Cystic Fibrosis

AUTHOR: Harinder P. Singh, MD

Definition

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by dysfunction of exocrine glands that involves multiple organ systems but chiefly results in chronic respiratory infections and pancreatic enzyme insufficiency.

Synonym

ICD-10CM CODES
E84.9		Cystic fibrosis, unspecified
E84.0		Cystic fibrosis with pulmonary manifestations
E84.11		Meconium ileus in cystic fibrosis
E84.19		Cystic fibrosis with other intestinal manifestations
E84.8		Cystic fibrosis with other manifestations

Epidemiology & Demographics

CF is the most common life-shortening genetic disease in Caucasians (one case per approximately 3200 births in Caucasians) and the second most common life-shortening childhood-onset inherited disorder in the U.S., behind sickle cell disease.
Worldwide it affects 80,000 children and adults.
Median age at diagnosis is 5.3 mo. Median survival is now >40 yr because of advancements in treatment.
Carrier screening is associated with a decrease in incidence of CF.

Physical Findings & Clinical Presentation

Meconium ileus
Failure to thrive in children
Increased anterior/posterior chest diameter
Basilar crackles and hyperresonance to percussion
Digital clubbing
Chronic cough
Abdominal distention
Greasy, foul-smelling feces
Clinical manifestations of CF are summarized in Box E1. Atypical presentations are summarized in Table E1
The frequency of selected GI manifestations in CF is summarized in Table E2
See Box E1

TABLE E2 Frequency of Selected GI Manifestations in CF ^∗

Organ	Manifestation	Frequency in All Patients (%)	Frequency in Adults (%)
Pancreas	Total achylia	85-90	85-90 ^∗
	Abnormal glucose tolerance	20-30	20-30
	Partial or normal function	10-15	10-15
	Pancreatitis	1-2 (all CF) 22 (PS-CF)	2-3
	Diabetes mellitus	4-7	4-7
Intestine	Meconium ileus	10-25
	Rectal prolapse	1-2
	Distal intestinal obstruction syndrome	3	18
	Intussusception	1	1-2
Liver	Fatty liver	7	20-60
	Focal biliary cirrhosis	2-3	11-70
	Portal hypertension	2-3	28
Biliary tract	Gallbladder abnormal, nonfunctional, or small	25	5-20
	Gallstones	8	10-25
	Bile duct strictures	1-20	1-20
Esophagus	GERD	Unknown	80

CF, Cystic fibrosis; GERD, gastroesophageal reflux disease; GI, gastrointestinal; PS-CF, CF with pancreatic sufficiency.

^∗Frequency may depend on the genotype.

From Feldman M et al: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

TABLE E1 Atypical Presentations of Cystic Fibrosis ^∗

Respiratory		Bronchiolitis/asthma Pseudomonas aeruginosa or Staphylococcus aureus colonization of the respiratory tract Staphylococcal pneumonia Nasal polyposis Nontuberculous mycobacterial infection
Gastrointestinal		Meconium plug syndrome Rectal prolapse Recurrent abdominal pain and/or right lower quadrant mass Hypoproteinemic edema Prolonged neonatal jaundice Biliary cirrhosis with portal hypertension Vitamin deficiency states (A, D, E, K) Acrodermatitis enteropathica-like eruption with fatty acid and zinc deficiency Recurrent pancreatitis
Genitourinary		Male infertility Female infertility
Other		Hypochloremic, hyponatremic alkalosis Mother of a child with cystic fibrosis

^∗Bold type signifies possible presentation in adolescents or adults with cystic fibrosis.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

BOX E1 Clinical Manifestations of CF

Upper Respiratory

Sinusitis
Mucous membrane hypertrophy, nasal polyposis

Lower Respiratory

Atelectasis
Emphysema
Infections
- Bronchitis, bronchopneumonia, bronchiectasis, lung abscess
Respiratory failure, right-sided heart failure

Bile salt deficiency
Pancreatic insufficiency
GERD
PUD
Meconium ileus
Volvulus
Peritonitis
Ileal atresia
Distal intestinal obstruction syndrome
- Fecal masses
- Intussusception
Rectal prolapse

Pancreatic

Pancreatitis
Nutritional failure
Diabetes mellitus
Calcification
Maldigestion with steatorrhea and azotorrhea
Vitamin deficiencies

