List of organization(s) consulted and/or supporting the ...archives.who.int/eml/expcom/expcom15/applications/immunoglobulin/i... · List of organization(s) consulted and/or supporting

ANNEX 1

List of organization(s) consulted and/or supporting the application

3.1 IPOPI’s National Member Organisations

• Argentina, Argentine Association for the help of Patients with Primary Immune Deficiencies

• Australia, Immune Deficiency Foundation of Australia

• Canada, Canadian Immunodeficiencies Patient Organisation

• Denmark, Immun Defekt Foreningen (IDF)

• Estonia, Estonian Patient Society for Primary Immunodeficiencies

• Finland, Immunipuutospotilaiden yhdistys r.y.

• France, Immuno-Deficience Primitive: Recherche, Information, Soutien (IRIS)

• Germany, Selbsthilfe Angeborene Immundefekte e. V. and Interessengemeinschaft Menschen mit Immundefecten e.V

• Hungary, Immunhianyos Gyermekekert Alapitvany

• Iceland, Lind - Icelandic Immune Deficiency Foundation

• India, Indian Patients Society for Primary Immunodeficiency (IPSPI)

• Iran, Iranian Primary Immunodeficiency Association

• Ireland, Primary Immunodeficiency Association Ireland (PIAI)

• Italy, Associazione Immunodeficienze Primitive (AIP)

• Morocco, Association Hajar de Soutien aux patients atteints de deficits immunitaires Primitfs

• New Zealand, Immunodeficiency Foundation – New Zealand

• Norway, Norwegian Immunodeficiency Organisation

• Poland, Association for Friend of Children with Primary Immunodeficiency

• South Africa, Primary Immunodeficiency Network of South Africa (PINSA)

• Spain, Asociation espanola deficits immunitarios primarios (AEDIP)

• Sweden, Primaer Immunbrist Organisationen (PIO)

• Switzerland, Schweizerische Vereinigung für Angeborene Immundefekte (SVAI)

• The Netherlands, Stichting voor Afweerstoornissen

• United Kingdom, The Primary Immunodeficiency Association (PIA)

• United States of America, Immune Deficiency Foundation (IDF) and Jeffrey Modell Foundation, (JMF)

• Yugoslavia (Serbia-Montenegro), Jugoslovenska organizacija za primaru immunodeficijenciju (YUGOPID)

3.2 International Organisations

• European Society for Immunodeficiencies (ESID)

• European Federation of Immunological Societies (EFIS)

• International Nursing Group for Immunodeficiencies (INGID) and their National Member Organisations (Names – see Website)

• Kawasaki Disease Foundation

• The Guillain-Barré Syndrome (GBS)/Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Foundation International

• The WHO’s Global Collaboration for Blood Safety

• The Plasma Protein Therapeutics Association (PPTA)

• The International Plasma Fractionation Association (IPFA)

• European Paediatric Society

3.3 National Organisations

• The GBS and CIDP Support Group of the United Kingdom

• The Idiopathic Thrombocytopenic Purpura Support Association of the United Kingdom

• United Kingdom Primary Immunodeficiency Network (UK PIN)

• Sociedad Argentina de Immunologia

• Sociedad Argentina de Pediatra

• Lithuanian Pediatric Society

• Lithuanian Society of Allergology and Clinical Immunology

• Australasian Society of Clinical Immunology and Allergy

• Iranian Primary Immunodeficiency Association

• Czech Society of Allergology and Clinical Immunology

• Hong Kong Society of Immunology

• Baltic Society for Pediatric Oncology and Hematology

• Spanish Paediatric Society

• Spanish Immunology Society

• Spanish Haematology Society

3.4 International Experts

In 2006, an international panel of leading experts in the field provided a consensus statement on the vital importance of therapeutic immunoglobulin to patients and of its cost-effectiveness (see Annex 2).

ANNEX 2

International Experts Consensus Statement As of October 13, 2006 As international authorities in the diagnosis and management of primary immunodeficiency diseases (PIDs) brought together by the International Union of Immunological Societies Primary Immunodeficiency Committee [IUIS-PID] and the Jeffrey Modell Foundation, we the undersigned provide a statement of the vital importance of therapeutic immunoglobulin (polyvalent human immunoglobulins) to our patients. This includes both intravenous (IV) and subcutaneous (SC) immunoglobulin. PIDs are conditions caused by inherent defects of the immune system that lead to recurrent, severe or unusual infections, which can be fatal. Therapeutic immunoglobulins are the only effective therapy for life-long treatment of some PIDs. Use of therapeutic immunoglobulin in PIDs is efficacious in preventing infection-related death, increases lifespan, preserves organ function, and improves quality of life. Such therapies have been shown to be safe and cost-effective. In this time of challenges we therefore need to emphasize the essential nature of immunoglobulin in treating PID patients, especially since immunoglobulin therapy is absolutely indispensable and irreplaceable for treatment of PIDs. Signed, ________________________ ________________________ _________________________

Helen Chapel, M.D. Chaim Roifman, M.D. Jordan Orange, M.D., Ph.D. Oxford Radcliffe Hospital Hospital for Sick Children, Toronto Children’s Hospital of Philadelphia ________________________ ________________________ _________________________ Mary Ellen Conley, M.D. Alain Fischer, M.D., Ph.D. Charlotte Cunningham-Rundles, M.D., Ph.D. St. Jude Children’s Research Hosp. Hôpital Necker-Enfants Malades Mount Sinai Medical Center ________________________ ________________________ _________________________ Reinhard Seger, M.D., Ph.D. Amos Etzioni, M.D. David B. Lewis, M.D.

University Children’s Hospital, Switzerland Technion-Israel Institute of Technology Stanford University School of Medicine

________________________ ________________________ _________________________

Raif Geha, M.D. Prof. Dr. med. Reinhold Schmidt Professor Lennart Hammarström Harvard Medical School Hannover Medical School Karolinska University Hospital in Huddinge ________________________ ________________________ _________________________ Ramsay Fuleihan, M.D. Timothy Niehues, M.D. Noorbibi Day-Good, Ph.D. Yale Child Health Research Center Universitats Klinikum Düsseldorf University of South Florida ________________________ ________________________ _________________________ Francisco A. Bonilla, M.D., Ph.D. Gary Kleiner, M.D., Ph.D. Jennifer Puck, M.D. Children’s Hospital Boston University of Miami University of California, San Francisco ________________________ ________________________ _________________________ Melvin Berger, M.D., Ph.D. Alessandro Aiuti, M.D., Ph.D. Hans D. Ochs, M.D. Case Western Reserve University San Raffaele Telethon Institute University of Washington School of Medicine School of Medicine for Gene Therapy, Italy Children’s Hospital Seattle ________________________ ________________________ _________________________

Martha Eibl, M.D. Lisa Kobrynski, M.D. Ricardo U. Sorensen, M.D. Biomedical Research Institute, Austria Emory University Louisiana State University Medical Center ________________________ ________________________ _________________________ E. Richard Stiehm, M.D. Mark Ballow, M.D. Talal Chatila, M.D. Mattel Children’s Hospital at UCLA Children’s Hospital of Buffalo David Geffen School of Medicine, UCLA ________________________ ________________________ _________________________ Teresa Español, MD, PhD Rasa Duobiene Xiao-Ming Gao, PhD

Immunology Unit. HUVH, Barcelona Lithuania Peking University, Beijing, China

________________________ ________________________ _________________________ Esther de Vries, MD, PhD Luigi D. Notarangelo, MD Bodo Grimbacher

Jeroen Bosch Hospital, Netherlands University of Brescia, Italy Universitätsklinikum Freiburg

________________________ ________________________ _________________________ Ashgar Aghamohammadi Eric Chan Regina Emuzyte Tehran Children Medical Center Queen Mary Hospital, Hong Kong Vilnius University Hospital

________________________ ________________________ _________________________ Richard Herriott Jiri Litzman Mimi Tang Aberdeen Royal Infirmary St Anne University Hospital, Brno Royal Children Hospital, Melbourne

________________________ ________________________ _________________________ Vytautas Usonis Surjit Singh Marianne Debré Vilnius University Children’s Hospital Chandigarh Hospital, India Hôpital Necker-Enfants Malades, Paris

________________________ ________________________ Olivier Hermine Goda Vaitkeviciene Hôpital Necker-Enfants Malades, Paris Vilnius University Children’s Hospital

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ANNEX 3

International availability

This is a list of the member organizations of the Plasma Protein Therapeutics Association (PPTA) and of the International Plasma Fractionation Association (IPFA) which manufacture and/or distribute Polyvalent Human Immunoglobulins: PPTA member companies (headquarters): Baxter One Baxter Parkway Deerfield IL 60015-4625 USA Tel: +1.847.948.2000 Biotest AG Landsteinerstraße 5, D-63303 Dreieich Postfach 10 20 40, D-63266 Dreieich Germany Tel: +49 61 03 / 8 01 - 0 Fax: +49 61 03 / 8 01 - 1 50 Grifols, S.A. Can Guasch, 2 08150 Parets del Vallès. Barcelona Spain Tel: +34.935.710.100 Fax: +34.935.710.381 Kedrion S.p.A Loc. Ai Conti 55020 Castelvecchio Pascoli Barga (Lucca) Italia Tel:+39 0583 19691 Fax +39 0583 1969878

Octapharma AG Seidenstraße 2 CH-8853 Lachen Switzerland Tel: +41.55.451.21.21 Fax: +41.55.451.21.10 Talecris Biotherapeutics Inc. 4101 Research Commons 79 T.W. Alexander Drive Research Triangle Park North Carolina 27709 USA Tel: +1.919.316.6300 ZLB Behring King of Prussia P.O. Box 61501 1020 First Avenue King of Prussia, PA 19406 USA Tel: +1.610.878.4000 Fax: +1.610.878.4009 IPFA Member Organizations: Netherlands Sanquin Blood Supply Foundation Plesmanlaan 125 1066 CX Amsterdam The Netherlands Tel.: +31 20 512 3764 Fax: +31 20 512 3640 Australia Australian Red Cross Blood Service 153 Clarence Street Sydney, NSW 2000 Australia Tel: +61 2 9229 4040 Fax: +61 2 9229 4487 Belgium Belgische Rode Kruis CAF-DFC Centrale Afdeling voor Fractionering cvba Avenue de Tyraslaan 109

Belgium Tel.:+32 2 264 6445 Fax:+32 2 262 2731 Canada Canadian Blood Services 1800 Alta Vista Dr. Ottawa ON K1G 4J5 Canada Tel: +1 613 739 2045 Fax: +1 613 739 2099 Canada Héma-Québec 4045, Boulevard Cote-Vertu Saint Laurent H4R 2W7 CANADA Tel.: +1 514 832 5000 Fax: +1 514 832 0267 England Bio Products Laboratory Dagger Lane, ELSTREE Herts, WD 6 3BX United Kingdom Tel.:+44 208 258 2252 Fax:+44 208 258 2603 Finland Finnish Red Cross Blood Service Mannerheimintie 5C SF 00100 HELSINKI Finland Tel.:+358 9612 09112 Fax:+358 9612 09155 France Laboratoire Français du Fractionnement et des Biotechnologies 3, Avenue des Tropiques B.P. 305 LES ULIS 91958 Courtaboeuf Cedex France Tel.:+33 1 6982 7262 Fax:+33 1 6982 7267

Greece Hellenic National Blood Center Olympic Winner Chr. Mantikas 7 Lekanes, Acharnon Attikis GR-136 71, GREECE Tel: +30 210 2410 000 (Central), Fax: +30 210 2410 119 Japan Japanese Red Cross Plasma Fractionation Center. 1007-31, Izumisawa, Chitose 066-8610, JAPAN Tel.: +81 123 28 3311 Fax: +81 123 28 3893 Scotland Scottish National Blood Transfusion Service Headquarters Unit Ellen's Glen Road EDINBURGH EH17 7QT Scotland UK Tel.: +44 131 536 5712 Fax: +44 131 536 5714 South Africa National Bioproducts Institute 10, Eden Road Private Bag X9043 PINETOWN 3600 South Africa Tel.: +27 31 719 6789 Fax: +27 31 708 5614 United States of America American Red Cross Plasma Services 2025 E Street, NW Washington DC-20006 United States of America Tel. +1 202 303 5534 Fax +1 202 303 0274

New Zealand New Zealand Blood Service, National Office 71 Great South Road P.O. Box 26611 Epsom, Auckland New Zealand Tel : +64 9 523 5744 Fax : +64 9 523 5754 Hong Kong Advantek Biologics Hong-Kong Ltd. Hong Kong Institute of Biotechnology (HKIB), Room 212 Biotechnology Avenue 12 Miles 2 Tai Po Road SHATIN, N.T. Hong Kong China Tel.: +852 2603 6039 Fax : +852 2869 6402 Brazil Hemobras SCN, Quadra 1 Projecao E-Ed Central Park, 15 andar 70710-500 Brasilia Brazil Tel. +55 61 3327 6523 Fax +55 61 3327 6523

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ANNEX 4

Bibliographic reference

Study type

Study aim Number of patients

Patient characteristics

Intervention Outcome measures Organisation/Contacts

Aghamohammadi, A. et al., Efficacy of IVIg on the prevention of pneumonia in patients with agammaglobulinaemia, FEMS Immunology & Medical Microbiology, 40:113-118

cohort evaluate the effectiveness IVIG treatment on the incidence of pneumonia in patients with agammaglobulinemia

23 mean age 11.5+/-5.4 years

Treatment with gamma-globulin - over a mean period of 6.8+/-4.1 years (range: 0.8-15.3 years) - the incidence of pneumonia requiring treatment or hospitalization decreased from 0.82 to 0.12 per patient per year (P=0.006). During IVIG replacement, hospitalization due to pneumonia decreased from 0.58 to 0.05 per patient per year (P=0.08) and the immunoglobulin G level (mean+/-S.D.) changed from 66.2+/-63.9 (range: 0-210 mg dl(-1)) to 552.4+/-199.1 (range: 136-942 mg dl(-1)) (P<0.001).

