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Cystic Fibrosis

By

Beryl J. Rosenstein

, MD, Johns Hopkins University School of Medicine

Last full review/revision Aug 2021| Content last modified Aug 2021
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Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency, hepatobiliary disease, and abnormally high sweat electrolytes. Diagnosis is by sweat test or identification of 2 cystic fibrosis-causing gene variants in patients with a positive newborn screening test result or characteristic clinical features. Treatment is supportive through aggressive multidisciplinary care along with small-molecule correctors and potentiators targeting the cystic fibrosis transmembrane conductance regulator protein defect.

Cystic fibrosis (CF) is the most common life-threatening genetic disease in the white population. In the US, it occurs in about 1/3,300 white births, 1/15,300 black births, and 1/32,000 Asian American births. Because of improved treatment and life expectancy, about 56% of patients in the US with CF are adults.

Etiology of Cystic Fibrosis

Cystic fibrosis is carried as an autosomal recessive trait Autosomal Recessive Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more by about 3% of the white population. The responsible gene has been localized on the long arm of chromosome 7. It encodes a membrane-associated protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The most common gene variant, F508del, occurs in about 85% of CF alleles; > 2000 less common CFTR variants have been identified.

CFTR is a cyclic adenosine monophosphate (cAMP)–regulated chloride channel, regulating chloride, sodium, and bicarbonate transport across epithelial membranes. A number of additional functions are considered likely. Disease manifests only in homozygotes. Heterozygotes may show subtle abnormalities of epithelial electrolyte transport but are clinically unaffected.

The CFTR variants have been divided into six classes based on how the variant affects the function or processing of the CFTR protein. Patients with class I, II, or III variants are considered to have a more severe genotype that results in little or no CFTR function, whereas patients with 1 or 2 class IV, V, or VI variants are considered to have a milder genotype that results in residual CFTR function. However, there is no strict relationship between specific variants and disease manifestation, so clinical testing (ie, of organ function) rather than genotyping is a better guide to prognosis. CFTR variants can involve frameshift (a deletion or insertion in a DNA sequence that shifts the way a sequence is read) or nonsense (stop) mutations.

Pathophysiology of Cystic Fibrosis

Nearly all exocrine glands are affected in varying distribution and degree of severity. Glands may

  • Become obstructed by viscid or solid eosinophilic material in the lumen (pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, and submaxillary glands)

  • Appear histologically abnormal and produce excessive secretions (tracheobronchial and Brunner glands)

  • Appear histologically normal but secrete excessive sodium and chloride (sweat, parotid, and small salivary glands)

Respiratory

Although the lungs are generally histologically normal at birth, most patients develop pulmonary disease beginning in infancy or early childhood. Mucus plugging and chronic bacterial infection, accompanied by a pronounced inflammatory response, damage the airways, ultimately leading to bronchiectasis Bronchiectasis Bronchiectasis is dilation and destruction of larger bronchi caused by chronic infection and inflammation. Common causes are cystic fibrosis, immune defects, and recurrent infections, though... read more Bronchiectasis and respiratory insufficiency. The course is characterized by episodic exacerbations with infection and progressive decline in pulmonary function.

Pulmonary damage is probably initiated by diffuse obstruction in the small airways by abnormally thick mucus secretions. Bronchiolitis Bronchiolitis Bronchiolitis is an acute viral infection of the lower respiratory tract affecting infants 24 months and is characterized by respiratory distress, wheezing, and/or crackles. Diagnosis is suspected... read more and mucopurulent plugging of the airways occur secondary to obstruction and infection. Chronic inflammation secondary to the release of proteases and proinflammatory cytokines by cells in the airways also contributes to lung injury. Airway changes are more common than parenchymal changes, and emphysema is not prominent. About 50% of patients have bronchial hyperreactivity that may respond to bronchodilators.

In the US, the prevalence of methicillin-resistant S. aureus (MRSA Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more Staphylococcal Infections ) in the respiratory tract is now about 25%; patients who are chronically infected with MRSA have more rapid decline in pulmonary function and lower survival rates than those who are not.

Colonization with Burkholderia cepacia complex occurs in about 2.6% of patients and may be associated with more rapid pulmonary deterioration.

Nontuberculous mycobacteria Nontuberculous Mycobacterial Infections Mycobacteria other than the tubercle bacillus sometimes infect humans. These organisms (called nontuberculous mycobacteria) are commonly present in soil and water and are much less virulent... read more , including Mycobacterium avium complex and M. abscessus, are potential respiratory pathogens. Prevalence is around 14% and varies with age and geographic location. Differentiating infection from colonization can be challenging.