Hepatobiliary

Mucus hypersecretion
Gallstones, atrophic gallbladder
Focal biliary cirrhosis
Portal hypertension ± esophageal varices
Hypersplenism

Reproductive

Females: Increased viscosity of vaginal mucus, decreased fertility
Males: Sterility; absent ductus deferens, epididymis, and seminal vesicles

Skeletal

Retardation of bone age
Demineralization
Hypertrophic pulmonary osteoarthropathy

Ophthalmologic

Venous engorgement
Retinal hemorrhage

Other

Salt depletion through excessive loss of salt through skin
Heat stroke
Hypertrophy of apocrine glands

From Feldman M et al: Sleisenger and Fortran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

Etiology

CF is an autosomal-recessive disease caused by mutations to the gene encoding for the CF transmembrane conductance regulator (CFTR) protein (Fig. E1) on chromosome 7; gene mutations organized into six classes (Table E3) have been associated with CF. About half of patients in the U.S. with CF are homozygous for the Phe508del mutation in CFTR, and >90% have at least one Phe508del allele. These mutations result in abnormalities in chloride transport and thus water flux across the surface of epithelial cells (Figs. E2 and E3); the resulting abnormally viscous secretions cause obstruction of glands and ducts in various organs (Fig. E4) and subsequent damage to exocrine tissue (recurrent pneumonia, atelectasis, bronchiectasis, diabetes mellitus, biliary cirrhosis, cholelithiasis, intestinal obstruction, increased risk of GI malignancies). The airway of CF patients shows an exuberant hyperinflammatory response to infection leading to progressive lung damage.

TABLE E3 Classes of Cystic Fibrosis Transmembrane Conductance Regulator Mutations

Class	Effect on CFTR	Functional CFTR	Presence of CFTR on Cell Membrane
I	Defective protein production due to premature termination of CFTR messenger RNA	No	No
II	Impaired protein processing due to misfolding (e.g., ΔF508 deletion)	No	No, CFTR is degraded in the cytoplasm
III	Defective regulation with reduced channel opening time (e.g., G551D mutation)	No	Yes
IV	Impaired function causing reduced chloride transport	Yes, but reduced in function	Yes
V	Reduced synthesis of normally functioning CFTR	Yes, but reduced in number	Reduced in number
VI	Impaired membrane insertion or stability	Yes, but reduced in number	Reduced in number

CFTR, Cystic fibrosis transmembrane conductance regulator; RNA, ribonucleic acid.

From Weinberger SE: Principles of pulmonary medicine, ed 7, Philadelphia, 2019, Elsevier.

Figure E4 Spectrum of cystic fibrosis disorders.

A comparison between findings in severe cystic fibrosis (CF) and milder forms of the disease is shown. Although manifestations are variable, severity in each organ system is generally consistent with degree of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction conferred by genotype. CBAVD, Congenital bilateral absence of the vas deferens; CUAVD, congenital unilateral absence of the vas deferens; DIOS, distal intestinal obstruction syndrome. ^∗Refers to CFTR-related metabolic syndrome or CFTR-related disorders.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Figure E3 Schematic of the mucociliary transport defect in cystic fibrosis (CF).

(A) In the healthy state, adequate airway surface homeostasis ensures effective transport of mucus extruding from airway surface goblet cells and the submucosal glands. The airway surface liquid (ASL) is maintained by fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) and fluid absorption via the epithelial sodium channel (ENaC) (inset at right) (CFTR, surface receptor in blue; ENaC, surface receptor in red). (B) In CF, the ASL is depleted through the absence of CFTR-mediated fluid secretion, accompanied by tonic fluid absorption via the ENaC. CFTR-dependent liquid dehydration decreases the depth of the ASL, including the periciliary layer, causing abnormal clearance of mucus from the epithelial cell surface in the airways. cAMP, Cyclic monophosphate.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Figure E2 Schema of Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mechanisms of Chronic Airway Disease

CFTR conducts several anions including chloride, bicarbonate, thiocyanate, and glutathione. The loss of CFTR function affects critical airway epithelial functions: (1) It increases the risk for dehydration of airway surface liquid (ASL) with loss of chloride efflux and associated increased sodium channel activity. (2) The loss of secreted bicarbonate and/or acidic pH of the ASL increases mucous viscoelasticity, resulting in failure of mucociliary transport. (3) Acidic pH in the ASL impairs normal innate immune clearance of bacteria. (4) Loss of thiocyanate impairs lactoperoxidase bacterial killing. (5) Loss of glutathione secretion depletes the antioxidant capacity of the airway, resulting in increased inflammation, increased mucous secretion, and increased mucous viscoelasticity. These factors lead to a vicious cycle of infection and inflammation that is progressive. ASL, Airway surface liquid; CFTR, cystic fibrosis transmembrane conductance regulator.

