendations therefore provide a comprehensive tool to implement primary prevention into national policies on RD in Eu-rope and elsewhere [27, 28].

Recognising that the rare diseases constitutes a world problem for which the transatlantic cooperation was an obvious necessity the International Rare Diseases Research Consortium (IRDiRC) (www.irdirc.org) was created in 2014 as a platform for cooperation between the European Union, USA and Canada. IRDiRC an-nounced a new vision and goals for 2017-2027. IRDiRC was conceived with two main goals: to contribute to the development of 200 new therapies and the means to diagnose most rare diseases by the year 2020. The goal to deliver 200 new therapies was achieved in early 2017, while the goal for diagnostics is considered to be reach-able as well. IRDiRC goals are to ‘enable all people liv-ing with a rare disease to receive an accurate diagnosis, care, and available therapy within one year of coming to medical attention’. The last six years have seen consid-erable progress on these goals: the goal to deliver 200 new therapies was achieved in early 2017 – three years earlier than expected – and the goal for diagnostics is within reach. These accomplishments were celebrated at the 3rd IRDiRC Conference in Paris in February 2017 [29].

From the IRDiRC perspective, an accurate molecular diagnosis [30] is essential for informed patient manage-ment and family counselling, as well as for rare disease research including natural history studies, biomarker identification and clinical trials. There are ~7000 rare diseases and the relevant gene is known (as of 2016) for approximately half of these, thus around 3500 are still without a defined molecular pathogenesis. In ad-dition, a significant fraction of rare disease patients are without a molecular diagnosis due to a lack of universal accessibility of diagnostic testing. For diagnostic testing to be available for the majority of rare diseases by the year 2020, IRDiRC must focus on the discovery of the genes for the 3500 phenotypes that are currently with-out an associated disease gene [31]. Another challenge faced is diagnostics beyond the exome, and approaches to overcome these barriers to gene discovery are lim-ited; the development of innovative approaches for dis-covery is required to solve these unsolved conditions, and IRDiRC aims to gather key researchers and review strategies to address this challenge [32]. International efforts to establish guidelines for the clinical reporting of genomic sequencing in a clinical setting, including the approach to report incidental findings, will expedite


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the delivery of high-throughput and cost-effective test-ing to the rare diseases patient community as a whole, e.g., guidelines for diagnostic next-generation sequenc-ing developed by EuroGentest and the European So-ciety of Human Genetics [33]. In addition, the neces-sary bi-directional flow between the clinic and research will be enabled by the IRDiRC Policies and Guidelines [34].

IRDiRC is focused on accelerating progress in the field of rare disease research through international cooperation and collaboration [30], with the ultimate goals of enabling the means to provide a diagnosis for all rare diseases patients, and to contribute to the devel-opment of new therapies for rare diseases. In order to increase the joint impact of rare diseases investment by funding agencies, industry, researchers, regulators, and rare diseases patient advocates, harmonization of ef-forts that address common roadblocks is needed. To as-sist in this task, IRDiRC developed a set of Policies and Guidelines [35], which are the principles that IRDiRC members agree to adhere to, focused on data sharing and standards, ontologies, diagnostics, biomarkers, patient registries, biobanks, natural history, therapeu-tics, models, publication and intellectual property, and communications about the Consortium. The IRDiRC Policies and Guidelines are the detailed and world-wide agreements of major public and private funding organizations to govern rare disease research, with the Consortium representing over 2 billion US dollar of in-vestments. While it is too early to fully gauge the depth and magnitude of impact on rare disease research and patient benefit, the IRDiRC Policies and Guidelines have already significantly contributed in improving transparency and collaboration in this field. IRDiRC is now making steps towards addressing gaps and barriers in rare disease research; Task Forces are established to specifically address some of these gaps through policy recommendations and/or technical solutions. Rare dis-ease research has made considerable progress in the last decade, and the IRDiRC Policies and Guidelines will further push the discovery progress of rare disease diag-nosis and treatment, thereby advancing this important field of research.

According to the European legislation, a medicinal product can qualify for orphan designation under cer-tain conditions. Today there are 221 orphan designa-tions from which 164 initial orphan marketing authori-sations and 22 extension of indication granted to date [36]. The medicine is assessed by the Committee of Orphan Medicinal Products (COMP) in the EMA (Eu-ropean Medicines Agency). The EMA will now publish an orphan maintenance assessment report for every orphan-designated medicine as part of a medicine’s Eu-ropean Public Assessment Report (EPAR) after the European Commission has adopted its marketing au-thorisation decision.

The European medicines regulatory system is based on a network of around 50 regulatory authorities from the 31 EEA countries (28 EU Member States plus Ice-land, Liechtenstein and Norway), the European Com-mission and EMA. This network is what makes the EU regulatory system unique.