Gastrointestinal

The pancreas, intestines, and hepatobiliary system are frequently affected. Exocrine pancreatic function is compromised in 85 to 95% of patients. An exception is a subset of patients who have certain "mild" residual function CFTR variants, in whom pancreatic function is unaffected. Patients with pancreatic insufficiency have malabsorption of fats, fat-soluble vitamins, and protein. Duodenal fluid is abnormally viscid and shows absence or diminution of enzyme activity and decreased bicarbonate concentration; stool trypsin and chymotrypsin are absent or diminished. Endocrine pancreatic dysfunction is less common, but impaired glucose tolerance or diabetes mellitus is present in about 2% of children, 20% of adolescents, and up to 50% of adults.

Other gastrointestinal (GI) problems include intussusception Intussusception Intussusception is telescoping of one portion of the intestine (intussusceptum) into an adjacent segment (intussuscipiens), causing intestinal obstruction and sometimes intestinal ischemia.... read more , volvulus, rectal prolapse Rectal Prolapse and Procidentia Rectal prolapse is painless protrusion of the rectum through the anus. Procidentia is complete prolapse of the entire thickness of the rectum. Diagnosis is by inspection. Surgery is usually... read more Rectal Prolapse and Procidentia , periappendiceal abscess, pancreatitis Overview of Pancreatitis Pancreatitis is classified as either acute or chronic. Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic... read more , an increased risk of cancer of the hepatobiliary tract Tumors of the Gallbladder and Bile Ducts Gallbladder and bile duct tumors can cause extrahepatic biliary obstruction. Symptoms may be absent but often are constitutional or reflect biliary obstruction. Diagnosis is based on ultrasonography... read more and GI tract (including of the pancreas Pancreatic Cancer Pancreatic cancer, primarily ductal adenocarcinoma, accounts for an estimated 57,600 cases and 47,050 deaths in the US annually (1). Symptoms include weight loss, abdominal pain, and jaundice... read more ), gastroesophageal reflux Gastroesophageal Reflux in Infants Gastroesophageal reflux is the movement of gastric contents into the esophagus. Gastroesophageal reflux disease (GERD) is reflux that causes complications such as irritability, respiratory problems... read more , esophagitis, and an increased prevalence of Crohn disease Crohn Disease Crohn disease is a chronic transmural inflammatory bowel disease that usually affects the distal ileum and colon but may occur in any part of the gastrointestinal tract. Symptoms include diarrhea... read more Crohn Disease and celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more Celiac Disease .

Other

Infertility occurs in 98% of adult men secondary to maldevelopment of the vas deferens or to other forms of obstructive azoospermia. In women, fertility is somewhat decreased secondary to viscid cervical secretions, although many women have carried pregnancies to term. Pregnancy outcome for both the mother and neonate is related to the mother's health.

Symptoms and Signs of Cystic Fibrosis

Respiratory

Fifty percent of patients not diagnosed through newborn screening present with pulmonary manifestations, often beginning in infancy. Recurrent or chronic infections manifested by cough, sputum production, and wheezing are common. Cough is the most troublesome complaint, often accompanied by sputum, gagging, vomiting, and disturbed sleep. Intercostal retractions, use of accessory muscles of respiration, a barrel-chest deformity, digital clubbing, cyanosis, and a declining tolerance for exercise occur with disease progression. Upper respiratory tract involvement includes nasal polyposis and chronic or recurrent rhinosinusitis.

Gastrointestinal

Meconium ileus due to obstruction of the ileum by viscid meconium may be the earliest sign and is present in about 10 to 20% of CF-affected neonates. It typically manifests with abdominal distention, vomiting, and failure to pass meconium. Some infants have intestinal perforation, with signs of peritonitis and shock. Infants with meconium plug syndrome have a delayed passage of meconium. They can have similar signs of obstruction or very mild and transient symptoms that go unnoticed. Older patients may have episodes of constipation or develop recurrent and sometimes chronic episodes of partial or complete small- or large-bowel obstruction (distal intestinal obstruction syndrome). Symptoms include crampy abdominal pain, change in stooling pattern, decreased appetite, and sometimes vomiting.

In infants without meconium ileus, disease onset may be heralded by a delay in regaining birth weight and inadequate weight gain at 4 to 6 weeks of age.

Occasionally, infants who are undernourished, especially if on hypoallergenic formula or soy formula, present with generalized edema secondary to protein malabsorption.

Pancreatic insufficiency is usually clinically apparent early in life and may be progressive. Manifestations include the frequent passage of bulky, foul-smelling, oily stools; abdominal protuberance; and poor growth pattern with decreased subcutaneous tissue and muscle mass despite a normal or voracious appetite. Clinical manifestations may occur secondary to deficiency of fat-soluble vitamins.

