Cystic Fibrosis

D R. DA K S H J H I MF I R S T Y E A R J U N I O R

R E S I D E N T

CYSTIC FIBROSIS

INTRODUCTION

• Cystic fibrosis (CF) is a monogenic disorder that presents as a multisystem disease.• was first described as a unique disease entity in

1938.• Most common lethal genetic disease in Causasians.• lethal autosomal recessive disease.• incidence: 1 in 2000-3000; predominantly Caucausian

populations (carrier frequency 1 in 22-28).• “Woe to the child which when kissed on the forehead

tastes salty. He is bewitched and soon will die” - old proverb.

INTRODUCTION

• Patients typically presented with intestinal obstruction or malnutrition and died from overwhelming pneumonia within the first year of life.• Over the last 40 years, the median survival with

CF has increased dramatically from 6 years in 1955 to 36 years in 2005.• The improvement in CF outcomes has paralleled

advances in antibiotic therapies, nutritional approaches, and the collection of clinical expertise into specialized treatment centers.

PATHOGENESIS

CF AND GENETICS

• Caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

• Anion channel

• ATP Binding Cassette family

• Regulates other ion channels (ENaC)

• Plays crucial roles in absorption and secretion

• Found mainly in wet epithelia

CFTR

• CFTR functions as a cAMP-activated ATP-gated anion channel.• increasing the conductance for certain anions (e.g.

Cl–) to flow down their electrochemical gradient.• ATP-driven conformational changes in CFTR open

and close a gate to allow transmembrane flow of anions down their electrochemical gradient.• found in the epithelial cells of many organs

including the lung, liver, pancreas, digestive tract, reproductive tract, and skin.• Mainly found in exocrine glands.• Normally, the protein moves chloride and

thiocyanate ions along the concentration gradient.

1. Sweat glands2. Mucus3. Digestive fluids

SWEAT GLAND PATHOPHYSIOLOGY

SWEAT GLAND PATHOPHSIOLOGY

• CFTR important for Cl- absorption• Na+ and Cl- generally reabsorbed• Cl- buildup = negative charge on luminal side• Decreased Na+ reabsorption• NaCl formation and secretion in sweat• Used as diagnostic factor

MUTATIONS

• The CFTR gene located on chromosome 7, on the long arm at position q31.2..• The mutations in the CFTR gene fall into five

major classes.• Classes I–III mutations are considered "severe," as

indexed by pancreatic insufficiency and high sweat NaCl values.• Class IV and V mutations can be "mild," i.e.,

associated with pancreatic sufficiency and intermediate/normal sweat NaCl values.

MUTATIONS

• Over 1900 mutations in the CFTR gene that can cause CF.• Most common is ΔF508.

LUNG PATHOPHYSIOLOGY

• CFTR plays a central role in the regulation of ion transport across airway epithelia.• In CF, dysregulation of airway surface liquid (ASL)

volume occurs as a consequence of ion transport dysfunction• impairing mucociliary clearance and, therefore, lung

defense.• Airway surfaces are coatedwith a thin layer of liquid,

the ASL, which is composed of a 1. periciliary layer (PCL) 2. more viscous mucus layer.


• The mucus layer, which normally floats on top of the PCL, efficiently traps inhaled pathogens and particulates.

• The mucus layer, which normally floats on top of the PCL, efficiently traps inhaled pathogens and particulates.

• The underlying PCL layer, in turn, provides a low viscosity environment in which cilia can beat freely and thereby propel the mucus layer toward the mouth.

• The PCL also acts as a lubricant layer that prevents adhesion of the mucus layer to cell surfaces.

• proper regulation of ASL volume and the hydration of its component layers are critical to the maintenance of mucus clearance.


• An adequate PCL height is necessary to allow ciliary beating.• Adequate hydration of the mucus layer is a key

determinant of its viscoelastic properties and transportability.


• CFTR important for Cl- secretion• CFTR also mediate ENaC activity• Net decrease in Cl- secretion and increase in Na+

absorption• Osmotically surface mucous dehydrated• Buildup compresses cilia resulting no mucous

movement• Infections.


