Cystic Fibrosis

Dr Barry Linnane

Paediatric Respiratory Consultant

Mid-Western Regional Hospital

Limerick

Introduction

• It is customary to start any discussion regarding cystic fibrosis (CF) by pointing out that it is the most common life-shortening genetic condition affecting the Caucasian population (Littlewood, in Cystic Fibrosis, 2007. p. 3 – 19)

• It is estimated there are approximately 60,000 affected individuals worldwide (Anselmo et al, in Pediatric Respiratory Medicine, 2008. p. 845 – 857)

• The prevalence of the disease varies amongst populations, but the average birth prevalence in Caucasian populations is likely to be approximately 1 in 2,500 births, with a CF carrier frequency of 1 in 25 people (Walters et al, in Cystic Fibrosis, 2007 p. 21 – 45)

• There are approximately 1,200 individuals with CF in Ireland (The Cystic Fibrosis Registry of Ireland Annual Report 2007)

• There are 30-40 infants born each year with CF in Ireland. The birth prevalence is approximately 1 in 1460, with a CF carrier frequency of 1 in 19 (Wallis C, in Kendig’s Disorders of the Respiratory Tract in Children, 2006, p866 – 872)

Definition

• There are numerous definitions of CF, all of which attempt to capture the essence of this complex disease, in a few succinct words. Dr Colin Wallis recently proposed the following definition:

“A possible definition for the disease CF could involve the following sequence of pathologic events:– Disease usually arises from two disease-causing mutations in the gene

encoding CFTR– Mutations result in changes to the fluid and electrolytes on cell surfaces– Changes may lead to abnormal secretions and inflammatory responses– These manifestations may predispose to obstruction and infection– Obstruction and infection may produce end-organ disease in tubular

structures such as the upper and lower airways, vas deferens, gut, liver, and pancreas, with secondary impact on growth and nutrition.” (Wallis C, in Kendig’s Disorders of the Respiratory Tract in Children, 2006, p866 – 872)

Genetics

• CF is an autosomal recessive condition

• In the late 1980s technical breakthroughs in gene analysis involving chromosome walking and jumping, and linkage disequilibrium analysis resulted in 1989 in the identification of the CF gene on the long arm of Chromosome 7 at the 7q31 locus (Kerem et al, 1989;245:1073) (Rommens et al, 1989;245:1059) (Riordan et al, 1989;245:1066)

• As per convention the gene takes on the name of the protein it codes for, in this case, the cystic fibrosis transmembrane regulator CFTR (more about that later)

• Over 1500 mutations of the CFTR gene have been identified (www.genet.sickkids.on.ca/cftr/)

• However, deltaF508 is the dominant mutation seen in over 70% of CF alleles in the Caucasian population worldwide

Genetics

• All the other mutations are individually rare, with only 11 found in more than 100 patients

• 94% of the Irish CF population carries the deltaF508 mutation on at least one chromosome, with 64% being homozygous for the mutation (The Cystic Fibrosis Registry of Ireland Annual Report 2007)

• The six next most common mutations are (The Cystic Fibrosis Registry of Ireland Annual Report 2007):– G551D– R117H– R560T/K– G542X– 1717-1 G-A– 621+1 G-T

5 major classes of CF mutations

• Extensive research into genotype-phenotype correlations, along with knowledge of the molecular mechanisms by which genetic mutations result in defective proteins, has led to a classification system for CF mutations (Welsh, et al, 1993;73:1251)

• It should be emphasized though, that most CFTR mutations result in the classical severe form of the disease

• Class I: defective protein synthesis (e.g. G542X, 1717-1 G-A, 621+1 G-T)

• Class II: defective protein processing (e.g. DF508)• Class III: defective regulation (e.g. G551D, R560T/K)• Class IV: defective conductance (e.g. (R117H)• Class V: reduced protein levels at the membrane

CFTR

• The CFTR protein is a chloride channel at the apical membrane of epithelial cells (Riordan et al, 1989;245:1066)

• It comprises of 1480 amino acids, and is part of the family of ATP-binding cassette (ABC) transporter proteins

• Phosphorylation by protein kinase, under the control of cAMP, and hydrolysis of ATP, are essential for activating the chloride channel

Normal mucociliary clearance

• To understand the abnormality that occurs in CF we must first understand what is normal

• The respiratory tract is lined by ciliated columnar epithelium

• Resting on top of the epithelium is the Airway Surface Liquid (ASL) which is composed of an outer (towards the lumen) mucous layer, and an inner watery Peri-Ciliary Layer (PCL) which bathes the cilia (Matsui, et al, 1998;102:1125)

• The PCL is approximately 7 microns deep, which is the length of an outstretched cilium