Rectal prolapse may occur in untreated infants and toddlers. Gastroesophageal reflux is relatively common among children and adults.

Other

Excessive sweating in hot weather or with fever may lead to episodes of hyponatremic/hypochloremic dehydration and circulatory failure. In arid climates, infants may present with chronic metabolic alkalosis Metabolic Alkalosis Metabolic alkalosis is primary increase in bicarbonate (HCO3−) with or without compensatory increase in carbon dioxide partial pressure (Pco2); pH may be high or nearly normal. Common causes... read more . Salt crystal formation and a salty taste on the skin are highly suggestive of CF. Adolescents may have retarded growth and delayed onset of puberty.

Diagnosis of Cystic Fibrosis

  • Newborn screening

  • May also be suggested by a positive prenatal screening test result, family history, or symptomatic presentation

  • Confirmed by a sweat test showing elevated sweat chloride on 2 occasions

  • Identifying 2 CF-causing variants (1 on each chromosome) is consistent with the diagnosis

  • May rarely be confirmed, in atypical cases, by demonstrating abnormal ion transport across the nasal epithelium or abnormal intestinal current measurements

Most cases of CF are first identified by newborn screening, but up to 10% are not diagnosed until adolescence or early adulthood. Despite advances in genetic testing, the sweat chloride test remains the standard for confirming a CF diagnosis in most cases because of its sensitivity and specificity, simplicity, and availability.

Newborn screening

Universal newborn screening for CF is now standard in the US. Screening is based on detecting an elevated concentration of immunoreactive trypsinogen (IRT) in the blood. There are two methods of following up on an elevated IRT level. In one method, a second IRT is done, which, if also elevated, is followed by a sweat test. In the other, more commonly used method, an elevated IRT level is followed by CFTR mutation testing, and, if 1 or 2 variants are identified, then a sweat test is done. For diagnosis, both methods have 90 to 95% sensitivity.

Sweat testing

In this test, localized sweating is stimulated with pilocarpine, the amount of sweat is measured, and the chloride concentration is determined. Although the sweat chloride concentration increases slightly with age, the sweat test is valid at all ages:

  • Normal: 30 mEq/L ( 30 mmol/L) (CF is unlikely.)

  • Intermediate: 30 to 59 mEq/L (30 to 59 mmol/L) (CF is possible.)

  • Abnormal: 60 mEq/L ( 60 mmol/L) (This result is consistent with CF.)

The results are valid after 48 hours of life, but an adequate sweat sample (> 75 mg on filter paper or > 15 mcL in microbore tubing) may be difficult to obtain before 2 weeks of age. False-negative results are rare but may occur in the presence of edema and hypoproteinemia or an inadequate quantity of sweat. False-positive results are usually due to technical error. Transient elevation of sweat chloride concentration can result from psychosocial deprivation (eg, child abuse, neglect) and can occur in patients with anorexia nervosa. A positive sweat test result should be confirmed by a 2nd sweat test or by identification of 2 CF-causing variants.

Intermediate sweat test results

A small subset of patients have a mild or partial CF phenotype and sweat chloride values that are persistently in the intermediate or even normal range. In addition, there are patients who have single-organ manifestations such as chronic or recurrent pancreatitis, isolated bronchiectasis, or congenital bilateral absence of the vas deferens along with findings suggestive of abnormal CFTR function. They do not meet criteria for a CF diagnosis and are classified as having a CFTR-related disorder. In some of these patients, the diagnosis of CF can be confirmed by the identification of 2 CF-causing variants, 1 on each chromosome. If 2 CF-causing variants are not identified, ancillary evaluations such as pancreatic function testing and pancreatic imaging, high-resolution chest CT, sinus CT, pulmonary function testing, urogenital evaluation in males, and bronchoalveolar lavage including assessment of microbial flora may be useful.

Additional potentially helpful diagnostic tests include expanded CFTR genetic analysis and measurement of nasal transepithelial potential difference (based on the observation of increased sodium reabsorption across epithelium that is relatively impermeable to chloride in patients with CF) and measurement of intestinal currents.

CFTR-related metabolic syndrome and CF screen positive, inconclusive diagnosis

Infants who have a positive newborn screening result and evidence of possible CFTR dysfunction but do not meet the diagnostic criteria for CF are classified as having CFTR-related metabolic syndrome (CRMS), also called CF screen positive, inconclusive diagnosis (CFSPID). CRMS/CFSPID is diagnosed in infants who have a positive newborn screen, are asymptomatic, and have either of the following:

  • Sweat chloride concentrations in the intermediate range and 0 or 1 CF-causing variant

  • Sweat chloride concentrations in the normal range and 2 CFTR variants, at least 1 of which has unclear phenotypic consequences

Most children with CRMS/CFSPID remain healthy, but over time around 10% will develop symptoms and meet criteria for a diagnosis of CF or a CF-related disorder. CRMS/CFSPID patients should be evaluated and monitored regularly in a CF care center.