OVERALL PATHOLOGY

• Sweat Glands :hypersecretion of salt• Lungs :mucous buildup + infection• Pancreas :fibrous cysts + blockage• GI Tract :blockage from thick feces• Liver : obstruction, possible cirrhosis• Male Reproduction : sterile

LUNG :SECONDARY PATHOGENESIS

• ASL dehydration produces progressive mucostasis.• Initiates a cascade of events that leads to clinically

apparent CF lung disease.• Firstly, thickened mucus secretions eventually

become adherent to airway surfaces with the loss of PCL volume, and begin to obstruct small airway lumens.• Mucus plugs and plaques not only provide a

protected environment in which bacteria can escape mechanical and immune-mediated clearance, but also create a unique environment that drastically alters bacterial gene expression.

LUNG :SECONDARY PATHOGENESIS

• Paradoxically, the center of a mucus plug is in fact anaerobic (pO2 less than 2 Torr) due to a combination of an increased diffusion distance for O2 as well as increased oxygen consumption by CF epithelia (owing to heightened Na+ transport).

• Within this environment, P. aeruginosa converts to an anaerobic mode of metabolism, increases alginate production, and ultimately establishes a biofilm structure.

• Organisms growing within the biofilm possess increased resistance to secondary host defense mechanisms (e.g., neutrophils and soluble antimicrobials).

• Failure of neutrophils to clear this infection, accompanied by the release of proteases and other harmful substances destroying lung tissue, ultimately leads to bronchiectasis.

LUNG PATHOGENESIS

Bacterial infection

Chronic inflammat

ionFibrosis

↓ Pulmonary function

CLINICAL ASPECTS

ASL dehydration and mucus plugging, also develops chronic airway inflammation without readily identifiable bacterial infection.• Current hypothesis to explain these findings include:

1. a low burden of typical bacteria avoids eradication in the dehydrated mucus environment of the CF lung and drives the inflammatory process in very early disease.

2. the presence of atypical, perhaps anaerobic, organisms are poorly identified with usual culture systems but dominate early disease and cause inflammation.

3. intermittent events, including viral infections and/or gastric aspiration drive the inflammatory process early in life.

• Regardless, these observations point to the very early onset of lung disease, even in asymptomatic infants, and the need to develop and institute effective interventions in this population.

CLINICAL ASPECTS

• Over a relatively short period of time, the CF lung becomes chronically infected with typical pathogens.

• In childhood, Haemophilus influenzae and Staphylococcus aureus are often identified first organisms to invade typically followed by the establishment of chronic Pseudomonas aeruginosa infection.

• Pseudomonas may take many morphologic forms, but mucoid phenotype signifies chronicity and the inability to eradicate this organism, even with aggressive antibiotic regimens.

• Other important pathogens that are encountered in CF include a variety of gram-negative bacteria, especially Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and the Burkholderia cepacia complex (Bcc).

CLINICAL ASPECTS

• Mycobacterial pathogens are also encountered in CF, including M. avium complex and M. abscessus.

• MAC is the most prevalent mycobacterial pathogen in CF, but often does not cause discernible clinical disease, as opposed to the much more problematic infection with M. abscessus.

• Viral infections, although probably not more frequent than in other populations, do appear to cause more morbidity and may be an important trigger of lung disease exacerbations.

• Fungi, particularly aspergillus species, are common colonizers but may cause allergic bronchopulmonary aspergillosis (ABPA).

• The primary cause of morbidity and mortality in CF patients is bronchiectasis and obstructive lung disease.• Pulmonary disease is present in 98% of patients with

CF by the time they reach adulthood.• A recurrent cough that becomes persistent is often

the first manifestation.• Airway hyperreactivity and wheezing are common in

children.• Pansinusitis with opacification of the paranasal

sinuses is a universal finding in nearly 30% patients with CF.

ACUTE EXCERBATIONS

• Exacerbations of CF lung disease are extremely important events in the life of a CF patient.• These periodic illnesses often remove the patient

from their usual work or school activities, are associated with significant reductions in quality of life, exact a large financial toll in terms of health care costs, and are associated with reduced survival.• Exacerbations are typically acute to subacute events

that are superimposed upon a previously stable clinical baseline.

• Patients usually report increased cough, sputum, fatigue, and weight loss during these episodes.

• Fever, leukocytosis, chest pain, and new infiltrates on chest radiographs are less consistent findings with exacerbations.• The inciting events that trigger an exacerbation have

not been clearly defined, although acute respiratory viral infection may be one important cause in addition to inadequate use of preventative therapies.