• The arrangement is part of the innate immune system of the respiratory tract, and works by trapping bacteria in the mucous layer which is then transported in a cephalic direction by the mucociliary elevator to be coughed and swallowed or expectorated – a process known as mucociliary clearance

From the nose to the bronchioles the airway is lined by pseudo-stratified columnar epithelium

CF is a disease of the airways

Airway lumen

Basement membrane

Epithelium

Peri-ciliary layer

Mucus layerAirway surface liquid

Cl-

CFTR ENaC

Na+

Ion Pump

Cl-

CFTR

Na+

H2OH2O

7 microns

Mucous layer

Peri-ciliary layer

Cl-

CFTR

Na+

H2OH2O

7 microns

Mucous layer

Peri-ciliary layer

Cl-

CFTR

Na+

H2OH2O

3 microns

Purulent tenacious mucous layer

Peri-ciliary layer

Normal mucociliary clearance

• The volume of the ASL is tightly regulated by an active process of ion transport

• Absorption of ASL: The epithelial Na channel (ENaC) actively transports Na from the ASL into the epithelial cell, with Cl following the electrochemical gradient, and H2O following the osmotic gradient

• Secretion of ASL: In contrast CFTR actively transports Cl out of the epithelial cell into the ASL, with Na and H2O following passively

• Therefore, if ASL volume is excessive, Na absorption increases, and as ASL reaches a physiological optimum Na absorption reduces, or stops. Cl secretion can then dominate if ASL volume is diminished.

CFTR in CF• In CF, derangement of CFTR in airway epithelium results in defective

epithelial ion transport by two mechanism

• Lack of functioning CFTR appears to release ENaC from tonic inhibition, which results in greater Na absorption, with Cl and H2O following, resulting in diminished ASL volume

• Defective CFTR is unable to secrete Cl, which would have resulted in Na and H2O following, to rehydrate the ASL

• The result of both of this processes is a reduction in the volume of the ASL, with the PCL dropping to a depth of 3 microns

• As a consequence mucociliary clearance is deranged, and mucous plaques adhere to the epithelium

• From this apparently innocuous start come all the devastating consequences of CF lung disease

Pathogenesis of airway disease

• Mucociliary clearance is inhibited, as described above

• The mucous is thick, and prevents penetration by immune cells (but not motile Pseudomonas aeruginosa)

• The unregulated ENaC channels consume increased energy, and oxygen, resulting in a relatively hypoxic environment in the mucous plaques

• The resultant micro-environment appears to specifically select for the typical CF airway pathogens, most notably P. aeruginosa

• The presence of airway pathogens initiates a marked immune response lead by neutrophils. The massive neutrophil response results in the production of neutrophil elastase at levels that overwhelm the innate anti-proteases (e.g. alpha1 anti-trypsin)

Pathogenesis of airway disease

• The resulting free neutrophil elastase degrades the structural proteins of the airway culminating in irreversible airway and parenchymal destruction

• The problem is exacerbated by three further processes

• Bacterial infection, and the resulting inflammation, induce increased mucin production

• DNA from necrotic neutrophils and bacteria increase the tenacity of airway mucous

• P. aeruginosa adapts to its new environment by producing biofilms which significantly reduce its susceptibility to eradication by antibiotics

Pancreatic disease

• The pancreatic acinus secretes isotonic liquid, which is then modified in the pancreatic duct, to produce a fluid rich in HCO3- (Steward, et al, 2005;67:377)

• Basolateral ion exchange mechanisms increase in the intracellular HCO3- concentration, with CFTR playing a role in transporting HCO3- into the lumin (Steward, et al, 2005;67:377)

• CFTR appears to act as a conduit for anions other than Cl-, in particular HCO3-, which is transported at about 40% efficiency when compared with Cl- (Steward, et al, 2005;67:377)

• In CF there is deficient secretion of HCO3-, and liquid, with resultant abnormally acidic and viscous ductal secretions, which likely lead to early activation of proteolytic enzymes within the gland, resulting in inflammation and destruction (Johansen, et al, 1968;1:455) (Kopelman, et al, 1985;312:329)

Sweat gland

• The observation that sweat electrolytes are abnormal in CF represents on the seminal discoveries in CF (Di Sant'Agnese 1953;12:549)

• Normally, isotonic sweat is produced in the sweat acinus, with Cl and Na being reabsorbed in the resorptive duct, resulting in hypotonic (Cl 10 – 50 mmol/L) sweat reaching the skin surface

• In the CF sweat gland, isotonic sweat is produced in the acinus, but the CFTR dependent resorption of Cl is deficient resulting in abnormally high sweat Cl levels ( 60 – 120 mmol/L) reaching the skin surface

• This forms the basis of the pilocarpine iontophoresis induction of sweating as part of the sweat test, which allows sufficient quantity of sweat for Cl and Na analysis, and hence the diagnosis of CF (Gibson, Cooke, 1959;23:545)

The genetics and pathology of CF come together when we focus

on diagnosis

Diagnosis

• The diagnosis of CF is usually made when an individual presents with suggestive clinical features such as recurrent chest infections, and evidence of malabsorption with failure to thrive and steatorrhoea; which is then confirmed on sweat testing with an elevated sweat chloride > 60 mmol/L.