Pancreatic tests

Pancreatic function should be assessed at the time of diagnosis, usually by measuring the concentration of human pancreatic elastase in stool. This latter test is valid even in the presence of exogenous pancreatic enzymes. Infants who are initially pancreatic sufficient and who carry 2 "severe" variants should have serial measurements to detect progression to pancreatic insufficiency.

Respiratory assessment

Chest imaging is done at times of pulmonary deterioration or exacerbations and routinely every 1 to 2 years. High-resolution chest CT may be helpful to more precisely define the extent of lung damage and to detect subtle airway abnormalities. Chest x-rays and CT may show hyperinflation, mucoid impaction, and bronchial wall thickening as the earliest findings. Subsequent changes include areas of infiltrate, atelectasis, and hilar adenopathy. With advanced disease, segmental or lobar atelectasis, cyst formation, bronchiectasis, and pulmonary artery and right ventricular hypertrophy occur. Branching, fingerlike opacifications that represent mucoid impaction of dilated bronchi are characteristic.

Sinus CT studies are indicated in patients with significant sinus symptoms or nasal polyps in whom endoscopic sinus surgery is being considered. These studies almost always show persistent opacification of the paranasal sinuses.

Chest Imaging Tests for Cystic Fibrosis

Pulmonary function tests are the best indicators of clinical status and response to therapy. In patients over 5 years of age, spirometry should be done routinely 4 times/year and at times of clinical decline. In infants, respiratory status can now be monitored by using a raised-volume rapid thoracoabdominal compression technique, which generates a partial flow-volume curve. In children 3 to 6 years of age, the multiple breath washout procedure can be used to generate a lung clearance index as a measure of ventilation inhomogeneity (1 Respiratory assessment reference Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Respiratory assessment reference ).

Pulmonary function tests done by spirometry indicate

  • A reduction in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced expiratory flow between 25% and 75% expired volume (FEF25-75), and FEV1/FVC ratio

  • An increase in residual volume and the ratio of residual volume to total lung capacity

Fifty percent of patients have evidence of reversible airway obstruction as shown by improvement in pulmonary function after administration of an inhaled bronchodilator.

Screening oropharyngeal or sputum cultures should be done at least 4 times/year, especially in patients not yet colonized with P. aeruginosa. Bronchoscopy/bronchoalveolar lavage is indicated when it is important to precisely define the patient’s lower airway microbial flora (eg, to direct antibiotic selection) or to remove inspissated mucus plugs.

Respiratory assessment reference

Carrier screening

CF carrier screening is available in the US and is recommended for couples who are planning a pregnancy or seeking prenatal care. If both potential parents carry a CFTR variant, prenatal screening of the fetus can be done by chorionic villus sampling or amniocentesis. Prenatal counseling in such cases is complicated by the wide phenotypic variability of CF and incomplete information on the clinical consequences of many of the CFTR variants that are identified through screening.

Prognosis for Cystic Fibrosis

The course is largely determined by the degree of pulmonary involvement. Deterioration is inevitable, leading to debilitation and eventual death, usually due to a combination of respiratory failure and cor pulmonale.

Prognosis has improved steadily over the past 5 decades, mainly because of early diagnosis and aggressive treatment before the onset of irreversible pulmonary changes. Median age at death in 2019 was 32.4 years. However, median predicted survival in the US for children born in 2019 is age 48.4 years. Long-term survival is significantly better in patients without pancreatic insufficiency. Outcomes are also affected by CFTR variant profile, modifier genes, airway microbiology, sex, ambient temperature, exposure to air pollutants (including tobacco smoke), adherence to prescribed therapies, and socioeconomic status. The FEV1 Respiratory assessment Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Respiratory assessment , adjusted for age and sex, is the best predictor of survival.

Treatment of Cystic Fibrosis

  • Comprehensive, multidisciplinary support

  • Antibiotics, inhaled drugs to thin airway secretions, and physical maneuvers to clear airway secretions

  • Inhaled bronchodilators and sometimes corticosteroids for responders

  • Usually pancreatic enzyme and vitamin supplementation

  • High-calorie diet (sometimes requiring supplemental enteral tube feedings)

  • In patients with specific variants, CFTR modulators consisting of a CFTR potentiator or combination of CFTR correctors and a CFTR potentiator

Comprehensive and intensive therapy should be directed by an experienced physician working with a multidisciplinary team that includes other physicians, nurses, dietitians, physical and respiratory therapists, mental health professionals, pharmacists, and social workers. The goals of therapy are maintenance of normal nutritional status, prevention or aggressive treatment of pulmonary and other complications, encouragement of physical activity, and provision of psychosocial support. The treatment regimen is complex and may take up to 2 hours each day. With appropriate support, most patients can make an age-appropriate adjustment at home and school. Despite myriad problems, the educational, occupational, and marital successes of patients are impressive.

