Cystic Fibrosis

Chapter: Cystic Fibrosis
McMaster Section Editor(s): Paul M. O’Byrne
Section Editor(s) in Interna Szczeklika: Ewa Niżankowska-Mogilnicka, Filip Mejza
McMaster Author(s): Andreas Freitag
Author(s) in Interna Szczeklika: Henryk Mazurek, Filip Mejza
Additional Information

Definition, Etiology, Pathogenesis Top

Cystic fibrosis (CF) is a genetic disorder causing abnormal secretion of the exocrine glands, mainly affecting the respiratory and gastrointestinal (GI) systems. It is caused by mutations of the CFTR gene encoding CFTR (cystic fibrosis transmembrane conductance regulator; a cellular membrane protein that acts on chloride ion channels in epithelial cells). Synthesis of the defective protein affects the transmembrane transport of sodium and chloride, resulting in lumen dehydration and reduction in water content of exocrine secretions and mucus. High concentrations of sodium chloride inactivate the enzymes and proteins involved in local response to infection.

Abnormalities of the respiratory system include increased mucus secretion and retention with secondary chronic infections (DNA released from dead neutrophils increases the mucus viscosity) leading to mucus plugging, segmental atelectasis, bronchiectasis, and cysts (subpleural cysts frequently cause pneumothoraces).

Abnormalities of the GI system affect the pancreas and include retention of pancreatic secretions, activation of proteolytic enzymes, inflammation, and dilation of the pancreatic ducts with fibrosis (hence the name cystic fibrosis), resulting in pancreatic exocrine insufficiency and diabetes mellitus. Areas of steatosis and biliary cirrhosis are found in the liver. The presence of thick secretions in the intestines may cause any combination of abdominal pain, bowel obstruction, gastroenteritis, colitis, and distal intestinal obstruction syndrome (DIOS).

Effects on other organs include obliteration and hypoplasia of the vas deferens (resulting in male infertility). Impaired chloride reabsorption in the sweat glands leads to elevated sweat chloride levels and salty sweat. Chronic rhinosinusitis and nasal polyps are common.

Clinical Features and Natural History Top

1. Symptoms: Chronic cough is usually the presenting pulmonary symptom. It is associated with the production of thick purulent sputum (frequently upon awakening). Other symptoms include dyspnea, wheeze, chest congestion, nasal congestion with chronic purulent secretions, epistaxis, and hemoptysis. The passage of bulky and foul-smelling stools (indicative of pancreatic insufficiency), flatulence, abdominal pain, bloating, and constipation with weight loss and failure to grow are common presenting features.

2. Physical findings: Rhonchi, rales, coarse breath sounds (upper lobe predominance), clubbing of digits, nasal polyps, and low body weight are common.

3. Natural history: The disease usually manifests in early childhood or infancy, uncommonly at a later age (in such cases it is associated with less severe and atypical symptoms). Typically the condition causes chronic destruction of the airways with subsequent involvement of the pulmonary parenchyma, ultimately leading to respiratory failure and death. Median age of survival (the age beyond which we expect 50% of babies with CF born today to live) in 2017 in Canada was 52.3 years.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to indirectness. Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2017 Annual Data Report. https://www.cysticfibrosis.ca/uploads/Registry%20Report%202017/2017%20Registry%20Annual%20Data%20Report.pdf. Accessed May 28, 2019. 

4. Pulmonary exacerbations: Deterioration of performance status, worsening cough, increased production of purulent sputum, chest congestion, fever, and increased dyspnea are usually accompanied by varying progression of the auscultatory, spirometric, and radiographic abnormalities and new or increased pathogens appearing in the sputum.

Diagnosis Top

Diagnosis is suggested by clinical symptoms or by the diagnosis of cystic fibrosis in siblings.

1. Diagnosis is confirmed by ≥1 of the following tests:

1) Sweat chloride [Cl] concentrations ≥60 mmol/L in 2 measurements carried out on different days.

2) Demonstration of a known mutation of both CFTR allele (this test is recommended in all patients and is crucial when [Cl] concentration measurements are not diagnostic).