• 18 % present with Meconium ileus in the neonatal period

• 15% present with a family history typically of an affected sibling

In 1998 the CFF issued a consensus statement on the diagnosis of CF

• Clinical manifestations

• Or

• CF history in a sibling

• Or

• positive newborn screening

• Positive sweat test

• Or

• positive nasal potential difference

• Or

• two disease causing mutations identified

Plus

In 1998 the CFF issued a consensus statement on the diagnosis of CF

• Clinical manifestations

• Or

• CF history in a sibling

• Or

• positive newborn screening

• Positive sweat test

• Or

• positive nasal potential difference

• Or

• two disease causing mutations identified

Plus

Symptoms at diagnosis (The Cystic Fibrosis Registry of Ireland Annual Report 2007)

Symptoms at diagnosis Percent of Total Median age at diagnosis (months)

Respiratory symptoms only

23 16.3

Gastrointestinal only 22 5.8

Gastrointestinal and respiratory

18 7.0

Meconium ileus 18 0.5

Family history 15 1.4

Unknown 4 3.5

Other 0.4 No information

Sweat Test

• The sweat test was first described by Gibson and Cooke in 1959 and forms the gold standard for the diagnosis of CF (Gibson, Cooke,1959;23:545)

• Guidelines for sweat testing have been published, and its is imperative they are closely followed in a laboratory with experience in sweat testing (Baumer, 2003;88:1126)

• The technique uses iontophoresis to drive pilocarpine into the skin to induce local sweating

• The sweat sample is collected either using the macroduct system or on filter paper

• A minimum sample of 15 microL is required using the macroduct system, and of 75 mg when using filter paper

Sweat Test

• Sweat Cl > 60 mmol/l is diagnostic of CF• Sweat Cl < 40 mmol/l rules out CF• Sweat Cl 40 – 60 mmol/l is equivocal

• Sweat Na should not be used to diagnose CF because values of up to 80 mmol/l can be seen in conditions other than CF

• However the sweat Na can be used to check the validity of the test as Na and Cl levels should be within 15 mmol/l of each other

• Sweat Cl > 160 mmol/l are physiologically impossible and if detected require the sweat test to be repeated

• Sweat conductivity should not be used

CF Respiratory Disease

Respiratory

• The fundamental problem in the CF airway is the build up of tenacious secretions resulting in airway occlusion, infection, inflammation, airway and lung parenchyma destruction, and bronchiectasis

• The central components of CF respiratory care are:– Airway clearance– Antibiotic therapy

Airway infection

Airway infection

• The term airway “colonization” has largely been abandoned when discussing airway pathogens, in favour of the term airway infection, recognising that the presence of pathogens in the lower airway is abnormal and associated with an inflammatory response.

• Repeated airway infection leads to sustained inflammation which results in time in irreversible airway and lung parenchyma destruction

• Respiratory failure remains the principal cause of premature death in patients with CF

• Much of the ongoing care of patients therefore is focused on managing airway infection

• It has been demonstrated that lower infection begins early in life, indeed in infancy

• S. aureus and H. influenza are the typical initial infecting organisms, followed later by P. aeruginosa

Cystic Fibrosis Foundation Patient Registry Annual Data Report 2005

S. aureus

• S. aureus is the most common organism infecting young children with CF (Elborn, et al,

1999;54:377), and remains an important pathogen throughout life, often present as a co-infection

• There remains some debate regarding the pathogenicity of S. aureus, as it may be present in sputum samples, in the absence of respiratory symptoms (Lyczak, et al, 2002;15:194)

• However, bronchoalveolar samples from infants diagnosed with CF by newborn screening demonstrate that in approximately 30% S. aureus can be detected, and its presence is associated with a significant inflammatory response (Armstrong, et al, 1997;156:1197)

• There remains controversy regarding the role of prophylactic anti-staph antibiotics

• Infants diagnosed by newborn screening and treated with long-term flucloxacillin for the first two years of life had, less frequent cough, less S. aureus isolates, lower admission rates ( 5 v 19), for shorter periods (2.2 v 6.4 days), despite receiving half the number of antibiotic courses (in addition to the flocloxacillin) (Weaver et al, 1994;70:84)

S. aureus

• A double blind placebo controlled trial of cephalexin as a long-term anti-staph prophylaxis started at mean age of 15 months, demonstrated reduced detection of S. aureus in airway cultures (6% v 30%), however there was no difference in clinical outcome measures, including lung function, x-ray scores, and nutrition. Most concerning was the increased detection of P. aeruginosa in the prophylactic cohort (26% v 13%) (Stutman, 2002;140:299)

• Currently the UK CF trust recommends the use of flucloxacillin as anti-staph prophylaxis up to two years of age. When S. aureus is detected after this, a two week course of anti-staph antibiotics is commenced.