From Kleiman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

Figure E1 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene Mutations and Molecular Consequences

Classes of defects in the CFTR gene product include the absence of synthesis (class I); defective protein maturation and premature degradation (class II); disordered regulation, such as diminished adenosine triphosphate binding and hydrolysis (class III); defective chloride conductance or channel gating (class IV); and a reduced number of CFTR transcripts due to a promoter or splicing abnormality (class V). Another class of defect has reduced protein stability at the cell surface (class VI, not shown).

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Diagnosis ⬆ ⬇

Differential Diagnosis

Immunodeficiency states
Celiac disease
Asthma
Recurrent pneumonia
Primary ciliary dyskinesia

Workup

A diagnosis of CF requires proof of both CFTR dysfunction (i.e., elevated sweat chloride ≥60 mmol/L measured twice, two disease-causing mutations in CFTR from each parental allele, or abnormal nasal potential difference) and one or more phenotypic features consistent with CF (e.g., chronic suppurative obstructive lung disease, pancreatic insufficiency). Table E4 describes diagnostic criteria for CF. Conditions suggesting the diagnosis of CF in adults and recommended diagnostic studies are described in Table E5.

TABLE E5 Approach to Diagnosis of Cystic Fibrosis in Adult Patients

Conditions Suggesting the Diagnosis of Cystic Fibrosis in Adults
Recurrent pancreatitis Male infertility Chronic sinusitis Nasal polyposis Nontuberculous mycobacterial infection Allergic bronchopulmonary mycosis Bronchiectasis
Recommended Diagnostic Studies
Sweat electrolyte determination Extended CFTR mutation analysis Nasal potential difference High-resolution CT scan to identify bronchiectasis CT scan of sinuses for polyposis Sputum induction or bronchoalveolar lavage to identify bacterial and fungal pathogens

CFTR, Cystic fibrosis transmembrane conductance regulator; CT, computed tomography.

From Goldman L, Schafer AI: Goldman’s Cecil medicine, ed 24, Philadelphia, 2012, Saunders.

TABLE E4 Diagnostic Criteria for Cystic Fibrosis (CF)

Presence of typical clinical features (respiratory, gastrointestinal, or genitourinary)
Or
A history of CF in a sibling
Or
A positive newborn screening test
*Plus*
Laboratory evidence for CFTR (CF transmembrane regulator) dysfunction:
Two elevated sweat chloride concentrations obtained on separate days
Or
Identification of two CF mutations
Or
An abnormal nasal potential difference measurement

CFTR, Cystic fibrosis transmembrane conductance regulator.

From Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

Laboratory Tests

Pilocarpine iontophoresis (sweat chloride test): Diagnostic of CF in children if sweat chloride is >60 mmol/L (>80 mmol/L in adults) on two separate tests on consecutive days. Repeat testing may be necessary because not all infants have sufficient quantities of sweat for reliable testing. It is recommended to perform testing on infants after 2 wk of age. Indications for sweat test and conditions with associated high electrolyte levels are summarized in Table E6. Table E7 describes conditions associated with false-positive and false-negative sweat test results.
DNA testing may be useful for confirming the diagnosis and providing genetic information for family members.
Sputum culture and sensitivity to identify bacteria leading to acute or chronic lung infection and subsequently to inform treatment (frequent bacterial infections with Staphylococcus aureus [both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA)], Pseudomonas aeruginosa [most common virulent respiratory pathogen], Stenotrophomonas maltophilia, and Burkholderia cepacia).
Bronchoalveolar lavage (BAL) may be used to aid in the early diagnosis of pulmonary infection in nonexpectorating patients; however, evidence for its clinical benefit is lacking. Trials have shown that among infants diagnosed with CF, BAL-directed therapy did not result in a lower prevalence of P. aeruginosa infection or lower total CF-CT score when compared with standard therapy at age 5 yr.
Low albumin level, increased 72-h fecal fat excretion.
Pulse oximetry or arterial blood gases: Hypoxemia.
Pulmonary function studies: Decreased total lung capacity, forced vital capacity, and pulmonary diffusing capacity.
Challenged urine bicarbonate excretion may offer a new, simple and safe quantification of CFTR function and the extent of pharmacologic improvement. A recent trail revealed that the CFTR modulator drug elexacaftor/tezacaftor/ivacaftor partially restored renal CFTR function in patients with CF and likely resulted in decreased risk for electrolyte disorders and metabolic alkalosis.¹

