Cystic Fibrosis 

Updated: Jun 26, 2019
Author: Girish D Sharma, MD, FCCP, FAAP; Chief Editor: Kenan Haver, MD 

Overview

Practice Essentials

Cystic fibrosis (CF) is a disease of exocrine gland function that involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients. Pulmonary involvement (see the image below) occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

Chest radiograph of a patient with advanced cystic Chest radiograph of a patient with advanced cystic fibrosis. Note marked hyperinflation, peribronchial thickening, and bilateral infiltrates with evidence of bronchiectasis especially of the upper lobes.

Signs and symptoms

Median age at diagnosis is 6-8 months; however, age at diagnosis varies widely. Clinical manifestations vary with the patient’s age at presentation.

Gastrointestinal (GI) symptoms may include the following:

  • Meconium ileus

  • Abdominal distention

  • Intestinal obstruction

  • Increased frequency of stools

  • Failure to thrive (despite adequate appetite)

  • Flatulence or foul-smelling flatus, steatorrhea

  • Recurrent abdominal pain

  • Jaundice

  • GI bleeding

Respiratory symptoms may include the following:

  • Cough

  • Recurrent wheezing

  • Recurrent pneumonia

  • Atypical asthma

  • Dyspnea on exertion

  • Chest pain

Genitourinary symptoms may include the following:

  • Undescended testicles or hydrocele

  • Delayed secondary sexual development

  • Amenorrhea

Physical signs depend on the degree of involvement of various organs and the progression of disease, as follows:

  • Nose – Rhinitis, nasal polyps

  • Pulmonary system – Tachypnea, respiratory distress with retractions, wheeze or crackles, cough (dry or productive of mucoid or purulent sputum), increased anteroposterior chest diameter, clubbing, cyanosis, hyperresonant chest on percussion

  • GI tract – Abdominal distention, hepatosplenomegaly, rectal prolapse, dry skin, cheilosis

See Clinical Presentation for more detail.

Diagnosis

Requirements for a CF diagnosis include either positive genetic testing or positive sweat chloride test findings and 1 of the following:

  • Typical chronic obstructive pulmonary disease (COPD)

  • Documented exocrine pancreatic insufficiency

  • Positive family history (usually an affected sibling)

Parameters for the sweat chloride test are as follows:

  • The reference value is less than 40 mmol/L

  • A value higher than 60 mmol/L of chloride is consistent with CF

  • A value of 40-60 mmol/L is considered borderline, and the test must be repeated

  • In babies aged 3 months or younger, a value of 30-60 mEq/L is considered borderline and requires retesting[1]

Imaging studies that may be helpful include the following:

  • Radiography (chest, sinus, abdomen)

  • CT of the chest (not yet advised as a routine modality in CF)

  • Ultrasonography

  • Contrast barium enema

Additional tests that may be warranted are as follows:

  • Genotyping

  • Nasal potential difference measurement

  • Pulmonary function testing

  • Bronchoalveolar lavage

  • Sputum microbiology

  • Immunoreactive trypsinogen

See Workup for more detail.

Management

The primary goals of CF treatment include the following:

  • Maintaining lung function as near to normal as possible by controlling respiratory infection and clearing airways of mucus

  • Administering nutritional therapy (ie, enzyme supplements, multivitamin and mineral supplements) to maintain adequate growth

  • Managing complications

Mild acute pulmonary exacerbations of CF can be treated successfully at home with the following measures:

  • Increasing the frequency of airway clearance

  • Inhaled bronchodilator treatment

  • Chest physical therapy and postural drainage

  • Increasing the dose of the mucolytic agent dornase alfa

  • Use of oral antibiotics (eg, fluoroquinolones)

Medications used to treat CF may include the following:

  • Pancreatic enzyme supplements

  • Multivitamins (including fat-soluble vitamins)

  • Mucolytics

  • Nebulized, inhaled, oral, or intravenous antibiotics

  • Bronchodilators

  • Anti-inflammatory agents

  • Agents to treat associated conditions or complications (eg, insulin, bisphosphonates)

  • Agents devised to reverse abnormalities in chloride transport (eg, ivacaftor[2] )

  • Inhaled hypertonic saline

Surgical therapy may be required for the treatment of the following respiratory complications:

  • Respiratory – Pneumothorax, massive recurrent or persistent hemoptysis, nasal polyps, persistent and chronic sinusitis

  • GI – Meconium ileus, intussusception, gastrostomy tube placement for supplemental feeding, rectal prolapse

Lung transplantation is indicated for the treatment of end-stage lung disease.[3]

See Treatment and Medication for more detail.

Background

Cystic fibrosis (CF) is the most common lethal inherited disease in white persons.[4] Cystic fibrosis is an autosomal recessive disorder, and most carriers of the gene are asymptomatic.

Cystic fibrosis is a disease of exocrine gland function that involves multiple organ systems but chiefly results in chronic respiratory infections, pancreatic enzyme insufficiency, and associated complications in untreated patients (see Clinical). Pulmonary involvement occurs in 90% of patients surviving the neonatal period. End-stage lung disease is the principal cause of death.

The diagnosis of cystic fibrosis is based on typical pulmonary manifestations, GI tract manifestations, a family history, and positive sweat chloride test results (see Workup). Newborn screening for cystic fibrosis is universally offered in the United States. As a result of the complex and multisystemic involvement of cystic fibrosis and the need for care by specialists, treatment and follow-up care at specialty centers with multidisciplinary care teams (ie, cystic fibrosis centers) is recommended (see Treatment).

Pathophysiology

Cystic fibrosis is caused by defects in the cystic fibrosis gene, which codes for a protein transmembrane conductance regulator (CFTR) that functions as a chloride channel and is regulated by cyclic adenosine monophosphate (cAMP). Mutations in the CFTR gene result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces.

Six classes of defects resulting from CFTR mutations have been described and are as follows[5] :

  • Complete absence of CFTR protein synthesis

  • Defective protein maturation and early degradation (caused by the most common mutation, ΔF508)

  • Disordered regulation (diminished ATP binding and hydrolysis)

  • Defective chloride conductance or channel gating

  • Diminished transcription due to promoter or splicing abnormality

  • Accelerated channel turnover from the cell surface

CFTR mutations have poor penetrance. This means that the genotype does not predict the pattern or severity of disease.

Defective CFTR results in decreased secretion of chloride and increased reabsorption of sodium and water across epithelial cells. The resultant reduced height of epithelial lining fluid and decreased hydration of mucus results in mucus that is stickier to bacteria, which promotes infection and inflammation. Secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues have increased viscosity, which makes them difficult to clear.

