Cystic Fibrosis

Cystic fibrosis (CF) is an inherited autosomal recessive disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is a cAMP-regulated chloride and bicarbonate channel, which also plays a major role in regulation of other ion channels. CFTR reduction or dysfunction leads to abnormal and increased secretions by exocrine glands, resulting in multiorgan-system involvement.

The hallmark of CF is increased viscosity of secretions in the lungs with subsequent endobronchial bacterial colonization and infection, as well as airway inflammation leading to bronchiectasis. Extrapulmonary involvement includes the gastrointestinal (GI), genitourinary (GU), and endocrine systems. The primary driver of morbidity is intermittent flaring of lung disease, known as pulmonary exacerbations, with potential, irreversible loss of lung function with each episode.

(Source: Airway Mucus Function and Dysfunction. N Engl J Med 2010.)

Genetics

CF is the most common autosomal recessive genetic disorder in white people, with a 1/25 carrier rate, and is less common in other populations. The relative frequencies of CFTR mutations vary among different racial and ethnic groups and geographic regions. Currently, more than 2,000 mutations have been identified in the CFTR gene, which fall under six major classes. The most common mutation, deltaF508, accounts for approximately 70% of all CF alleles. Disease genotype may predict the patient’s phenotype and guide CFTR modulator therapy.

(Source: CFTR Modulator Therapy for Cystic Fibrosis. N Engl J Med 2017.)

Screening

Currently, all 50 states in the United States test for CF in the newborn screen. Newborn screening has been shown to reduce morbidity, improve early nutritional status, and, ultimately, life expectancy. Screening algorithms evaluate immunoreactive trypsinogen (IRT), with elevated levels prompting further testing (repeat IRT, sweat testing, or analysis for CFTR mutations). The American College of Obstetricians and Gynecologists (ACOG) recommends offering carrier genetic screening to all women before pregnancy (preconception or prenatally). Expanded and full CFTR gene sequencing is guided by risk assessment.

Early Manifestations

Early manifestations of CF tend to be gastrointestinal with later onset of clinically apparent pulmonary involvement:

• meconium ileus: the earliest clinical manifestation of CF

• frequent bacterial respiratory infections, bronchiectasis

• failure to thrive

• respiratory pathogens typical of the CF airway (e.g., Pseudomonas aeruginosa, Burkholderia cepacia)

• nasal polyps

(Source: Patient Registry Annual Data Report2021. Cystic Fibrosis Foundation Patient Registry 2015 Annual Data Report Bethesda, Maryland ©2022 Cystic Fibrosis Foundation.) Figure reproduced with permission from Cystic Fibrosis Foundation Patient Registry, Cystic Fibrosis Foundation. Annual Data Report 2021. Bethesda, MD, USA.)

Pulmonary Findings

Spirometry: obstructive lung disease manifested by reduced FEV₁/FVC (forced expiratory volume in one second/forced vital capacity)

Physical exam: rhonchi, rales, wheezing, evidence of hyperinflation, digital clubbing

(Adapted from: New-Onset Clubbing Associated with Lung Cancer. N Engl J Med 2008.)

Imaging: atelectasis, consolidation, hyperinflation, bronchiectasis with predilection for upper lobes

Chest radiograph of a 17-year-old male with cystic fibrosis. The posteroanterior view shows diffuse bronchiectasis and hyperinflation. Courtesy of Mengdi Lu.

Microbiology: respiratory pathogens typical of the CF airway (see graph above); specific pathogens, including P. aeruginosa, MRSA, and B. cepacia are associated with accelerated lung-function decline

Complications: pneumothorax, hemoptysis, allergic bronchopulmonary aspergillosis, pulmonary arterial hypertension

Extrapulmonary Manifestations

• exocrine pancreatic insufficiency with greasy, foul-smelling stools

• sinus disease and nasal polyps

• CF-related diabetes mellitus and metabolic syndrome

• failure to thrive

• distal intestinal obstruction syndrome (DIOS)

• CF-related renal insufficiency

• fertility issues (congenital absence of the vas deferens)

Management

Pillars of management for pulmonary exacerbations include antibiotics, airway clearance, and nutritional optimization. With advances in management in each of these domains and the advent of gene therapies, estimated median survival for patients born after 2014 has dramatically improved to age 56 years.