3) Abnormal nasal transepithelial electrical potential difference or transepithelial potential difference in rectal mucosa biopsy.

2. Other diagnostic tests:

1) Chest radiographs and high-resolution computed tomography (HRCT) reveal pulmonary abnormalities (depending on the stage of the disease, the earliest and most severe lesions are usually observed in the upper lobes), including various combinations of airway thickening, dilation of the bronchi (bronchiectasis), subpleural cysts or bullae, peripheral circular or linear opacifications, recurrent consolidation or segmental atelectases with the “tree-in-bud” appearance, hilar lymphadenopathy, and pneumothorax.

2) Lung function tests can reveal obstructive respiratory flow pattern with significant hyperinflation (increased total lung capacity [TLC], functional residual capacity [FRC], residual volume [RV], and RV/TLC ratio). Repeat spirometry at every visit and full pulmonary function testing on a yearly basis is recommended.

3) Sputum microbiology (or less frequently bronchoalveolar lavage, throat swab): Bacterial infection is initially caused by Staphylococcus aureus or Haemophilus influenzae and later Pseudomonas aeruginosa (PsA). Less prevalent pathogens include Achromobacter xylosoxidans, Stenotrophomonas maltophilia, Aspergillus species, and Burkholderia cepacia complex. Sputum is usually sent every 3 to 6 months and with pulmonary exacerbations.

4) Laboratory tests:

a) Reduced fecal levels of elastase 1, trypsin, and chymotrypsin with increased fecal excretion of fats (72-hour fecal fat collection).

b) Increased serum liver enzyme levels (particularly alkaline phosphatase, gamma-glutamyl transferase [transpeptidase]).

c) Increased erythrocyte sedimentation rate, C-reactive protein, and white blood cell counts (especially during exacerbations).

d) Oral glucose tolerance test (repeat every year, as this allows for early diagnosis of CF-related diabetes mellitus).

e) Pulse oximetry, arterial blood gases (when hypoxemic), or both. Routine blood testing including fat-soluble vitamin levels (A, D, E, K) should be performed yearly.

5) Ultrasonography to assess the liver (suggested every 2 years).

6) Bone densitometry (suggested every 2 years).

7) Incremental exercise testing (cycle ergometry; 6-minute walk test) annually for patients who are dyspneic or have moderate to severe disease.

Treatment Top

Nonpharmacologic Management

1. Respiratory physiotherapy repeated systematically several times—usually twice—a day (postural drainage assisted by chest percussion or vibration, effective coughing techniques, and use of simple support devices [eg, Flutter, Acapella]) are recommended. Earlier physiotherapy studies compared to doing nothing demonstrated a variable improvement in pulmonary function, reduction of daily symptoms, increased sputum expectorated, and decreased future pulmonary exacerbations. The best evidence in current practice is usually seen with postural drainage with chest percussion and vibration or the use of Positive Expiratory Pressure (PEP) masks. During exacerbations, physiotherapy should be intensified (3-4 times a day), particularly in patients with atelectasis or mucus plugging. A regular exercise program is indicated in all patients, especially those who are dyspneic or have more severe disease.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness to long term effect and variable results. Radtke T, Nolan SJ, Hebestreit H, Kriemler S. Physical exercise training for cystic fibrosis. Cochrane Database Syst Rev. 2015 Jun 28;6:CD002768. doi:10.1002/14651858.CD002768.pub3. PubMed PMID: 26116828. Psychological assessment and counseling is important in that anxiety and/or depression is prevalent, especially in those with moderate to severe disease.

2. Nutritional management: Suggest a high-protein, high-fat (35%-40% of calories from fat), and high-calorie (130%-150% of normal daily requirement) diet, supplemented with enzyme preparations and vitamins (particularly fat-soluble vitamins A, D, E, and K) for patients with pancreatic insufficiency (85% of Canadian CF patients).

3. Immunoprophylaxis: All vaccines should be administered as in the general population, with particular emphasis on vaccination against pertussis and measles. Patients with liver disease should receive vaccination coverage against hepatitis A and B. All patients should be vaccinated against influenza every year.