Pseudomonas Aeruginosa

• P. aeruginosa is the most common chronic airway infection affecting patients with CF. The prevalence of infection increases with age. By the third decade up to 80% of patients are infected (Gibson et al, 2003;168:918)

• Chronic P. aeruginosa infection is difficult to eradicate and is associated with more respiratory symptoms, worse general health (Pamukcu et al 1995;19:10), more rapid decline in lung function (Kerem et al, 1990;116:714), more rapid deterioration in CXR scores (Demko et al, 1995;48:1041) and significantly worse survival (Lyczak et al, 2002;15:194) (Emerson et al, 2002;34:91)

• The ability of P. aeruginosa to change from a non-mucoid to mucoid phenotype by inducing bio-film formation, is an important feature in the establishment of chronic infection (Lyczak et al, 2002;15:194)

• Bio-films protect the organism from destruction by both neutrophils and antibiotics (Drenkard et al, 2002;416:695) (Costerton et al, 1999;284:1318)

• There are three different strategies for the antibacterial treatment of P. aeruginosa, depending on the clinical situation: first isolation, infective exacerbation, and chronic infection

1. First isolation

• Initially P. aeruginosa isolates are non-mucoid, motile, and are present in low density, thus presenting an opportunity for eradication (Rosenfeld et al, 2001;32:356).

• There is no consensus regarding the best eradication regime, but they all involve early aggressive treatment with anti-pseudomonal antibiotics

• Three weeks of nebulised colistin (1MU bd if < 2 yo, and 2 MU bd if > 2 yo) with 2-3 weeks of oral ciprofloxacin is as effective (80%) in initial eradication as three months of nebulised colisitin with 3 weeks of oral ciprofloxacin, but the three month treatment regime increased the interval to re-infection from 9 to 18 months (Frederiksen et al 1997;23:330) (Taccetti et al, 2005;26:458)

1. First isolation

• 28 days treatment with twice daily nebulised Tobramycin (300mg) for inhalation (TOBI) eradicated P. aeruginosa from 8 of 8 children less than 6 y/o, compared with just 1 of 13 children treated with placebo (Gibson et al, 2003;167:841)

• Inhaled tobramycin (80mg) for one year eradicated P. aeruginosa from 14 of 15 patients (Ratjen et al, 2001;358:983) (Wiesemann et al, 1998;25:88)

• When P. aeruginosa is detected again after eradication it is typically a new strain, rather than a re-emergence of partially treated original strain (Munck et al, 1998;32:288) (Taccetti et al, 2005;26:458)

2. Acute exacerbation

• An acute exacerbation is characterised by an increase in respiratory symptoms and signs, along with a reduction in lung function - typically a drop in FEV1 > 10% (Dakin et al, 2001;31:436) (Marshall, 2004;169:781). Reduced energy, and appetite, along with weight loss often also present.

• Minor exacerbations are typically treated with two weeks of oral ciprofloxacin (a quinolone), in addition to usual inhaled medications, and an increase in physiotherapy

• More significant infections typically require an increase in physiotherapy, along with anti-pseudomonal IV antibiotics for 14 days

• Usually two antibiotics are started; a beta-lactam antibiotic (e.g. ceftazidime, tazobactum + piperacillin, meropenum) plus an aminoglycoside (e.g. tobramycin, gentamicin, amikacin)

3. Chronic infection

• Chronic P. aeruginosa infection is defined as the culture of P. aeruginosa in 2 or more airway samples over a six month period (UK CF Trust 2001)

• Long-term use of nebulised antibiotics has been shown to be beneficial – it should be noted that this is long-term treatment, rather than prophylaxis

• Overall, only approximately 10% of the nebulised drug is delivered to the lungs (Le Conte et al, 1993;147:1279)

• Long-term nebulised tobramycin for inhalation (300mg twice daily) has been demonstrated to be safe, and to improve quality of life, increase lung function and reduce exacerbation rate (Ramsey et al, 1999;340:23) (Ramsey et al, 1993;328:1740) (Quittner et al, 2002;33:269) (Moss et al, 2002;121:55)

3. Chronic infection

• Tobi is to be given with the Pari LC Plus nebuliser with Pari TurboBoy compressor

• Nebulised Colistin has also been used for some time, particularly in Europe (Littlewood et al, 2000;94:632)