Results from a recent study [37] confirm that the number of medicines for rare diseases has increased since after 2010 and that the number of medicines in use and the resources spent vary widely among Euro-pean countries. Despite these differences, some medi-cines are available in all countries and are mostly indi-cated for treating rare cancers and immune diseases. Similarly, the European Organisation for Rare Diseases (EURORDIS) study in 2010 showed that oncology medicines for rare diseases were the most widely avail-able in nine European countries analysed [38]. Further-more, our mean time to first continuous use seems to be comparable with the findings from the 2007 EU-RORDIS study that included 17 European countries [39]. The study reports the mean European time to first use of orphan medicines as 341 days (0.93 y) after mar-keting authorization. In the study, the average time to first continuous use assessed for orphan medicines was 1.6 years, which seems longer, but it represents uninter-rupted use and includes the times of slower European markets. The study demonstrated that times to first use for orphan and non-orphan medicines did not dif-fer in the biggest markets, whereas some smaller mar-kets needed more time to introduce orphan medicines compared with non-orphan medicines, which could be due to higher prices. In Europe, half of the medicines for rare diseases introduced (orphan or not) are in use within 1 year after marketing authorization. The most successful countries in providing numerous medicines to the market in the quickest time are Germany, Nor-way, Finland, Sweden, and France, as observed previ-ously. These countries also have specific mechanisms to improve patient access to these medicines and to grant full or substantial reimbursement from public resources. Italy and Spain have introduced several medicines for rare diseases, but it takes them longer than 1 year until the medicines are first used. In addition, Italy enables full reimbursement of orphan medicines, whereas Spain covers medicines with therapeutic advantage. Austria and The Netherlands also provide many medicines in a short time and substantially cover orphan drugs. Simi-larly, Ireland is fast in enabling first use, but reimburse-ment depends on community and national schemes that may not cover the medicine. Also, the number of medicines reported is quite low and does not represent total product availability.

Smaller markets, such as the Bulgarian, Croatian, Czech, Greek, Hungary, Polish, Romanian, Slovenian, and Slovakian markets, offer between one-third and one-half of the medicines analyzed, which is a signifi-cant number of medicines for rare diseases. However, the time to first use is much longer and more variable in these markets than in the larger European markets.

The fight against inequalities and inequities for the access to orphan drugs for all the patients of rare diseas-es around the EU constitutes a very relevant objective for the coming years even if the prices of such medica-ments are a serious handicap for a single approach in all the European Union. The growth of pharmaceutical ex-penditures due to new high-cost innovative medicines, under the current institutional framework, creates fi-nancial challenges to health systems. The recognition


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that the current path of growth cannot be continued in-definitely leads to the search of new ways to ensure that innovation “that matters” is produced, that patients have access to innovation and that health systems are financially sustainable. This context leads to the discus-sion of innovative payment models for new medicines (including orphan medicinal products) that improves the way the three above-mentioned objectives are met. It is unlikely that a single payment model will be opti-mal for all situations. Some broad principles should be observed when defining specific payment models for in-novative medicines and deciding on rewarding R&D in pharmaceutical products [40].

In 2017, the PRIority MEdicines (PRIME) scheme was launched by the EMA (European Medicines Agency). This initiative was launched in March 2016 to provide early and enhanced support to medicines that can potentially address patients’ unmet medical needs, came into its second year of application. The EMA ad-opted a total of 81 eligibility recommendations in 2017, 20% more than in 2016. The success rate for acceptance into PRIME remained low, with only one out of five applications being successful, to ensure the Agency fo-cuses on the most promising medicines.

A last example of European Union cooperation in fields having an influence in the rare diseases policy is the Health technology assessment (HTA). HTA is a research-based tool to support decision-making in healthcare. HTA assesses the added value of new or existing health technologies – medicines, medical de-vices and diagnostic tools, surgical procedures, as well as measures for disease prevention, diagnosis or treat-ment – compared with other health technologies. The HTA process is performed by currently about 50 Eu-ropean HTA agencies. Fragmented approaches from HTA agencies may have a negative impact on R&D investment in Europe. The Commission adopted its legislative initiative on 31 January 2018 [41]. The pro-posed regulation on HTA aims to strengthen EU-level cooperation among Member States for assessing health technologies. According to the Commission, it would not only make innovative health tools reach patients faster, but also boost innovation and improve competi-tiveness of the European healthcare sector, which ac-counts for 10% of the EU’s GDP. Building on existing EU cooperation on HTA, including the HTA Network and the EUnetHTA Joint Action (www.eunethta.eu), the proposal would provide the basis for a permanent, sustainable cooperation.