Treatment of agammaglobulinemia with IVIG significantly reduced the incidence of pneumonia and hospital admission. Intensive management and regular monitoring is required in order to fully prevent severe respiratory complications

Department of Allergy of Children's Medical Center, Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran

Scientific and medical evidence demonstrating the effectiveness of immunoglobulins in the treatment of primary immunodeficiencies


Study type




Australian Health Ministers’ Advisory Council, Blood and Blood Products Committee report: Review of the Use and Supply of Intravenous Immunoglobulins in Australia, June 2000

Review Growing concern on the part of clinicians, patients, and other interested parties over a perceived chronic shortage of IVIG in Australia led to the a national review of the use and supply of IVIG

Australian Health Ministers’ Advisory Council, Blood and Blood Products Committee


Study type




Ballow M. Clinical and Investigational considerations for the use of IGIV therapy. Am J Health Syst Pharm 2005; 62:S12�8

Case study

Clinical uses of IGIV therapy for a number of autoimmune and inflammatory diseases are discussed, as well as the probable mechanisms by which IGIV exerts its immunoregulatory and antiinflammatory actions. Case studies are also presented to examine practical considerations in the selection of IGIV products for patients at risk for adverse events

While numerous mechanisms have been proposed to explain the beneficial effects of IGIV, the specific mechanisms remain elusive. Patient outcomes can be affected by IGIV product characteristics. The choice of an IGIV product should be matched to the patient's risk-factor profile

Department of Pediatrics, Women and Children's Hospital of Buffalo, SUNY Buffalo School of Medicine and Biomedical Sciences, 219 Bryant Street, Buffalo, NY 14222, USA. [email protected]


Study type




Borte M., Oertelt C., Hogy B. Treatment of patients with primary antibody deficiencies in Germany. Klin Padiatr. 2005 Sep-Oct;217(5):276-80

Survey/questionnaire

Assess the present status of immunoglobulin therapy in German patients with antibody deficiencies.

230 13 pediatricians and 5 specialists for internal medicine were interviewed.

A disease questionnaire was used during standardized interviews. Information was sought on the treating physician and center, the kind of immunodeficiency and its complications. Furthermore, details on the Ig therapy, routine diagnostic procedures and concomitant medication were asked.

The majority of centers followed current guidelines concerning monthly immunoglobulin doses and desired IgG trough levels, but often aimed at the lower end of these recommendations.

Klinik fur Kinder- und Jugendmedizin am Stadtischen Klinikum St. Georg Leipzig, Akademisches Lehrkrankenhaus der Universitat Leipzig. [email protected]

Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol 2002; 109:1001�4

Observational

Document the effectiveness of intravenous immunoglobulin treatment on the incidence of pneumonia in patients with CVID.

50 Patients with laboratory-confirmed CVID mean current age, 42 +/- 16.3 years; age range, 10-78 years; 20 male and 30 female patients

Performed chart reviews and interviews of patients with laboratory-confirmed CVID seen at our clinical center. The number of episodes of pneumonia was documented before and after treatment with immunoglobulin replacement therapy.

The treatment of CVID with IVIG significantly reduces the incidence of pneumonia.

Division of Clinical Immunology, Department of Medicine, The Mount Sinai Medical Center, New York, NY, USA


Study type




Chapel H. et al, The comparison of the efficacy and safety of intravenous versus subcutaneous Ig replacement therapy. Clin.Immunol.2000;20:94�100

International, multicenter, open label, crossover study was designed

Compare the efficacy of immunoglobulin replacement therapy given intravenously versus subcutaneously to prevent infections in patients with primary antibody deficiency syndromes

40 Patients were randomized to receive either subcutaneous or intravenous immunoglobulin replacement therapy for 1 year. In the second year, patients were switched to the alternative treatment, enabling patients to act as their own controls.

There are no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.

Department of Immunology, John Radcliffe Hospital, Oxford, England.

Chapel, H. et al, Immunoglobulin replacement therapy by self-infusion at home, Clin Ecp Immunol 73:160-162

Follow up study

Establish if regular self infusion at home is feasible and safe.

12 Ten with common variable hypogammaglobulinaemia and two with hypogammaglobulinaemia secondary to chronic lymphocytic leukaemia (CLL)

Patients taught to self-infuse their intravenous immunoglobulin replacement therapy.

Excellent patient compliance results from greater convenience and control over their own lives, in addition to time and money saved by the hospital.



Study type




Eijkhout HW. et al The effect of two different dosages of IVIg on the incidence of recurrent infections in patients with PID. A randomizeddouble�blind , mulicenter crossover trial. Ann. Inter.Med 2001; 135:165�174

randomized double-blind , mulicenter crossover trial

To determine whether doubling the standard dose of intravenous immunoglobulin would affect the incidence and duration of infections

43 Patients with hypogammaglobulinemia, 41 of whom completed the protocol

Patients received standard-dose immunoglobulin therapy for 9 months, followed by a 3-month washout period, and high-dose intravenous immunoglobulin therapy for 9 months, or vice versa

In patients with hypogammaglobulinemia, doubling the standard dose of intravenous immunoglobulin significantly reduced the number and duration of infections.

CLB, Medical Department, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands. [email protected]


Study type




Gardulf A, Nicolay U, Asensio O, Bernatowska E, Bock A, Carvalho BC, Granert C, Haag S, Hernandez D, Kiessling P, Kus J, Pons J, Niehues T, Schmidt S, Schulze I, Borte M. Rapid Subcutaneous IgG Replacement Therapy is Effective and Safe in Children and Adults with Primary Immunodeficiencies-A Prospective, Multi-National Study. J Clin Immunol. 2006 Apr 26; [Epub ahead of print]

Prospective multi-national study.

Evaluate the (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation

60 16 children, 44 adults

All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls

The SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections

Department of Laboratory Medicine, Section of Clinical Immunology, The Swedish Centre for Immunodeficiencies, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. [email protected]


Study type




Lim D.L., Thong B.Y., Ho S.Y., Shek L.P., Lou J., Leong K.P., Chng H.H., Lee B.W. Primary immunodeficiency diseases in Singapore--the last 11 years. Singapore Med J. 2003 Nov;44(11):579-86

Questionnaire

To describe the clinical features, disease complications, treatment modalities and overall outcome of 39 local patients with Primary Immunodeficiency Diseases (PID) in Singapore over the last 11 years

39 Age: three weeks to 69 years between January 1990 and December 2000

Patient data were collated from case files and compiled using a standard questionnaire.

Antibody deficiencies are the most common form of PID in Singapore. Treatment with antibiotics, IVIG and HSCT are the main therapeutic modalities currently available. Early referral to an immunologist is needed to achieve good outcomes

Department of Paediatrics, The Children's Medical Institute, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. [email protected]

Sacher RA. Intravenous immunoglobulin consensus statement. Journal of Allergy and Clinical Immunology, October 2001, part 2 Vol 108 No 4, 139-146

Consensus statement

Address the safe and effective uses of intravenous immunoglobulin (IVIG) preparations.

Following 1 1/2 days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared a consensus statement.

All currently available IVIG preparations are safe and effective in treating the conditions for which they have been licensed; however, their efficacy in treating other conditions remains to be established. the risks of IVIG therapy are minimal, and adverse events, which are rare, can often be alleviated by reducing the rate or volume of infusion.


Study type




Ochs HD, Buckley RH, Pirofsky B, Fischer SH, Rousell RH, Anderson CJ, et al. Safety and patient acceptability of intravenous immune globulin in 10% maltose. Lancet 1980; 2:1158-1159

Double-blind trial

Evaluate the safety and patient acceptance of two preparations of modified (reduced and alkylated) immune globulin for intravenous use.

29 Immunodeficient patients

Patients received three consecutive monthly infusions (100 or 150 mg/kg immune globulin) of one preparation before being crossed over to the other. One preparation was formulated as a 5% solution in 10% maltose (IGIV-maltose), the other did not contain maltose (IGIV).

IGIV-maltose is safe and will permit rapid infusion of large doses of immune globulin, thus improving the management of patients with antibody deficiency diseases.

Orange et al. Use of human Ig in human disease: A review of evidence by members of the primary Immunodeficiency committe of the Am. Acad.Allergy and Immunology. J�Allergy Clin.Immunol 2006; 117, S525�53

Systematic review

to examine the evidence for efficacy of Ig therapies in the whole range of immunological diseases

n/a PIDs and autoimmune diseases

IVIg for replacement or immune modulation

Diseases can be considered as indications for Ig therapy depending on the level of evidence and the disease severity.

AAAAI investigative paper by Expert Committee


Study type




Remvig L, Andersen V, Hansen NE, Karle H. Prophylactic effect of self-administered pump-driven subcutaneous IgG infusion in patients with antibody deficiency: a triple-blind cross-over study comparing P-IgG levels of 3 g l-1 versus 6 g l-1. Journal of internal medicine 1991; 229:73-77.

A triple-blind cross-over.

Comparitson P-IgG levels of 3 g l-1 versus 6 g l-1.

8 Adult patients with hypoimmunoglobulinaemia.

Patients were randomly allocated to initiation of low- or high-level IgG-substitution. IgG was administered subcutaneously, at 50 or 150 mg ml-1, 20 ml per infusion, by means of a pocket-portable electric infusion pump. Infusions were given 2 to 4 times weekly for 24 months, with a change of dose regimen after 12 months.

A plasma IgG concentration of 6 g l-1 can readily be achieved by subcutaneous IgG substitution, and the prophylactic effect is superior to that obtained with a plasma IgG concentration of 3 g l-1.

Department of Medicine TTA, Rigshospitalet, Copenhagen, Denmark.


Study type




Roifman CM, Gelfand EW. Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in patients with hypogammaglobulinemia. The Pediatric infectious disease journal 1988; 7:S92-S96

Comparative study

Evaluate and compare high vs low dose therapy in patients with hypogammaglobulinemia and sinopulmonary disease.

To achieve minimum trough serum IgG levels of 500 mg/dl, 0.6 g/kg was administered every 4 weeks.

High dose therapy with immune serum globulin suitable for intravenous administration appears to be the treatment of choice in patients with sinopulmonary disease.

Division of Immunology and Rheumatology, Hospital for Sick Children, Toronto, Canada.

Roifman et al, Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency: a randomized double-blind trial, International Immunopharmacology 3 (2003) 1325- 1333.

Randomized, double-blind, parallel group, therapeutic equivalence trial.

Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in PID

172 PID patients aged 1-75 years, and receiving IGIV therapy were enrolled.

For 9 months, patients were treated with IGIV-C or IGIV-SD in accordance with the patient's individualized treatment regimen utilized before study entry.

No evidence of viral transmission was observed. IGIV-C appears to be superior to IGIV-SD in preventing validated sinopulmonary infections, especially acute sinusitis, in patients with PID.

Division of Immunology and Rheumatology, Hospital for Sick Children, Toronto, Canada.


Study type




Steele RW, Augustine RA, Steele RW, Tannenbaum AS, Charlton RK. A comparison of native and modified intravenous immunoglobulin for the management of hypogammaglobulinemia. American Journal of the Medical Sciences 1987; 293(2):69-74.

Double-blind, crossover protocol.

Compare native and modified intravenous immunoglobulin for the management of hypogammaglobulinemia.

10 Patients with severe hypogammaglobulinemia.

Patients received 6 monthly infusions of either native or modified intravenous immunoglobulin (IVIG) followed by 6 monthly infusions of the other product. Clinical parameters were monitored on a daily basis and serum was obtained at 24 hours, 3 weeks, and 4 weeks after each infusion for measurement of total IgG, specific antibodies, and opsonizing antibodies against Streptococcus pneumoniae types 5, 12F, and 14.