Most patients with cystic fibrosis have severe chronic lung disease and exocrine pancreatic insufficiency. Additional manifestations include the following:

  • Nasal polyposis

  • Pansinusitis

  • Rectal prolapse

  • Chronic diarrhea

  • Pancreatitis

  • Cholelithiasis

  • Cirrhosis or other forms of hepatic dysfunction

Sinus disease

The exact mechanism by which malfunctioning CFTR causes sinus disease is not completely understood. Chloride ions cannot be excreted, sodium is excessively absorbed, and water passively follows. This desiccates the mucosal surface and alters the viscosity of the normal mucus blanket, which alone can lead to obstruction of sinus ostia.[6]

Additional abnormalities exist in these patients, including ciliary dysfunction, increased inflammatory mediators, and increased colonization with Pseudomonas aeruginosa, all of which further impair normal sinus clearance and aeration.[7] Chronic sinus infection and inflammation are the net result.

Lung disease

Most deaths associated with cystic fibrosis result from progressive and end-stage lung disease. In individuals with cystic fibrosis, the lungs are normal in utero, at birth, and after birth, before the onset of infection and inflammation (except possibly for the presence of dilated submucosal gland ducts in the airways). Shortly after birth, many persons with cystic fibrosis acquire a lung infection, which incites an inflammatory response. Infection becomes established with a distinctive bacterial flora. A repeating cycle of infection and neutrophilic inflammation develops.

Cleavage of complement receptors CR1 and C3bi and immunoglobulin G (IgG) by neutrophil elastase (NE) results in failure of opsonophagocytosis, leading to bacterial persistence. NE also causes production of the neutrophil chemoattractant interleukin (IL)–8 from epithelial cells and elastin degradation and acts as secretogogue, thereby contributing to persistence of inflammation and infection, structural damage, impaired gas exchange, and, ultimately, end-stage lung disease and early death.

One study reported that exposure to secondhand smoke adversely affects both cross-sectional and longitudinal measures of lung function in individuals with cystic fibrosis.[8] Variations in CFTR and a cystic fibrosis–modifier gene (TGFβ1) amplify the negative effects of secondhand smoke exposure.

Intestinal disease

Defects in CFTR lead to reduced chloride secretion with water following into the gut. This may result in meconium ileus at birth and in distal intestinal obstruction syndrome (DIOS) later in life.

In addition, other pathologic disorders complicate the simple relationship between the apical chloride and water secretion and the disease. The pancreatic insufficiency decreases the absorption of intestinal contents.

Mechanical problems associated with inflammation, scarring, and strictures may predispose the patient to sludging of intestinal contents, leading to intestinal obstruction by fecal impaction or to intussusception. Adhesions may form, leading to complete obstruction. A complete obstruction may require resection, leading to loss of absorptive epithelium of the distal ileum.

Meconium ileus

The meconium of fetuses with cystic fibrosis and meconium ileus has increased viscosity and decreased water content compared with those of healthy controls. The developmental sequence of mucin secretion in the fetal intestine is not fully understood, although the CFTR ion channel defect possibly leads to dehydration of intraluminal contents.

Meconium in patients with meconium ileus also has higher protein and lower carbohydrate concentration than that in control populations. Albumin is the major protein in the meconium of infants with meconium ileus, and is present in concentrations 5-10 times higher than normal.[9] In addition, there is a significant increase in the liver's production of intraluminal glutamyltranspeptidase (GGTP) and 5'-nucleotidase, which enters the meconium and promotes meconium ileus.

The addition of albumin to normal meconium makes it viscid; the addition of pancreatic protease liquefies the viscid mass. This led to the belief that pancreatic insufficiency played a central role in the pathogenesis of meconium ileus, although pancreatic insufficiency is not the sole cause of abnormal meconium in meconium ileus. In 1988, however, Lands et al reported 2 infants with cystic fibrosis and meconium ileus, aged 9 and 11 months, who displayed no clinical evidence of pancreatic insufficiency.[10]

In the murine model of cystic fibrosis, developed in 1992, newborn mice had severe intestinal obstruction at birth with minimal pulmonary or pancreatic involvement. These animal studies support the concept that meconium ileus may occur in patients with sufficient pancreatic activity. The lack of concordance between meconium ileus and severity of pancreatic disease suggests that intraluminal intestinal factors contribute to meconium ileus development.

Abnormal intestinal motility may also contribute to meconium ileus development. Some patients with cystic fibrosis have prolonged small intestinal transit times. Diseases other than cystic fibrosis in which there is abnormal gut motility (eg, Hirschsprung disease, chronic intestinal pseudo-obstruction) have been associated with meconium ileus–like disease, suggesting that decreased peristalsis may allow increased resorption of water, thus favoring meconium ileus development.

Pancreatic disease

As a part of normal digestion, stomach acid is neutralized by pancreatic bicarbonate, leading to the optimal pH for pancreatic enzyme action. Reduced bicarbonate secretion in response to secretin stimulation has been demonstrated in patients with cystic fibrosis with both pancreatic insufficiency and sufficiency. Reduced bicarbonate secretion affects the digestion so that neither endogenous nor exogenous pancreatic enzymes can work at their optimal pH.

Other factors, such as reduced water content of secretions, precipitation of proteins, and plugging of ductules and acini, prevent the pancreatic enzymes from reaching the gut. Autodigestion of the pancreas occasionally leads to pancreatitis.

Most patients with cystic fibrosis (90-95%) have pancreatic enzyme insufficiency and present with digestive symptoms and/or failure to thrive early in life. Onset of pancreatic insufficiency varies, however, and may occur in patients older than 6 months. Some patients never develop pancreatic insufficiency.

Patients with pancreatic insufficiency typically present with poor weight gain in association with frequent stools that are malodorous, greasy, and associated with flatulence and colicky pain after feeding. The combination of increased energy intake demand at baseline, the added energy intake demand of chronic disease, difficulty sustaining energy uptake because of malabsorption, and anorexia associated with ongoing lung inflammation leads to poor weight gain.

Pancreatic insufficiency predisposes patients to poor absorption of fat-soluble vitamins A, D, E, and K. Symptomatic deficiency of any of these vitamins can occur before diagnosis or as a later complication of the disease.

Liver disease

Absence of functional CFTR in epithelial cells lining the biliary ductules leads to reduced secretion of chloride and reduction in passive transport of water and chloride, resulting in increased viscosity of bile. The biliary ductules may be plugged with secretions. If this process is extensive, obstructive cirrhosis complicated by esophageal varices, splenomegaly, and hypersplenism may occur.

Secondary involvement of the liver may also occur because of involvement of other organs. For example, malnutrition may be associated with hepatic steatosis, and right heart failure caused by chronic hypoxia may result in passive congestion of the liver.

Gallstones are more prevalent in patients with cystic fibrosis than in age-matched control subjects. As many as 15% of young adults with cystic fibrosis have gallstones, irrespective of the status of their pancreatic function. Abnormal mucin in the gallbladder and malabsorption of bile acids in a patient with PI result in a higher frequency of gallstones.