(See also the Cystic Fibrosis Foundation's comprehensive treatment guidelines for all age groups.)

Respiratory

Treatment of pulmonary problems centers on prevention of airway obstruction and prophylaxis against and control of pulmonary infection. Prophylaxis against pulmonary infections includes maintenance of pertussis Diphtheria-Tetanus-Pertussis Vaccine Vaccines that contain diphtheria toxoid, tetanus toxoid, and acellular pertussis help protect against diphtheria, tetanus, and pertussis, but they do not prevent all cases. For more information... read more , Haemophilus influenzae Haemophilus influenzae Type b (Hib) Vaccine Haemophilus influenzae type b (Hib) vaccines help prevent Haemophilus infections but not infections caused by other strains of H. influenzae bacteria. H. influenzae causes many childhood infections... read more , varicella Varicella Vaccine Varicella vaccination provides effective protection against varicella (chickenpox). It is not known how long protection against varicella lasts. But, live-virus vaccines, like the varicella... read more , Streptococcus pneumoniae Pneumococcal Vaccine Pneumococcal disease (eg, otitis media, pneumonia, sepsis, meningitis) is caused by some of the > 90 serotypes of Streptococcus pneumoniae (pneumococci). Vaccines are directed against many of... read more , and measles Measles, Mumps, and Rubella (MMR) Vaccine The measles, mumps, and rubella (MMR) vaccine effectively protects against all 3 infections. People who are given the MMR vaccine according to the US vaccination schedule are considered protected... read more immunity; annual influenza vaccination Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention (CDC), vaccines for influenza are modified annually to include the most prevalent... read more ; and COVID-19 vaccination COVID-19 Vaccine COVID-19 vaccines provide protection against COVID-19. COVID-19 is the disease caused by infection with the SARS-CoV-2 virus. There are multiple COVID-19 vaccines currently in use worldwide... read more in accordance with current recommendations from the Advisory Committee on Immunization Practices (ACIP). In patients exposed to influenza, a neuraminidase inhibitor can be used prophylactically or at the first signs of infection. Giving palivizumab to infants with CF for prevention of respiratory syncytial virus infection Prevention Respiratory syncytial virus and human metapneumovirus infections cause seasonal lower respiratory tract disease, particularly in infants and young children. Disease may be asymptomatic, mild... read more has been shown to be safe, but efficacy has not been documented.

Airway clearance measures consisting of postural drainage, percussion, vibration, and assisted coughing (chest physiotherapy Chest Physiotherapy Chest physiotherapy consists of external mechanical maneuvers, such as chest percussion, postural drainage, and vibration, to augment mobilization and clearance of airway secretions. It is indicated... read more ) are recommended at the time of diagnosis and should be done on a regular basis. In older patients, alternative airway clearance measures, such as active cycle of breathing, autogenic drainage, positive expiratory pressure devices, and vest therapy (high-frequency chest wall oscillation), may be effective. Regular aerobic exercise is recommended; it may also help airway clearance. For patients with obstructive sleep apnea, continuous positive airway pressure Treatment Obstructive sleep apnea (OSA) is episodes of partial or complete closure of the upper airway that occur during sleep and lead to breathing cessation. Symptoms include snoring and sometimes restless... read more may be beneficial.

For patients with reversible airway obstruction, bronchodilators may be given by inhalation. Corticosteroids by inhalation usually are not effective. Oxygen therapy is indicated for patients with severe pulmonary insufficiency and hypoxemia.

Mechanical ventilation or extracorporeal membrane oxygenation (ECMO) is typically not indicated for chronic respiratory failure. Their use is typically restricted to patients with good baseline status in whom acute reversible respiratory complications develop, in association with pulmonary surgery, or to patients in whom lung transplantation is imminent. Noninvasive positive pressure ventilation Noninvasive positive pressure ventilation (NIPPV) Mechanical ventilation can be Noninvasive, involving various types of face masks Invasive, involving endotracheal intubation Selection and use of appropriate techniques require an understanding... read more nasally or by face mask also can be beneficial.

Oral expectorants are sometimes used, but few data support their efficacy. Cough suppressants should be discouraged.