This study showed equivalent efficacy of native IVIG as compared with reduced and alkylated IVIG during maintenance therapy for hypogammaglobulinemia.

ANNEX 5


Study type




Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized, controlled clinical trial. New England Journal of Medicine 1988; 319(14):902-907.

double-blind study

Evaluate intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia.

84 Patients with chronic lymphocytic leukemia who were judged to be at increased risk of bacterial infection. Eligible patients had hypogammaglobulinemia, a history of infection, or both.

Patients received intravenous immunoglobulin G (400 mg per kilogram of body weight) or a placebo every three weeks for one year.

Selected patients with chronic lymphocytic leukemia who are at risk of bacterial infection can be substantially protected from this complication by the regular intravenous administration of immunoglobulin.

World-wide cooperative group for CLL c/o Dept Immunology , John Radcliffe Hospital, Oxford

Scientific and medical evidence demonstrating the effectiveness of immunoglobulins in the treatment of secondary immunodeficiencies


Study type




Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG.Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for Immunoglobulin Replacement Therapy in Multiple Myeloma.: Lancet. 1994 Apr 30;343(8905):1059-63.

'randomised, double-blind, placebo-controlled, multicentre trial

To evaluate intravenous immunoglobulin (IVIg) as prophylaxis against infection

82 patients with stable multiple myeloma

received monthly infusions of IVIg at 0.4 g/kg body weight or an equivalent volume of placebo (0.4% albumin) intravenously for 1 year

Infections by aetiology, type, severity,duration IVIg can be given safely to plateau-phase myeloma patients. It protects against life-threatening infections and significantly reduces the risk of recurrent infections. The individuals who benefit most can be identified prospectively by measuring IgG antibody responses to pneumococcal immunisation.

Dept Immunology , John Radcliffe Hospital, Oxford


Study type




Molica S, Musto P, Chiurazzi F, Specchia G, Brugiatelli M, Cicoira L, et al. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 81(2):121-6, 1996;-Apr.

crossover study

Investigation of the superiority of low-dose IVIG prophylaxis over empirical treatment of infections.

42 CLL patients with hypogammaglobulinemia (IgG < 600 mg/dL) and/or a history of at least one episode of severe infection in the 6 months preceding inclusion in the study.

Patients randomly allocated to receive either an infusion of 300 mg/kg IVIG every 4 weeks for 6 months or no treatment. Then they were switched to observation or IVIG for another 12 months; finally, they received IVIG or no therapy for 6 more months.

A protective effect against infections is demonstrated for low-dose IVIG in the present study. A benefit was shown in patients who completed either 12 or 6 months of IVIG prophylaxis.

Divisione di Ematologia, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy.


Study type




Chapel H, Dicato M, Gamm H, Brennan V, Ries F, Bunch C, et al. Immunoglobulin replacement in patients with chronic lymphocytic leukaemia: a comparison of two dose regimes. British Journal of Haematology 88(1):209-12, 1994.

Randomized double-blind study.

Determine prospectively the dose regime required for intravenous immunoglobulin (IVIg) therapy used prophylaxis against infection in patients with secondary hypogammaglobulinaemia due to a low-grade lymphoproliferative disease.

34 Patients received IVIg at either 500 or 250 mg/kg every 4 weeks for 1 year.

The rates of infection seen were similar to those in IVIg groups of previous studies and strikingly different from those in the placebo group in the previously randomized placebo-controlled study.

Department of Immunology, John Radcliffe Hospital, Oxford.

ANNEX 6


Study type




Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile. Pharmacol Ther. 2004 Jun;102(3):177-93

Observational report

Review of the evidence based indications and safety profile of IVIG in the treatment of neuromuscular diseases.

Future studies are needed to (a) find the appropriate dose and frequency of infusions that maintain a response; (b) address pharmacoeconomics, comparing the high cost of i.v.Ig to the cost of the other therapies, which, although less expensive, cause significantly more long-term side effects; (c) determine why some patients respond better than others; and (d) examine the merits of combining i.v.Ig with other immunosuppressive drugs.

Neuromuscular Diseases Section, National Institute of Neurological Diseases and Stroke, National Institutes of Health, MSC 1382, Room 4N248, Building 10, 10 Center Drive, Bethesda, MD 20892-1382, USA. [email protected]

Scientific and medical evidence demonstrating the effectiveness of immunoglobulins in the treatment of Guillain-Barré Syndrome and Chronic Inflammatory Demyelinating Polyneuropathy


Study type




Ephrem A, Misra N, Hassan G, Dasgupta S, Delignat S, Van Huyen JP, Chamat S, Prost F, Lacroix-Desmazes S, Kavery SV, Kazatchkine MD. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin. Clin Exp Med. 2005 Dec;5(4):135-40

Review Discussion on the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.

INSERM U430 and Universite Pierre et Marie Curie (UPMC-Paris 6), Hopital Broussais, 96 Rue Didot, 75014, Paris, France.


Study type




Fergusson D, Hutton B, Sharma M, Tinmouth A, Wilson K, Cameron DW, Hebert PC. Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review. Transfusion. 2005 Oct;45(10):1640-57

Systematic Review

A systematic review was conducted of randomized controlled trials (RCTs) evaluating IVIG for all neurologic indications for which there was at least one published trial.

Thirty-seven trials representing 14 conditions were identified

A systematic search strategy was applied to MEDLINE (1966-June 2003) and the Cochrane Register of Controlled Trials (June 2003) to identify potentially eligible RCTs comparing IVIG to placebo or an active control.

IVIG is more effective than placebo for treatment of relapsing-remitting multiple sclerosis and idiopathic chronic inflammatory demyelinating polyneuropathy. There is also potential benefit for treatment of multifocal motor neuropathy, myasthenia gravis, dermatomyositis, stiff-person syndrome, and Lambert-Eaton myasthenic syndrome.

Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada. [email protected]

Harel M, Shoenfeld Y. Intravenous immunoglobulin and Guillain-Barre syndrome. Clin Rev Allergy Immunol. 2005 Dec;29(3):281-7

Report Report on IVIg and GBS

The efficacy, safety, and availability of IVIg makes it the treatment of choice in many patients with GBS.

Department of Internal Medicine B and Research Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel.


Study type




Hughes RA, Raphael JC, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD002063

Systematic data review

Determine the efficacy of intravenous immunoglobulin for treating Guillain-Barre syndrome.

Included all randomised and quasi-randomised trials

Searched the Cochrane Neuromuscular Disease Group Trials Register (March 2005), MEDLINE (January 1966 to March 2005) and EMBASE (January 1980 to March 2005) using the terms 'Guillain-Barre syndrome' and 'acute polyradiculoneuritis'

Randomised trials in severe disease show that IVIg started within two weeks from onset hastens recovery as much as plasma exchange. Treatment with IVIg is significantly more likely to be completed than plasma exchange. In children, IVIg probably hastens recovery compared with supportive care alone.

Guy's, King's and St Thomas' School of Medicine, Department of Clinical Neuroscience, 2nd Floor, Hodgkin Building, Guy's Campus, London, UK, SE1 1UL. [email protected]


Study type




Hughes RA, Bouche P, Cornblath DR, Evers E, Hadden RD, Hahn A, Illa I, Koski CL, Leger JM, Nobile-Orazio E, Pollard J, Sommer C, Van den Bergh P, van Doorn PA, van Schaik IN. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2006 Apr;13(4):326-32

Consensus guidelines

Prepare consensus guidelines on the definition, investigation and treatment of CIDP

Disease experts and a patient representative considered references retrieved from MEDLINE and Cochrane Systematic Reviews in May 2004 and prepared statements which were agreed in an iterative fashion. The Task Force agreed on good practice points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered.

Statements which were agreed in an iterative fashion were prepared.

Guy's, King's and St Thomas' School of Medicine, Department of Clinical Neuroscience, 2nd Floor, Hodgkin Building, Guy's Campus, London, UK, SE1 1UL. [email protected]


Study type




Lavrnic D, Romic M, Kacar A, Stojanovic-Rakocevic V, Stevic Z, Vujic A, Basta I, Marjanovic I, Bogdanovic G, Apostolski S. [High doses of immunoglobulin G in the therapy for severe forms of myasthenia gravis and Guillain-Barre syndrome] Vojnosanit Pregl. 2006 Jan;63(1):37-42

Analytical report

Aim of this report was to present the clinics experience in the treatment of severe forms of myasthenia gravis (MG) and Guillain-Barre syndrome (GBS).

80 53 patients with severe forms of myasthenia gravis. 27 patients with very severe forms of Guillain-Barre syndrome.

Analyzed the efficacy and safety of immunoglobulin G therapy in patients with severe forms of myasthenia gravis and Guillain-Barre syndrome.

The study clearly demonstrated the high efficacy of IVIG therapy in the treatment of severe forms of myastehnia gravis and Guillain-Barre syndome.

Klinicki centar Srbije, Institut za neurologiju, Beograd


Study type




Nobile-Orazio E, Terenghi F. IVIg in idiopathic autoimmune neuropathies: analysis in the light of the latest results. J Neurol. 2005 May;252 Suppl 1:I7-13

Review Review of the effectiveness of IVIg in the treatment of idiopathic autoimmune neuropathies including GBS, CIDP, MMN, representing a useful option or, as in MMN, the gold standard for their treatment.

High-dose IVIg is effective in the treatment of idiopathic autoimmune neuropathies.

Department of Neurological Sciences, Giorgio Spagnol Service of Neuroimmunology, Dino Ferrari Centre and Centre of Excellence for Neurodegenerative Diseases, Milan University, 20089 Rozzano, Milan, Italy. [email protected]


Study type




Shahar E, Current therapeutic options in severe Guillain-Barre syndrome. Clin Neuropharmacol. 2006 Jan-Feb;29(1):45-51. Review.

Review article

Reviews the current immunomodulatory options in severe GBS.

In cases of severe GBS, IVIG is recommended as the first-line drug using a total empiric dose of 2 g/kg administered over 2 consecutive days, especially in children proven highly effective with negligible adverse effects.

Child Neurology Unit, Meyer Children Hospital, Rambam Medical Center, Rappaport School of Medicine, Haifa, Israel. [email protected]

Steck AJ. Use of intravenous immunoglobulin in neurological disorders. Rev Med Suisse. 2005 Apr 27;1(17):1167-70

Report The use of IVIg in the treatment of GBS, CIDP and MMN is well established. Other conditions, such as dysglobulinemic neuropathy, myasthenia gravis, multiple sclerosis and inclusion body myositis may also benefit from the administration of intravenous immunoglobulins.

Service de neurologie, Hopital universitaire de Bale, 4031 Bale. [email protected]


Study type




Yata J, Nihei K, Ohya T, Hirano Y, Momoi M, Maekawa K, Sakakihara Y; Study Group for Pediatric Guillain-Barre Syndrome. High-dose immunoglobulin therapy for Guillain-Barre syndrome in Japanese children. Pediatr Int. 2003 Oct;45(5):543-9.

Open-labeled study

Evaluate the efficacy of IVIg in the treatment of paediatric GBS in Japan.

11 Younger than 15 years old, and diagnosed as having moderate or severe GBS.

IVIg (400 mg/kg per day) was administered to patients for five consecutive days. Predefined outcome measures were defined on a seven-point scale of motor function (Hughes' functional grade [FG]).

IVIg is a safe and effective treatment for childhood GBS, which shortens the time to recovery.

Zeidman LA, Fahey CD, Grinblatt DL, Harsanyi K. Immunoglobulin for concurrent Guillain-Barre and immune thrombocytopenic purpura. Pediatr Neurol. 2006 Jan;34(1):60-2

Case study

Present a patient with both conditions who experienced prompt resolution of neurologic and hematologic sequelae after intravenous immunoglobulin therapy was initiated within 12 hours of presentation.

1 Patient has both ITP and GBS.

Experienced prompt resolution of neurologic and hematologic sequelae after intravenous immunoglobulin therapy was initiated within 12 hours of presentation.

Case provides further evidence that GBS and ITP can occur simultaneously and that the prompt initiation of intravenous immunoglobulin is an effective monotherapy leading to prompt resolution of both conditions and prevention of further sequelae.

McGaw Medical Center of Northwestern University, Chicago, Illinois, USA.

�

ANNEX 7


Study type




Beck C.E., Nathan P.C., Parkin P.C., Blanchette V.S., Macarthur C. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials

Review and meta-analysis of randomized controlled trials.

Compare the effectiveness of corticosteroids with intravenous immune globulin (IVIG) for the initial treatment of children with acute immune thrombocytopenic purpura (ITP).

1248 abstracts were reviewed, 55 articles were retrieved, and 10 studies were included.

Studies were identified from eight electronic databases, meeting abstracts, expert consultation, and hand-searched reference lists. Two authors independently reviewed potentially eligible studies and extracted data.