• The effectiveness of long-term nebulised Colistin has been demonstrated, with improved symptoms, reduced bacterial load, and maintenance of lung function (Littlewood, et al, 1985;1:865) (Jensen et al, 1987;19:831)

• However, there is some limited evidence that nebulised Tobramycin is superior to Colistin in maintaining lung function (Hodson et al, 2002;20:658)

Burkholderia Cepacia

• Burkholderia is a genus which contains several species. Initially the species were phenotypically indistinguishable, but were identified through molecular genetic typing as distinct genomovars (I – IX) (Vandamme et al, 1997;47:1188)

• The Burkholderia species can now be identified phenotypically, with the nine genomovars which cause lung disease in CF collectively referred to as the Burkholderia Cepacia Complex (Coenye et al, 2003;41:2797)

B. multivorans Genomovar I

B. cepacia Genomovar II

B. cenocepacia Genomovar III

B. stabilis Genomovar IV

B. vietnamiensis Genomovar V

B. dolosa Genomovar VI

B. ambifaria Genomovar VII

B. anthinia Genomovar VIII

B. pyrrocinia Genomovar IX

Burkholderia Cepacia Complex

• B. cenocepacia (previously Genomovar III), and B. multivorans (previously Genomovar I) cause the majority of infections in the CF population

• B. cenocepacia is particularly problematic

– It is highly transmissible among CF patients

– Approx 1/3 of patients infected will develop Cepacia Syndrome, which results in systemic signs of sepsis, weight loss, CXR infiltrates, a rapid decline in lung function, and early death within weeks, to months, despite maximal antimicrobial therapy. (Jones et al, 2004;59:948)

– There are some patients who remain well despite the presence of B. cenocepacia in their airways, however the majority with chronic infection have a more rapid decline in lung function, with a worse prognosis, than those with chronic Pseudomonas infection (McCloskey et al, 2001;170:28)

– It is typically resistant to most antibiotics, however, meropenum or ceftazidime, in combination with an aminoglycoside, may be useful, with co-trimoxazole added as a third agent (Aaron et al, 2000;161:1206)

Non-tuberculous mycobacterium

• Mycobacterium avium complex (MAC) and Mycobacterium abscessus account for 70% and 15% respectively of non-tuberculous mycobacterial (NTM) infection in CF patients, with M. abscessus being the more virulent of the two (Olivier et al, 2003;167:828)

• NTM tend to be transiently detected in the airways, with only a minority of patients developing clinically relevant disease. (Olivier et al, 2003;167:835)

• The ATS guidelines for the diagnosis of NTM infection are:– Three sequential positive airway cultures– A decline in lung function– New changes on CT scanning (ATS, 1997;156:S1-25)

• However, as NTM is often a co-infection with Pseudomonas, it is prudent to treat Pseudomonas infection first, and if there is no clinical improvement, to then start anti-NTM therapy

• Rifampicin, ethambutol, azithromycin and ciprofloxacin have been shown to be useful. Imipenem, and amikacin (IV or nebulised) may also be used in difficult cases. Treatment should be continued for one year with negative sputum cultures. (Leitritz et al, 2004;139:209) (Forslow et al, 2003;92;910) IFN-gamma may also have a role, in some cases (Hallstrand et al, 2004;24:367).

ABPA

• Aspergillus is a fungus which is commonly found in the airway samples of patients with CF (prevalence of 1 – 60%) (Stevens et al, 2003;37(suppl):S225)

• On many occasions it is simply a non-pathological colonizer of the airway, however a hypersensitivity reaction may develop to its presence resulting in allergic bronchopulmonary aspergillosis (ABPA)

• Diagnostic criteria for ABPA are :– The occurrence of asthma symptoms– New CXR changes– A four fold increase in IgE titres, or Ige > 500 iU/L– Increased specific IgE RAST to aspergillus or positive skin prick test– Eosinophilia > 500/mm3 – Positive sputum culture (CF UK Trust Antibiotic treatment for CF, 2nd Ed, 2002;

available at www.cftrust.org.uk )

ABPA

• Treatment– 0.5-1mg/kg/day Prednisolone for two weeks, with gradual

tapering of the dose over 2 – 3 months

– The role of anti-fungals is not clear, but treatment with itraconazole is often initiated with steroid treatment (Stevens et al, 2003;37(suppl):S225)

Stenotrophomonas maltophilia

• Stenotrophomonas maltophilia does not appear to have a significant impact on lung function or mortality (Goss et al, 2002;166:356).

• It does not appear to be transmitted between patients, and the majority of patients only have it transiently in their airways (Goss et al, 2004;59:955)

• There are no clinical trials of antibiotic treatment for S. maltophilia, however as some patients may go on to develop chronic infection, first isolates should probably be treated. Equally patients who are symptomatic, and/or deteriorating, should have antibiotics prescribed which are effective against S. maltophilia.