Urogenital disease

Congenital absence of vas deferens may result in male infertility. Undescended testicles or hydroceles may be present in boys. Fertility is possibly decreased in females. Amenorrhea may occur in females with severe nutritional or pulmonary involvement.

Etiology

Cystic fibrosis is an autosomal recessive disease caused by defects in the CFTR gene, which encodes for a protein that functions as a chloride channel, and also regulates the flow of other ions across the apical surface of epithelial cells. In 1989, the CF locus was localized through linkage analysis to the long arm of human chromosome 7, band q31.[11]

Thus far, 1893 CFTR mutations have been identified.[12] Half of affected individuals of northern European descent are homozygous for the ΔF508 mutation, which is the deletion of a single phenylalanine residue at amino acid 508 of the CFTR gene (a class II defect). Another 25%-30% have one copy of ΔF508 plus another mutation.[13]

Certain alleles cluster with increased frequency in specific populations. For example, W1282X is common in Ashkenazi Jews, and A455E is common both in Dutch people and in individuals from northern Quebec. Δ1152H is the third most prevalent allele in Ashkenazi and other ethnic Jewish groups. The prevalence of Δ1152 mutation in Jewish populations comprises 5.2% of all CFTR mutations.

CFTR mutations result in abnormalities of cAMP-regulated chloride transport across epithelial cells on mucosal surfaces. The failure of chloride conductance by epithelial cells and associated water transport abnormalities result in viscid secretions in the respiratory tract, pancreas, GI tract, sweat glands, and other exocrine tissues. Increased viscosity of these secretions makes them difficult to clear.

Genotype-phenotype correlation demonstrates that ΔF508 homozygosity nearly always confers a pancreatic exocrine insufficiency. Individuals with 1 or 2 copies of missense mutations (eg, R117H) tend to be pancreatic sufficient and have milder disease.

The incidence of meconium ileus is higher in patients who are homozygous for ΔF508 or who have ΔF508 plus G542X. Conversely, not all patients with these genotypes have meconium ileus, so other non -CFTR factors must be involved in meconium ileus pathogenesis.

The incomplete correlation of genotype with phenotype suggests either an environmental component of organ dysfunction or modifying genes that are only recently being characterized.[14] The role of modifier genes is supported by the fact that neonates with cystic fibrosis who have intestinal obstruction most commonly have abnormalities in 2 or more CFTR modifier genes. In contrast, older children develop obstruction mostly as a result of environmental factors, such as introduction of pancreatic enzymes causing a stricture.[15, 16]

Studies in murine CF models have shown an increase in mast cells and neutrophils as part of the immune response. For example, the KITL gene plays a vital role in the differentiation of mast cells, as demonstrated by a decreased expression of MCPT2. Another focus includes the proteins selectin and intercellular adhesion molecule–1 (ICAM-1), which facilitate neutrophil extravasation. Neutrophils and mast cells release proteases, prostaglandins, and histamine, influencing mucus production.

A research model found in CFTR- knockout gene mice highlighted the importance of MCLCA3 expression in goblet cells. This gene influences mucus production, among other activities, and its expression was noted to be diminished in these mice. Correction of this deficiency increased survival and decreased intestinal disease. In humans, this finding may translate to applications such as correcting modifier genes (eg, HCLCA1) in order to improve outcomes in patients with CF.[17]

Additional genetic modifiers include a 129/Sv allelic contribution in mice that yields a milder inflammatory response in CF and is potentially linked to chromosomes 1, 9, and 10. The regulation of these genes and processes helps explain the range of phenotypic variability in similar genetic mutations.

Epidemiology

Cystic fibrosis is an autosomal-recessive disease. Its estimated heterozygote frequency in white people is up to 1 in 20. Each offspring of 2 heterozygote parents has a 25% chance of developing cystic fibrosis.

Cystic fibrosis is the most common lethal hereditary disease in the white population. In the United States, the prevalence is as follows:

  • Whites of northern European origin - 1 case per 3,200-3,500 population

  • Hispanics - 1 case per 9,200-9,500 population

  • African Americans - 1 case per 15,000-17,000 population

  • Asian Americans - 1 case per 31,000 population

The worldwide incidence varies from 1 per 377 live births in parts of England to 1 per 90,000 Asian live births in Hawaii. The higher frequency in Asian American or African American populations compared with native Asians or Africans reflects white admixture.[18]

Race demographics

The distribution of CFTR mutations varies according to the background of patients; for example, ΔF508 is the most common mutation found in the white population of northern European origin. Variability in clinical features between people of different races with same genotype has not been reported.

Clinical manifestations are similar in black and white populations, except that a poorer nutritional status is observed in black patients. Black patients with cystic fibrosis are younger at diagnosis and have poorer nutritional status and pulmonary function than white patients with cystic fibrosis. Whether this is genetic or due to socioeconomic factors is unclear; low socioeconomic status is associated with significantly worse pulmonary outcomes in patients with cystic fibrosis.

Sex demographics

Compared with males, females with cystic fibrosis have greater deterioration of pulmonary function with increasing age and younger mean age at death.[19] Although it has been suggested that the increase in hormone secretion with puberty in females may interfere with the defense mechanisms of the immune system, thereby promoting progressive pulmonary involvement, the immune system in patients with cystic fibrosis is fundamentally intact.

Prognosis

Worldwide, the median survival age in patients with cystic fibrosis varies from country to country; it is highest in the United States.[20] Median survival age is 36.9 years, but progress in medical and surgical treatment options have improved the prognosis over the last few decades. An individual with cystic fibrosis born in the United States today is expected to survive longer than 40 years.[21] The median survival age is higher in males than in females.

With current treatment strategies, 80% of patients should reach adulthood. Nevertheless, cystic fibrosis remains a life-limiting disease, and a cure for the disease remains elusive.

The clinical presentation, age at diagnosis, severity of symptoms, and rate of disease progression in the organs involved widely vary. Sweat abnormalities may result in heat stroke and salt depletion, especially in infants. Mucocele and mucopyocele associated with chronic sinusitis and nasal polyps can cause erosion of the sinus wall, resulting in CNS complications from the space-occupying effect of mucopyocele or from associated complications.[22]

GI tract complications include pancreatic involvement. Pancreatic tissue damage leads to diabetes mellitus in 8-12% of patients older than 25 years. Excessive administration of exogenous pancreatic enzymes can result in fibrosing colonopathy. Intestinal complications range from meconium ileus with associated complications during the neonatal period (12% of neonates with cystic fibrosis) to distal intestinal obstruction syndrome, rectal prolapse, peptic ulcer, and gastroesophageal reflux.

