Cystic Fibrosis

Cystic fibrosis (CF) is a multisystem, autosomal recessive genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR gene is responsible for chloride transport across the epithelial cell membrane, which affects the generation of fluids in the lung, gastrointestinal system, and sweat. In the absence of a normally functioning CFTR protein, generated secretions become thicker and more viscous. The mucus generated within the lungs cannot be adequately cleared and leads to recurrent infection, chronic inflammation, and colonization with resistant organisms.

CF differs from non-CF bronchiectasis in that symptoms may present in early childhood and novel therapeutics that modify the CFTR protein have been shown to improve lung function, pulmonary exacerbations, and quality of life. We present a general guide to the approach to cystic fibrosis in adults. For pediatric management please refer to the Pediatric Pulmonology rotation guide.

(Source: Origins of Cystic Fibrosis Lung Disease. N Engl J Med 2015.)

Assessment

History: Although CF care is primarily pulmonary focused, it is a multisystem disease, which differentiates it from many other bronchiectatic syndromes. When assessing a patient for a potential diagnosis of CF, it is helpful to organize the history by organ system.

• Sinus disease: Manifesting as sinusitis, recurrent infection, polyposis (in up to one-third of patients), and headache. (Guidance on the management of sinus disease is provided in the Allergy/Immunology rotation guide.)

• Pulmonary disease: Manifesting as daily cough with tenacious sputum production, dyspnea, intermittent hemoptysis, chest pain, and recurrent infection.

• Pancreatic disease: The majority of patients will develop some form of pancreatic disease due to organ destruction that can manifest as recurrent pancreatitis, malabsorption of fat/protein (leading to steatorrhea and malnutrition), fat-soluble vitamin deficiency, and CF-related diabetes (impaired glucose tolerance due to pancreatic destruction and impaired insulin secretion).

• Hepatobiliary disease: Biliary cirrhosis can be seen in patients due to thickened/obstructed bile. Cholelithiasis is also common.

• Gastrointestinal disease: Meconium ileus in a newborn is highly suggestive of an underlying diagnosis of CF (up to 90% of these patients have CF). After birth, recurrent distal intestinal obstruction syndrome (DIOS) can occur due to viscous secretions in the bowels. DIOS manifests as a small-bowel obstruction with severe abdominal pain and an inability to pass stool or flatus.

• Bone disease: CF patients have lower bone densities and increased risk of fracture. The reasons are likely multifactorial, but contributors include poor nutrition (including vitamin D malabsorption), decreased physical activity due to respiratory limitations, hypertrophic osteoarthropathy, and chronic steroid use.

• Infertility: The majority of men (>95%) with CF will be infertile due to defects in sperm transport and congenital bilateral absence of vas deferens (although spermatogenesis is normal). Women with CF are less fertile than those without CF due mainly to malnutrition and thickened cervical mucus production.

Physical examination: The physical examination can be very informative in the diagnosis and follow-up of a patient with CF:

• patients with CF tend to be young

• low body mass index and cachexia in patients with malnutrition

• resting tachypnea and tachycardia

• patients or parents may describe salty-tasting skin or sweat

• evidence of chronic hypoxemia, including cyanosis and digital clubbing; if hypoxemia is severe, patients may develop cor pulmonale or pulmonary hypertension

• auscultation of the lungs is usually abnormal with varying degrees of rhonchi, wheeze, and crackles

• chronic cough productive of purulent sputum and exertional dyspnea

• nonpulmonary physical exam findings include sinusitis, nasal polyposis, hepatosplenomegaly, and arthropathy

Investigations

The diagnosis of CF can be made when the following criteria are met:

1. clinical suspicion due to any of the following:

• positive newborn screen

• sibling with a diagnosis of CF

• clinical symptoms consistent with CF in at least one organ system

2. CFTR dysfunction as determined by:

• elevated sweat chloride ≥60 mmol/L (on two occasions)

• presence of two disease-causing CFTR alleles on each parent allele

• abnormal nasal potential difference (the voltage measured between the nasal mucosa and skin elsewhere [usually the arm] is less than -40 mV)

Other investigations are based on the downstream effects of CF.

