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 a 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 (current life expectancy in patients with CF in North America is approximately 47 years).Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to observational data from possibly self-selected and incomplete cohorts in Canada and USA. Median age of survival surpasses 50 years of age for Canadians with cystic fibrosis. Cystic Fibrosis Canada. http://www.cysticfibrosis.ca/median-age-of-survival-surpasses-50-years-of-age-for-canadians-with-cystic-fibrosis/. Published October 15, 2014. 

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

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

1. The diagnosis is confirmed by ≥1 of the following tests:

1) Sweat [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. 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 work 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).

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, SaO2 <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 (administer an inhaled beta2-agonist before the saline inhalation); inhaled dry powder mannitol 400 mg bid (an inhaled beta2-agonist must be administered before inhalation). Mannitol is currently approved in Australia and the UK.

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 allergen-induced 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 U of lipase/kg per meal and 250 U/kg with snacks. If necessary, increase the dose by 150-250 U/kg per meal to a maximum of 2500 U/kg per meal (do not exceed 7000-12,000 U/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 Pseudomonas aeruginosa 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 a more severe 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 (NTB) infection. Repeat sputum testing for NTB 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 age 6 and older for the eradication of Pseudomonas aeruginosa after the first documented culture of sputum or throat swab. For CF patients who are chronically infected with P aeruginosa, 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. Alternatively, aztreonam (75 mg nebulized tid) given in 1-month cycles (on alternating months) has shown similar results and is equally effective when compared to tobramycin. Another alternative, colistin (1 million U nebulized bid) given in a similar manner, has shown similar results. For patients with CF who have more frequent pulmonary exacerbations or have 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. Ivacaftor (150 mg bid) increases the activity of the defective cystic fibrosis transmembrane conductance regulator CFTR protein in patients (>6 years old) with the G551D CFTR mutation. Substantial improvements are seen in lung function, risk of pulmonary exacerbations, respiratory symptoms, weight, and concentration of sweat chloride.Evidence 4Strong recommendation (benefits clearly outweigh downsides; 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 less clear long-term effects of medication. Note: The strong recommendation reflects high value placed on clinical benefits and less value on very high cost of medication. 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.

Treatment of 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 Haemophilus influenzae and Staphylococcus aureus (semisynthetic penicillins or beta-lactamase–resistant cephalosporins or clarithromycin) as well as Pseudomonas aeruginosa (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, SaO2 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 work 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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