Liver involvement may result in a fatty liver (30-60% of patients), focal biliary cirrhosis, multinodular biliary cirrhosis, and associated portal hypertension. Portal hypertension occasionally causes death through esophageal varices. The prevalence of cholecystitis and gallstones is higher in patients with cystic fibrosis than in other individuals.

Delayed puberty and reduced fertility are other complications; most males are azoospermic because of agenesis of the vas deferens. Female fertility is probably only mildly impaired, and many successful pregnancies have been reported in women with cystic fibrosis.

Severity of pulmonary disease determines prognosis and ultimate outcome. Pulmonary involvement is progressive: beginning as bronchitis, bronchiolitis, and then bronchiectasis, pulmonary involvement leads to cor pulmonale and end-stage lung disease. Cause of death is generally respiratory failure and cor pulmonale.

A review of 6750 deaths due to cystic fibrosis in England and Wales from 1959-2008 reported that female sex and low socioeconomic status are associated with poorer outcomes than male sex and high socioeconomic status.[23]

A study of 1517 patients with cystic fibrosis who were registered with the UK Cystic Fibrosis Registry showed that lower muscle mass, shorter stature, and a low body mass index are associated with increased mortality.[24]

In a prospective observational study of 3142 patients from the Cystic Fibrosis Foundation Registry, weight for age percentile at 4 years of age was associated with improved clinical outcomes including lung function, fewer complications of cystic fibrosis and better survival through the age of 18.[25]

Patient Education

Provide counseling at the time of initial diagnosis, including information regarding inheritance and risk for recurrence in subsequent pregnancies, and instruct patients and parents regarding appropriate airway clearance technique and the need for chest physical therapy. Also, instruct patients and parents regarding the use of various drug delivery devices, such as valved holding chambers, and nebulizers, and the methods for modifying the pancreatic enzyme dosage.

Discuss when to contact cystic fibrosis center personnel (eg, for acute pulmonary exacerbation or complications) with patients and parents, and be prepared to counsel families regarding the impact of the diagnosis on the emotional life of parents, siblings, and members of the extended family.

 

Presentation

History

Median age at diagnosis of cystic fibrosis is 6-8 months; two thirds of patients are diagnosed by 1 year of age. The age at diagnosis varies widely, however, as do the clinical presentation, severity of symptoms, and rate of disease progression in the organs involved. Clinical manifestations vary with the patient's age at presentation.

Neonates may present with meconium ileus or, rarely, with other features such as anasarca. Patients younger than 1 year may present with wheezing, coughing, and/or recurring respiratory infections and pneumonia. GI tract presentation in early infancy may be in the form of steatorrhea, failure to thrive, or both.

Patients diagnosed later in childhood or in adulthood are more likely to have pancreatic sufficiency and often present with chronic cough and sputum production. Approximately 10% of patients with cystic fibrosis remain pancreatic sufficient; these patients tend to have a milder course.

Gastrointestinal tract manifestations

Meconium ileus occurs in 7-10% of patients with cystic fibrosis. Patients with simple meconium ileus usually present with abdominal distension at birth, eventually progressing to failure to pass meconium, bilious vomiting, and progressive abdominal distension.

Patients with complicated meconium ileus present more dramatically at birth with severe abdominal distention, sometimes accompanied by abdominal wall erythema and edema. Abdominal distention may be severe enough to cause respiratory distress.

Other GI manifestations in neonates include intestinal obstruction at birth and various surgical findings (eg, volvulus, intestinal atresia, perforation, meconium peritonitis). Less commonly, passage of meconium may be delayed (>24-48 hours after birth) or cholestatic jaundice may be prolonged.

Infants and children present with increased frequency of stools, which suggests malabsorption (ie, fat or oil drops in stools), failure to thrive, intussusception (ileocecal), or rectal prolapse.

Patients with pancreatic insufficiency have fat-soluble vitamin deficiency and malabsorption of fats, proteins, and carbohydrates (however, malabsorption of carbohydrates is not as severe as that of fats and proteins). Patients present with failure to thrive (despite an adequate appetite), flatulence or foul-smelling flatus, recurrent abdominal pain, and abdominal distention.

Malabsorption results in steatorrhea, characterized by frequent, poorly formed, large, bulky, foul-smelling, greasy stools that float in water. Cloth diapers, if used, are difficult to clean. Alternatively, some patients have anorexia without obvious steatorrhea.

Patients may present with a history of jaundice or gastrointestinal tract bleeding as a result of hepatobiliary involvement.

Respiratory tract manifestations

Patients present with a chronic or recurrent cough, which can be dry and hacking at the beginning and can produce mucoid (early) and purulent (later) sputum. Prolonged symptoms of bronchiolitis occur in infants. Paroxysmal cough followed by vomiting may occur.

Recurrent wheezing, recurrent pneumonia, atypical asthma, pneumothorax, hemoptysis, and digital clubbing are all complications and may be the initial manifestation. Dyspnea on exertion, history of chest pain, recurrent sinusitis, nasal polyps, and hemoptysis may also occur.

Urogenital tract manifestations

Undescended testicles or hydrocele may be present in boys. Males are frequently sterile because of the absence of the vas deferens. Therefore, male infertility may be one of the presentations.

Fertility is maintained, although possibly decreased, in females. Secondary sexual development is often delayed. Amenorrhea may occur in females with severe nutritional or pulmonary involvement.

Physical Examination

Physical signs depend on the degree of involvement of various organs and the progression of disease.

Nose examination may reveal the following:

  • Rhinitis

  • Nasal polyps

Findings related to the pulmonary system may include the following:

  • Tachypnea

  • Respiratory distress with retractions

  • Wheeze or crackles

  • Cough (dry or productive of mucoid or purulent sputum)

  • Increased anteroposterior diameter of chest

  • Clubbing

  • Cyanosis

  • Hyperresonant chest upon percussion (crackles are heard acutely in associated pneumonitis or bronchitis and chronically with bronchiectasis)

Findings related to the GI tract include the following:

  • Abdominal distention

  • Hepatosplenomegaly (fatty liver and portal hypertension)

  • Rectal prolapse

  • Dry skin (vitamin A deficiency)

  • Cheilosis (vitamin B complex deficiency)

Examination of other systems may reveal the following:

  • Scoliosis

  • Kyphosis

  • Swelling of submandibular gland or parotid gland

  • Aquagenic wrinkling of the palms (AWP)

One study reported an association between AWP and cystic fibrosis.[26] Among patients with cystic fibrosis, a greater degree of AWP is observed in patients who are homozygous for the ΔF508 mutation.