Long-term daily inhalation therapy with dornase alfa (recombinant human deoxyribonuclease) or with 7% hypertonic saline has been shown to slow the rate of decline in pulmonary function and to decrease the frequency of respiratory tract exacerbations.

Pneumothorax can be treated with closed chest tube thoracostomy How To Do Surgical Tube Thoracostomy Surgical tube thoracostomy is insertion of a surgical tube into the pleural space to drain air or fluid from the chest. Pneumothorax that is recurrent, persistent, traumatic, large, under tension... read more How To Do Surgical Tube Thoracostomy drainage. Open thoracotomy or thoracoscopy with resection of pleural blebs and mechanical abrasion of the pleural surfaces is effective in treating recurrent pneumothoraces.

Mild to moderate hemoptysis is treated with antibiotics (oral/aerosol or IV depending on severity of hemoptysis and severity of infection) and airway clearance. Massive or recurrent hemoptysis is treated by bronchial artery embolization or rarely by focal lung resection.

Oral corticosteroids are indicated in infants with prolonged bronchiolitis and in patients with refractory bronchospasm, allergic bronchopulmonary aspergillosis Treatment Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus species (generally A. fumigatus) that occurs almost exclusively in patients with asthma or, less... read more Treatment (ABPA), and inflammatory complications (eg, arthritis, vasculitis). Long-term use of alternate-day corticosteroid therapy can slow the decline in pulmonary function, but because of corticosteroid-related complications, it is not recommended for routine use. Patients receiving corticosteroids must be closely monitored for evidence of diabetes and linear growth retardation.

Allergic bronchopulmonary aspergillosis is also treated with systemic corticosteroids and an oral antifungal drug.

Ibuprofen, when given over several years at a dose sufficient to achieve a peak plasma concentration between 50 and 100 mcg/mL (242.4 and 484.8 micromol/L), has been shown to slow the rate of decline in pulmonary function, especially in children 5 to 13 years of age. The appropriate dose must be individualized based on pharmacokinetic studies.

Chronic rhinosinusitis is very common. Treatment options include nasal saline irrigation, low-pressure isotonic nasal irrigation, intranasal dornase alfa nebulization, and sinonasal topical antibiotics. Sinus surgery may be helpful in cases refractory to medical management. An intranasal corticosteroid spray is recommended to treat allergic rhinitis.

CFTR modulators

CFTR corrector and potentiator drugs are indicated for about 90% of the variants carried by CF patients. CFTR modulators are not available for patients with class I frameshift and nonsense mutations.

Ivacaftor is a small-molecule oral drug given chronically that potentiates the CFTR ion channel in patients with specific CFTR variants. It may be used in patients 4 months of age and older who carry at least 1 copy of a specific variant potentiated by ivacaftor.

Lumacaftor, tezacaftor, and elexacaftor are small-molecule oral drugs that partially correct the defective CFTR protein by altering protein misfolding in patients who carry the F508del variant or other specified variants.

The combination of lumacaftor and ivacaftor can be given to patients 2 years of age and older who carry 2 copies of the F508del variant.

The combination of tezacaftor and ivacaftor can be given to patients 6 years of age and older who carry 2 copies of the F508del variant or other specified variants.

The triple combination of elexacaftor, tezacaftor, and ivacaftor can be given to patients 6 years of age and older who carry at least 1 copy of the F508del variant or 1 copy of certain rare variants.

These drugs can improve pulmonary function, increase weight, improve exocrine pancreatic function, decrease the frequency of pulmonary exacerbations and hospitalizations, improve quality of life, and reduce and sometimes normalize sweat chloride concentrations. The indications for ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor are based on the patient's CFTR variants and age and are changing rapidly. Although all of these drugs can be helpful, only ivacaftor and the combination of elexacaftor, tezacaftor, and ivacaftor are considered to be highly effective modulator therapy.

Antibiotics

For mild pulmonary exacerbations, a short course of oral antibiotics should be given based on culture and sensitivity testing. The drugs of choice for methicillin-sensitive staphylococcus are a penicillinase-resistant penicillin (eg, cloxacillin or dicloxacillin), a cephalosporin (eg, cephalexin), or trimethoprim/sulfamethoxazole. Erythromycin, amoxicillin/clavulanate, a tetracycline, or linezolid may be used. For patients colonized with methicillin-resistant S. aureus (MRSA), a course of oral trimethoprim/sulfamethoxazole, clindamycin, linezolid, or a tetracycline may be effective. For patients colonized with P. aeruginosa, a short course of inhaled tobramycin or aztreonam lysine (eg, 4 weeks) and/or an oral fluoroquinolone (eg, 2 to 3 weeks) may be effective. Fluoroquinolones have been used safely in young children.