Children treated with corticosteroids for acute ITP are 26% less likely to have a platelet count >20,000/mm3 after 48 hours of therapy, when compared with children treated with IVIG. Given the importance of low platelets in the pathogenesis of intracranial hemorrhage (ICH), this difference may hold important clinical implications.

Division of Paediatric Medicine, The Hospital for Sick Children, and the University of Toronto, Toronto, Ontario, Canada. [email protected]

Scientific and medical evidence demonstrating the effectiveness of immunoglobulins in the treatment of Idiopathic (Immune) Thrombocytopenic Purpura


Study type




Diaz Conradi A., Diaz de Heredia C., Tusell Puigbert J., Quintana Riera S., Tobena Boada L., Ortega Aramburu J.J. Chronic and recurrent immune thrombocytopenic purpura. An Pediatr (Barc). 2003 Jul;59(1):6-12. Spanish.

Retrospective and descriptive study.

Assess the outcome and treatment response in patients with chronic or recurrent ITP.

38 16 (42 %) presented chronic forms and 22 (58 %) presented recurrent forms of ITP.

Performed a retrospective, descriptive study of patients attended in the pediatric hematology outpatient clinic between January 1999 and December 2001.

The most effective treatment for recurrent forms of ITP was IVIg. In chronic forms, splenectomy is an effective alternative when the risk of hemorrhage is high, while a watchful attitude seems to be the best option when this risk is absent. Although the number of patients treated with intravenous anti-D immune globulin was low, good results were achieved.

Hospital Mutua de Terrassa. Barcelona. Spain. [email protected]


Study type




Ephrem A, Misra N, Hassan G, Dasgupta S, Delignat S, Van Huyen JP, Chamat S, Prost F, Lacroix-Desmazes S, Kavery SV, Kazatchkine MD. Immunomodulation of autoimmune and inflammatory diseases with intravenous immunoglobulin. Clin Exp Med. 2005 Dec;5(4):135-40.

Review Discussion on the mechanisms by which IVIg exerts immunomodulatory effects in immune pathologies.

INSERM U430 and Universite Pierre et Marie Curie (UPMC-Paris 6), Hopital Broussais, 96 Rue Didot, 75014, Paris, France.


Study type




Sandoval C., Visintainer P., Ozkaynak M. F., Tugal O., Jayabose S. Clinical features and treatment outcomes of 79 infants with immune thrombocytopenic purpura. Pediatr Blood Cancer. 2004 Jan;42(1):109-12

Retrospective analysis

Determine the clinical features and treatment outcomes of infants with immune thrombocytopenic purpura (ITP).

79 Infant ITP patients treated from 1987 to 2002.

The data abstracted comprised age, gender, clinical features, and treatment outcomes. A score test for the trend in the odds ratios was used to determine the risk of chronic ITP with advancing age. The infants were compared to a group of contemporaneous older children with regard to bleeding severity and incidence of chronic ITP.

Infants with ITP respond favorably to treatment and are less likely to develop chronic ITP compared to older children.

Department of Pediatrics and the Graduate School of Health Sciences, New York Medical College, Valhalla, New York 10595, USA. [email protected]

Zeidman LA, Fahey CD, Grinblatt DL, Harsanyi K. Immunoglobulin for concurrent Guillain-Barre and immune thrombocytopenic purpura. Pediatr Neurol. 2006 Jan;34(1):60-2

Case study

Present a patient with both conditions who experienced prompt resolution of neurologic and hematologic sequelae after intravenous immunoglobulin therapy was initiated within 12 hours of presentation.

1 Patient has both ITP and GBS.

Experienced prompt resolution of neurologic and hematologic sequelae after intravenous immunoglobulin therapy was initiated within 12 hours of presentation.

Case provides further evidence that GBS and ITP can occur simultaneously and that the prompt initiation of intravenous immunoglobulin is an effective monotherapy leading to prompt resolution of both conditions and prevention of further sequelae.

McGaw Medical Center of Northwestern University, Chicago, Illinois, USA.

ANNEX 8


Study type




Aghamohammadi A, Farhoudi A, Nikzad M, Moin M, Pourpak Z, Rezaei N, Gharagozlou M, Movahedi M, Atarod L, Afshar AA, Bazargan N, Hosseinpoor AR. Adverse reactions of prophylactic intravenous immunoglobulin infusions in Iranian patients with primary immunodeficiency. Ann Allergy Asthma Immunol. 2004 Jan;92(1):60-4

Observational

To evaluate the adverse reactions of intravenous immunoglobulin therapy in patients with primary immunodeficiency

71 common variable immunodeficiency (31 patients), X-linked agammaglobulinemia (25 patients), IgG subclass deficiency (5 patients), hyper-IgM syndrome (2 patients), and ataxia-telangiectasia (8 patients)

Infused with intravenous immunoglobulin

Intravenous immunoglobulin is a well tolerated medical agent for patients with antibody deficiency. However, to prevent occurrence of immediate adverse reactions during infusion in these patients, physicians should perform a detailed history and proper physical examination and check the titer of anti-IgA

Department of Allergy and Clinical Immunology of Children's Medical Center, Immunology Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Clinical evidence demonstrating the safety of immunoglobulins


Study type




Brennan VM, Salome-Bentley NJ, Chapel HM; Immunology Nurses Study.Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin.: Clin Exp Immunol. 2003 Aug;133(2):247-51.

Observational

To evaluate the adverse reactions of intravenous immunoglobulin therapy in patients with primary immunodeficiency

13,508 infusions in 459 patietns

children and adults who received infusions from medical or nursing staff as well as those self-infusing IVIg for PIDs


no severe reactions occurred and the reaction rate was low at 0.8%. This figure could have been lower, 0.5%, if predisposing factors responsible for some reactions had been considered before infusion.

Dept of Immunology, John Radcliffe Hospital, Oxford, UK

Brennan VM, Cochrane S, Fletcher C, Hendy D, Powell P.Surveillance of adverse reactions in patients self-infusing intravenous immunoglobulin at home.J Clin Immunol. 1995 Mar;15(2):116-9.

Observational

To evaluate adverse reactions occurring in primary-antibody-deficient patients self-infusing intravenous immunoglobulin at home

2031 infusions in 119 patients

primary-antibody-deficient patients self-infusing intravenous immunoglobulin at home


There were 19 events in 2031 infusions, and all resolved without medical aid. No serious reactions occurred. Excluding those reactions in which predisposing factors were identified, the overall reaction rate was 0.7%.

UK Nurses group, c/o Dept of Immunology, John Radcliffe Hospital, Oxford, UK


Study type




Björkander et al, Prospective open-label study of pharmacokinetics, efficacy and safety of a new 10% liquid IVIG in patients with hypo- or agammaglobulinemia, Vox Sanguinis (2006) 90, 286-293.

Prospective, open-label, non-controlled, multicentre study

Evaluate the pharmacokinetics, efficacy and safety of a newly developed 10% liquid immunoglobulin preparation in patients with primary immunodeficiency diseases.

22 A total of 194 infusions with the new 10% liquid immunoglobulin preparation were administered.

The new 10% liquid immunoglobulin preparation was well tolerated and shown to have an excellent pharmacokinetic, efficacy and safety profile. The liquid formulation provides convenience to patients and healthcare professionals.

SU/Sahlgrenska, Gothenburg, Sweden.

Chapel H.et al The comparison of the efficacy and safety of intravenous versus subcutaneous Ig replacement therapy. Clin.Immunol.2000;20:94-100

An international, multicenter, open label, crossover study.

To compare the efficacy of immunoglobulin replacement therapy given intravenously versus subcutaneously to prevent infections in patients with primary antibody deficiency syndromes.

40 Patients were randomized to receive either subcutaneous or intravenous immunoglobulin replacement therapy for 1 year. In the second year, patients were switched to the alternative treatment, enabling patients to act as their own controls.

There are no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.



Study type




Gardulf A. et al Subcutaneous immunoglobulin replacements in patients with primary ID: Safety and costs. Lancet 1995; 345: 365�69

Collect information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes and compare costs between the different replacement regimes.

165 69 women, 96 men, aged 13-76 years with primary hypogammaglobulinaemia or IgG-subclass deficiencies

Data were compiled from questionnaires filled in by the patients and from their medical records.

Subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. It was possible to reach serum IgG concentrations similar to those by the intravenous therapy and it was found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.

Department of Clinical Immunology, Karolinska Institute, Huddinge University Hospital, Sweden


Study type




Gardulf A, Nicolay U, Asensio O, Bernatowska E, Bock A, Carvalho BC, Granert C, Haag S, Hernandez D, Kiessling P, Kus J, Pons J, Niehues T, Schmidt S, Schulze I, Borte M. Rapid Subcutaneous IgG Replacement Therapy is Effective and Safe in Children and Adults with Primary Immunodeficiencies-. J Clin Immunol. 2006 Apr 26; [Epub ahead of print]

A Prospective, Multi-National Study

Evaluate (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation.

60 16 children, 44 adults

All patients received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls.

The SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections

Department of Laboratory Medicine, Section of Clinical Immunology, The Swedish Centre for Immunodeficiencies, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. [email protected]

Harel M, Shoenfeld Y. Intravenous immunoglobulin and Guillain-Barre syndrome. Clin Rev Allergy Immunol. 2005 Dec;29(3):281-7.

Report Its efficacy, safety, and availability make IVIg the treatment of choice in many patients with GBS.

Department of Internal Medicine B and Research Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel.


Study type




Kempf C, Stucki M, Boschetti N.Pathogen inactivation and removal procedures used in the production of intravenous immunoglobulins. Biologicals. 2006 Mar 30; [Epub ahead of print]

Report State-of-the-art manufacturing processes provide a high safety standard by incorporating virus elimination procedures into the manufacturing process. Based on their mechanism these procedures are grouped into three classes: partitioning, inactivation, and virusfiltration

ZLB Behring AG, Wankdorfstr. 10, CH-3000 Bern 22, Switzerland; Department of Chemistry & Biochemistry, University of Bern, Freiestr. 3, CH-3012 Bern, Switzerland

Lavrnic D, Romic M, Kacar A, Stojanovic-Rakocevic V, Stevic Z, Vujic A, Basta I, Marjanovic I, Bogdanovic G, Apostolski S. [High doses of immunoglobulin G in the therapy for severe forms of myasthenia gravis and Guillain-Barre syndrome] Vojnosanit Pregl. 2006 Jan;63(1):37-42

Analytical report

To present our experience in the treatment of severe forms of myasthenia gravis (MG) and Guillain-Barre syndrome (GBS)

80 53 patients with severe forms of myasthenia gravis, and 27 patients with very severe forms of Guillain-Barre syndrome.

Analyzed the efficacy and safety of immunoglobulin G therapy.

The investigation clearly demonstrated the high efficacy of IVIG therapy in the treatment of severe forms of myastehnia gravis and Guillain-Barre syndome.

Klinicki centar Srbije, Institut za neurologiju, Beograd


Study type




Tabor E., The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1, Transfusion, Volume 39, 11-12/99

Report There has been no transmission of HBV, HCV, or HIV by US-licensed plasma derivatives since the introduction of effective virus-inactivation procedures. This means, essentially, that there has been no transmission of these viruses since the end of 1987; the sole exception is IGIV, by which there has been no transmission since 1994.

Office of Blood Research and Review, Food and Drug Administration, Bethesda, Maryland, USA.


Study type




Wolf H.H., Davies S.V., Borte M., Caulier M.T., Williams P.E., Bernuth H.V., Egner W., Sklenar I., Adams C., Spath P., Morell A., Andresen I. Efficacy, tolerability, safety and pharmacokinetics of a nanofiltered intravenous immunoglobulin: studies in patients with immune thrombocytopenic purpura and primary immunodeficiencies. Vox Sang. 2003 Jan;84(1):45-53

Phase II/III studies

Demonstrate the efficacy, safety and pharmacokinetics of the modified product, comparing the nanofiltered IVIG (IVIG-N) with its parent product, Sandoglobulin, in patients with chronic ITP and PID.

63 ITP (n = 27) ITP patients with platelet counts of < 20 x 10(9)/l were treated with Sandoglobulin or IVIG-N infusions at a dose of 0.4 g/kg body weight on five consecutive days. PID patients were treated for 6 months with Sandoglobulin or IVIG-N at doses of 0.2-0.8 g/kg, infused at 3- or 4-week intervals.

IVIG-N is efficacious, well tolerated and safe in patients with ITP and PID. Its pharmacokinetic properties were comparable to those of Sandoglobulin.

Department of Haematology and Oncology, University Hospital, Halle, Germany.

European Commission

European Primary ImmunodeficienciesConsensus Conference

ConsensusStatement

EU PID Consensus Conference 2006

Executive Summary On 19-20 June 2006, the International Patient Organisation for Primary Immunodeficiencies (IPOPI), the European Society for Immunodeficiencies (ESID), the International Nurses Group for Immunodeficiencies (INGID) and the European Federation for Immunological Societies (EFIS) in partnership with the European Commission, held a two-day Consensus Conference on Primary Immunodeficiencies (PIDs) at the Paul-Ehrlich-Institut in Langen, Germany.