A study by Kelly et al sought to characterize cortical and trabecular volumetric bone mineral density (vBMD), geometry, and biomechanical competence in children with CF and determine their relationship to growth, body composition, and disease severity. The study found that trabecular and cortical bone deficits are common in children and adolescents with cystic fibrosis and that females are at particular risk of poor bone health.[27, 28]

Meconium ileus

Often, examination reveals dilated loops of bowel with a doughy character that indent on palpation. The rectum and anus are usually narrow, a finding possibly misinterpreted as anal stenosis.

Signs of peritonitis include tenderness, abdominal wall edema, distention, and clinical evidence of sepsis. A palpable mass may indicate pseudocyst formation. Often, the neonate is in extremis and needs urgent resuscitation and surgical exploration.

Atypical manifestations

Clinical variants have been described, such as adult males with bilateral absence of the vas deferens who have little other clinical involvement. Absence of the vas deferens is considered an atypical presentation of cystic fibrosis, and 80% of men with this presentation have at least one CFTR gene mutation. Zielenski et al reported that the most common of these mutations is the IVS8/5T mutation.[29]

Another atypical manifestation of cystic fibrosis is polyuria and polyphagia in an infant. Despite not having any initial intestinal symptoms, such as diarrhea, an infant in Belgium with failure to thrive was initially treated for diabetes insipidus before being diagnosed with cystic fibrosis.[30] Although a sweat test result may be abnormal in diabetes insipidus, cystic fibrosis must be excluded upon any positive sweat test result.

Complications

The following are potential complications of cystic fibrosis:

  • Nasal polyps

  • Chronic and persistent sinusitis with complications such as mucopyocele formation

  • Bronchiectasis

  • Atelectasis

  • Pneumothorax

  • Hemoptysis

  • Hypertrophic pulmonary osteoarthropathy

  • Allergic bronchopulmonary aspergillosis (ABPA)

  • Gastroesophageal reflux

  • Pulmonary hypertension

  • Cor pulmonale

  • End-stage lung disease

  • Pancreatitis

  • Cystic fibrosis–related diabetes mellitus

  • Meconium ileus

  • Distal intestinal obstruction syndrome

  • Rectal prolapse

  • Vitamin deficiency (especially fat-soluble vitamins)

  • Fatty liver

  • Focal biliary cirrhosis

  • Portal hypertension

  • Liver failure

  • Cholecystitis and cholelithiasis

  • Rickets

  • Osteoporosis

 

DDx

 

Workup

Approach Considerations

The diagnosis of cystic fibrosis (CF) is based on typical pulmonary manifestations, GI tract manifestations, a family history, and positive sweat test results.

Requirements for a CF diagnosis include either positive genetic testing or positive sweat chloride test findings (>60 mEq/L) and 1 of the following:

  • Typical chronic obstructive pulmonary disease

  • Documented exocrine pancreatic insufficiency

  • Positive family history (usually affected sibling)

Prenatal, Neonatal, and Postnatal Testing

Prenatal

Prenatal diagnosis allows the clinician to prepare for the medical and psychological needs of the parents, fetus, and newborn before, during, and after delivery.

Noninvasive CFTR analysis involves a technique for recovering DNA from cells obtained by buccal brushing. This technique can be used to determine the carrier status of the parents of a fetus with suspected CF based on sonographic findings of meconium ileus.

These tests are highly specific and are improving. One commercial test screens for 97 of the most common CF mutations. Although more than 1600 CF mutations exist, the 97 mutations covered by this test represent 98% of mutations responsible for the disease. In addition, results with this test are available in 5-8 days, versus 2-3 weeks with complete gene sequencing.

Screening tests do not screen for all possible mutations, and several types screen for just a few of the more common genetic mutations. Therefore, it is important to understand the implications of positive or negative results depending on the brand of screening test used.

Amniocentesis can provide subsequent fetal evaluation when both parents have identified CF mutations.

When only one or neither parent has an identified CF mutation but the couple has a previous child with CF, the status of the fetus can be predicted by restriction fragment length polymorphism (RFLP) analysis. Genetic material from both parents, the affected sibling, and the fetus must be available for RFLP testing. If the results predict CF in the fetus, referral to a tertiary care facility facilitates genetic counseling and consultation with specialists in maternal-fetal medicine.

If DNA analysis or amniocentesis tests are refused or if results are nondiagnostic, the authors recommend close sonographic follow-up at 6-week intervals.

Neonatal

Newborn screening for CF is universally required in the United States. All screening algorithms in current use in the United States rely on testing for immunoreactive trypsinogen (IRT) as the primary screen for cystic fibrosis.[31] The presence of high levels of IRT, a pancreatic protein typically elevated in infants with cystic fibrosis, warrants second level testing in the form of repeat IRT testing, DNA testing, or both.

A 2008 study from Massachusetts noted a decreasing incidence of cystic fibrosis identified by newborn screening, possibly resulting from more widespread preconception identification of cystic fibrosis carriers.[32] CFTR related metabolic syndrome (CRMS) is used to describe infants identified to have elevated levels of immunoreactive trypsinogen on newborn CF screening, have sweat chloride value of less than 60 mmol/L; have two CFTR mutations, at least one of which is not clearly categorized as CF causing and thus do not meet the Cystic Fibrosis Foundation guidelines for CF diagnosis. The Cystic Fibrosis Foundation published guidelines for the management of such infants.[33]

Postnatal

Suspect CF in patients with fetal or neonatal bowel obstruction and perform diagnostic tests as soon as possible.

From 75 to 80% of males with congenital bilateral absence of vas deferens (CBAVD) have been shown to possess a CFTR mutation for CF. With this condition, one may palpate the epididymis head; however, the structures derived from the Wolffian ducts under the control of the gonads, caudal epididymis, and vas deferens are absent. This anomaly may prove useful when looking for immediate support regarding a diagnosis of CF.

In adult males, obstructive azoospermia, in the absence of any other obvious cause (eg, vasectomy), provides additional corroborative evidence for the diagnosis of CF. Confirm results from semen analysis by obtaining a testicular biopsy.

A diagnosis of CF should be confirmed or refuted by a sweat test that meets all National Committee for Clinical Laboratory Standards (NCCLS) criteria. A sweat test may be performed any time after the first 48 hours of life if the neonate is not edematous.

Mutation analysis, performed on buccal or on blood cells using a Guthrie card, helps confirm the diagnosis if it yields at least one known CF mutation. Refer patients with confirmed CF to a regional or satellite CF center for counseling and education about this complex chronic disease. CF center physicians can also assist in postoperative management of nutritional or respiratory problems. To obtain a list of accredited centers, call 1-800-FIGHT CF or see the Cystic Fibrosis Foundation Web site.

Sweat Chloride Test

Several methods are used to conduct a sweat test. Performed properly, the quantitative pilocarpine iontophoresis test (QPIT) to collect sweat and perform a chemical analysis of its chloride content is currently considered to be the only adequately sensitive and specific type of sweat test.[1]

For reliable results, collect at least 50 mg or, preferably, 100 mg of sweat, a quantity that may be difficult to obtain from young infants. This test can be inaccurate in very young infants or if an inadequate volume is collected.[34] Never pool sweat from multiple sites to obtain the required quantity because the rate of sweating determines electrolyte content.