RESPIRATORY COMPLICATIONS

1. Bronchiectasis: occurs as a result of destruction of lung tissue and erosion of the bronchial cartilage.

2. Atelectasis: Lobar and segmental atelectasis occurs in about 5% of patients. This complication is most prevalent in the first 5 years of life and thereafter has a diminishing frequency. The right lung is the site of atelectasis in the majority of patients.

3. Pneumothorax : is a more frequent complication .The overall incidence is about 1%/yr, and increases with age and disease severity, so that about 20% of CF adults will experience at least one pneumothorax.

LUNG COMPLICATIONS

4. Hemoptysis: is a common event in older CF patients. Minor to massive hemoptysis may occur .Massive hemoptysis is increasingly common in older patients, with an average annual incidence of 0.87 percent.5. Allergic bronchopulmonary aspergillosis (ABPA): develops in 1% to 10% of patients at some time in their lives. 6. Pleural effusions and empyema: are uncommon in patients with CF, but pleuritic symptoms and signs may accompany exacerbations of lung disease.

• Staphylococcal and pseudomonal empyemas have been described, but respiratory tract infections usually spare the pleural space.

7. Respiratory failure: leads to death in greater than 90% of CF patients.

RADIOLOGICAL FINDINGS

• The earliest radiographic change is usually hyperinflation of the lungs, reflecting obstruction of small airways.

• The degree of hyperinflation generally increases with age.

• As bronchitis progresses, peribronchial cuffing becomes increasingly prominent.

• Mucous impaction in airways may be seen as branching finger-like shadows.

• Evidence of bronchiectasis, such as enlarged ring shadows and cysts, is common by 5 to 10 years of age.

• peripheral rounded densities are noted during acute exacerbations and may disappear with treatment, leaving residual cysts.

RADIOLOGICAL FINDINGS

• Subpleural blebs often become evident during the second decade of life and are most prominent along the mediastinal border.

• For reasons that remain unexplained, the right upper lobe usually displays the earliest and most severe changes.

• With advancing disease, the pulmonary artery segments become more prominent.

• A relatively small and vertical cardiac shadow is typical, but the heart enlarges with onset of cor pulmonale.

• Hilar adenopathy is rarely prominent.• Lobar or segmental atelectasis is uncommon but is

most often seen in infants or small children.

PULMONARY FUNCTION TESTS

• Newborns with CF are thought to have normal lung function.• However, within weeks to months, many infants

with CF show evidence of increased airway resistance, gas trapping, and diminished flow rates.• In general, patients progress from initial reductions

in maximum midexpiratory flow rates to reductions in forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) and then to diminished vital capacity and total lung volumes.• The progression occurs from peripheral airway

obstruction to more generalized obstruction and then to acquisition of a restrictive component.

DIAGNOSTICS

1. New born screening • Since October 2007, newborn screening for CF has

been in place throughout the whole of the UK.• NHS of U.K. has made it mandatory for screening of

newborns for cystic fibrosis.• Immunoreactive trypsinogen (IRT) is measured on a

dried blood spot obtained on the Guthrie card at day 6 of life.

• Samples with abnormally raised IRT levels will undergo CFTR mutation screening as per the flow chart

• An increased IRT must be followed by direct diagnostic testing (typically with the sweat chloride test).

DIAGNOSTICS

2. Sweat testing(pilocarpine iontophoresis)

• remains the “gold standard” diagnostic test because genetic screening only identifies a small number of the most common mutations.

• The results of this test are abnormal in the large majority of patients with CF.(about in 98% of patients).

• However, the test must be repeated at least twice, and an adequate sample containing at least 75 mg of sweat must be collected over a 30-min period.

• Approximately 1% of patients with CF have normal sweat chloride test results.