More than 100 experts in clinical immunology, PID care, public health, genetics, EU/national ministries of health and agencies, academic centres, public health laboratories, industry, professional organisations and patient groups were brought together to identify and develop public health strategies for PID.

PIDs are a diverse group of more than 100 immune disorders, many of which result from single-gene defects. The defects lead to increased susceptibility to recurrent and persistent infections. If PIDs are left un/misdiagnosed, the immune system remains compromised leading to chronic illness, disability, reduced working capacity, decreased quality of life for patients and families, permanent organ damage or even death.

At the conference, the multi-discipline experts concluded that;

PIDs are widely undiagnosed and there is a lack of awareness of PID among the general public, healthcare professionals, healthcare policy makers and implementers.

Effective therapies for PIDs exist and early treatment saves lives, prevents morbidity and improves quality of life. There is also evidence that early treatment is cost effective.

There is a significant disparity of care within and across EU member states.

The multi-discipline experts developed a Consensus Statement containing these conclusions and also approved a series of recommendations that focus on three key areas where priority action is needed to be taken by Member State governments of the EU;

Awareness and education

Clinical protocols to reliably identify PIDs Epidemiological studies into the prevalence and incidence of PIDs and

their impact on public health and costs.

www.eupidconference.com

International patient registries expanded to assess the clinical presentation, natural history and genetic patterns of PIDs.

Health campaigns developed to raise awareness of PIDs among the general public.

Education programmes targeting the general public, healthcare professionals and healthcare policy makers and implementers.

Screening and diagnosis.

Practical tools for efficient diagnosis of PID made available in every country.

Evaluation of diagnostic tools for PID and research into the feasibility of screening programmes to prevent damage.

Treatment and management.

EU guidelines developed to provide equal access to treatment and assure an optimum standard and quality of patient care in the appropriate treatment setting.

Cross country initiatives set up to allow exchange of expert experience and education.

EU treatment centre networks established in order to determine disease outcomes.

Safe immunoglobulin treatments available to all patients who require antibody replacement.

The following report includes the full Consensus Statement and summaries of the presentations given at the EU PID Consensus Conference. Full copies of the presentations and further details can be found at the conference web site: www.eupidconference.com.


European Primary Immunodeficiencies Consensus Statement

In partnership with the European Commission, the International Patient

Organisation for Primary Immunodeficiencies (IPOPI), the European Society

for Immunodeficiencies (ESID), the International Nurses Group for

Immunodeficiencies (INGID) and the European Federation for Immunological

Societies (EFIS) held a two-day EU Consensus Conference on Primary

Immunodeficiencies (PIDs) on 19-20 June 2006 at the Paul-Ehrlich-Institut in

Langen, Germany.

Attending this conference were representatives drawn from physician, patient,

nurse, industry and health policy maker networks from across the EU.

Together, the expert attendees of this conference agreed this Consensus

Statement on PIDs which focuses on:

The extent of the negative impact PIDs currently have on healthcare

systems and undiagnosed patients.

The disparities of care and treatment that exist for people with PIDs across

the EU.

Examples of immediate actions and initiatives that EU Member State

governments can take to reduce the burden of PIDs in three key areas:

1. Awareness and Education

2. Screening and Diagnosis

3. Treatment and Management


1. Awareness & Education

Consensus Statement

I. General public

There is a lack of awareness of PIDs amongst the general public, There is misunderstanding of the impact of PIDs on schooling, work and

social life of individual patients, The huge differences between PIDs and HIV/AIDS are not understood.

II. Healthcare professionals

Due to a failure to include applied Immunology within professional training programmes, there is a lack of awareness of PIDs by:

o First line healthcare professionals (family GPs, doctors, nurses, midwives) i.e. lack of awareness of symptoms,

o Secondary healthcare professionals (doctors in community and teaching hospitals) i.e. lack of understanding of availability and efficacy of treatments,

o Allied professionals (physiotherapists, dieticians, genetics nurse specialists, pharmacists, psychologists, dentists).

III. Healthcare policy makers and implementers

There is a lack of awareness among healthcare policy makers, at national and EU level of the negative impact on healthcare resources caused by the chronic under diagnosis of PIDs,

There is a lack of understanding of the level of disease prevention that could be obtained if PIDs were adequately diagnosed.

Recommendations for Action:

I. General public To increase awareness of PIDs, public health campaigns and educational programmes are needed; this is enabled by development, implementation and evaluation of:

Updated, translated (for non-native speakers) and adjusted (for special groups) material used for the recognition of potential patients,

Material suitable for primary school curricula, including books, leaflets, letters for parents and information for school nurses to distribute,

Material suitable for public health campaigns worldwide; this might include awareness days, as well as standard TV, print and internet advertisements to be used (with translations) in all EU member states,


Inclusion of a PIDs story line in national TV soap-operas.

II. Healthcare professionals

To increase awareness of PIDs, better education is needed; this is enabled by:

Provision of standards for basic and applied immunology training in the core content for medical & nursing schools, with particular emphasis on PIDs,

Coupling nurse education with protocols for vaccine failures and recognition of excessive numbers of infections,

Integrating basic and applied immunology teaching, particularly alongside immunisation, into programmes for training fellows in general paediatric internal medicine, rheumatology, respiratory medicine, and infectious disease,

Distribute information used for education of all groups on accessible websites,

Enabling accrual of educational credits from shared material, Reciprocation of information on PIDs, including guidelines and education,

at professional meetings of related medical specialties, Including PIDs as a topic in continued professional development for

related medical specialists in career posts, physiotherapists, nurses and midwives.

III. Healthcare policy makers and implementers at EU and national levels i.e. EU level: Institutions, Parliament, Member states, EMEA. National level: regulators, legislators, national advisory bodies, Insurers. Worldwide level: WHO, pharmaceutical companies, vaccine manufacturers

To increase awareness of PIDs by:

Studies on impact of diseases and therapy, coupled with epidemiology, public health impact and cost effectiveness studies to demonstrate savings and improvement in quality of life,

Strong patient organisations in all EU countries, with identification of prominent patient advocates,

Easily accessible information for health managers/insurers, Regular publications from national registries.


2. Screening & Diagnosis

Consensus Statement

PIDs are widely under diagnosed. Early identification of PIDs will: Save lives, Improve health, quality of life, and lifespan in identified patients through

adequate treatment, Enable genetic counseling and prenatal diagnosis within the family. Tools for identification of PIDs are: Diagnostic guidelines for recognition of symptomatic patients, Appropriate immunologic and genetic laboratory tests, Screening tests for suitable diseases. Recommendations for Action:

I. Gathering Information

Clinical protocols are needed to reliably identify PIDs; these can be created by development, implementation and evaluation of: Diagnostic guidelines on a scientific basis, Standardised diagnostic criteria for PIDs. Assessment of the impact of PIDs on the community is needed; this is enabled by epidemiologic studies to assess: The prevalence and incidence of PIDs in the population, The impact of PIDs on public health, The impact of PIDs on health care costs. International PID registries enable future diagnostic processes by identifying: The pattern of clinical presentation of these diseases, The natural history of the various PIDs (morbidity, mortality,

complications), Relationships between clinical disease patterns and genetic backgrounds.

II. Appropriate Diagnostic Tools

Practical tools for efficient diagnosis of PIDs are needed in every country; this is enabled by availability of: Simple diagnostic tests at the local level, Immunologic tests in specialist diagnostic centres at the national level,


Elaborate tests through networks of excellence across Europe. Appropriate evaluation of diagnostic tools is needed; this is enabled by: Development of age-matched reference values for all diagnostic

immunologic tests, Regular quality control of immunologic laboratories. Research on the feasibility of screening programmes for PIDs is needed to prevent damage, including: Development of suitable tests, Assessment of costs and benefits, Evaluation of ethical aspects, Development of management guidelines for identified patients. 3. Treatment & Management

Consensus Statement

Effective therapies for PIDs exist. Early treatment saves lives, prevents morbidity and improves quality of life. Experts have reported that early treatment of PIDs is cost effective. Safety of immunoglobulin treatments are a priority. There is a significant disparity of care within and across EU Member States: There is a lack of specialised care in many countries, There are wide variations in the availability and funding of existing

therapies, The availability of self treatment at home is inconsistent throughout the

EU. There are not enough trials for new therapeutic strategies. Variation in methods in post marketing surveillance trials of products makes effective comparative analysis difficult.

Recommendations for Action:

I. Guidelines

Develop and implement European guidelines to ensure equal access to treatment within the EU for those with PIDs, assuring an optimum standard and quality of patient care in the appropriate treatment setting.


II. Education & Expertise Exchange

Cross country initiatives should be developed to allow the exchange of expert experience and education in order to: Organise specialist nurse/midwife training courses in the EU, Fund medical & nurse specialists to visit other immunology centres, Educate related healthcare professionals, Support the on-going development of the ESID registry.

III. Centre Networks

EU diagnosis and treatment centre networks should be established to develop methods in order to determine disease outcomes through: Standardising clinical trials and post marketing surveillance, Using the online professional registry facility from ESID.

IV. Treatment

Adequate funding should be made available to provide: Optimum levels of treatment in each EU Member State, Safe immunoglobulin treatments, The appropriate supply of treatment, specifically immunoglobulins, for PID

patients requiring this life saving therapy.


�

ANNEX 10

IPOPI Questionnaire Results

The value and importance of early diagnosis and proper treatment of immunodeficiencies 1. Do you regularly see patients with an immunodeficiency who have spent years being treated for symptoms but not for the underlying cause, because of an incorrect diagnosis? YES = 100% Note: Yes but becoming less frequent than ten years ago (Scotland) 2a. Age Range - First diagnosis of an immune deficiency (years of age) COUNTRY HOSPITAL 0-5 5-15 15-25 25-45 45-65 > 65 South Africa Tygerberg

Children’s Hospital X

Iran Children Medical Center Hospital, Tehran

X

India Chandigarh Hospital X

Hong Kong Queen Mary Hospital X

Spain Vall d’Hebron Hospital, Barcelona

X

Scotland Western Infirmary Hospital, Glasgow X

Total in % 16,6 66,6 16,6

2b. # Years of symptoms before diagnosis was made (years) COUNTRY HOSPITAL 0-2 2-4 4-6 6-10 > 10 > 20 South Africa Tygerberg



X




X

Scotland Western Infirmary Hospital, Glasgow

Ranges vary widely with even distribution (from months to 20 years)

Total in % 20 60 20

3. When treated with immunoglobulins, do patients with an immunodeficiency need less medical care? 83,4 % = YES 16,6% = They require different care with a different emphasis. Not certain that total and presumably nursing time is less. 4. Infection rate of PID patients not treated with immunoglobulin replacement therapy (number of times per year) COUNTRY HOSPITAL < 1 1-2 2-5 5-10 > 10 South Africa Tygerberg



X




X


Total in % 33,3 50 16,6

5. Most common infection types developed by PID patients who are not on immunoglobulin replacement therapy Sinusitis, Otitis Media, Pneumonia, respiratory infections, GI infection, CNS infection, gastrointestinal infections, skin infections, encapsulated bacteria, diarrhea, conjunctival infections

6a. RATE OF HOSPITALIZATION - PATIENTS WITH SEVERE IMMUNODEFICIENCY WHO ARE NOT TREATED WITH IMMUNOGLOBULIN COUNTRY HOSPITAL < 1 in 5

years 1-2 in 5 years

1-2 in 2 years

1-2 in 1 year

2-5 in 1 year

> 5 in 1 year

South Africa Tygerberg Children’s Hospital X


X




X


X (But

variable)

Total in % 16,6 16,6 66,6

6b. RATE OF AMBULATORY CARE - PATIENTS WITH SEVERE IMMUNODEFICIENCY WHO ARE NOT TREATED WITH IMMUNOGLOBULIN COUNTRY HOSPITAL < 1 in 1

year 1-2 in 1 year

2-5 in 1 year

5-10 in 1 year

> 10 in 1 year

South Africa Tygerberg Children’s Hospital X


X




X


X (Depends on family doctor)

Total in % 50 50

7. IMPACT OF TREATEMENT WITH IMMUNOGLOBULIN ON QUALITY OF LIFE COUNTRY HOSPITAL None Poor Significant Very

significant South Africa Tygerberg



X




X


Total in % 100

8. In your experience, would you say that immunoglobulin replacement therapy for patients with an immunodeficiency is cost-effective as unnecessary costs such as use of antibiotics, increased hospitalization and ambulatory care are avoided? 84,4% = YES 16,6% = It is cost effective due to a broader range of socio-economic benefit that are not just limited to healthcare costs e.g. social insurance / security payments etc (Scotland)

PRIMARY IMMUNE DEFICIENCY DISEASES IN AMERICA

THE FIRST NATIONAL SURVEY OF PATIENTS AND SPECIALISTS

Prepared by: Schulman, Ronca & Bucuvalas, Inc.