Multidisciplinary teams are paramount to CF care and include pulmonologists, psychiatrists and psychologists, endocrinologists, gastroenterologists, nurses, physical therapists, dieticians, social workers, and respiratory therapists. When possible, it is recommended to be cared for in an accredited CF center that has all these resources available.

Routine assessment in CF care involves careful monitoring of lung function, growth parameters, and management of extrapulmonary disease.

Diagnostics

• Spirometry: Monitoring of spirometry to track lung function over time is a critical component of routine care.

• Microbiology: Respiratory cultures are collected via throat swab or expectorated sputum every 3 months for surveillance of pathogens. Bronchoalveolar lavage may be useful in patients with acute respiratory decline or those who cannot expectorate.

Antibiotics

• Chronic use of inhaled antibiotics with antipseudomonal properties (tobramycin, aztreonam lysine, colistin) have been shown to reduce pulmonary exacerbations and improve lung function. These are used in cycles of 28 days on treatment alternating with 28 days off treatment.

Airway Clearance and Inhaled Therapies

• Airway clearance therapy (ACT) aids the expectoration of thick airway secretions. Modalities include aerobic exercise, manual percussion, postural drainage, active cycle of breathing, oscillating positive expiratory pressure devices, and high-frequency chest-wall oscillation with vests.

• Mucolytics (e.g., dornase alfa and hypertonic saline) may be useful adjuncts to airway clearance both in chronic disease and acute exacerbations.

• Bronchodilators may be useful in selected patients with concomitant asthma or recurrent wheeze.

Nutrition

• Monitoring and optimization of nutritional status and growth parameters (e.g., weight-for-age, BMI) have been associated with improved lung function and survival.

• Enteral nutrition with gastrostomy tube placement is a consideration in patients who require additional nutritional supplementation.

• Patients with pancreatic insufficiency require pancreatic enzyme replacement therapy (PERT) and fat-soluble vitamin supplementation (A, D, E, K). Salt supplementation may be required.

Anti-Inflammatory Therapies

• high-dose ibuprofen

• chronic azithromycin

• glucocorticoids (inhaled and systemic)

CFTR Modulators

• These agents improve CFTR transport in amenable variants and function, leading to increased pulmonary function and reduced pulmonary exacerbations.

• Triple therapy with elexacaftor, tezacaftor, and ivacaftor (ETI) restores CFTR function in a number of CF genotypes, including the deltaF508 mutation. Thus, the majority of patients with CF are eligible to receive this CTFR corrector, which was approved by the FDA in 2019 in patients aged ≥12 years, and subsequently in children aged ≥2 years.

• The elexacaftor and tezacaftor components help in the transport of the CFTR protein to the cell surface and ivacaftor helps potentiate its activity, making it effective in multiple classes of CFTR mutations beyond deltaF508.

• ETI can provide durable improvement in FEV1 upwards of 10% and a significant decrease in sweat chloride.

• ETI is generally well tolerated, but hepatotoxicity and neuropsychiatric adverse effects have been observed

• Other CFTR modulators are available (tezacaftor/ivacaftor or ivacaftor monotherapy), but ETI is preferred in patients who tolerate it.

Acute Pulmonary Exacerbations

Acute pulmonary exacerbations are recognized by a constellation of symptoms including:

• worsening cough

• increased respiratory secretions

• dyspnea

• hemoptysis

• hypoxemia

• acute lung-function decline

• changes in pulmonary exam (including new rales, decreased appetite, weight loss, and fatigue)

• fever (but not a typical feature because infection is generally endobronchial)

Viral respiratory infections, particularly in children with CF compared to adults, and nonadherence to medication and airway clearance regimens may precipitate an acute pulmonary exacerbation, although a clear trigger is not always identified. Other mechanisms leading to pulmonary exacerbations include changes in microbial composition (e.g., acquisition of a new bacterial pathogen in the airways) and increases in bacterial concentration.

Management of acute pulmonary exacerbations includes early initiation of antibiotics, increased airway clearance, and nutritional optimization. Targeted antibiotics are delivered by oral, intravenous, and/or inhaled routes, with antibiotic selection guided by known respiratory pathogens from prior culture data.

Lung transplantation may be pursued in patients with end-stage lung disease. Indicators of disease severity that may prompt evaluation for transplant include FEV₁<30% predicted, hypercapnia, and persistent oxygen requirement.