Current macroduct collection methods allow adequate analysis with smaller volumes of sweat. If a macroduct coil is used for collection, then sweat must be stimulated with a disposable Pilogel electrode using the Webster Sweat Inducer for 5 minutes. After 30 minutes, the minimum acceptable sample is 15 µL.

The sweat chloride reference value is less than 30 mmol/L. A value of more than 60 mmol/L of chloride in the sweat is consistent with a diagnosis of cystic fibrosis.[35]  The values of 30-60 mEq/L may represent heterozygous carriers, these carriers cannot be accurately identified with a sweat chloride test.[34]

The sweat test must be performed at least twice in each patient, preferably several weeks apart. Values of 40-60 mmol/L are considered borderline, and the test must be repeated because these values have been found to be consistent with the diagnosis in some patients with typical features.

Repeat a sweat test to confirm positive results. Repeat a sweat test with negative results if clinical features suggestive of cystic fibrosis are present. Some patients with genetically documented cystic fibrosis and typical symptoms have consistently negative results on sweat tests.

Other causes of elevated levels of sweat chloride include the following:

  • Untreated adrenal insufficiency

  • Glycogen storage disease

  • Type I fucosidosis

  • Hypothyroidism

  • Vasopressin-resistant diabetes insipidus

  • Ectodermal dysplasia

  • Malnutrition

  • Mucopolysaccharidosis

  • Panhypopituitarism

  • Familial cholestasis

  • Familial hypoparathyroidism

  • Atopic dermatitis

  • Iatrogenic causes (ie, infusion of prostaglandin E1, improper technique)

Imaging Tests

Radiography

On chest radiography, initial changes are hyperinflation and peribronchial thickening. Progressive air trapping with bronchiectasis may be apparent in the upper lobes. With advancing pulmonary disease, the following findings may be noted:

  • Pulmonary nodules resulting from abscesses

  • Infiltrates with or without lobar atelectasis

  • Marked hyperinflation with flattened domes of the diaphragm

  • Thoracic kyphosis

  • Bowing of the sternum

Pulmonary artery dilatation and right ventricular hypertrophy associated with cor pulmonale is usually masked by marked hyperinflation. Several radiologic scoring systems are recognized. An example of chest radiography in cystic fibrosis is shown in the image below.

Chest radiograph of a patient with advanced cystic Chest radiograph of a patient with advanced cystic fibrosis. Note marked hyperinflation, peribronchial thickening, and bilateral infiltrates with evidence of bronchiectasis especially of the upper lobes.

On sinus radiography, panopacification of the sinuses is present in almost all patients with cystic fibrosis, and its presence is strongly suggestive of the diagnosis. Conversely, absence of panopacification strongly suggests that cystic fibrosis is not present.

Abdominal radiography

In about 71% of uncomplicated meconium ileus cases, abdominal radiography reveals a characteristic pattern of unevenly dilated loops of bowel with variable air-fluid levels. Air-fluid levels may be absent because of the viscid nonliquid nature of the inspissated meconium.

Bubbles of gas may become evident as air mixes with the tenacious meconium. While this soap bubble appearance (or Neuhauser sign) depends on the viscosity of the meconium and is not a constant feature, this radiographic feature is highly suggestive of meconium ileus. Although none of these features alone is diagnostic for meconium ileus, they strongly suggest the diagnosis when combined with a family history of CF.

Radiologic findings in complicated meconium ileus vary based on the associated complication. Speckled calcification visible on abdominal plain radiography strongly suggests intrauterine intestinal perforation and meconium peritonitis. Visible obstruction and a large dense mass with a rim of calcification suggest a pseudocyst. In 1970, however, Leonidas et al reported no radiologic findings that suggest a complication in a third of patients with complicated meconium ileus.[36]

In utero perforation can lead to meconium peritonitis or meconium pseudocyst formation; only postoperative evaluation may differentiate between CF-related and non–CF-related meconium peritonitis or meconium pseudocyst formation.

Chest CT scanning

Though chest CT scanning is not yet advised as a routine modality in patients with CF and there are concerns about exposure to radiation and the high cost of the procedure, chest CT scanning has been used to diagnose lung involvement, such as an onset of bronchiectasis. High-resolution chest CT scans are reported to be more sensitive than traditional spirometry in detecting changes in lung disease severity. In a recently published prospective study of 81 children with CF, Brody chest scan scores and Wisconsin and Brasfield chest radiograph scores were significantly associated with future lung disease severity.[37] Such quantitative chest imaging has a potential to help clinicians to identify patients at risk of future lung disease progression. CT mosaic attenuation is associated with lung disease.[38]

Ultrasonography

Prenatal sonographic characteristics associated with meconium ileus include hyperechoic masses (ie, inspissated meconium in the terminal ileum), dilated bowel, and inability to visualize the gallbladder. Normal fetal meconium, when visualized in the second and third trimesters, is usually hypoechoic or isoechoic to adjacent abdominal structures. (Hyperechoic mass is defined as a mass with greater sonographic density than liver or bone.)

The sensitivity of intra-abdominal echogenic masses for CF detection reportedly ranges from 30%-70%. This finding as a sonographic marker of meconium ileus is plagued by difficulties, including subjective assessment of echogenicity and extensive differential diagnoses.

In addition to meconium ileus, hyperechoic bowel may occur with Down syndrome, intrauterine growth retardation, prematurity, in utero cytomegalovirus (CMV) infection, intestinal atresias, abruptio placenta, and fetal demise. The importance of hyperechoic fetal bowel relates to gestational age at detection, ascites, calcification, volume of amniotic fluid, and presence of other fetal anomalies.

Furthermore, a prenatal diagnosis of meconium ileus using the sonographic feature of hyperechoic bowel must consider the parents' a priori risk. The positive predictive value of hyperechoic masses in a high-risk fetus is estimated at 52%, while the predictive value for a low-risk fetus is just 6.4%.

While reviews of pregnancies with 1-in-4 risk of CF show a 25%-60% association between hyperechoic bowel and CF, this association is less prevalent in the general population. In 1992, Dicke and Crane reviewed 12,776 fetal sonograms performed after 14 weeks' gestation and noted hyperechoic bowel in 30 (0.2%) of these patients. Of these, 13.3% had CF. This team also reported a 16.7% associated risk of perinatal death, a 23.3% risk of growth retardation, and a 3.3% risk of genetic abnormality.[39]

Note that hyperechoic bowel is a normal variant in both the second and third trimesters. Hyperechoic bowel, when it occurs as an isolated event early during the second trimester, may represent a normal variant and indicates the need for follow-up prenatal examinations. Although an increased risk of meconium ileus and CF is associated with hyperechoic bowel, the prevalence, degree of risk, and decisions involving prenatal management remain uncertain.