The proposal covers new medicines and certain new medical devices. It focuses the future coopera-tion (the “joint work”) on assessing clinical aspects of HTA, namely: the description of the health problem addressed by the health technology and the current

use of other health technologies addressing that health problem; the description and technical characterisation of the health technology; the relative clinical effective-ness and the relative safety of the health technology. Member States would continue to be responsible for assessing non-clinical (e.g. economic, social, ethical, organisational) aspects of HTA, as well as for making decisions on pricing and reimbursement.

The proposal provides for joint work in four areas: i) joint clinical assessments focusing on the most innova-tive health technologies with the most potential impact for patients; ii) joint scientific consultations, whereby health technology developers (i.e. the pharmaceuti-cal industry and medical-device manufacturers) can seek advice from HTA authorities; iii) identification of emerging health technologies (“horizon scanning”), with a view to identifying promising health technologies at an early stage; and iv) continuing voluntary coopera-tion on other aspects of HTA.

The cooperation would be Member State-driven, with the Commission hosting a secretariat to provide administrative, scientific and IT support. Participa-tion in the joint clinical assessments and use of the joint clinical assessment reports at Member State-level would become mandatory after six years: following the regulation’s entry into force, the Commission proposes a three-year period for adopting tertiary legislation, and another three-year (transitional) period to allow Mem-ber States to fully adapt to the new system. Parliament’s Committee on the Environment, Public Health and Food Safety adopted the rapporteur’s draft report on 13 September 2018. The committee report was endorsed in plenary on 3 October 2018 with 200 amendments to the Commission proposal.

All these European achievements after years of ac-tion, are envisaged to be instrumental in guiding policy and research in the field of rare diseases in the forth-coming years looking for a fruitful and beneficial future for rare disease patients and stakeholders.


of European Union, in the framework of the Joint Ac-tion for Rare Diseases, Project n. 677024 “Promoting Implementation of Recommendations on Policy, Infor-mation and Data for Rare Diseases - RD-ACTION”.




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22. European Commission Expert Group on Rare Diseases. Recommendation on Ways to Improve Codification for Rare Diseases in Health Information Systems. Adopted at the 3rd meeting of the Commission Expert Group on Rare Diseases 12-13 November 2014. Available from: https://ec.europa.eu/health/sites/health/files/rare_disea-ses/docs/recommendation_coding_cegrd_en.pdf.

23. Orphanet. Orphanet 2013 Activity Report. Available from: www.orpha.net/orphacom/cahiers/docs/GB/Acti-vityReport2016.pdf.

24. RD-Action. Data and Policies for rare Diseases. Re-view Document of Existing Technical Implementations for Rare Disease Coding. Deliverable 5.1 issued on the 31/05/2016 by the WP5 members of the RD-ACTION European Joint Action. Available from: www.rd-action.eu/wp-content/uploads/2016/06/677024_D5.1_INTE-GRATED_FINAL_2.pdf.

25. Schwartz B. European Joint Programme on Rare Dise-ases. Annual Joint Programming Conference. Brussels, 7 of November 2017. Available from: www.era-learn.eu/documents/ejprdp2pnov2017.pdf.

26. EUROCAT (European Surveillance of Congenital Ano-malies) and EUROPLAN (European Project for Rare Di-seases National Plans Development). Recommendations on policies to be considered for the primary prevention of congenital anomalies in National Plans and Strategies on Rare Diseases. Available from: www.eurocat-network.eu/content/EUROCAT-EUROPLAN-Primary-Preventions-Reccomendations.pdf.

27. Taruscio D, et al. European recommendations for prima-ry prevention of congenital anomalies: a joined effort of EUROCAT and EUROPLAN projects to facilitate in-clusion of this topic in the National Rare Disease Plans. Publ Health Genom. 2014;17(2):115-23. doi: https://doi.org/10.1186/s13023-015-0251-8: 10.1159/000360602

28. Taruscio D, et al. Primary prevention of congenital ano-malies: recommendable, feasible and achievable. Pub Health Genom. 2015;18(3):184-91. doi: https://doi.org/10.1186/s13023-015-0251-8: 10.1159/000379739

29. International Rare Diseases Research Consortium (IR-DiRC). Third IRDiRC Conference. Paris, France, 8-9 February 2017. Available from: www.irdirc.org/activities/irdirc-conferences/3rd-irdirc-conference/.

30. Lochmüller H, et al. The International Rare Diseases Research Consortium: Policies and Guidelines to ma-ximize impact. Eur J Hum Genet. 2017;25(12):1293-302. doi: https://doi.org/10.1186/s13023-015-0251-8: 10.1038/s41431-017-0008-z

31. Boycott KM, Rath A, Chong JX, et al. International coo-peration to enable the diagnosis of all rare genetic disea-ses. Am J Hum Genet. 2017;100:695-705.