TABLE E6 Sweat Test (Quantitative Pilocarpine Iontophoresis): Indications and Conditions With High Electrolyte Levels

Indications		Conditions With High Sweat Electrolyte Levels
Siblings with CF Chronic pulmonary symptoms Persistent cough Recurrent respiratory infection Bronchitis Bronchiectasis Lobar atelectasis Failure to thrive (stunting of growth) Rectal prolapse Nasal polyposis Intestinal obstruction of newborn Meconium ileus Jaundice in early infancy Cirrhosis in childhood or adolescence Portal hypertension Adult males with aspermia or azoospermia Heat stroke Hypoproteinemia Hypoprothrombinemia		CF Ectodermal dysplasia Glycogen storage disease, type 1 Adrenal insufficiency Familial hypoparathyroidism Fucosidosis Pitressin-resistant diabetes insipidus Mucopolysaccharidosis Familial cholestasis syndrome Environmental deprivation syndrome Acute respiratory disorders (croup, epiglottitis, viral pneumonia) Chronic respiratory disorders (bronchopulmonary dysplasia) α₁-Antitrypsin deficiency

CF, Cystic fibrosis.

From Feldman M et al: Sleisenger and Fordtran’s gastrointestinal and liver disease, ed 10, Philadelphia, 2016, Elsevier.

TABLE E7 Conditions Associated With False-Positive and False-Negative Sweat Test Results

With False-Positive Results

Eczema (atopic dermatitis)
Ectodermal dysplasia
Malnutrition/failure to thrive/deprivation
Anorexia nervosa
Congenital adrenal hyperplasia
Adrenal insufficiency
Glucose-6-phosphatase deficiency
Mauriac syndrome
Fucosidosis
Familial hypoparathyroidism
Hypothyroidism
Nephrogenic diabetes insipidus
Pseudohypoaldosteronism
Klinefelter syndrome
Familial cholestasis syndrome
Autonomic dysfunction
Prostaglandin E infusions
Munchausen syndrome by proxy

With False-Negative Results

Dilution
Malnutrition
Edema
Insufficient sweat quantity
Hyponatremia
Cystic fibrosis transmembrane conductance regulator mutations with preserved sweat duct function

From Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

Imaging Studies

Chest x-ray (Fig. E5): May reveal focal atelectasis, peribronchial cuffing, bronchiectasis, increased interstitial markings, hyperinflation
High-resolution chest CT scan (Fig. E6): Bronchial wall thickening, cystic lesions, ring shadows (bronchiectasis)

Figure E6 CT scans of the chest in cystic fibrosis.

A, A 12-yr-old boy with moderate lung disease. Airway and parenchymal changes are present throughout both lungs. Multiple areas of bronchiectasis (arrows) and mucous plugging (arrowheads) can be seen. B, A 19-yr-old girl has mostly normal lung with one area of saccular bronchiectasis in the right upper lobe (arrows) and a focal area of peripheral mucus plugging in the right lower lobe (arrowhead). Lung density is heterogenous, with areas of normal lung (open arrow) and areas of low attenuation reflecting segmental and subsegmental air trapping (asterisk).

From Kliegman RM: Nelson textbook of pediatrics, ed 21, Philadelphia, 2020, Elsevier.

Figure E5 Cystic fibrosis.

Cystic fibrosis is aptly named. Chest x-ray findings include increased interstitial density of fibrosis and cystic changes of lung parenchyma similar to chronic obstructive pulmonary disease. Bronchiectasis (dilation of bronchi, potentially eroding into bronchial arteries and presenting with hemoptysis) may be visible on chest x-ray as large and thickened bronchioles, particularly when viewed in short axis (when bronchioles are oriented perpendicular to the frontal plane). This 15-yr-old with cystic fibrosis presented with cough and dyspnea. Does she have pneumonia? Comparison with prior x-rays showed no changes. A, Posterior-anterior chest x-ray. B, Lateral chest x-ray. C, Close-up of A showing bronchiectasis.