• S. maltophilia is resistant to a broad range of antibiotics. Ceftazidime may be useful, or IV piptazo and an aminoglycoside. Oral co-trimoxazole also has useful activity (Krueger et al, 2001;41:71).

Haemophilus Influenzae

• Haemophilus influenzae is detected frequently in the airways of patients with CF, and is often detected early in the course of the disease (Armstrong et al 1997;156:1197)

• Although there is little evidence that it causes significant pathology, it is however pathogenic in non-CF bronchiectasis (Bilton et al, 1995;8:948)

• It is often associated with increased symptoms and when this is the case it should be treated with an oral antibiotic such as co-amoxiclav (Rayner et al, 1990;65:255)

Airway clearance

Airway clearance

• Daily physiotherapy forms the cornerstone of CF airway clearance

• Historically postural drainage and percussion was used, although there are a wide number of modalities now available.

Percussion technique

• Postural drainage involves placing the patient in positions that allows gravity to assist mucous clearance (there are 12 positions, although the head down position is now generally avoided because of concerns regard gastro-oesophageal reflux)

• The technique requires an assistant to percus over the chest for 2-10 minutes, usually followed by deep breathing and huffing

• The technique is now mostly used on infants and young children

Active Breathing technique

• Active cycle of breathing techniques involve cycles of controlled tidal breathing at functional residual capacity, with deep breath thoracic expansion, and forced expiration using huffing

• Autogenic drainage involves controlled breathing in three phases; un-stick (at low lung volumes), collect (at mid lung volumes), and evacuate (at high lung volumes). It is designed to bring secretions from peripheral airways more centrally. Cough is suppressed until the final breath at high lung volume. Ventilation of peripheral airways is also likely enhanced.

Positive pressure techniques

• Positive expiratory pressure (PEP) mask involves a mask with a resistor which generates pressure (typically 10-20 cmH2O) during expiration (Falk, et al, 1984;65:423)

• The technique involves tidal breathing against the pressure on exhalation, for about 12 breaths, followed by forced expiration

• Oscillating PEP is similar to the PEP system described above, with the addition of an oscillating valve that generates intermittent acceleration and deceleration of airflow during the manoeuvre

• These flow transients occur at a frequency of approx 2 – 32 Hz, with pressures from 5 – 25 cmH2O, and are sometimes described as “micro-coughs” thus promoting mucous clearance

• The technique involves a deep breath into the inspiratory reserve (but not to total lung capacity), a 3 second breath hold, followed by active expiration over 3 seconds into the expiratory reserve (but not to residual volume). The technique is repeated 10 – 15 times followed by a huff to initiate expectoration

• The Flutter and Acapella are the usual devices used. The are similar, but the Acapella can generate a PEP of 10-20 cmH2O at end expiration

High frequency chest compression

• There are several companies producing their own version of “the vest”

• It consists of a compressor system which delivers large volumes of air at frequencies of 5 – 25 Hz, to an inflatable jacket worn over the patient’s chest

• The pressure pulses can be adjusted (typically between 0 – 20 cmH2O), as well as the frequency

• Higher oscillating frequencies result in higher flow rates, and more shear force to dislodge mucous. Higher pressure increases both flow and volume, but is more uncomfortable

• The vest appears to provide clinically effective airway clearance, however it does not appear to be superior to previously describe techniques, and as such it is difficult to justify its cost ($15,000)

Treatment options to improve airway clearance

Dornase alfa (pulmozyme)

• Due to neutrophil and bacterial breakdown, CF sputum has DNA levels 3-5 times higher than normal

• Recombinant human dornase (rhDNAse), also known as Dornase alfa, or its trade name Pulmozyme, hydrolyses extracellular DNA, thus improving mucociliary clearance

• Pulmozyme is administered using the Portaneb compressor and a jet nebuliser such as the Sidestream neubuliser

• Fuchs et al demonstrated 15 years ago that 6 months of pulmozyme treatment improved FEV1 by approximately 6%, as well as reducing exacerbations and improving well being (Fuchs, et al, 1994;331:637)

• These findings have been replicated, leading to a recent review recommending pulmozyme for all patients over 6 years old, especially those with chronic Pseudomonas infection (Conway, et al, 2002;34:242)

Hypertonic saline

• Hypertonic saline (HS) is an airway clearance adjunct which appears to work by temporarily hydrating the airway and inducing coughing

• There is a stepwise increase in mucuciliary clearance from 0.9%, to 3%, to 7% hypertonic saline (Robinson, et al, 1997;52:900)

• HS was shown to be inferior to Pulmozyme in a cross over trial in children. However, there was significant heterogeneity in the response, with some children (35%) having greater than 10% improvement in their FEV1. This group included some who did not respond to Pulmozyme (Suri, et al, 2001;358:1316)

• A recent Cochrane review concluded that HS did not demonstrate an improvement in lung function, however did recommend its use as it improved quality of life and reduced frequency of exacerbations (2009;2:CD001506)

Anti-inflammatory medication

Steroids

• A Cochrane review of the use of oral corticosteroids concluded that 1 – 2 mg/kg alternate day prednisolone slow the progression of lung disease, but at the expense of a negative, and potentially irreversible, affect on height, along with the development of impaired glucose metabolism, and of cataracts (Cheng et al, 2000;(2):CD000407). Long-term, high dose steroids, therefore are not used to treat patients with CF. The role of low dose steroids (e.g. 5 – 10mg per day) is yet to be defined.

