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Pulmonology - Cystic Fibrosis - Fast Facts | NEJM Resident 360

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.

Model of Host-Defense Defects in the Airway of a Person with Cystic Fibrosis

(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 and 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 can be very informative in the diagnosis and follow-up of a patient with CF:

• CF patients 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 hemoglobin A1c, 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 breathing, external percussion, cardiovascular exercise)

• smoking avoidance or cessation

• adequate systemic hydration

• seasonal influenza vaccination and dual pneumococcal vaccine (13- and 23-valent)

• 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: indicated in patient with a diagnosis of asthma (patients with CF often have a codiagnosis of asthma)

• CFTR-modulator therapy: In the last decade, significant advances have been made in CFTR-modulator therapy. These drugs target the underlying defect in the CFTR protein. They are oral medications that restore or improve the function of the CFTR protein in vivo*.* The types of modulators are:

  • 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 showed similar efficacy in patients with various genotypes. In a trial published in 2019, two modulators with a potentiator in patients with 90% of the alleles that lead to CF showed improvement in lung function and fewer exacerbations.

Progress in Molecularly Targeted Therapies for Cystic Fibrosis

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

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