Provided by an educational grant from Bayer Corporation.


1

Background: Immune Deficiency Diseases

Primary immune deficiency diseases represent a class of disorders in which there is an intrinsic defect in the human immune systems (rather than immune disorders that are secondary to infection, chemotherapy, or some other external agent). In some cases, the body fails to produce any or enough antibodies to fight infection. In other cases, the cellular defenses against infection fail to work properly. There are more than 80 different primary immune deficiency diseases currently recognized by the World Health Organization. Medical recognition of primary immune deficiency disease is only fifty years old. Although these disorders may have existed in antiquity, it was not until the development of antibiotics that infections could be controlled long enough to recognize there was an underlying defect in the immune system. Also, the parallel development of gamma-globulin in World War II provided a replacement therapy for the antibody deficiency forms of immune deficiency. Although primary immune deficiency diseases are often described as rare disorders, the true population prevalence of these diseases, either individually or in the aggregate, is not well established. The major health surveys conducted by the government in the United States, the National Health Interview Survey and the National Health and Nutrition Examination Survey, do not collect information on primary immune deficiency diseases. No comprehensive population survey has even been undertaken by the federal government to estimate the prevalence or the population characteristics of these diseases in the United States. Hence, although these diseases are clinically described in the medical literature, there is no comprehensive portrait available of the patient with primary immune deficiency disease. Survey of Patients with Primary Immune Deficiency Diseases

In 1995, the Immune Deficiency Foundation undertook the first national survey of the state of primary immune deficiency diseases in the United States. The survey has a number of objectives. First, the survey sought to provide an estimate of the general magnitude of primary immune deficiency in the American population, if not a precise estimate of population prevalence. Second, the survey sought to describe the general population characteristics of persons with these disorders. Third, the survey sought to describe the health of persons with primary immune deficiency diseases, both with and without treatment. Fourth, the survey sought to identify problems in access to treatment in this population. All of these goals are related to the primary objective of the Immune Deficiency Foundation: improving the diagnosis and treatment of persons with primary immune deficiency diseases. The survey was designed for IDF by Schulman, Ronca and Bucuvalas, Inc. (SRBI), a national public opinion research organization. SRBI analyzed the survey data and prepared their report for the Foundation.


2

The survey was designed within the constraints of primary immune deficiency diseases. In the absence of a rigorous set of symptom criteria that would uniquely define primary immune deficiency disease, the survey population must be restricted to the sub-population who already has a diagnosis of primary immune deficiency disease. Many persons with immune deficiency diseases may be relatively asymptomatic. Others may have chronic and/or unusual infections that are the hallmark of immune deficiency, but have not yet been diagnosed with the underlying disorder. This survey is restricted to the population who have been tested and diagnosed with a primary immune deficiency disease. No clinical confirmation of the diagnosis has been incorporated into the study, so the survey is restricted to persons who report a physician diagnosis of a primary immune deficiency disease. Since primary immune deficiency diseases are comparatively rare, and diagnosed cases of the condition will be rarer still, population screening to obtain a national sample of persons with these disorders was not feasible. However, it is possible to develop a relatively complete sampling frame for physicians who are most likely to treat these disorders. So, a multi-stage sampling strategy was developed to obtain a large, national sample of persons diagnosed with primary immune deficiency diseases. The first stage in the sampling process was to construct a sampling frame of the specialists who were most likely to follow patients with primary immune deficiency diseases. This includes the major medical associations and societies of specialties related to immune diseases (immunology and infectious diseases), chairmen of pediatric departments in medical centers, and previously identified treating physicians in IDF mailing lists and registries. The combined sampling frame included a total of 17,451 physicians (Figure 1). The second stage in the sampling process was to conduct a systematic survey of this population to identify the sub-population who currently sees patients with primary immune deficiency diseases. The survey identified the most common of these disorders by name in order to reduce ambiguity about which disorders are primary immune

Figure 1SAMPLING FRAME FOR SPECIALISTS

• APS/Society for Pediatric Research 2,448• American Academy of Pediatrics

(Allergy and Immunology Sections) 1,073• American Academy of Allergy and Immunology 4,402• American Society for Clinical Investigations 2,251• Infectious Disease Society of America 3,839• Clinical Immunology Society 956• Pediatric Department Chairman 233• IDF Mailing List Physicians 2,410• CGD Registry Physicians 4,114• TOTAL UNDUPLICATED CASES 17,451


3

Figure 2Number of Patients Seen with PID

N um ber of PIDs Seen

Specialists w ith PIDS

Total PIDs

1-4 632

5-9 353

10-14 149

15-24 145

25-49 103

50+ 105

TOTAL 1,502 21,312

Source: IDF Survey of Specialists

deficiency diseases. A total of 1,502 physicians from the sampling frame reported that they were currently treating one or more patients with these disorders. The third stage in the sampling process was to send patient questionnaires to these physicians for distribution to their patients with primary immune deficiency disease. In addition, this questionnaire was sent to all self-identified patients in the IDF database. A total of nearly 3,000 questionnaires were completed and returned by unique patients. This includes 1,289 adult patients, 1,190 parents or guardians of children with primary immune deficiency diseases, and 335 where the respondent did not identify themselves as the patient or caregiver. The sampling frame used for the survey does not provide complete coverage of physicians treating patients with primary immune deficiency diseases, nor by extension the patients themselves. The multi-stage sampling process introduces opportunity for non-sampling bias, even among the truncated sampling frame. In the absence of any denominator for the number of questionnaires distributed to eligible patients, we cannot estimate the response rate to the patient survey or adjust for non-response bias. Nonetheless, the sampling and field procedures produced a large, geographically diverse and relatively unclustered sample of persons with primary immune deficiency diseases in the United States. Although it is less than a perfect sample, it will remain the definitive sample until a better one can be obtained. Size of the Population of Primary Immune Deficiency Diseases The survey of specialists identified approximately 1,500 doctors who saw patients with primary immune deficiency diseases. Nearly half of these specialists reported that they saw four or fewer patients with these diseases. Two thirds of treating specialists reported that they followed less than ten of these patients. However, more than 100 specialists reported that they saw 50 or more primary immune deficient patients in their practice. In summary, 1,502 specialists in the United States reported that they were currently following a total of more than 21,000 patients with primary immune deficiency diseases (Figure 2).


4

Figure 4How Many Persons with PID in US?

• Specialists report 21,312–May be some double counting within groups–Less than half of specialists with patients returned survey

• Primary care estimate is at least 25,000–Some may have more than one PID patient–Unlikely to be double counting within primary care–May be some double counting between primary care doctors and specialists

BEST GUESS IS 50,000 DIAGNOSED CASES

A national survey of primary care doctors provides supplementary estimates of the number of patients with primary immune deficiency diseases. Among adult primary care specialties, approximately one in ten doctors in direct patient care on an outpatient

basis reported having one or more patients with primary immune deficiency diseases. One in five pediatricians reported having one or more patients with a primary immune deficiency disease. If we assume the minimum number of one patient per physician, this survey would yield an estimated 24,500 patients with primary immune deficiency disease being treated by primary care doctors (Figure 3).

How many persons within the United States have been diagnosed with a primary immune deficiency disease? The sample survey of specialists yields an absolute count of 21,000 patients followed by specialists. The sample survey of primary care doctors yields a population projection of 24,500 cases, assuming one patient per doctor. There may be some double counting of patients between specialists in group practices, as well as double counting of patients who are seen by both specialists and primary care doctors. At the same time, approximately half of the specialists known to the Immune Deficiency Foundation as treating patients did not respond to the survey. So, although the number of patients with primary immune deficiency diseases in the United States cannot be projected with any statistical certainty, a total of 50,000 diagnosed cases would be a reasonable estimate (Figure 4).

Figure 3Primary Care Doctors and PID’s

SPECIALTY NUMBER INDIRECT PATIENTCARE

PERCENTwith PID*

Minimumestimate ofPID’s

GeneralPractice

15,842 10% 1,582

FamilyPractice

49,902 10% 4,990

OB/GYN 30,296 12% 3,636

InternalMedicine

76,628 9% 6,897

Pediatrics 37,125 20% 7,425

TOTAL 209,793 24,532

Source: National Survey of Genetic Issues, National Center for Genome Resources, N=521.


5

Characteristics of the Patient Population

An estimate of the relative distribution of the primary immune deficiency diseases by diagnosis is provided by the specialist survey. The specialists were asked how many patients they were seeing by major diagnosis.

The most commonly reported primary immune deficiency diseases were:

Common Variable Immune Deficiency (5,291), Selective IGA Deficiency (5,237) and IgG Subclass Deficiency (4,943). Nonetheless, specialists reported a substantial number of less common disorders such as X-linked Agammaglobulinemia (811), Severe Combined Immune Deficiency (798), Complement Disorders (725), Ataxia Telangiectasia (502), Hyper IgM (391) and Wiskott-Aldridge Syndrome (369). Since the survey of physicians is limited to a sample of specialists who see primary immune deficiency diseases, these counts provide an estimate of the relative prevalence of the individual disorders, not a population count of these diseases. Moreover, since the sample is restricted to specialists, the more serious and complex disorders may be disproportionately represented in the sample (Figure 5). The prevalence of specific diagnoses in the patient sample is similar to the specialist survey. The most common diagnosis is Common Variable Immune Deficiency, which accounts for a third (34%) of the patient sample. The next most common diagnoses are IgG Subclass Deficiency (24%) and IgA Subclass Deficiency (17%). X-linked Agammaglobulinemia is the fourth most common (8%) of the primary immune deficiency diseases in the patient sample. Smaller proportions of patients report Severe Combined Immune Deficiency (4%), Chronic Granulomatous Disease (4%), Hyper IgM (2%), DiGeorge Anomaly (2%), Wiskott-Aldrich Syndrome (1%) and Ataxia Telangiectasia (1%). Twelve percent report other diagnoses (Figure 6).

Figure 5Number of Patients by Condition

5,291

5,237

4,943

811

802

798

725

715

502

391

369

754

0 1,000 2,000 3,000 4,000 5,000 6,000

Common Variable

Selective IGA

IgG Subclass

X-Linked Agamma

CGD

SCID

Complement

DiGeorge

Ataxia

Hyper IgM

Wiskott

Other

Source: IDF Survey of Specialists


6

Despite the non-probability sampling procedures for the patient survey, the geographic distribution of the patient sample closely mirrors the total population of the United States. Among the nearly 3,000 patients in the sample, the place of birth is reported in all 50 states and the District of Columbia. There is a somewhat higher proportion of

patients born in the Mid-Atlantic region (21%) than the total population (15%); while a somewhat lower proportion of patients from the East North Central region (13%) than the total population (17%). In the other seven Census divisions, the patient and population distributions are virtually identical. There are almost no cases in the sample of patients born outside of the United States (Figure 7).

Figure 6Patients with PID by Reported Diagnosis

12%

1%1%

34%

24%17%

8%

4%

4%

2%

2%

0% 10% 20% 30% 40%

Common Variable

IgG Subclass

IgA Subclass

X-Linked Agamma

Severe Combined

CGD

Hyper IgM

DiGeorge

Wiskott-Aldritch

Ataxia

Other

Source: IDF Patient Survey N=3,046

Figure 7Patient and Population Distribution in USA

5%

15%17%

7%

18%

6%

11%

6%

16%

7%

21%

16%

4%

9%

5%

18%

6%

13%

0%

5%

10%

15%

20%

25%

Ne wEngland

M idAtlantic E NorthCe ntral

W NorthCe ntral

S Atlantic E SouthCe ntral

W SouthCe ntral

M ountain Pacific

Population Patients

Source: US Census and IDF Patient Survey


7

Like the geographic distribution, the gender distribution of persons with primary immune deficiency diseases mirrors the general population. Among patients with primary immune deficiency diseases, 48% are male and 52% are female (Figure 8). Primary immune deficiency diseases are no longer child disorders. About 10% of patients are under six years of age. Twenty percent are aged six to twelve. And, another 10% are adolescents, aged thirteen to seventeen. Sixty percent of patients with primary immune deficiency diseases are adults, aged 18 or older. Indeed, a quarter of patients are aged 45 or older. Five percent are aged 65 or older (Figure 9).

Figure 8Gender of Patients with PID

52%

48% M aleFemale


Figure 9Current Age of Patients with PID

5%

7%

10%

20%

10%

40%

10%

10%

15%

13%

0% 10% 20% 30% 40% 50%

Less than 6

6-12

13-17

Net Under 18

18-24

25-34

35-44

45-54

55-64

65+



8

Diagnosis Only 12% of patients were initially diagnosed with a primary immune deficiency disease before one year of age. A total of 38% were diagnosed before age six. And a majority (50%) was diagnosed before they were twelve years of age. Nonetheless, 43% of persons with primary immune deficiency diseases were not diagnosed until they were an adult (Figure 10).