Non-steroidal anti-inflammatory drugs (NSAIDS) – Ibuprofen

• Ibuprofen reduces the rate of decline in lung function, however concerns regarding gastrointestinal and renal side effects have limited its universal use (Konstan et al, 1995;332:848)

Macrolides

• Azithromycin, although an antibiotic, appears to have anti-inflammatory affects on the CF airway. It has been demonstrated that patients over 6 years of age, taking azithromycin three days per week, had a higher FEV1 by approx 6% when compared to the placebo group (Equi et al, 2002;360:978) (Saiman et al, 2003;290:1749)

Nutrition

Nutrition

• Intensive long-term nutritional support is central to the ongoing care of patients with CF

• It has been clearly demonstrated that poor body weight and height are independent risk factors of mortality (Sharma et al, 2001;56:746) (Beker et al, 2001;101:438)

• Effective nutritional support has been demonstrated to slow the rate of decline in lung function (Steinkamp et al, 2002;57:596)

• Energy requirements vary considerably and depend significantly on the clinical status of the patient. Energy requirements can be increased secondary to infection, inflammation, increased work of breathing, and decreased lung function (Bell et al,

2000;30:553). Energy needs in undernourished adolescents with CF can be up to 120-150% of those without CF (Pencharz et al, 1984;3(suppl):s147)

• Many patients fail to meet their target calorie intake as a result of several factors such as; anorexia, gastro-oesophageal reflux, abdominal pain, and increased sputum production (Kawchak et al, 1996;129:119) (White et al, 2004;3:1)

Nutrition

• Evidence from northern Europe suggests up to 95% of patients are pancreatic insufficient (Littlewood et al, 2000;2:205). From a limited number of patients in whom the data was available in the Irish CF registry, approximately 88% of patients under 18 years of age are pancreatic insufficient (The Cystic Fibrosis Registry of Ireland Annual Report 2007).

• If symptoms of malabsorption are evident, a stool sample for faecal elastase should be taken, and pancreatic enzyme replacement therapy (PERT) started (Borowitz et al, 2005;11:524).

• Enzymes come as enteric coated acid-resistant preparations

• Different strengths are available but typically a capsule contains 10,000 of lipase

• Fat soluble vitamins A, D, E and K are also replaced

Nutrition

• Infants typically begin with a starting dose of 2500IU lipase or in practical terms half a scoop of Kinder Creon per breastfeed or 120mls of breastmilk substitute that provides approx  < 4.5g of fat ( ie 500 IU lipase per gram of dietary fat)  The dose is then titrated according to weight gain and bowel symptoms - frequency, odour, texture and  colour. 

• For older children dosing is approached on an individual basis. The dose usually ranges between 500 -4000 IU per gram of dietary fat aiming for the lowest effective dose. Weight gain, growth and bowel symptoms are monitored and dosages adjusted accordingly.

• Fat intake is relatively high relative to body weight in infancy but decreases with time. Infants ingest approx 5g of fat per Kg of body weight per day whereas older adolescents and adults ingest about 2g of fat per Kg of body weight per day. The enzymes are distributed throughout the day by matching lipase to the amount of fat in food and drinks.

• The maximum recommended dosage for children and adults is 4,000 IU lipase  / g of fat or  10,000 IU lipase /Kg/ day

Meconium Ileus (MI)

• Clinical presentation– Infants present with bowel obstruction within the first 48 hours of

life

– Vomiting (often bile stained)

– Abdominal distension

– Failure to pass meconium

– Right lower quadrant mass may be palpable

Meconium Ileus (MI)

• X-ray findings– PFA reveals distended bowel loops, usually with no air-fluid

levels

– Right lower quadrant speckled “ground glass” appearance seen in approx 30 – 50 % of cases (but also seen in other cases of neonatal bowel obstruction e.g. Hirschprung’s disease, small bowel atresia)

– Contrast enema may demonstrate micro-colon, and demonstrate the site of obstruction at the distal ileum

Meconium ileus

• Approximately 40% of cases are complicated by; intestinal atresia, volvulus, or antenatal perforation with meconium peritonitis

• Therapy is aimed at decompression and relief of the obstruction

• Uncomplicated MI can be treated in the first instance with gastrograffin enema

• If this fails to relieve the obstruction surgical intervention is required. This involves a laparotomy with irrigation of the obstructed ileum. Temporary ileostomy may be required to allow ongoing irrigation, and to allow the microcolon time to resolve

• Note; MI is not pathognomonic of CF with pancreatic insufficiency, therefore the diagnosis, and pancreatic status should always be confirmed

CF related diabetes

• As discussed above, exocrine pancreatic function is lost in approximately 90% of patients with CF. In the majority of cases this has occurred at the time of presentation in infancy or during the pre-school years.