32. Matthijs G, Souche E, Alders M, et al. Guidelines for


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diagnostic next-generation sequencing. Eur J Hum Ge-net. 2016;24:2-5.

33. Baynam G, Broley S, Bauskis A, et al. Initiating an un-diagnosed diseases program in the Western Australian public health system. Orphanet J Rare Dis. 2017;12:83.

34. Ayoglu B, Chaouch A, Lochmuller H, et al. Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies. EMBO Mol Med. 2014;6:918-36.

35. International Rare Diseases Research Consortium (IR-DiRC). IRDiRC Policies and Guidelines. Available from: www.irdirc.org/about-us/about/.

36. European Medicines Agency. Orphan Medicines Figu-res 2000-2018. Available from: www.ema.europa.eu/documents/other/orphan-medicines-figures-2000-2018_en.pdf.

37. Deticek A, et al. Patient Access to Medicines for Rare Diseases in European Countries. Value in Health 2018; 21: 553-560. https://doi.org/10.1016/j.jval.2018.01.007.

38. Le Cam Y. Inventory of access and prices of orphan drugs across Europe: a Collaborative work between National

Alliances on Rare Diseases & EURORDIS (2010). Avai-lable from: https://img2.eurordis.org/newsletter/pdf/mar-2011/ERTC_13122010_YLeCam_Final.pdf.

39. Bignami F. EURORDIS survey on orphan drugs availabi-lity in Europe. 6th Eurordis Round Table of Companies Workshop. Barcelona, 9 July 2007. Available from: www.eurordis.org/IMG/pdf/2007ODsurvey-eurordis.pdf.

40. European Commission. Innovative payment models for high-cost innovative medicines. Report of the Expert Pa-nel on effective ways of investing in Health (EXPH). Lu-xembourg: European Commission; 2018. Available from: https://ec.europa.eu/health/expert_panel/sites/expertpa-nel/files/docsdir/opinion_innovative_medicines_en.pdf.

41. European Commission. Proposal for a Regulation of the European Parliament and of the Council on He-alth Technology Assessment and amending Directive 2011/24/EU (Text with EEA relevance) {SWD(2018) 41 final} - {SWD(2018) 42 final}. COM(2018) 51 final 2018/0018 (COD). Brussels, 31.1.2018. Available from: https://ec.europa.eu/health/sites/health/files/technology_assessment/docs/com2018_51_en.pdf.

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Book Reviews, Notes aNd CommeNts

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LA MENTE IN FIAMMEUn nuovo approccio alla depressioneEdward BullmoreMilano: Bollati Boringhieri; 2019.226 p.ISBN 978-88-339-3199-9€ 24,00 [The inflamed mind. A radical new approach to depression]

If you ever had a month in your life in which you had disturbed sleep, failed to find joy, no longer considered pleasant activities… pleasant, lost or gained a consider-able fraction of your body weight, and even contemplat-ed suicide as a foreseeable option, then, we are sorry to welcome you to depression, one of the most common illnesses worldwide. It is so common that almost any-one of us either went through it or had a close relative facing such a debilitating disease during lifetime. Un-fortunately, it never rains but it pours. Whilst the blunt numbers (300 million affected people worldwide) are still counting, the available weapons to contrast this epidemic have a very limited efficacy: why are current treatments so poor? Can we do something to improve them?

Edward Bullmore provides his cogent personal view to these fundamental questions in “The inflamed mind: A radical new approach to depression”, a thorough, thought-provoking, and extremely well-articulated es-say in which the principal message is that depression is not just a mental disorder but rather an integrated bodi-ly response to an inflammatory agent. Specifically, the core proposition of the book is that – rather than repre-senting the outcome of pathologic processes occurring in our neurons – depression may also stem from an in-flammatory response occurring far away from the brain, but sneaking into the site of our thoughts and emotions through previously unexplored backdoors. Ultimately, this exciting theory – if proven correct – may unravel one of the causes of depression and, most importantly, potentially disclose new avenues in the treatment of this disease.

Let alone the scientific interest, this book is a must-read for every scholar with an interest in depression. It is scientific dissemination at its best, and an extremely erudite one: the book spans from common-life facts to philosophy (at length) and then to evolution, immunol-ogy and neuroscience. Bullmore makes the description

of such a complex biological phenomenon accessible to its readership. Let’s be honest though: it is not for everyone. We are afraid that a discussion of this book won’t be the main topic during the half-time interval of a Serie-A football match, but history may prove us wrong.