One reason for late diagnosis is the absence of a family history of these disorders. Only 2% of patients had a father with a primary immune deficiency disease and 4% had a mother with one of these diseases. It is somewhat more common for patients to have a brother (8%) or sister (5%) with this disorder. About one in ten

patients (11%) report other family members with a history of these diseases. But, three quarters (76%) of patients with primary immune deficiency diseases have no family history (Figure 11).

Figure 10Age at Diagnosis with PID

12%

26%

12%

8%

23%

18%

2%

0% 5% 10% 15% 20% 25% 30%

Less than one

1-5

6-11

12-17

18-39

40-64

65+


Figure 11Family History of PID

2%

4%

8%

5%

11%

76%

0% 20% 40% 60% 80%

Father

Mother

Brother

Sister

Other Family Member

No Family History

Source: IDF Patient Survey N=


9

The importance of early diagnosis of these diseases is demonstrated by medical history prior to diagnosis. Although most patients are diagnosed before age twelve, 70% of patients report being hospitalized prior to diagnosis. Seventeen percent were

hospitalized only once prior to diagnosis. A third (32%) were hospitalized 2 to 5 times prior to diagnosis. Ten percent reported being hospitalized 6 ton 10 times before diagnosis. And, twelve percent of persons with primary immune deficiency diseases report more than 10 hospitalizations before diagnosis (Figure 12).

Also, despite the relatively early age of diagnosis, many patients report the onset of serious or chronic health conditions prior to diagnosis. The majority of patients with primary immune deficiency diseases report sinusitis (68%), bronchitis (55%), pneumonia (51%) and repeated ear infections (51%) prior to diagnosis. Nearly a third (30%) report frequent diarrhea prior to diagnosis. Although far less common, relatively high rates of malabsorption (9%), sepsis (5%), meningitis (4%) and hepatitis (3%) are reported prior to diagnosis (Figure 13).

Figure 12Times Hospitalized before Diagnosis

None30%

One17% 2-5

32%

6-1010%

11-206%

21+5%


Figure 13Conditions before Diagnosis

68%

5%

51%

17%55%

2%

30%

51%

3%

9%

4%

0% 10% 20% 30% 40% 50% 60% 70%

Arthritis

Bronchitis

Cancer

Diarrhea

Ear Infections

Hepatitis

Malabsorbtion

Meningitis

Pneumonia

Sepsis

Sinusitis



10

Treatment Seven out of ten (70%) patients with primary immune deficiency disease report that they have been treated with intravenous gammaglobulin (IVIG) for their disorder (Figure 14). IVIG use is most common for X-linked Agammaglobulinemia (94%),

Common Variable Immunodeficiency (92%) and Hyper IgM (89%). It is also reported by a majority of patients with Severe Combined Immune Deficiency (80%), Wiskott-Aldrich Syndrome (75%), and IgG Subclass Deficiency (74%). It is least commonly used for DiGeorge Anomaly (24%) and Chronic Granulomatous Disease (12%) (Figure 15).

Figure 14Treated with IVIG: All PID’s

No30%

Yes70%


Figure 15

IVIG Use (Ever) by Diagnosis70%

47%

75%

92%

74%

41%

94%

80%

12%

89%

24%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Common Variable

IgG Subclass

IgA Subclass

X-Linked Agamma

Severe Combined

CGD

Hyper IgM

DiGeorge

Wiskott-Aldritch

Ataxia

Other

Source: IDF Patient Survey


11

A small proportion of persons with primary immune deficiency diseases began IVIG use in the late 1970’s and early 1980’s in clinical trials. The chart of year began using IVIG reveals a strong rising demand for this product. In the three years prior to the survey, the proportion of immune deficient patients beginning IVIG use was 8%, 10% and 12% respectively. This represents an increase in the total population of immune deficient patients on IVIG at 15% per annum. This is probably identical to the annual increase in the immune deficient population in the United States (Figure 16). The impact of treatment, including IVIG therapy, on primary immune deficiency diseases is reflected in the prevalence of serious and chronic conditions before and after diagnosis. Arthritis (17%-20%), which is aged related, and hepatitis (2.9%-3.7%) are the only conditions that are more common after diagnosis than before. There is a small, but

statistically significant decline in the rate of sinusitis (68%-65%), malabsorption (9%-8%), and sepsis (5%-4%) after diagnosis. There is a much more dramatic decline after diagnosis in pneumonia (51%-27%), ear infections (51%-27%), bronchitis (55%-40%), and chronic diarrhea (30%-24%) (Figure 17).

Figure 16Year Began IVIG Use

0%

2%

4%

6%

8%

10%

12%

14%

78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95


Figure 17Conditions: Before and After Diagnosis

12%

20%

2%

24%

27%

4%

8%

2%

27%

4%

65%68%

5%

51%

4%

7%

17%

55%

2%

30%

51%

3%

9%

40%

0% 10% 20% 30% 40% 50% 60% 70%

None of These

Arthritis

Bronchitis

Cancer

Diarrhea

Ear Infe ctions

He patitis

Malabsorbtion

Me ningitis

Pne umonia

Sepsis

Sinusitis

After

Before

Source: IDF Patient Survey


12

Although seventy percent of patients had been hospitalized prior to diagnosis, nearly half (48%) reported no hospitalization since diagnosis. Another 14% reported only one hospitalization since diagnosis. By contrast, about one in ten patients reported 11-20 (4%) or more than 20 hospitalizations (5%) since diagnosis (Figure 18). Current Health More than two thirds of patients with primary immune deficiency diseases describe their current health status as good or better. Specifically, 10% describe their

current health status as excellent, 24% as very good, and 34% as good. Twenty-two percent describe their current health as only fair. Only 8% of patients report their current health status as poor or very poor, while 2% are deceased (Figure 19).

Figure 18Hospitalized since Diagnosis

20+ Times5%

11-20 T imes4%

6-10 Times8%

2-5 T imes21%

O ne14%

None48%


Figure 19Current Health Status

Deceased2%

Poor/Very Poor8%

Only Fair22%

Good34%

Very Good24%

Excellent10%



13

Most patients with primary immune deficiency diseases report only slight (28%) or no physical limitations (42%) as a result of health. A fifth (21%) report moderate limitations as a result of their health. One in ten (9%) reports severe physical limitations as a result of their health (Figure 20).

Three quarters of patients with primary immune deficiency diseases

(76%) report no hospital nights in the past year. Another 6% report one to two hospital nights in the past year. Eight percent report 3-7 hospital nights in the past year. And, 10% of patients with primary immune deficiency diseases report more than a week (8+ nights) in the hospital in the past year (Figure 21).

Figure 20Current Physical Limitation

None42%

Slight28%

Moderate21%

Severe9%


Figure 21Hospital Nights in Past Year

15+6%

8-144%

3-78%

1-26%

None76%



14

Cost, Coverage and Barriers to Care Most persons with primary immune deficiency diseases have some form of health insurance coverage. The majority (57%) has insurance through an employer group policy. Seventeen percent belong to an HMO. And, another 6% belong to an other group policy, while 6% have an individual policy. Only 11% have Medicaid coverage, 11% have Medicare coverage, and 4% are covered by a state or county health program. Only two percent report none of these (Figure 22). Although most patients are covered by some form of health insurance or public health program, many have experienced insurance problems. Fifteen percent have had a health insurance application denied, while 5% have had a policy cancelled. Sixteen percent have had conditions excluded from their coverage. Twenty percent have had

treatment delayed by their insurance carrier, while 18% have had treatment denied by their carrier. Three percent of patients with primary immune deficiency disease say that they have exceeded the lifetime cap of the insurance coverage. Only a quarter (25%) of persons with primary immune deficiency diseases have not experienced any of these health insurance problems (Figure 23).

Figure 22Health Insurance Coverage of Patient

2%

9%

57%

6%

17%

4%

6%3%

11%

11%

0% 10% 20% 30% 40% 50% 60%

Employer Group

Other Group

HM O

State or County

Individual Policy

COBRA

M edicare

M edicaid

Other

None of These


Figure 23Insurance Problems

15%

5%

16%

18%

20%

3%

25%

0% 5% 10% 15% 20% 25% 30%

Application Denied

Policy Cancelled

Conditions Excluded

Treatment Denied

Treatment Delayed

Cap Exceeded

None of these



15

The majority of persons with primary immune deficiency disease have experienced barriers to treatment as a result of cost or insurance coverage. Twelve percent have not seen a doctor, and 11% have not seen a specialist when they needed to because of cost or coverage. Five percent did not go to the hospital and one percent did not have an operation when needed because of cost or coverage. Even more commonly, 16% stretched out a prescription, 11% did not fill a prescription and 10% reduced the amount or stretched out the schedule for IVIG. Only 38% of persons with primary immune deficiency disease have not experienced any of these treatment problems as a result of cost or coverage (Figure 24). In order to pay for their treatment, 40% of patients with primary immune deficiency disease have used their savings. A substantial proportion have taken out bank

loans (11%) or borrowed from others (24%) to pay for treatment. Others have sold their stock (8%), sold their car (4%) or sold their house (2%) to pay for treatment. Barely half of patients with primary immune deficiency disease (52%) have never had to resort to using their savings, borrowing or selling their possessions to pay for treatment (Figure 25).

Figure 24Due to Cost or Insurance Coverage

11%

16%

10%

12%

11%

5%

1%

38%

0% 5% 10% 15% 20% 25% 30% 35% 40%

Didn't obtain rx

Stretched out rx

IVIG reduced/stretched

Didn't see doctor

Didn't see specialist

No hospital

No operation

Any of these


Figure 25In Order to Pay for Treatment

40%

8%

4%

2%

11%

24%

52%

0% 10% 20% 30% 40% 50% 60%

Used Savings

Sold stocks

Sold car

Sold house

Bank loan

Borrowed from others

Any of these



16

Conclusions

Primary immune deficiency diseases are a set of comparatively rare genetic disorders. Nonetheless, the survey suggests that approximately 50,000 persons in the United States have been diagnosed with one of these diseases. Hence, primary immune deficiency diseases are more common in the United States than some better known genetic disorders, including hemophilia (less than 15,000), cystic fibrosis (30,000) and Huntington’s Disease (30,000), among others. Half of all persons with primary immune deficiency diseases are not diagnosed until they are adolescents or older. In some cases, this may represent adult or delayed onset of symptomatic disease. In other cases, however, this represents late diagnosis of the condition despite unusual, serious, or repeated infections. One problem for early diagnosis is that the vast majority of patients have no family history of immune deficiency disease. The cost of late diagnosis is a heavy burden of disease on the patient. The majority of patients suffered two or more hospitalizations before diagnosis. The majority experienced repeated ear infections, bronchitis, and pneumonias before diagnosis, which may cause permanent limitations. In addition, some suffered serious infections and potentially life-threatening infections before diagnosis, including sepsis, meningitis and hepatitis. Treatment significantly reduces the burden of disease among persons with primary immune deficiency diseases. The prevalence of pneumonia, bronchitis, diarrhea and repeated ear infections drops significantly after diagnosis. Nearly half of persons with primary immune deficiency diseases have had no hospitalizations since diagnosis. Two thirds of persons with primary immune deficiency diseases describe their current health as good, very good or excellent. Most say their health causes no limitations or only slight limitations on work, play and other activities. Three quarters have had no hospitalizations in the past year. The most common form of treatment for primary immune deficiency diseases is intravenous gammaglobulin (IVIG). Seven out of ten patients report being treated with IVIG for their condition. The proportion of PID patients being treated with IVIG has been increasing at a rate of about fifteen percent per annum in recent years.

Most patients are covered by some form of health insurance or health plan, most commonly through employer group insurance. Nonetheless, a quarter of persons with primary immune deficiency disease report experiencing insurance problems as a result of their condition. In addition, over half report using savings, selling property or borrowing to pay for treatment. As a result of cost or lack of coverage, nearly two out of five patients with primary immune deficiency disease has missed needed doctor or hospital visits, failed to fill prescriptions or reduced the amount or frequency of their treatment.


17

Despite a generally positive outlook after diagnosis for most patients with primary immune deficiency diseases, the survey finds that a significant portion of the patient population faces barriers to timely and effective treatment of their condition. In addition, a significant number of patients with primary immune deficiency disease are only diagnosed after multiple hospitalizations. The long-term outlook for most patients with primary immune deficiency diseases, while good, could be greatly improved by earlier diagnosis and better access to appropriate care and treatment.