• Detailed pulmonary investigations should be done, including pulmonary function testing, arterial blood gasses, 6-minute walk distance, and sputum culture (including fungal and acid-fast bacilli). Pulmonary testing should be followed over time.

• Endocrine and nutritional markers including glycated hemoglobin, bone mineral density, fat-soluble vitamin levels, and oral glucose tolerance should also be followed.

Treatment

Certain treatment principles have been shown to benefit patients with CF and improve both quality of life and life span:

• airway clearance using inhaled medications to thin mucoid secretions (e.g., hypertonic saline or DNase)

• physical therapy (e.g., active cycle of breathing, external percussion, oscillating positive expiratory pressure [PEP] devices, percussive vests, cardiovascular exercise)

• smoking avoidance or cessation

• adequate systemic hydration

• vaccinations including seasonal influenza vaccination, dual pneumococcal vaccine (13- and 23-valent), and Covid-19 vaccination

• chronic antibiotics:

  • Chronic azithromycin therapy is recommended for its anti-inflammatory effect in patients with CF not colonized with nontuberculous mycobacteria.

  • Chronic antimicrobial therapy with an inhaled antipseudomonal agent (e.g., tobramycin, aztreonam) is recommended in those with Pseudomonas aeruginosa colonization due to a more rapid decline in pulmonary function with this organism.

• bronchodilation and inhaled glucocorticoids: Short-term use of beta2-adrenergic-receptor agonists can benefit individuals with bronchial hyperreactivity and prevent bronchospasm associated with inhaled therapies. However, evidence is not sufficient to recommend chronic, daily use of a beta2-adrenergic-receptor agonist. Bronchodilator therapy and inhaled glucocorticoids are indicated in patients with a co-diagnosis of asthma.

• CFTR-modulator therapy: In the last decade, significant advances have been made in CFTR-modulator therapy. These oral medications target the underlying defect in the CFTR protein and restore or improve CFTR protein function. Preliminary evidence suggests that treatment with CFTR modulators decrease infertility rates in women. All CF patients should undergo CFTR genotyping to determine if they are eligible for modulator therapy. The types of modulators are as follows:

  • Correctors (e.g., lumacaftor, tezacaftor, and elexacaftor) correct misfolded CFTR proteins.

  • Potentiators (e.g., ivacaftor) enhance the function of CFTR protein that has reached the cell surface. Multiple trials have examined potentiator therapy with or without combination corrector therapy. In the first trial, published in 2011, ivacaftor alone was associated with improvements in lung function, pulmonary exacerbations, symptoms, weight, and sweat chloride concentrations, compared with placebo, in patients with the G551D mutation (about 5% of patients with CF have this variant on one allele). Combination therapies with a potentiator and a corrector were associated with similar efficacy in patients with various genotypes. In a trial published in 2019, triple-combination therapy with two modulators with a potentiator (elexacaftor-tezacaftor-ivacaftor) was associated with improvement in lung function and fewer exacerbations in the 90% of CF patients with either one or two copies of the Phe508del CFTR mutation.

(Source: Realizing the Dream of Molecularly Targeted Therapies for Cystic Fibrosis. N Engl J Med 2019.)

Acute Pulmonary Exacerbations

No accepted criteria exist for an acute exacerbation. However, common symptoms include:

• new or increased cough

• sputum production

• dyspnea

• increased fatigue

• fever

Patients with acute exacerbations often have reductions in pulmonary function testing as measured by FEV₁.

Treatment includes continuation of the chronic treatment regimen, including inhaled therapies for airway clearance, chest physiotherapy, and optimization of non-pulmonary CF-related disease. Systemic antibiotic therapy is recommended and should be tailored to patients’ prior respiratory culture data. Information is insufficient regarding general use of glucocorticoids in patients with CF exacerbations. Therefore, glucocorticoids are not routinely administered in this context.