After an introductory section, the psychiatrist Ed-ward Bullmore takes the reader where everything start-ed: a dental clinic. In the hours after the removal of a tooth root, the Author felt a worsening of his mood which rapidly improved shortly thereafter. This episode remained silent in the Author’s memories for ages. Yet, after years and after having seen many depressed pa-tients (many of which without an efficient cure), he had an insight which prompted him to connect his tempo-rary blue with the inflammation caused by the tooth root removal. The seed is now planted, Bullmore has whispered his theory in the reader’s ear and, from now on, the reader won’t stop thinking about his personal experience and try to find analogies.

From this point onwards, the Author details his the-ory reconciling and integrating diverse disciplines. And the reading is a joy. From a medical perspective, the Au-thor describes all the phases that led to the production of the current treatment of depression. In particular, Bullmore drifts from medicine to philosophy to criticise the “Cartesian dualistic view” – brain and body as inde-pendent entities – that for more than 350 years plagued the consideration of mental disturbances. According to him, the “body” vs “mind” dualism has hampered the development of appropriate treatments whereby it segregated mental illnesses to the brain and prevented scholars from considering the possibility that the body-outside-of-the-brain directly affected the mind-inside-the-brain. This is the main reason why, while other fields of medicine have recently spotted major leaps in knowledge and treatment, depression has been invari-ably approached with the same old-fashioned, yet valid in many patients, treatment (the famous selective se-rotonin reuptake inhibitor, SSRI, and psychotherapy).

Then, Bullmore delves into solid scientific data to sup-port his theory: many instances of depression depend on secondary effects exerted, at the level of the brain, by proteins secreted in response to infections. The data in support of this theory range from epidemiology, to clinical studies and animal models. For example, he notices that some biomarkers of the immune response (e.g. cytokines) are higher in depressed patients than in healthy subjects; furthermore, he describes prospective studies indicating that a person that has suffered from a major inflammatory state early in life has a probability to develop depression which is much higher than that observed in the general population. Laboratory studies presented in a fully intelligible fashion support these findings. Together, these data do not prove that all de-pressed patients are also inflamed, or the contrary, but

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they highlight that depression and inflammation often coexist. Then, the author further details his hypothesis by providing the cellular and molecular mechanism that may link a tooth root removal with depression: cyto-kines, microglia, neurons, and a plentiful of other bio-logical jargons are all clarified and smoothly bridged to mental disorders. Finally, all this rich and entertaining bulk of knowledge is summoned to provide the reader with the answers to the original questions of the book: Why are current treatments so poor? Probably because our approach to depression is still remarkably biased by the Cartesian dualism.

Can we do something to improve our current treat-ment of depression? Yes, provided that we contemplate the possibility of a paradigm shift in the field of mental

disorders. Specifically, the cross-fertilization between psychiatric and “somatic” disciplines shall result in the advocated personalised medicine. This will rest upon innovative biomarkers that will first allow stratifying patients based on their inflammatory history and then treat them accordingly.

Whether this book will contribute to such a paradigm shift is unknown; whether the paradigm shift will im-prove the quality of life of patients is yet unknown too; that readers will enjoy the book is known…

Edoardo Pisa1, 2 and Simone Macrì2

1 Sapienza Università di Roma, Rome, Italy 2 Istituto Superiore di Sanità, Rome, Italy

[email protected]

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Publications from international organizations on Public HealtH

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Edited byAnna Maria Rossi

FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS (FAO)

The State of Food Security and Nutrition in the World 2019. Safeguarding against economic slow-downs and downturns. Rome: Food and Agriculture Organization of the United Nations. 2019; 239 p. Job Number: CA5162EN ISBN 978 92 513 1570 5 This year’s report presents evidence that the absolute num-ber of people who suffer from hunger continues to slowly increase. The report also highlights that food in-security is more than just hunger. For the first time, the report provides evidence that many people in the world, even if not hungry, experience moderate food insecurity as they face uncertainties about their ability to obtain food and are forced to compromise on the quality and/or quantity of the food they consume. This phenom-enon is observed globally, not only in low- and middle-income countries but also in high income countries. The report also shows that the world is not on track to meet global nutrition targets, including those on low birthweight and on reducing stunting among children under five years. Moreover, overweight and obesity continue to increase in all regions, particularly among school-age children and adults. The report stresses that no region is exempt from the epidemic of overweight and obesity, underscoring the necessity of multifaceted, multisectoral approaches to halt and reverse these wor-rying trends.