4. Oxygen therapy: Recommended for patients who are hypoxemic (PaO2 ≤55 mm Hg, SpO2 <88%); it may also improve exercise performance in those who demonstrate hypoxemia with physical activities.

Pharmacotherapy

1. Mucolytics (individual or combined): Inhaled dornase alpha 2.5 mg once daily (especially in patients with moderate to severe disease); inhaled hypertonic (3-5 mL of 3%-7%) saline; inhaled dry powder mannitol 400 mg bid. An inhaled beta2-agonist must be administered before inhalation of mucolytics. Mannitol is currently approved in Australia and the United Kingdom.

2. Bronchodilators are commonly used before the administration of inhaled mucolytics, physiotherapy, inhaled saline solutions, or prior to exercising in patients who have shown postbronchodilator improvement of symptoms or spirometry results.

3. Inhaled glucocorticoids: Only in patients with coexistent asthma or allergic bronchopulmonary aspergillosis (ABPA).

4. Pancreatic enzymes (for pancreatic insufficient patients) should be administered with each meal at individually adjusted doses. In adults, the starting dose is 500 IU of lipase/kg per meal and 250 IU/kg with snacks. If necessary, increase the dose by 150 to 250 IU/kg per meal to a maximum of 2500 IU/kg per meal (do not exceed 7000-12,000 IU/kg/d).

5. Fat-soluble vitamins A, D, E, and K are recommended on a daily basis. Their doses should be adjusted on the basis of serum vitamin levels or evidence of end organ damage (CF-related liver or bone disease). The vitamins should be taken together with pancreatic enzymes.

6. Oral nonsteroidal anti-inflammatory drugs (NSAIDs): Azithromycin (a commonly used antibiotic, but in this instance used for its anti-inflammatory and purported immune-modulating properties) 250 or 500 mg (patients ≥36 kg body weight) 3 times/wk (particularly in patients with PsA infection).Evidence 3Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered because long-term effects are less clear. Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2012 Nov 14;11:CD002203. doi:10.1002/14651858.CD002203.pub4. Review. PubMed PMID: 23152214. This may be beneficial long term in patients with more advanced lung disease and those who are prone to more frequent pulmonary exacerbations. Clinical effectiveness should be reevaluated every 6 to 12 months. Before the initiation of long-term treatment, sputum tests must be performed to exclude nontuberculous mycobacterial (NTM) infection. Repeat sputum testing for NTM should be performed every 6 months thereafter while receiving azithromycin. Ibuprofen given orally in high doses, maintaining a serum concentration of 50 to 100 microg/mL in patients with CF (6-18 years old), can slow the progression of lung disease. This is usually not recommended for the adult population.

7. Chronic antimicrobial treatment: Inhaled preservative-free tobramycin (300 mg nebulized bid for 1 month) is strongly recommended in patients aged ≥6 years for the eradication of PsA after the first documented culture of sputum or throat swab. For CF patients who are chronically infected with PsA, preservative-free tobramycin (300 mg nebulized bid) administered in 1-month cycles (on alternating months) has been shown to be effective in maintaining or improving lung function, reducing respiratory symptoms, and reducing the risk for future pulmonary exacerbations. Tobramycin via a dry powder inhaler (4 capsules or 112 mg bid) has shown similar results in comparison with tobramycin inhaled solution (TIS). Aztreonam lysine inhaled solution (75 mg nebulized tid) given in 1-month cycles (on alternating months) has shown similar results and is equally effective when compared with tobramycin. Colistin (polymyxin E), commercially manufactured as colistin sulfate or colistimethate sodium, has been used in an inhaled format for the chronic treatment of PsA infection in CF. When compared with placebo, it has demonstrated similar results to that of TIS. Older studies using inhaled colistimethate sodium (1 million IU bid) when compared with TIS appeared to be less effective; however, this may be due to a dose-dependent effect and/or type of colistin preparation used. More conventional dosing of colistimethate sodium would be 240 to 480 mg/d in divided dosing (bid). Colistimethate sodium via a dry powder inhaler (75-150 mg bid) has been shown to be comparable to TIS in this patient population. Liposomal amikacin (590 mg nebulized once daily) versus placebo has shown comparable results to TIS and has been shown to be noninferior in comparison to TIS. Levofloxacin inhaled solution (240 mg nebulized bid) has also been shown to be as effective as TIS short term. The new inhaled antibiotics (aztreonam lysine, liposomal amikacin, levofloxacin) are also delivered by a much more efficient nebulizer system, which reduces times of treatment and increases dosage/deposition into the airways. This is also true of the dry powder inhalers increasing ease of use and compliance long term. For patients with CF who have more frequent pulmonary exacerbations or more severe pulmonary impairment, the use of continuous inhaled and/or oral antipseudomonal antibiotics is often prescribed. Long-term administration of oral antibiotics for the treatment of chronic Staphylococcus aureus is not recommended.