For moderate-to-severe pulmonary exacerbations, especially in patients colonized with P. aeruginosa, IV antibiotic therapy is advised. Patients often require hospital admission, but carefully selected patients can safely receive some of the therapy at home. Combinations of the aminoglycoside tobramycin (or sometimes amikacin) plus a cephalosporin, extended-spectrum penicillin, fluoroquinolone, or monobactam with antipseudomonal activity are given IV, usually for 2 weeks. The usual starting dose of tobramycin is 10 to 12 mg/kg IV once every 24 hours to provide a peak blood level of 20 to 30 mcg/mL (43 to 64 micromol/L) and a trough blood level of < 1 mcg/mL (2 micromol/L). However, higher doses may be required to achieve acceptable serum concentrations. Because of enhanced renal clearance in patients with CF, large doses of some penicillins may be required to achieve adequate serum levels. For patients colonized with MRSA, vancomycin or linezolid can be added to the IV regimen.

In patients who are chronically colonized with P. aeruginosa, antibiotics delivered by inhalation improve clinical parameters and possibly reduce the bacterial burden in the airways. The long-term use of alternate-month inhaled tobramycin or aztreonam lysine therapy along with continuous (every month) oral azithromycin given 3 times/week may be effective in improving or stabilizing pulmonary function and decreasing the frequency of pulmonary exacerbations.

Eradication of chronic P. aeruginosa colonization is not usually possible. It has been shown, however, that early antibiotic treatment around the time the airways are initially infected with P. aeruginosa may be effective in eradicating the organism for some period of time. Treatment strategies vary but usually consist of a 4-week course of inhaled tobramycin, aztreonam, or colistin. Patients who have a clinically significant nontuberculous mycobacterium infection may require long-term therapy with a combination of oral, inhaled, and IV antibiotics.

Patients with allergic bronchopulmonary aspergillosis (ABPA) or lower airways aspergillus infection may require prolonged oral or IV therapy with an antifungal azole and/or systemic corticosteroids.

Gastrointestinal

Neonatal intestinal obstruction can sometimes be relieved by enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material; otherwise, surgical enterostomy to flush out the viscid meconium in the intestinal lumen may be necessary. After the neonatal period, episodes of partial intestinal obstruction (distal intestinal obstruction syndrome) can be treated with enemas containing a hyperosmolar or iso-osmolar radiopaque contrast material or acetylcysteine, or by oral administration of a balanced intestinal lavage solution. A stool softener such as dioctyl sodium sulfosuccinate or lactulose may help prevent such episodes. Ursodeoxycholic acid, a hydrophilic bile acid, is often used in patients with liver disease caused by CF, but there is little evidence to support its efficacy in preventing progression from bile stasis to cirrhosis.

Pancreatic enzyme replacement should be given with all meals and snacks to patients with pancreatic insufficiency. The most effective enzyme preparations contain pancrelipase in pH-sensitive, enteric-coated microspheres or microtablets. Infants are usually started at a dose of 2000 to 5000 IU lipase per 120 mL of formula or per breastfeeding session. For infants, the capsules are opened and the contents are mixed with acidic food. After infancy, weight-based dosing is used starting at 1000 IU lipase/kg/meal for children < 4 years and at 500 IU lipase/kg/meal for those > 4 years. Usually, half the standard dose is given with snacks. Doses > 2,500 IU lipase/kg/meal or > 10,000 IU lipase/kg/day should be avoided because high enzyme dosages have been associated with fibrosing colonopathy. In patients with high enzyme requirements, acid suppression with an H2 blocker or proton pump inhibitor may improve enzyme effectiveness.

Diet therapy includes sufficient calories and protein to promote normal growth—30 to 50% more than the usual recommended dietary allowances may be required (see Table: Recommended Dietary Reference Intakes* for Some Macronutrients, Food and Nutrition Board, Institute of Medicine of the National Academies Recommended Dietary Reference Intakes* for Some Macronutrients, Food and Nutrition Board, Institute of Medicine of the National Academies Nutrition is the science of food and its relationship to health. Nutrients are chemicals in foods that are used by the body for growth, maintenance, and energy. Nutrients that cannot be synthesized... read more ). Diet therapy also includes a normal-to-high total fat intake to increase the caloric density of the diet, a water-miscible multivitamin supplement in double the recommended daily allowance, supplementation with vitamin D3 (cholecalciferol) in patients with vitamin D deficiency or insufficiency, and salt supplementation during infancy and periods of thermal stress and increased sweating. Infants receiving broad-spectrum antibiotics and patients with liver disease and hemoptysis should be given additional supplemental vitamin K. Formulas containing protein hydrolysates and medium-chain triglycerides may be used instead of modified whole-milk formulas for infants with severe malabsorption. Glucose polymers and medium-chain triglyceride supplements can be used to increase caloric intake.