Pesticide residues in food 2018 - Report 2018 - Joint FAO/WHO Meeting on Pesticide Residues.Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues Berlin, Germany, 18–27 September 2018. Rome: Food and Agricul-ture Organization of the United Nations. 2019; 668 p. (FAO Plant Production and Protection Paper; 234) Job Number: CA2708EN ISBN 978 92 513 1156 1 During the meeting the FAO Panel of Experts was re-sponsible for reviewing pesticide use patterns (use of good agricultural practices), data on the chemistry and composition of the pesticides and methods of analysis for pesticide residues and for estimating the maximum residue levels that might occur as a result of the use of the pesticides according to good agricultural use prac-tices. The WHO Core Assessment Group was responsi-ble for reviewing toxicological and related data and for estimating, where possible and appropriate, acceptable daily intakes (ADIs) and acute reference doses (AR-

fDs) of the pesticides for humans. This report contains information on ADIs, ARfDs, maximum residue levels, and general principles for the evaluation of pesticides. The recommendations of the Joint Meeting, including further research and information, are proposed for use by member governments of the respective agencies and other interested parties.

World Food and Agriculture - Statistical Pocket-book 2018. Rome: Food and Agriculture Organiza-tion of the United Nations. 2018; 255 p. Job Number: CA1796EN ISBN 978 92 513 1012 0 This pocketbook presents, at a glance, selected key indicators on agri-culture and food security, and is meant to serve as an easy-to-access and quick reference for all stakeholders and partners involved in policy formulation or decision-making processes. The indicators are presented in two sections, one thematic and one country-specific; they are organized along four main themes: 1) The setting, that measures the state of the agricultural resource base by assessing the supply of land, labour, capital and in-puts; 2) Hunger dimensions, which gauges the state of food insecurity and malnutrition, and highlights the four dimensions – availability, access, stability and uti-lization – that determine the scale of hunger and the shape of undernourishment; 3) Food supply, which evaluates the past and present productive capacity of world agriculture, together with the role of trade, in meeting the world’s demand for food, feed and other products; and 4) Environment, which examines the sus-tainability of agriculture in the context of the pressure it exerts on its ecological surroundings.

INTERNATIONAL LABOUR ORGANIZATION (ILO)

Kjellstrom T, Maître N, Saget C, et al. Working on a warmer planet: The effect of heat stress on pro-ductivity and decent work. Geneva: ILO. 2019, 103 p. ISBN 978 92 213 2967 1 The phenomenon of heat stress refers to heat received in excess of that which the body can tolerate without physiological impairment. It is one of the major consequences of global warming. By 2030, the equivalent of more than 2 per cent of total working hours worldwide is projected to be lost every year, either because it is too hot to work or because workers have to work at a slower pace. This report shows the impact of heat stress on productivity and decent work for virtually all countries in the world. It presents innovative solutions based on social dialogue

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to promote occupational safety and health for the most vulnerable groups of workers.

Addati L, Cattaneo U, Esquivel V, et al. Care work and care jobs for the future of decent work. Gene-va: ILO. 2018, 526 p. Sw.fr.40.00/US $ 40.00 ISBN 978 92 213 1642 8 The report analyses the ways in which unpaid care work is recognized and organized, the ex-tent and quality of care jobs and their impact on the well-being of individuals and society. A key focus of this report is the persistent gender inequalities in house-holds and the labour market, which are inextricably linked with care work. These gender inequalities must be overcome to make care work decent and to ensure a future of decent work for both women and men. The re-port contains a wealth of original data drawn from over 90 countries and details transformative policy measures in five main areas: care, macroeconomics, labour, social protection and migration. It also presents projections on the potential for decent care job creation offered by remedying current care work deficits and meeting the related targets of the Sustainable Development Goals.

UNITED NATIONS PROGRAMME ON HIV/AIDS (UNAIDS)

Global AIDS update 2019 — Communities at the centre. Defending rights, breaking barriers, reach-ing people with HIV services. Geneva: Joint United Nations Programme on HIV/AIDS. 2019, 316 p. The epidemic is changing: in 2018, more than half of all new HIV infections were among key populations—sex workers, people who use drugs, gay men and other men who have sex with men, transgender people and prison-ers—and their partners. Globally, new HIV infections among young women (aged 15–24 years) were reduced by 25% between 2010 and 2018. This is good news, but of course, it remains unacceptable that 6,000 adoles-cent girls and young women become infected with HIV every week. The AIDS response has demonstrated what is possible when people organize and assert their rights. When communities organize and people empower each other, oppression can be replaced by rights and access to HIV services can be accelerated. Peer-to-peer coun-sellors, community health workers, door-to-door service providers, grass-roots activists and networks of people living with or affected by HIV all have key roles to play in the response to HIV. As this report shows, communi-ty leadership in the AIDS response helps to ensure that HIV services are relevant to, and reach, the people who need them the most. Communities play a critical role in holding decision-makers to account and demanding political leadership.

