Cystic Fibrosis

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 an autosomal recessive condition 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 leading to mucus plugging, segmental atelectasis, bronchiectasis, and cysts (subpleural cysts may lead to 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, resulting in pancreatic exocrine insufficiency and CF-related diabetes mellitus. Areas of steatosis and biliary cirrhosis, which may progress to 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, meconium ileus (in newborns), 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. Reduced bone mineral density is also common, leading to increased rates of fractures and kyphoscoliosis.

Clinical Features and Natural History Top

1. Symptoms:

1) Pulmonary 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.

2) Extrapulmonary symptoms: Patients often experience some form of sinus disease, which can manifest as nasal congestion, headaches, cough (upper airway cough syndrome triggered by postnasal drip), or acute sinus infections. GI manifestations are also common and include passage of bulky and foul-smelling stools (indicative of pancreatic insufficiency), flatulence, abdominal pain, bloating, and constipation. Weight loss and failure to grow are common presenting features, especially in children. Lung disease may lead to pulmonary hypertension and its sequela.

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 2019 in Canada was 54.3 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. Accessed May 8, 2021. https://www.cysticfibrosis.ca/registry/2019AnnualDataReport.pdf

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. Sometimes a rapid decline in forced expiratory volume in 1 second (FEV1), even in the absence of symptoms, may be considered an exacerbation.

Diagnosis Top

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

1. Diagnosis is confirmed when both of the following criteria are met:

1) Evidence of CFTR dysfunction, including ≥1 sweat chloride [Cl] concentration ≥60 mmol/L in 2 measurements carried out on different days, demonstration of pathologic mutations of both CFTR alleles (one from each parent), and/or abnormal nasal transepithelial electrical potential difference or transepithelial potential difference in rectal mucosa biopsy.

2) Other features of cystic fibrosis, including ≥1 positive newborn screen, features consistent with CF, or a positive family history.

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, centrilobular nodularity with a “tree-in-bud” appearance, hilar lymphadenopathy, and pneumothorax. Computed tomography (CT) of the sinuses may be considered for assessment of sinus opacification to assist with diagnosis or to characterize the extent of sinus involvement.

2) Lung function tests can reveal obstructive respiratory flow pattern (low FEV1/forced vital capacity [FVC]) 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 for culture every 3 to 6 months and during 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 [ALP]).

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 (US) to assess the liver if liver enzymes are abnormal. In children US can be used for screening.

6) Bone densitometry (suggested every 1-5 years depending on T or Z scores).

Treatment Top

Nonpharmacologic Management

1. Respiratory physiotherapy repeated systematically several times—usually twice a day (active cycle of breathing techniques, and use of simple support devices [eg, Flutter, Acapella]) are recommended. Earlier physiotherapy studies demonstrated a variable improvement in pulmonary function, reduction of daily symptoms, increase in sputum expectorated, and decrease in the number of future pulmonary exacerbations. 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. Psychologic 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, targeting a body mass index (BMI) percentile >50%. This diet may be 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. Vaccination: 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) has been shown to improve lung function and reduce the rate of exacerbations.Evidence 3Strong recommendation (benefits clearly outweigh harms; 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 due to the risk of bias. Yang C, Montgomery M. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev. 2021 Mar 18;3(3):CD001127. doi: 10.1002/14651858.CD001127.pub5. PMID: 33735508; PMCID: PMC8094421. Inhaled hypertonic (3-5 mL of 3%-7%) saline has been shown to reduce pulmonary exacerbations and marginally improve lung function.Evidence 4Strong 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 intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2018 Sep 27;9(9):CD001506. doi: 10.1002/14651858.CD001506.pub4. PMID: 30260472; PMCID: PMC6513595. An inhaled beta2-agonist must be administered before inhalation of mucolytics.

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. Chronic inhaled antimicrobial treatment: Inhaled preservative-free tobramycin (300 mg nebulized bid for 1 month) is 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). Inhaled aztreonam, colistin, and levofloxacin regimens via nebulizer systems have also been developed for chronic treatment of PsA infection in CF with similar results to those of TIS. For patients with CF who have more frequent pulmonary exacerbations or more severe pulmonary impairment, the use of continuous inhaled antibiotics is often prescribed.Evidence 5Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of intervention). Quality of Evidence lowered due to the risk of bias. Smith S, Rowbotham NJ, Regan KH. Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis. Cochrane Database Syst Rev. 2018 Mar 30;3:CD001021. doi: 10.1002/14651858.CD001021.pub3. Epub ahead of print. PMID: 29607494. Long-term administration of oral antibiotics for the treatment of chronic Staphylococcus aureus is not recommended.