8. CFTR modulators: CFTR modulators aim to improve CFTR function by targeting the underlying protein defect that causes CF. There are 2 classes of CFTR modulators: CFTR correctors and potentiators. Correctors are agents that increase the delivery and amount of functional CFTR protein to the cell surface, resulting in increased ion transport. Potentiators increase the ion channel activity of CFTR protein located at the cell surface, resulting in increased ion transport. Clinically significant improvements include an increase in lung function (forced expiratory volume in 1 second [FEV1], by ~4%-7% in absolute terms), quality of life, and weight with a reduction in pulmonary exacerbations (by about 30%-40% in relative terms), respiratory symptoms, and sweat chloride concentration. The strength of any recommendations regarding their use reflects relative value placed on clinical benefits and on high cost of medication. Use is restricted to specific situations and prescribers (the cost may be as high as $250,000 per year).

1) Ivacaftor (trade name Kalydeco) is taken orally bid (150 mg for patients aged ≥6 years; 75 mg [weight >14 kg] or 50 mg [weight 7-14 kg] for those aged 12 months to 6 years). It is a CFTR potentiator that has been shown to be clinically effective in CF patients with at least one G55ID (class III) CFTR mutation.Evidence 4High Quality of Evidence (high confidence that we know true effects of the intervention). Ramsey BW, Davies J, McElvaney NG, et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185. PubMed PMID: 22047557; PubMed Central PMCID: PMC3230303.Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010 Nov 18;363(21):1991-2003. doi: 10.1056/NEJMoa0909825. PubMed PMID: 21083385; PubMed Central PMCID: PMC3148255.    

2) Lumacaftor/ivacaftor (trade name Orkambi) is taken orally bid (patients aged 2-5 years: weight <14 kg, 1 package 100 mg/25 mg or weight >14 kg, 1 package 150 mg/188 mg; patients aged 6-11 years: 2 tablets 200 mg/250 mg bid; patients aged ≥12 years: 2 tablets 400 mg/250 mg). It is a combination CFTR corrector/potentiator that has been shown to be clinically effective in CF patients who are homozygous for F508del (50% CF patients; class II mutation).Evidence 5High Quality of Evidence (high confidence that we know true effects of the intervention). Konstan MW, McKone EF, Moss RB, et at. Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med. 2017 Feb;5(2):107-118. doi: 10.1016/S2213-2600(16)30427-1. Epub 2016 Dec 21. PubMed PMID: 28011037.Wainwright CE, Elborn JS, Ramsey BW, et al; TRAFFIC Study Group; TRANSPORT Study Group. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015 Jul 16;373(3):220-31. doi: 10.1056/NEJMoa1409547. Epub 2015 May 17. PubMed PMID: 25981758; PubMed Central PMCID: PMC4764353.