UNAIDS Gender Action Plan - First progress report. Geneva: Joint United Nations Programme on HIV/AIDS. 2019, 16 p. The UNAIDS Gender Action Plan is a tool for transformative change with its targets and commitments paving the way towards a gender-

equal workplace. Today more than ever before, gender parity is an urgent priority and essential to UNAIDS’ legitimacy and effectiveness. The first year of UNAIDS Gender Action Plan 2018–2023 coincided with a time of global gender upheaval. People around the world, led by women and connected by social media, are united against gender inequality. Within just one year, the Plan has made remarkable progress. It has put in motion nine and successfully accomplished eleven of the 30 commitments. At the same time, evidence is mount-ing that gender equality between women and men in all of their diversity is not only a good in itself, but serves and benefits all people. A more gender equal society is healthier and more productive. A more gender equal workforce is more effective and innovative and delivers bigger growth.

Tuberculosis and HIV — Progress towards the 2020 target. Geneva: Joint United Nations Pro-gramme on HIV/AIDS. 2019, 12 p. Most countries are not on track and too many people living with HIV are still dying from TB which is preventable and curable. The most vulnerable and the marginalized are still out of reach of HIV and TB services and in around 40 coun-tries the number of TB deaths among people living with HIV is increasing. The epidemics of TB and HIV are closely interlinked. Yet, too often, TB and HIV activi-ties are not coordinated—a missed opportunity that is costing lives. This is unacceptable. The world is moving closer to meeting the United Nations target of reducing tuberculosis (TB) deaths among people living with HIV by 75% by 2020. Between 2010 and 2017, TB deaths among people living with HIV fell by 42% and many countries are now on track to achieving the target by 2020. Five have already done so, ahead of schedule.

UNITED NATIONS ENVIRONMENT PROGRAMME (UNEP)

UN Environment 2018 Annual Report. Putting the environment at the heart of people’s lives. Nairobi: United Nations Environment Programme. 2019, 44 p. UN Environment released its 2018 Annual Report, highlighting the organization’s work on issues from fighting pollution of the air and sea to helping nations meet their goals of reducing greenhouse gas emissions. “While 2018 was a challenging year, we saw hope in growing action and global commitment to new ways of doing business that tackle the environmental challenges we face,” said UN Environment Acting Ex-ecutive Director Joyce Msuya. “Our role in highlighting best practices, advocating action and bringing together governments, civil society and businesses once again proved critical.”

Frontiers 2018/19: Emerging issues of environ-mental concern. Nairobi: United Nations Environment Programme. 2019, 80 p. The UN Environment Frontiers series links new science to outcome-oriented policies in

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relation to the health of the environment and its sustain-ability. The 2018/19 edition continues the tradition of highly referenced texts accompanied by illustrative info-graphics and featuring the interactivity of links to videos on related research and information. Frontiers 2018/19 explores the emerging environmental issues facing the planet. It was launched on 4 March 2019 prior to the fourth UN Environment Assembly in Nairobi, Kenya. The report covers five key emerging issues: the latest de-velopments in synthetic biology; the critical advantages of landscape connectivity; the complex interactions and vulnerability of permafrost peatlands; the challenges of widespread nitrogen pollution; and the hazards of mal-adaptation in a world of climate change.

WORLD HEALTH ORGANIZATION (WHO)

RESPECT women: Preventing violence against women. Geneva: World Health Organization. 2019, 24 p. WHO reference number: WHO/RHR/18.19 Vio-lence against women is a major public health problem rooted in gender inequality, and is a gross violation of women’s human rights affecting the lives and health of millions of women and girls. Aiming to end violence against women, a package/framework for policymak-ers with infographics on prevention of violence against women was developed, based on the UN framework for action to prevent violence against women from 2015 and updated new evidence.

WHO global report on traditional and comple-mentary medicine 2019. Geneva: World Health

Organization. 2019, 226 p. Order number: 11500949 Sw.fr.40.00/US $ 48.00 ISBN 978 92 415 1543 6 This report is structured in five parts: national framework for traditional and complementary medicine (T&CM); product regulation; practices and practitioners; the challenges faced by countries; and, finally, the country profiles. Apart from the section on practices and prac-titioners, the report is consistent with the format of the report of the first global survey in order to provide a useful comparison. The section on practices and prac-titioners, which covers providers, education and health insurance, is a new section incorporated to reflect the emerging trends in T&CM and to gather new informa-tion regarding these topics at a national level. All new information received has been incorporated into indi-vidual country profiles and data graphs.