From Broder JS: Diagnostic imaging for the emergency physician, Philadelphia, 2011, Saunders.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

Mucus clearance (i.e., using postural drainage techniques, chest percussion, pneumatic vest, acapella)
Encouragement of regular exercise and proper nutrition (daily caloric intake of 120% to 200% of healthy population)
Psychosocial evaluation and counseling of patient and family members

Acute General Rx

Primary goal of CF treatment related to pulmonary disease is to maintain lung function as near to normal as possible by controlling respiratory infections and clearing airways of mucus (Fig. E7, Table E8). Antibiotic therapy is directed toward either prevention or treatment of acute exacerbations. Treatment of acute pulmonary exacerbations is based on the results of sputum Gram stain and culture and sensitivity. S. aureus infections are treated with either cefazolin 1.5 g q6h or nafcillin 2 g q4 to 6h. MRSA should be treated with vancomycin 45 to 60 mg/kg/day in three divided doses or with linezolid 600 mg q12h or with ceftaroline 600 mg q8h. P. aeruginosa infections can be treated with piperacillin-tazobactam 4.5 g q6h or with cefepime 2 g q8h, or with meropenem 2 g q8h plus ciprofloxacin 750 mg PO q12h. Treatment of CF exacerbations should be aimed at least at mucoid P. aeruginosa and S. aureus (i.e., piperacillin-tazobactam and ciprofloxacin). Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and sustained improvement in weight but had no effect on microbiologic outcomes in children with early P. aeruginosa. Inhaled antibiotics (aztreonam or tobramycin) can also be used and can achieve high airway concentration with lower systemic side effects. Intermittent administration of inhaled tobramycin has been reported to be beneficial in CF.
Airway clearance with mucolytic recombinant human deoxyribonuclease (DNase [dornase alfa]) 2.5 mg qd or bid given by aerosol for patients ≥6 yr of age with viscid sputum. It lowers the viscosity of sputum. It is useful to improve mucociliary clearance by liquefying difficult-to-clear pulmonary secretions. It is, however, very expensive. It is most beneficial in patients with forced vital capacity values >40% of predicted. Its cost can be decreased by using alternate-day rhDNase therapy. Inhaled hypertonic saline is also suggested to use for airway clearance, although albuterol should be inhaled immediately before hypertonic saline to limit bronchospasm. All patients who produce sputum should be engaged in some form of chest physiotherapy in conjunction with the described therapies.
Bronchodilators for patients with airflow obstruction.
Glucocorticoids may be used in selected patients during an exacerbation that has characteristics of an acute asthmatic episode (e.g., chest tightness, wheezing, acute symptomatic response to inhaled beta-adrenergic agonists). Routine use of corticosteroids not recommended in adults. Boys with CF who have received alternate-day treatment with prednisone have shown persistent growth impairment after treatment is discontinued.

Figure E7 Cystic fibrosis (CF) therapeutics by category.

This figure depicts the mechanisms and possible therapeutics for CF airway pathology. CF therapeutics attempt to address defective cystic fibrosis transmembrane conductance regulator (CFTR) function by genetic-based therapy or modulation of CFTR expression or function; to address the diminished airway surface liquid, abnormally viscous mucus, and disrupted mucociliary clearance; and, finally, to treat chronic airway infection and inflammation. When respiratory failure develops, lung transplantation is the remaining option.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

TABLE E8 Supportive Cystic Fibrosis Therapeutics by Category

Agent		Predominant Mechanism of Action
Restoration of Airway Surface Hydration
Hypertonic saline ^∗		Osmotic increase of airway hydration; expectorant
Mannitol ^†		Osmotic increase of airway hydration; expectorant
Mucolytics
Dornase alfa		Cleavage of DNA polymers
Antiinflammatory
Ibuprofen		Reduction of airway inflammation
Antiinfectives
Inhaled tobramycin		Chronic treatment of Pseudomonas aeruginosa
Inhaled aztreonam		Chronic treatment of P. aeruginosa
Dry powder tobramycin		Chronic treatment of P. aeruginosa
Azithromycin		Antiinflammatory/antiinfective for chronic P. aeruginosa infection
Nutritional Therapies
AquADEKs		Restoration of fat-soluble vitamin levels
Pancrelipase		Restoration of pancreatic enzyme levels

^∗Therapy commonly used but not approved by the U.S. Food and Drug Administration.