3) Tezacaftor/ivacaftor (trade name Symdeko) taken orally (1 tablet [tezacaftor 100 mg/ivacaftor 150 mg] in the morning and 1 tablet [ivacaftor 150 mg] in the evening, 12 hours apart). It is a new combination CFTR corrector/potentiator that has been shown to be clinically effective in CF patients aged ≥12 years who are either homozygous or heterozygous for F508del mutation (50% CF patients are homozygous, 75% CF patients are heterozygous).Evidence 6High Quality of Evidence (high confidence that we know true effects of the intervention). Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. N Engl J Med. 2017 Nov 23;377(21):2013-2023. doi: 10.1056/NEJMoa1709846. Epub 2017 Nov 3. PubMed PMID: 29099344.Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis. N Engl J Med. 2017 Nov 23;377(21):2024-2035. doi: 10.1056/NEJMoa1709847. Epub 2017 Nov 3. PubMed PMID: 29099333; PubMed Central PMCID: PMC6472479.

Additional combination CFTR correctors/potentiators are currently being studied in CF patients with similar or more encouraging results. Other therapeutic approaches under development and study focus on bypassing the defective CFTR protein to restore ion balance. This includes agents that may be used to block sodium hyperabsorption through the epithelial sodium channel.

Treatment of Pulmonary Exacerbations

1. Intensification of physiotherapy, particularly in patients with atelectasis. This should be performed in combination with the use of nebulized hypertonic saline tid to qid.

2. Pharmacotherapy:

1) Early treatment with an antibiotic (intravenous or oral, frequently plus inhaled, but not an inhaled antibiotic alone) for at least 10 days (on average 14-21 days). While waiting for sputum culture results, use combined empiric treatment to cover H influenzae and S aureus (semisynthetic penicillins or beta-lactamase–resistant cephalosporins or clarithromycin) as well as PsA (oral ciprofloxacin and inhaled aminoglycoside or colistin). In patients with more severe exacerbations, administer intravenous beta-lactams [eg, ceftazidime, piperacillin, ticarcillin] combined with an aminoglycoside. Alternatively, carbapenems (imipenem or meropenem) or aztreonam may be used. Clinical improvement is usually achieved no earlier than after 4 to 7 days of treatment.

2) Consider a short-term systemic glucocorticoid treatment (eg, prednisone 1 mg/kg/d or 40-50 mg/d for 7-10 days) in patients with severe exacerbations, and particularly with severe chronic obstructive pulmonary disease, allergic bronchopulmonary aspergillosis, or asthma.

3. Mechanical ventilation (usually noninvasive) is indicated in acute respiratory failure that is caused by a reversible cause or in patients with chronic respiratory failure awaiting lung transplantation.

4. Distal intestinal obstruction syndrome: Appropriate oral/intravenous hydration and laxatives (eg, polyethylene glycol), rectal suppositories, or contrast (eg, gastrografin) enema. In rare cases, colonoscopy or surgical intervention may be necessary.

Surgical Treatment

In patients with severe life-threatening hemoptysis, radiology-guided embolization and, if not effective or not available, lobectomy may be indicated. Refractory bronchopleural fistulas unresponsive to chest tube drainage may require surgical pleurodesis or bullectomy (or both). In chronic respiratory failure, early referral for lung transplantation should be considered. In patients with advanced liver disease, consider liver transplantation.

Follow-Up Top

Every 3 months assess nutritional status, perform spirometry, SpO2 measurement, and sputum microbiology. Ideally, all patients should be seen regularly at a CF center or, if unavailable, by a CF specialist at least twice a year. Follow-up chest radiographs should be repeated in cases of severe exacerbations, suspected complications, or rapid decline in pulmonary function. Annual blood testing should be performed with particular attention to assessing liver disease, CF-related diabetes mellitus, fat-soluble vitamins, and nutritional status. Annual full pulmonary function testing, incremental exercise testing, and bone densitometry should be considered in patients with moderate to severe lung disease.

Complications Top

Respiratory complications: Atelectasis, pneumothorax, hemoptysis, allergic bronchopulmonary aspergillosis, pulmonary hypertension.

Extrapulmonary complications: Cor pulmonale, diabetes mellitus, cholelithiasis or cholangitis, fatty liver disease, cirrhosis, acute pancreatitis, DIOS, gastroesophageal reflux disease, hypertrophic osteoarthropathy, osteopenia or osteoporosis, infertility.

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