- 1 -Brussels, March 17th, 2004

Primary Immune Deficiency Diseases in the European Union

Consequences of Late Diagnosis of Primary Immune Deficiency Diseases

Janne Björkander, MD, PhD

Immune Deficiency Unit

Dept of Respiratory Medicine and Allergology

Sahlgrenska University Hospital

Göteborg, Sweden

ANNEX 12



Antibody Deficiencies – IgG Subclass

• IgG subclass deficiencies are the most common among the immune deficiencies, probably around 1/250 in adult Swedish population

• Typical symptoms range from slightly increased viral infections to repeated severe bacterial infections – which can result in non reverseable lung damage

• They can be treated when diagnosed

• IgG subclass deficiences were first recorded in 1970 by Schur et al, and are the subject on on-going research

• IgG subclass deficiencies are of great importance economically and socio-economically because they result in frequent infections which lead to increased hospital visits and patient suffering



Diagnostic Procedures

• Diagnosis is often missed because a physician needs to recognise the difference between increased normal infectiousness (eg. in a person who has frequent contact with small children), or an unnormal increase.

• We use six “warning signs” to help with this identification in adults (see table)

• The diagnosis can be done with a simple blood test measuring the level of IgG subclass antibodies



Warning Signs

1. At least four antibiotic demanding respiratory tract infections per year for at least 3 years (such as bronchitis)

2. At least two severe bacterial infections like sepsis, meningitis, osteomyelitis or soft tissue infections

3. At least two X-ray verified sinusitises or pneumonias

4. One X-ray verified chronic sinusitis

5. No or low efficacy or recurrent infections after antibiotic treatment

6. Known primary immune deficiency in the family



Consequences of Late Diagnosis

• The next slides illustrate the negative impact that late diagnosis of PI’s can have in terms of:– The health of two patients

– The need of healthcare services



Male patient born 1942 (1)

Patient Background:

Healthy childhood. Normal military service. Store house worker. Married. Two daughters. Heavy smoker for 20 years. Ex-smoker since 1980.

Medical History:

Gastritis since 1960. Chronic obstructive pulmonary disease (COPD) since 1980. Sarcoidosis diagnosed 1994. Pneumococcus pneumonia x 2. Repeated exacerbations of COPD from 1996 (see tables).

By 2000, this patient was suffering from shortness of breath, hecould not walk up the stairs, he had had pneumonia twice and he was getting frequent lung infections.



Male patient born 1942 (2)

April 2000 the patient was investigated and found to have low antibody levels.

Antibody replacement therapy (immunoglobulin) was instituted after 18 months of follow up.

The following tables show the decrease in the number of hospitalvisits needed, and the conditions suffered by this patient, once they were diagnosed and treated for their immune deficiency.



Male patient born 1942 (3)Before Antibody Replacement (Ig) Treatment

41 days8 visitsTotal, 18 months

Acute bronchitis304-052001-04-03


Pneumonia512-132000-12-08



Pneumococc. sepsis509-292000-09-25

Idem806-022000-05-26

COPD exacerbation605-092000-05-04

DaysOutHospital entries



Male patient born 1942 (4)After Antibody Replacement (Ig) Treatment

16 days5 visitsTotal 18 months


Gastroenteritis312-022002-11-30


504-072002-04-04

Pneumococcus pneumonia210-282001-10-27


Result of diagnosis and treatment: no hospitalisations were needed during the following 11 months.



Male Patient Born 1942, Conclusion

Impact of Diagnosis & Treatment on Need for Hospitalisation:

The patient reduced his need of hospital visits from 8 periods and 41 days during 18 months run in, to 5 visits and 16 days during the treatment period of 18 months. Importantly, treatment has stopped the function of the patient’s lungs deterioating, as they had been prior to treatment.

Impact of Diagnosis & Treatment on Patient’s Quality of Life:

The patient has found a marked improvement to his quality of life, he appreciatesthe need for less hospital visits, has been impressed that his infections are lesssevere and more easily handled, and appreciates the increased overall general well being he experiences between periods of infection.



Female Patient Born 1928 (1)

Patient Background:

Retired mental nurse. Ex-smoker since 1978, heavily exposed to passive smoking. Hospitalised in 1987 because of angina.

Medical History:

No family history of lung diseases. Parents and a brother both died from heart attacks. History of obstructive lung disease for 25 years. From 1993-98, like most patients with chronic obstructive chest disease, she developed and was treated for emphysema. During this time her lungs continued to deterioriate.

By 1998, this patient could not walk up the stairs, or further than 25 m because of breathlessness.



Female Patient Born 1928 (2)

In 1998 she was investigated immunologically and was found to how antibody levels (IgG1 and IgG3). She was then treated with antibody replacement therapy.

The following tables show the decrease in the number of hospitalvisits needed, and the conditions suffered by this patient, once they were diagnosed and treated for their immune deficiency.



Female Patient Born 1928 (3)Before Antibody Replacement (Ig) Treatment

437 visitsTransport











587 visitsTransport













166 days18 visitsTotal, 18 months follow up

1006-1698-06-07

605-1998-05-14

1705-0598-04-20

3204-0498-03-03




Female Patient Born 1928 (6)After Antibody Replacement (Ig) Treatment

335 visitsTotal 18 months







Result of diagnosis and treatment: During the next 36 months 2000-02, no visits were needed due to infections



Female Patient Born 1928 (7), Conclusion

Impact of Diagnosis & Treatment on Need for Hospitalisation:

The patient reduced the number of hospital visits from 18 periods and 166 days during the 18 months run in, to 5 visits of 33 days during the treatment period of 18 months. During the following 36 months she had no need for further hospital visits caused by infections.

Impact of Diagnosis & Treatment on Patient’s Quality of Life:

Due to the late diagnosis, her lungs have been irreversibly damaged. However, the treatment has stopped the damage increasing. The patient appreciates the need for less hospital visits and that her infections are less severe and more easily handled. She can now perform daily tasks, such as walking to near-by shops.

�



Primary Immune Deficiency DiseasesQuality of Life and Healthservice Costs:

Why Diagnosis & Optimal Treatment is Good for the Patient & Good for Healthcare Systems & Services

Ann GardulfR.N., PhD, Associate Professor

Department of Clinical ImmunologyKarolinska University Hospital

Karolinska InstitutetStockholm, Sweden

[email protected]

ANNEX 13



Effects of Diagnosis and Treatment

Improved Quality of Life (QoL)

Lower Costs



Scientific Publications Related to Patient-reported health and QoL

Children (3- 13 years)

Adults (14-74 years)

Europe

J Allergy Clin Immunol Gardulf, Nicolay,Asensio, Bernatowska, Böck, Costa-Carvalho et al.

2004

Adults 23-76 years

Norway

PhD-thesis, Oslo Univeristy, Norway

Höybråten Sigstad 2003

Adults (18-76)

Denmark, Norway, Sweden

J Adv NursGardulf, Björvell, Andersen, Bjorkander, Ericson, Frøland et al

1995

Adults (18-66 years)

Sweden

Clin Exp ImmunolGardulf, Björvell, Gustafson, Hammarström, Smith

1993

PatientsJournalAuthorsYear

• The following slides demonstrate that antibody replacement therapy improves the health and QoL for patients with PI’s



1. How Treatment with Antibody Replacement Therapy (IgG) improves the QoL for patients by preventing infections

Intravenous IgG (IVIG) Subcutaneous IgG SCIG



If Not Diagnosed and Thereby Treated…

• … adults with PI’s have a worse QoL as compared to healthy individuals

• The higher the score, the worse the QoL

Gardulf, Björvell, Gustafson et al.

Clin Exp Immunol 1993;92:200-4

0

10

20

30

Mobility

Well-be

ingSoc

ialFati

gue

WorkRecre

ation

SIP

scor

e

PI adults Healthy

*SIP: Sickness Impact Profile



0

10

20

30Mob

ilityW

ell-be

ingSoc

ialFati

gue

Work

Recrea

tion

SIP

scor

e

Before IgGSCIG 18 months

But with Antibody Replacement (IgG) Therapy…

• … the QoL significantly improves

• The higher the score, the worse the QoL

Gardulf, Björvell, Gustafson et al.

Clin Exp Immunol 1993;92:200-4



Patient stories

• The Swedish National Health Insurance Company wanted an early retirement for this 32 year old woman

• She was given antibody replacement therapy (subcutaneous IgG) – today she is working full-time



Patient stories

• The 44 year old man worked full-time but was completely exhausted at the end of the day

• He had difficulties participating in family and social life, could not participate in recreational activites

• ”I have gained a new life”



2. How Home-Therapy Improves the QoL for Patients



The SC replacement therapy opens the door to home-therapy

• Safe

• Easy for the patients and parents to learn and use

• Gardulf, Hammarström, Smith, Lancet, 1991• Thomas, Brennan, Chapel, Lancet, 1993• Gardulf, Andersen, Björkander et al., Lancet 1995• Abrahamsen, Sandersen, Bustnes, Pediatrics, 1996• Gaspar, Gerritsen, Jones, Arch Dis Child, 1998• Chapel, Spickett, Ericson et al, J Clin Immunol, 2000• Hansen, Smith, Gardulf, Clin Immunol, 2002• Radinsky & Bonagura, J Allergy Clin Immunol, 2003



Patient Reports on the QoL Advantages of Home Therapy

Adult patients’ opinions of the home-therapy categorised in five groups/areas:

Independence/freedom/flexibility

No travelling to hospitals

Less time away from work or school

A sense of being less sick or disabled

Resources made availiable to other patients

Gardulf, Björvell, Andersen, Björkander et al.J Adv Nurs 1995;21:917-27



Home Antibody Replacement Therapy:Patients Report the Difference Made to Their Lives

Independence/freedom/flexibility

I can travel without any problems. Now I feel I can contribute to my own well-being, I am no longer just a ’patient’ or a ’case’.” (Woman , aged 27)

You feel less sick when you don’t have to visit the hospital so often. Freedom!” (Man, aged 29)

The home treatment means greater independence and flexibility.” (Man, aged 45)

Gardulf, Björvell, Andersen, Björkander et al. J Adv Nurs 1995;21:917-27



A sense of being less sick or disabled

I find the home treatment outstanding. Now I live a normal life and I don’t feel disabled any longer. It makes me so happy.” (Woman , aged 51)

Home treatment gives me the opportunity to live like a ’normal’ human being. If anyone feels disabled by the antibody deficiency, home treatment reduces this feeling to a minimum.” (Man, aged 62)

Gardulf, Björvell, Andersen, Björkander et al.J Adv Nurs 1995;21:917-27

Home Antibody Replacement Therapy:Patients Report the Difference Made to Their Lives



PI Children and Their Families Gain QoL by Home-Therapy*

• Less limitations in personal time and less emotional distress due tothe childs PID

• Less limitations in family activities, school, work & social activities

• Less disruptions in family activities and fewer cancellations or changed plans at last minute affecting work and social life

• Less tension or fewer conflicts at home

• Better therapy convenience, comfort, treatment flexibility and pleasantness of treatment atmosphere

• Freedom to travel

The parents to children with PI reported significantly

Manuscript submitted



Diagnosis and Treatment: Lower Costs for Society and Patients

Direct Costs

Indirect Costs



Number of one-day visits 17to hospital for antibodyreplacement therapy

Number of children/parents 15

Number of days lost 255from work to attend hospitaltherapy

Home-Therapy: Lower Healthcare Service Needs



Subcutaneous Home Therapy: The Annual Costs for the Patients

Hospital treatment Home-therapy

”Out-of-pocket expenses” 265 40

Costs of travelling time 1,135 0

Cost of treatment time 1,465 1,365

Total patient-borne cost 2,865 1,405

Gardulf, Möller, JonssonInt. J. of Technology Assessment in Health Care 1995;11:345-53(Costs given in $US (1993 prices))



Conclusions

• Scientific studies show patient reported health and QoL is significantly improved by optimal antibody treatment



Conclusions


• Home-therapy has been shown to further increase the QoL for patients with PI’s and their families



Conclusions



• The introduction of home-therapy programmes leads to substantial savings for healthcare services, patients and their families



Conclusions



• The introduction of home-therapy programmes leads to substantial savings for healthcare services, patients and their families

• Mechanisms are needed to ensure that learnings of new treatment developments can be effectively shared & utilised by physicians and nurses throughout the European Union



• Late diagnosis of immune deficiencies and infections lead to disability and irreversible organ damage (irrespective of smoking history)

• Undiagnosed and untreated patients need greater use of hospital services

• About 70% of patients with antibody deficiencies (IgGsd) respond well to treatment with antibody replacement therapy (immunoglobulins) with decreased number of infections and increased wellbeing (p<0.0001)

• These findings are verified in new data to be published: Olinder-Nielsen AM, Forsberg P, Granert C, Vietorisz A, Björkander JIg prophylaxis in 350 adults with IgG subclass deficiency and recurrent respiratory tract infections; 2000 patient-years

Summary of Findings

Documents

List of organization(s) consulted and/or supporting the ...archives.who.int/eml/expcom/expcom15/applications/immunoglobulin/i... · List of organization(s) consulted and/or supporting