In patients who fail to maintain adequate nutritional status, enteral supplementation via gastrostomy or jejunostomy may improve growth and stabilize pulmonary function (see Overview of Nutritional Support Overview of Nutritional Support Many undernourished patients need nutritional support, which aims to increase lean body mass. Oral feeding can be difficult for some patients with anorexia or with eating or absorption problems... read more ). The use of appetite stimulants to enhance growth may be helpful in some patients.

Other

Cystic fibrosis-related diabetes (CFRD) is caused by insulin insufficiency and shares features of both type 1 and type 2 diabetes. Insulin is the only recommended treatment. Management includes an insulin regimen, nutrition counseling, a diabetes self-management education program, and monitoring for microvascular complications. The plan should be carried out in conjunction with an endocrinologist and a dietitian with experience in treating both CF and diabetes.

Patients with symptomatic right heart failure should be treated with diuretics, salt restriction, and oxygen.

Recombinant human growth hormone (rhGH) may improve pulmonary function, increase height and weight and bone mineral content, and reduce the rate of hospitalization. However, because of the added cost and inconvenience, rhGH is not commonly used.

Surgery may be indicated for localized bronchiectasis or atelectasis that cannot be treated effectively with drugs, nasal polyps, chronic rhinosinusitis, bleeding from esophageal varices secondary to portal hypertension, gallbladder disease, and intestinal obstruction due to a volvulus or an intussusception that cannot be medically reduced.

Liver transplantation has been done successfully in patients with end-stage liver disease.

Bilateral cadaveric lung and live donor lobar transplantation has been done successfully in patients with advanced pulmonary disease, as well as combined liver-lung transplantation for patients with end-stage liver and lung disease.

Bilateral lung transplantation for severe lung disease is becoming more routine and more successful with experience and improved techniques. Among adults with CF, median survival posttransplant is about 9 years.

End-of-life care

The patient and family deserve sensitive discussions of prognosis and preferences for care throughout the course of illness, especially as the patient's pulmonary reserves become increasingly limited. Most people facing the end of life with CF will be older adolescents or adults and will be appropriately responsible for their own choices. Thus, they must know what is in store and what can be done.

One mark of respect for patients living with CF is to ensure that they are given the information and opportunity to make life choices, including having a substantial hand in determining how and when to accept dying. Often, discussion of transplantation is needed. In considering transplantation, patients need to weigh the merits of longer survival with a transplant against the uncertainty of getting a transplant and the ongoing (but different) burden of living with an organ transplant.

Deteriorating patients need to discuss the eventuality of dying. Patients and their families need to know that most often dying is actually gentle and not profoundly symptomatic. When appropriate, palliative care Palliative care Dying patients can have needs that differ from those of other patients. So that their needs can be met, dying patients must first be identified. Before death, patients tend to follow 1 of 3... read more , including sufficient sedation, should be offered to ensure peaceful dying. A useful strategy for the patient to consider is to accept a time-limited trial of fully aggressive treatment when needed, but to agree in advance to parameters that indicate when to stop aggressive measures (see Do-Not-Resuscitate (DNR) Orders and Physician Orders for Life-Sustaining Treatment (POLST) Do-Not-Resuscitate (DNR) Orders and Physician Orders for Life-Sustaining Treatment (POLST) The do-not-resuscitate (DNR) order placed in a patient’s medical record by a physician informs the medical staff that CPR should not be done in the event of cardiac arrest. This order has been... read more ).

Key Points

  • Cystic fibrosis is caused by carrying 2 variants of the gene for a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates chloride, sodium, and bicarbonate transport across epithelial membranes.

  • The main complications involve the lungs, with damage to the small and large airways and chronic and recurrent bacterial infections, particularly by Pseudomonas aeruginosa.

  • Other major consequences include pancreatic malfunction, leading to malabsorption of nutrients and vitamins with consequent impaired growth and development, and, in older patients, diabetes.

  • Airway clearance measures (eg, postural drainage, percussion, vibration, assisted coughing) are begun at diagnosis and done on a regular basis; regular aerobic exercise is recommended.

  • Drugs that correct or potentiate CFTR can help patients who have certain CFTR variants.

  • Antibiotics are given early in any pulmonary exacerbation; drug selection may be based on culture and sensitivity testing.

  • Diet should be supplemented with pancreatic enzymes, high-dose vitamins, and 30 to 50% more calories derived primarily from fat.

More Information

The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

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