Prenatal ultrasonographic findings of dilated bowel in association with CF have been reported less frequently than findings of hyperechoic bowel.

In meconium ileus, bowel dilatation is caused by a meconium obstruction but mimics similar findings in the following conditions:

  • Midgut volvulus

  • Congenital bands

  • Bowel atresia

  • Intestinal duplication

  • Internal hernia

  • Meconium plug syndrome

  • Hirschsprung disease

However, studies that show correlation between dilated fetal bowel and meconium ileus suggest that dilated fetal bowel warrants parental testing for CF and continued sonographic surveillance of the fetus.

In addition to the findings of increased abdominal echogenicity and bowel dilation, the inability to visualize the gallbladder on fetal ultrasonography is associated with CF. Combined with other sonographic features, nonvisualization of the gallbladder can help detect the disease prenatally. However, exercise caution in interpreting an absent gallbladder because the differential diagnosis includes biliary atresia, omphalocele, and diaphragmatic hernia.

Sonographic characteristics of fetal bowel obstruction are neither sensitive nor specific for meconium ileus. In general, a rate of sonographic detection for meconium ileus or meconium peritonitis can be up to 19%. Interpretation of these sonographic findings must consider the fetus' risk of CF. While ultrasonographic findings that suggest meconium ileus in a high-risk fetus indicate a high probability of CF, similar suspicious findings in a low-risk fetus warrant consideration of DNA testing or, at the very least, serial follow-up examinations.

Lung Clearance Index

Demonstration of ventilation heterogeneity by lung clearance index (LCI) is a sensitive marker for CF pulmonary disease even in young children and LCI findings have been correlated with CT lung findings,[40] however, LCI is mostly used in clinical trials and studies.

Hyperpolarized Gas Lung MRI

Ventilation MRI using hyperpolarized gas has been shown to detect ventilation heterogeneity. This technique could be used to detect and monitor early lung disease.[41, 42]

 

Genotyping

Genotype testing is recommended for individuals with a positive family history and for couples planning a pregnancy. It is not necessarily indicated for the general population.[18]

More than 1893 CF mutations have been identified.[12] In the commercially available CF gene sequencing method, the entire coding region, splice junction sites, and promoter region of the CFTR gene are amplified from genomic DNA by polymerase chain reaction (PCR) and then subjected to nucleotide sequence analysis on an automated capillary DNA sequencer.

A finding of 2 CFTR mutations in association with clinical symptoms is diagnostic. This test can detect more than 98% of disease-causing mutations in whites; the detection rate is lower in black, Hispanic, and Asian populations. Therefore, failure to find 2 abnormal genes does not exclude the disease.

In November 2013, the FDA approved 4 next-generation gene sequencing devices for clinical use in CF. Two of the devices are used to screen and diagnose CF by detecting DNA changes in the CF transmembrane conductance regulator (CFTR) gene[43, 44] : the Illumina MiSeqDx Cystic Fibrosis 139-Variant Assay, which checks specific points in the patient's CFTR gene sequence to detect known variants in the gene, and the Illumina MiSeqDx Cystic Fibrosis Clinical Sequencing Assay, which sequences a large portion of the CFTR gene to detect any difference in the CFTR gene compared with a reference CFTR gene.

The other 2 FDA-approved devices are the Illumina MiSeqDx instrument platform, which analyzes the genes, and the Illumina Universal Kit reagents, which isolate and create copies of the genes of interest from patient blood samples.[43, 44] These 2 devices comprise the first FDA-regulated test system that allows laboratories to develop and validate sequencing of any part of a patient’s genome.[43, 44]

Nasal Potential Difference Measurement

Potential difference (PD) in voltage measured from nasal mucosa and the reading obtained by a reference electrode inserted into the forearm correlates with the movement of sodium across cell membranes, which is a physiologic function rendered abnormal by a CFTR mutation. The nasal PD (NPD) is a sensitive test of electrolyte transport that can be used to support or refute a diagnosis of CF.

A normal mean value standard error (SE) is 0.9-24.7 mV; an abnormal value is 1.8-53 mV. When measurements are repeated after mucosal perfusion with amiloride to block an epithelial sodium channel, the drop in PD is greater in patients with cystic fibrosis (73%) than in control subjects (53%). Subsequent perfusion with chloride-free solution and isoproterenol produces a sharp increase in the PD in normal subjects but has little effect when CFTR function is abnormal.

As a result of the lack of commercially available equipment and the practical difficulties with NPD measurement, this test is performed in only a few research centers to diagnose CF in patients in whom making a diagnosis is difficult or a sweat test is not technically possible because of skin problems.

Pulmonary Function Testing

Infant lung function testing using raised volume rapid thoracic compression (RVRTC) whole body plethysmography is gaining wider acceptance; however, its use is mostly confined to specialized and research centers. This testing has been successfully used to demonstrate airway obstruction in young infants with CF.[45, 46]

Standard spirometry may not be reliable until patients are aged 5-6 years; however, some younger patients can be taught to do reproducible maneuvers. Partial flow-volume curves may show abnormalities in addition to an elevated airway resistance and hyperinflation.

The forced oscillation technique (FOT), which uses the impulse oscillometry system (IOS), can be used successfully in younger children. Airway resistance measured by IOS has been found to be similar to the airway resistance measured by body plethysmography, and this technique has been successfully used to measure lung function in young patients with CF who are unable to perform spirometry.[47]

Typically, peripheral airway involvement resulting from CF manifests as an obstructive defect with airtrapping and hyperinflation; oxyhemoglobin desaturation may occur because of a ventilation-perfusion mismatch. In the early stages, forced expiratory volume in 1 second (FEV1) may be normal, and forced expiratory flow (FEF) after 25-75% of vital capacity has been expelled (FEF 25-75) is reduced, suggesting small airway involvement.

Progression of disease has been correlated with a change in FEV1. A 2012 Danish study, using a longitudinal modeling technique specifically aimed at analyzing long sequences of repeated measurements of FEV1 measurements in CF patients reported that on average a change in FEV1 of greater than 13% (ie, twice the error SD to give a 95% confidence range) is likely to represent a true within-patient variation over time, whereas a lesser change may be due to transient (recoverable) fluctuation.[48]

The associated air trapping results in an elevated ratio of residual volume to total lung capacity (RV/TLC). With hyperinflation, TLC is also increased. In patients with advanced disease, extensive lung changes with fibrosis are reflected as restrictive changes characterized by declining TLC and vital capacity.