FALSE POSITIVE SWEAT TEST RESULTS

• Adrenal insuffi ciency• Anorexia nervosa• Atopic dermatitis• Autonomic dysfunction• Celiac disease• Familial cholestasis• Fucosidosis• Glucose-6-phosphate dehydrogenase defi ciency• Glycogen storage disease, type I• Hypogammaglobulinemia• Hypoparathyroidism• Hypothyroidism (untreated)• Klinefelter syndrome• Mucopolysaccharidosis, type I• Malnutrition• Nephrogenic diabetes insipidus• Nephrosis• Prostaglandin E1 infusion, long-term• Pseudohypoaldosteronism

DIAGNOSTICS

3. Molecular diagnosis: according to GUIDELINES, reasons for full genotyping include the following:• Any child diagnosed with CF:

1. facilitates screening for other family members.2. allows prenatal diagnosis of future pregnancies.• Since the advent of the first mutation-specific therapy ivacaftor, and on-going clinical trials of other small molecule CFTR-modulators, all CF patients MUST be genotyped. Full gene sequencing should be carried out when there is diagnostic doubt (especially in ethnic minorities).• In newborn siblings of affected children, cord blood should be taken at the time of birth (arrange with mother in clinic, give form and blood bottle).

• Generally older siblings will have a sweat test for diagnosis rather than genetic analysis. The latter would detect carriers, which is something that should be postponed until the sibling is old enough to decide whether they wish to know their carrier status (usually mid teens and older).• To aid confirmation of diagnosis in case of borderline

sweat test. However, genotype analysis should not be used to guide prognosis in an individual child, except rarely (and very cautiously) in the case of mutations usually associated with pancreatic sufficiency (e.g. R117H).

LIMITATIONS OF MUTATION ANALYSIS

• Due to the large number of identified mutations, and the extreme rarity of many of these, it is only practical to screen for a few on a routine basis.• Clearly therefore failure to detect mutations does

not exclude the diagnosis. The above is of particular importance in a child of non-Caucasian origin.• There is now a specific panel of mutations, which

are common in the Asian community.• It is therefore CRITICALLY IMPORTANT that in every

case the child’s ethnic origin is included on the request form so that the most likely mutations can be looked for.

DIAGNOSTICS

4. Potential Diff. across the respiratory epithelium• This is a research tool to aid in the diagnosis of CF.• Difficult in small children as requires cooperation,

but may be useful in older indeterminate cases (over 8-10 years).• The abnormal transport of chloride leads to a very

negative PD across the nasal epithelium.• Nasal perfusion with amiloride hydrochloride and

with chloride-free solutions leads to characteristic changes in the PD.

5. Stool elastase:• may be supportive of the diagnosis.• low in CF with pancreatic insufficiency (usually <15

mcg/g).1. Normal : > 200 mcg/g stool2. Mild/moderate pancreatic insufficiency :100-200

mcg/g stool3. Severe pancreatic insufficiency :< 100 mcg/g stool

DIAGNOSTIC CRITERIA ACCORDING TO ACCP

• Elevated sweat chloride level ≥ 60 mmol/L on two occasions or• Identification of mutations known to cause CF in both CFTR genes

or• In vivo demonstration of characteristic abnormalities in ion

transport across the nasal epithelium plus• One or more phenotypical features of CF

1. Sinopulmonary disease2. Characteristic GI or nutritional disorders3. Obstructive azoospermia4. Salt loss syndrome or• Sibling with CF

or• Positive NBS result

TREATMENT

• The primary objectives of CF treatment are to control infection, promote mucus clearance, and improve nutrition. • Experience has repeatedly demonstrated that

attention to preventive aspects of lung care and psychosocial factors is important.

PHYSICAL MEASURES TO PROMOTE AIRWAY CLEARANCE

• The use of postural drainage with chest percussion to clear mucus is based on the concept that cough clears mucus from large airways but chest vibrations are necessary to move secretions from the small airways where expiratory flow rates are low.

• When patients were receiving chest physical therapy on a regular basis, the only immediate effect documented was an increase in peak expiratory flow rate 30 minutes after therapy.

• However, after 3 weeks without chest physical therapy, both FVC and flow rates were significantly reduced.

• Theoretically, chest physical therapy might prevent or delay inspissation of mucus in small airways.

INHALED HYPERTONIC SALINE FOR AIRWAY CLEARANCE

• Inhaled hypertonic saline (HS) osmotically draws water onto airway surfaces.• Indeed, because of the limitation with respect to Cl-

permeability of CF airway epithelia, inhaled salt may remain on CF airway surfaces longer, and hence be osmotically more active, than on normal airway surfaces.• Recent data suggest that the rehydrating effect of

inhaled HS (7%, four times daily) produces short term (2-wk) effects that restore mucus clearance and improve lung function and quality of life.