Drinking coffee, mate, and very hot beverages. Geneva: World Health Organization. 2019, 504 p. Or-der number: 17200116 Sw.fr.75.00/US $ 90.00 (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans; 116) ISBN 978 92 832 0154 0 This volume of the IARC Monographs presents evaluations of the carcinogenic hazard to humans of drinking coffee and very hot beverages including, but not limited to, mate. An IARC Monographs Working Group reviewed epi-demiological evidence, animal bioassays and co-carci-nogenicity studies, and mechanistic and other relevant data to reach conclusions as to the carcinogenic hazard to humans of drinking coffee, mate, and very hot bever-ages. The Working Group assessed more than 1000 ob-servational and experimental studies that investigated the association between cancer at more than 20 sites with drinking coffee, mate, and very hot beverages.

Instructions to Authors

MANUSCRIPT SUBMISSIONManuscripts should be submitted online to www.annali-iss.eu. The submission should include:• cover letter where the authors declare that the manuscript has not been published or submitted for publication elsewhere;• manuscript; • tables and figures;• author’s contribution statement (individual contribution to the manuscript);• conflict of interest statement (a conflict of interest exists when authors or their institutions have financial or personal relationship with other people or organizations that could inappropriately bias conduct and findings of the study);• permission to reproduce figures, if appropriate.Receipt of author’s paper will be acknowledged by an e-mail containing an identification number which should be used in future correspondence.

REVIEW PROCEDUREEach paper submitted to Annali is subjected to the fol-lowing procedures:• it is reviewed by the Editor-in-Chief for general suitability;• if it is judged suitable, qualified referees are selected and a peer review process takes place (occasional contribu-tions, such as commentaries, papers submitted on invita-tion, etc. are accepted without peer review);• based on the recommendations of the referees and re-plies of the authors, the Editor-in-Chief decides whether the article should be accepted, modified or rejected;• once the paper has been accepted, authors will receive proofs from the editorial office, which should be correct-ed and returned (usually within three working days).

MANUSCRIPT PRESENTATIONPlease ensure that your manuscript follows these guide-lines. Manuscripts should be written in good English, as con-cisely as possible to allow a clear understanding of the text. The title should be followed by the complete name of the authors, their affiliations – in the original language – town and country. The name and address, telephone and e-mail of the corresponding author should also be indicated. On the same page a running head of no more than 40 charac-ters (including spaces) should be included. Original articles should normally be organized into differ-ent sections (i.e.: Introduction, Materials and methods, Results, Discussion, Conclusions). In the Methods sec-

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• the review should be no longer than 10 000 words, including about 100 references, four tables and three figures.

FORMATTING GUIDELINES Text• Use Times New Roman font, 10 point, single spaced;• do not use the automated features of your application (endnotes, headers, footers, especially for references);• type a single space at the end of each sentence;• avoid using bold characters to emphasise words or sen-tences within the text;• indicate clearly titles of chapters and subchapters avoid-ing numbering.

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REFERENCESAll references in the text must be numbered in square brackets, i.e. [1, 2, 3-6], and mentioned at the end of the article in the order in which they are quoted. They should conform to the “Recommendations for the Conduct, Re-porting, Editing, and Publications of Scholarly Work in Medical Journals” (www.icmje.org), according to the fol-lowing examples. Titles of periodicals should be abbreviated in accordance with the Medline abbreviation of the US National Li-brary of Medicine (www.nlm.nih.gov/bsd/aim.html). On-line journal articles can be cited using, in addition to the complete citation, the DOI number.

Articles in journalBozzuto G, Ruggieri P, Molinari A. Molecular aspects of tumor cell migration and invasion. Ann Ist Super Sanità. 2010;46(1):66-80. DOI: 10.4415/ANN_10_01_09

Books and chapters in a bookGodlee F, Jefferson T. Peer review in health sciences. London: BMJ Books; 1999.Van Weely S, Leufkens HGM. Background paper: orphan diseases. In: Kaplan W, Laing R (Eds). Priority medicines for Europe and the world – a public health approach to

innovation. Geneva: World Health Organization; 2004.

ProceedingsFadda A, Giacomozzi C, Macellari V. Comparative measurements to validate a new telemetric pressure in-soles system. In: 2. International Symposium on meas-urement, analysis and modelling of human functions. 1. Mediterranean Conference on measurement. Workshop on evaluation check of traceability. Proceedings. Geno-va: June 14-16, 2004. p. 425-7.

Technical reportsDella Seta M, Di Benedetto C, Leone L, Pizzarelli S, Siegmund U. ETHICSWEB technical guides. Manual for the creation of standards and guidelines for sharing infor-mation about knowledge organization systems on ethics and science. Roma: Istituto Superiore di Sanità; 2011. (Rapporti ISTISAN, 11/32).

Legislation Italia. Decreto legislativo 29 ottobre, n. 419. Riordi-namento del sistema degli enti pubblici nazionali, a norma degli articoli 11 e 14 della legge 15 marzo 1997, n. 59. Gazzetta Ufficiale – Serie Generale n. 268, 15 ottobre 1999.

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