^†Therapy approved in the U.S., Europe, Australia, and New Zealand; other approvals under consideration.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Chronic Rx

CF transmembrane conductance regulator (CFTR) modulators are a class of drugs that act by improving production, intracellular processing, and/or function of the defective CFTR protein. The indications and efficacy of these drugs depend upon the CFTR mutations in the individual patient. Table E9 summarizes approved therapeutics targeting each CFTR mutation class. In 2019 the triple combination therapy was approved in the U.S. For individuals with F508del homozygote who are ≥6 yr old triple therapy (elexacaftor-tezacaftor-ivacaftor) is recommended. Both triple and dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) have demonstrated efficacy in this population. For homozygotes ≤6 yr, only dual therapy is approved at this time. For individuals with F508del heterozygote ≥6 yr, triple therapy is recommended. Like other drug combinations for CF, elexacaftor/tezacaftor/ivacaftor (Trikafta) is very expensive and must be taken indefinitely. Individuals with residual function mutation without F508del, dual therapy with tezacaftor-ivacaftor or monotherapy with ivacaftor is recommended.
Pneumococcal, influenza, SARS-CoV-2, and all other childhood vaccines.
Antibiotic regimens are employed for early eradication and treatment of chronic infections with P. aeruginosa (inhaled tobramycin and aztreonam) and MRSA (rifampin).
Azithromycin is recommended for many patients due to its benefits from antiinflammatory and/or antibacterial properties. Should be started on patients ≥6 yr of age with persistent P. aeruginosa in airway cultures for inhibition of neutrophil migration and elastase production. Ibuprofen has a limited role as an agent to reduce airway inflammation. Inhaled glucocorticoids are appropriate for CF patients who have signs and symptoms of asthma.
Long-term pancreatic enzyme replacement for pancreatic insufficiency containing varying amounts of lipase, protease, and amylase.
Proper nutrition and vitamin supplementation (including fat-soluble vitamins A, D, E, and K).
Treatment of impaired glucose tolerance and CF-related diabetes. Insulin is the only recommended treatment for CF-related diabetes.

TABLE E9 Approved Therapeutics Targeting Each CFTR Mutational Class

CFTR Modulator Class	Molecule	CFTR Mutations Affected	CFTR Mutation Class Affected
Potentiator	Ivacaftor	G551D/S Non-G551D gating mutations Surface localized CFTR alleles F508del	II III IV V
Correctors	Lumacaftor (VX-809) (in combination with ivacaftor)	F508del (homozygous)	II
	Tezacaftor (VX-659) (in combination with ivacaftor)	F508del (homozygous)F508del heterozygous (with residual function mutation)	II
	Elexacaftor (VX-445) (in combination with tezacaftor and ivacaftor)	F508del (homozygous or heterozygous)	II

CFTR, Cystic fibrosis transmembrane conductance regulator.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Disposition

Bronchiectasis develops early in the course of CF, being detectable in infants as young as 10 wk of age and is persistent and progressive. Recent data reveal that neutrophil elastase activity in BAL fluid in early life is associated with early bronchiectasis in children with CF.
More than 50% of children with CF live beyond age 20 yr. During the past 2 decades, survival among patients with late-stage CF has lengthened substantially. Survival has improved at the rate of 1.8% annually during the past decade.
Lung transplantation is the only definitive treatment; 3-yr survival after transplantation exceeds 50%.
Obstructive azoospermia is present in >98% of postpubertal males.
The SERPINA Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at a greater risk of developing severe liver disease with portal hypertension.

Referral

Lung transplantation is advised in selected patients. Key indications for lung transplantation referral include FEV₁ <50% of predicted, rapidly progressive respiratory deterioration, increasing number of hospital admissions, massive hemoptysis, recurrent pneumothorax, arterial partial pressure of oxygen <55 mm Hg, arterial partial pressure of carbon dioxide >50 mm Hg, multidrug-resistant organisms (although most centers will deny transplant to patients with Burkholderia colonization), and wasting. Young female patients should be referred earlier because of overall poorer prognosis. Selected patients must undergo double lung transplant.
Genotype analysis is recommended for individuals with a positive family history.

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

Suggested Readings ⬆