7. Chronic macrolide therapy: Azithromycin 250 daily or 500 mg thrice weekly is recommended in patients who are chronically infected with Pseudomonas spp.Evidence 6Strong 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 in the long term in patients with more advanced lung disease and in 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.

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. CFTR modulators have led to significant improvements in lung function, rate and severity of pulmonary exacerbations, quality of life, weight gain, respiratory symptoms, and sweat chloride concentration. With the advent of novel combination treatments, ~90% of patients with CF are now eligible for CFTR modulator therapy. These new therapies have proven to be highly efficacious, however, the cost ranges from $250,000 to $300,000 per year for one patient (in Canada).

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 ≥1 G55ID (class III) CFTR mutation (5%-10% of patients with CF).Evidence 7High 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 first-generation combination CFTR corrector/potentiator that has been shown to be clinically effective in CF patients who are homozygous for F508del (50%-60% CF patients; class II mutation).Evidence 8High 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 second-generation 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.Evidence 9High 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.

4) Elexacaftor-Tezacaftor-Ivacaftor taken orally (2 tablets [elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg] in the morning and 1 tablet [ivacaftor 150 mg] in the evening, 12 hours apart). The triple therapy combination regimen has shown to be clinically effective in patients with CF aged ≥12 years who carry 1 copy of delF508 mutation.Evidence 10High Quality of Evidence (high confidence that we know true effects of the intervention). Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819. doi: 10.1056/NEJMoa1908639. Epub 2019 Oct 31. PMID: 31697873; PMCID: PMC7282384.

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.

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) Steroids are not typically recommended, unless patients have coexisting asthma or allergic bronchopulmonary aspergillosis (ABPA).

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 transplant.

Surgical Treatment

1. Hemoptysis: In patients with severe life-threatening hemoptysis, radiology-guided embolization and, if not effective or not available, lobectomy may be indicated. In less severe cases use IV antibiotics, as most often hemoptysis is driven by infection. You can also use vitamin K and tranexamic acid, either oral or inhaled (see Hemoptysis).

2. Refractory bronchopleural fistulas unresponsive to chest tube drainage may require surgical pleurodesis or bullectomy (or both). Consult transplant thoracic surgeon before doing this, as it may affect future transplant options. In chronic respiratory failure, early referral for lung transplant should be considered.

3. Lung transplant referral should be discussed with patients aged ≥18 years no later than when FEV1 is <50% predicted and rapidly declining (>20% relative decline over 12 months), or FEV1 is <40% with markers of shortened survival (eg, 6-minute walk tests [6MWT] <400 m, hypoxemia, hypercarbia, pulmonary hypertension, BMI <18 kg/m2, >2 exacerbations per year requiring IV antibiotics, massive hemoptysis, pneumothorax). Patients should also be referred when FEV1 <30% predicted regardless of other markers. Common CF-related modifiable barriers to lung transplant should be considered (but should not preclude referral), including nutritional status, diabetic management, deconditioning, mental health issues, and adherence to therapies.

Follow-Up Top

Every 3 months assess nutritional status, perform spirometry, SpO2 measurement, and sputum microbiology.

Every year blood testing should be performed with particular attention to assessing liver disease (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transferase [GGT]), CF-related diabetes mellitus (via 2-h 75-g oral glucose tolerance test, starting at the age of 10 years), fat-soluble vitamins, and nutritional status.

Every 5 years, starting at the age of 40 years, colonoscopy should be performed.

In Canada, patients with CF should be regularly followed up in a specialized CF clinic. Visits usually occur every 3 months or more often in certain situations. Follow-up chest radiographs should be performed in the case of severe exacerbations, suspected complications, or rapid decline in pulmonary function. Bone densitometry can be considered every 1 to 5 years depending on previous T/Z scores.

Complications Top

Respiratory complications: Atelectasis, pneumothorax, hemoptysis, obstructive sleep apnea, 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.