• Islet cell secretion, as part of the endocrine function of the pancreas, is lost in a much smaller proportion of patients.

• This occurs over time, with prevalence increasing with increasing age, from approximately 5% in 10 – 14 y/o, to 12.6% in 15 – 19 y/o (Koch et al, 2001;31:1), to approximately 24% in those over 20 y/o (Lanng et al, 1995;311:655)

• Abnormal glycaemic control in CF related diabetes (CFRD) is characterised by impaired and delayed insulin secretion resulting in insulinopenia (Moran et al, 1998;133:10). Of note, glucagon secretion is also impaired (Lanng et al, 1995;311:655).

• Of note, there is only one reported case of ketoacidosis in a CF patient, in the literature (Atlas et al, 1992;146:1457)

CF related diabetes

• The onset of CFRD is clearly associated with increased mortality (Koch et al, 2001;31:1), particularly in female patients (Milla et al, 2005;28:2141)

• Lung function decreases significantly faster in patients with CFRD (Rosenecker et al, 2001;6:345)

• Patients are at risk of microvascular complications of diabetes (such as retinopathy, nephropathy and neuropathy) (Dolan et al, 1986;314:991), but not the macrovascular complications such as athersclerosis (Schlesinger et al, 1997;16:365a), although this could change with improving survival.

• It is also becoming clear that lung function and clinical status can decline in the pre-diabetic period (Lanng et al, 1992;151:684)

• Insulin treatment, even at low doses, has been demonstrated to improve lung function and weight (Dobson et al, 2002;87:430), although clear treatment guidelines are yet to be developed, particularly for the pre-diabetic period

CF associated liver disease

• The reported prevalence of CF associated liver disease (CFALD) varies widely depending on the definition of liver disease

• A postmortem study in adults found evidence of liver disease in over 70% of cases (Vawter et al, 1979;14(pt 2):357)

• A longitudinal French study detected CFALD in 18%, 29% and 41% of children at 2, 5 and 12 years of age, but only 6 – 8 % of these went on to develop cirrhosis (Lamireau et al, 2004;41:920)

• The majority of patients develop overt signs of liver disease in the first 12 years of life (Corbett et al, 2004;145:327)

• The characteristic lesion in CFALD is focal biliary cirrhosis (Vawter et al, 1979;14(pt 2):357)

• Ursodeoxycholic acid (Urso) improves biochemical markers of CFALD as well as histological changes (O’Brien et al, 1992;33:387) (Lindblad et al, 1998;27:166), however there is no clear evidence that it alters the long-term course of CFALD

Reproductive health

• Males with CF are sterile due to congenital bilateral absence of the vas deferens resulting in azoospermia (Kaplan et al, 1968;279:65)

• The seminal vesicle is often absent or atrophic resulting in low volume semen (McCallum et al, 2000;118:1059)

• Normal spermatogenesis takes place in the testicles which are histology normal (McCallum et al, 2000;118:1059)

• Libido and erectile function are normal, however chronic ill-health can have a negative impact on both (Sawyer et al, 2005;60:326)

• Women with CF have anatomically normal reproductive tracts (Oppenheimer et al, 1970;77:991)

• Although cervical mucous is likely to be abnormal and impair conception, with reports that 75% of women who tried to conceive became pregnant (Odegaard et al 2002;81:693), all women with CF should be considered fertile

Atypical (non-classic) CF

• It is now recognized that mutations in the CFTR gene give rise to a range of phenotypes that includes classic CF, and reaches to single organ pathologies

• The term “mild” or “atypical” CF refers to children and adults who present without signs of significant respiratory disease, or malabsorption, but instead may have sinus disease, pancreatitis or male infertility, amongst other symptoms (Wallis, in Cystic Fibrosis 2007, p99 – 108)

• Affected individuals may have normal, borderline or abnormal sweat tests, and one, two, or no, CF causing mutations identified (Gooding, in Cystic Fibrosis 2007, p209 – 224)

• It is generally accepted that the diagnosis of “classic” CF is not appropriate for these individuals and the initiation of arduous therapies is inappropriate and unlikely to be of benefit.