AEROSOLIZED RHDNASE

• The lysis of viscous DNA with the recombinant enzyme DNase offers benefit to some patients with purulent airway secretions.• When taken once daily, aerosolized DNase reduced

relative risk of respiratory exacerbations by 28% and improved FEV1 approximately 6% above baseline over 6 months.• Not all patients had objective improvement in lung

function, but symptomatic benefit occurred in many of treated patients without improved lung function.• Daily inhalation slows the usual decline in lung

function and decreases the frequency of exacerbations.

NOVEL AIRWAY SURFACE REHYDRATING AGENTS

• A number of novel agents are being developed to treat CF airways dehydration. For example, as an alternative osmotic agent, inhaled mannitol (“Bronchitol”) is being developed as a dry powder inhalation and is currently in phase III clinical testing.• There are also novel small molecules in development

designed to redirect CF ion transport from absorptive to secretory modes.• An extracellular ATPase resistant analogue of UTP,

INS37217, is currently completing phase III testing.

NOVEL AIRWAY SURFACE REHYDRATING AGENTS

• Like endogenous ATP, INS37217 slows Na+ absorption and activates Ca2+-activated Cl- channel-mediated Cl- secretion in CF airways to rehydrate surfaces.• long-acting, potent, and safer amiloride derivatives

(e.g., GS9411) are being developed for inhalation in an HS vehicle to greatly amplify the hydrating effect of HS.

ANTIBIOTICS

• Lung infection is the major source of morbidity and mortality in CF.

• Antibiotics are the mainstay of therapy designed to control progression of disease.

• In general, antibiotic therapy should be predicated on the presence of symptoms and guided by the identification of organisms from the lower respiratory tract.

• There is evidence that early and vigorous use of antibiotics produces better results than delaying the administration of antibiotics until symptoms are well developed or advanced.

• Another principle of antimicrobial therapy in CF is that dosages need to be higher than for non–CF-related chest infections.

ANTIBIOTICS

• Both total body clearance and volume of distribution are considerably greater for CF than for other patients.• Large doses are needed to achieve therapeutic levels

in the infected and mucus- or pus-filled endobronchial space.• The choice of antibiotics optimally should be based

on the results of sputum culture and sensitivity testing.• For patients with nonproductive cough, specimens

are best obtained by throat swab placed just above the glottis during repetitive coughing.

BRONCHODILATORS

• ß- Agonists can be nebulized, administered by metered-dose inhalers, or given orally.• Caution should be exercised concerning long-term

therapy with these agents because animal studies show that administration of large amounts of ß-adrenoceptor agonists cause submucosal gland hypertrophy and presumably a hypersecretory state.• CF patients seem to be less tolerant of theophylline

because of frequent gastrointestinal irritation.

CORTICOSTEROIDS

• An initial double-blind controlled study of alternate-day oral corticosteroid administration demonstrated better maintenance of pulmonary function and fewer exacerbations of lung disease requiring hospitalization over a 4-year period.• However, widespread use of oral or inhaled

corticosteroids should be avoided.

ANTI-INFLAMMATORY THERAPY WITH IBUPROFEN

• A study of high-dose ibuprofen over 4 years indicated that CF patients younger than age 13 years with mild lung disease have remarkable slowing of decline of lung function (eightfold) as compared with placebo control subjects.• No effect was documented in patients older than

13 years. There were few side effects, but most of the eldely patients were taking antacids or H2- receptor blockers.

OTHER RESPIRATORY THERAPIES

• Mucolytics, expectorants, and cough suppressants have been used for relief of chest symptoms.• Expectorants, which assist in the elimination of

airway secretions during cough, probably do not achieve that objective.• Long-term administration of iodides to patients with

CF has been associated with a high incidence of goiter and hypothyroidism.• Mucolytics such as N-acetylcysteine are injurious to

respiratory epithelium and promote bronchitis when used regularly.

SYSTEMIC AGENTS DESIGNED TO RESTORE CYSTIC FIBROSIS TRANSMEMBRANE REGULATOR FUNCTION

• Two classes of small molecule therapeutics are under development for treatment of CFTR mutant protein.• The first class is aimed to improve the maturation of

misfolded mutant CFTR (e.g., F508 CFTR). A first such compound, VX809, is in phase I testing.• The second class is aimed at mutant CFTRs that

have normally folded, and are targeted to the apical membrane, but function poorly. VX770 is currently in phase II clinical testing.

GENE TRANSFER TECHNOLOGY

• It is technically possible using genetically engineered viral vectors to transfer the wild-type CFTR gene to respiratory epithelial cells in vitro, where it can be expressed at least for days to weeks.• Work is ongoing at the laboratory level on adeno-

associated virus–, lentiviral-, and paramyxoviral-based vectors for this purpose.

NUTRITION

• Approximately 90% of patients with CF require mealtime pancreatic enzymes, packaged as granules that are coated with acid-resistant material to promote delivery to the small intestine.

• Capsules containing 4000 to 24,000 units of lipase are available.

• Numbers of capsules taken should be adjusted based on weight gain, presence or absence of abdominal cramping, and the character of stools.

• Dosage should be limited to current guidelines (~2500 lipase units/kg/meal), because a large total daily dose of enzymes has been associated with fibrosing colonopathy.

• Vitamins A and D are supplied by a daily multiple vitamin preparation. Vitamin E, 100 to 200 units daily.

NUTRITION

• Vitamin K is given sporadically to treat bleeding complications or to correct prolonged prothrombin times.

• Other vitamins and trace minerals may be deficient and require supplementation on a selective basis.

Psychosocial Factors • As with any chronic disease, compliance with therapy

and ability to function fully are highly dependent on the patient's attitude.

• Approaches that promote a positive self-concept and foster the ability of patients to take control of their medical management, and enable them to participate fully in life events, are likely to promote well-being and perhaps longevity.

TREATMENT OF LUNG COMPLICATIONS

• Hypercapnic and hypoxemic respiratory failure in CF are primarily due to progressive obstructive airway disease with alveolar hypoventilation and ventilation-perfusion mismatching.

• Low-flow oxygen is effective at relieving nocturnal, exertional, and resting hypoxemia and does not usually cause significant hypercapnia.

• The use of supplemental oxygen in children has been discouraged because nocturnal oxygen did not improve survival or prevent the development of cor pulmonale in one controlled trial.

• Supplemental oxygen in accordance with the guidelines established for chronic obstructive pulmonary disease is recommended for adults to avoid development of pulmonary hypertension.


• Diuretics, inotropic agents, and theophylline produce few benefits and are rarely used.• Cor pulmonale is a late complication of airway

obstruction, and no treatment options beyond those for the primary disease processes are effective.• Ventilatory assistance is effective in CF patients with

acute respiratory failure caused by reversible insults but produces few long-term benefits in patients with respiratory failure due to irreversible lung damage caused by CF bronchiectasis.• The airway disease generally progresses, however,

and long-term ventilatory support is rarely feasible.


• Atelectasis is best treated by vigorous standard therapy, including airway clearance and antibiotics.• ABPA responds to standard doses of systemic

corticosteroids. Inhaled steroids and the oral antifungal agent itraconazole may prove to be useful.• Pneumothorax can be observed for spontaneous

resolution if small and minimally symptomatic. • A pneumothorax more than 20% of the hemithorax

volume, compromising ventilation or causing hypotension, requires tube drainage. • Recurrences are very common and may require

thoracoscopic talc poudrage or surgical pleural abrasion.


• Hemoptysis requires treatment of airway infection and supplemental vitamin K if the prothrombin time is prolonged due to inadequate absorption.• Massive hemoptysis may resolve with such

conservative therapy and modest cough suppression for 1 to 2 days.• Bronchial artery embolization provides more

definitive control, which usually persists for more than 6 months.

TRANSPLANTATION

• Lung transplantation has become an accepted therapy for respiratory failure secondary to CF.

• Heartlung transplant has been largely replaced by sequential double-lung transplant because of limited organ availability.

• The transplanted lungs remain free of CF, but are subject to secondary infection, acute rejection, and chronic rejection (bronchiolitis obliterans syndrome).

• The 5-year survival is 48%, as good as that of lung transplant recipients with other causes of lung disease.

• Living lobar transplantation is an effective alternative to conventional cadaveric lung transplants.

THANKS

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Cystic Fibrosis