Lung clearance index (LCI) calculated from multiple breath inert gas (sulfur hexafluoride-SF6/helium gas mixture) washout has been used to demonstrate ventilation inhomogeneity, an early marker of lung disease in young children with CF.[49, 50, 51] LCI is a sensitive early marker of CF in young children, comparable with high-resolution CT scanning (HRCT), and is gaining wider acceptance by clinicians and researchers.[52]

Bronchoalveolar Lavage and Sputum Microbiology

Airway inflammation is the hallmark of lung disease in patients with CF. Studies suggest that airway inflammation is present even in the absence of infection.

Bronchoalveolar lavage fluid usually shows a high percentage of neutrophils, and recovery of Pseudomonas aeruginosa from bronchoalveolar lavage fluid supports the diagnosis of CF in a clinically atypical case.

Sputum microbiology

The most common bacterial pathogens in the sputum of patients with cystic fibrosis are as follows:

  • Haemophilus influenzae

  • Staphylococcus aureus

  • Pseudomonas aeruginosa

  • Burkholderia cepacia

  • Escherichia coli

  • Klebsiella pneumoniae

Findings of P aeruginosa, especially the mucoid form, support the diagnosis of cystic fibrosis in children.

Immunoreactive Trypsinogen

Immunoreactive trypsinogen (IRT) is a pancreatic enzyme that can help with diagnosing CF in neonates with meconium ileus when IRT relative ratios are elevated greater than the 99th percentile. IRT plus sweat test was shown to increase sensitivity and specificity in screening.

In a study by Steven et al, only 2 of 29 patients with intestinal obstruction from meconium ileus had a normal IRT relative ratio, supporting a false-negative rate of 7%; however, when checked at days 9 and 12, the IRT relative ratio was elevated above the 99th percentile. IRT levels cannot be used to differentiate between simple and complicated meconium ileus.[53]

Monitoring the detectability of IRT over the first 5 years of life has also shown that the eventual absence of this enzyme correlates with severe CF. This finding is also indicative of a negative correlation between the start of pancreatic enzyme replacement and the end of IRT detectability.[54]

Contrast Barium Enema

When meconium ileus is suspected on the basis of clinical and radiographic evidence, a contrast barium enema may be performed for diagnosis. One study showed a barium enema to be diagnostic in 45 (52%) patients. If meconium ileus is likely, follow the contrast enema with a therapeutic water-soluble contrast (Gastrografin) enema.

Some physicians advocate water-soluble contrast initially for both diagnosis and treatment. Controlled dilutions of Gastrografin remain the agent of choice for diagnosis and evacuation of inspissated meconium.

Fluoroscopically monitor contrast instillation in patients with meconium ileus to visualize a small-caliber colon (described as the microcolon of disuse), which often contains small "rabbit pellets" (ie, scybala) of meconium.

Progression of the contrast proximally may also outline pellets of inspissated meconium. Contrast that is successfully refluxed proximal to the obstruction allows observation of the dilated loops of small bowel.

In addition, evidence supports performing contrast enema using fluoroscopy in very low birth weight infants (average gestation age and weight, 27 wk and 788 g) in order to ensure that contrast reaches the distal ileum. Lack of contrast reflux to the distal ileum was found to be associated with unsuccessful relief of the obstruction.[55]

 

Treatment

Approach Considerations

As a result of the complex and multisystemic involvement of cystic fibrosis (CF) and the need for care by specialists, treatment and follow-up care at specialty centers with multidisciplinary care teams (ie, cystic fibrosis centers) is recommended.

At the time of initial confirmation of the diagnosis, the patient should undergo baseline assessment, investigations, and initiation of therapy. In addition, patient/parent education, including counseling and instructions regarding airway clearance techniques and the use of equipment (eg, nebulizer, spacer for metered-dose inhaler), is recommended.

When a patient presents with complications necessitating hospital admission, these objectives can be obtained during hospitalization. Follow-up outpatient visits are scheduled at 2-3 monthly intervals. Hospital admission is required for treatment of acute pulmonary exacerbation and severe complications.

The primary goals of CF treatment include the following:

  • Maintaining lung function as near to normal as possible by controlling respiratory infection and clearing airways of mucus

  • Administering nutritional therapy (ie, enzyme supplements, multivitamin and mineral supplements) to maintain adequate growth

  • Managing complications

Mild acute pulmonary exacerbations of cystic fibrosis can be treated successfully at home with the following measures:

  • Increasing the frequency of airway clearance

  • Inhaled bronchodilator treatment (especially if bronchial hyperresponsiveness is present or as part of airway clearance [inhaled bronchodilator followed by chest physical therapy and postural drainage])

  • Chest physical therapy and postural drainage

  • Increasing the dose of the mucolytic agent dornase alfa (Pulmozyme)[88]

  • Use of oral antibiotics (eg, oral fluoroquinolones)

Medications used to treat patients with cystic fibrosis may include the following:

  • Pancreatic enzyme supplements

  • Multivitamins (including fat-soluble vitamins)[86]

  • Mucolytics

  • Nebulized, inhaled, oral, or intravenous antibiotics

  • Bronchodilators

  • Anti-inflammatory agents

  • Agents to treat associated conditions or complications (eg, insulin, bisphosphonates)

  • Agents devised to potentially reverse the abnormalities in chloride transport (eg, ivacaftor[2] , lumacaftor/ivacaftor[56] , tezacaftor/ivacaftor[80, 81] )

In addition to mucolytics such as dornase alfa, hypertonic saline inhalation has been proposed as a therapy to increase hydration of airway surface liquid in patients with CF.[57, 87] Elkins et al reported that patients receiving 7% hypertonic saline (4 mL via nebulizer bid) had improved lung function and fewer pulmonary exacerbations, compared with patients receiving normal saline in a similar fashion.[58] Hypertonic saline was not associated with worsening bacterial infections or inflammation.

The Pulmonary Therapies Committee of Cystic Fibrosis Foundation recommends long-term use of hypertonic saline for patients with cystic fibrosis aged 6 years or older to improve lung function and to reduce the number of exacerbations.[59]

When meconium ileus is diagnosed prenatally, the authors recommend immediate referral to a tertiary care facility equipped to manage the needs of the mother, fetus, neonate, and family. A multidisciplinary team of perinatologists, neonatologists, obstetricians, pediatric surgeons, and CF specialists is prepared for the delivery of these high-risk neonates.

The team performs serial sonographic examinations on a monthly basis prior to delivery, a procedure that allows early detection of potential complications to prepare clinicians for special or urgent medical or surgical needs upon delivery.

The cystic fibrosis transmembrane conductance regulator (CFTR), ivacaftor (Kalydeco), was approved by the FDA in January 2012. A study by Ramsey et al observed lung function improvement at 2 weeks that was sustained through 48 weeks. The study also observed improvements in risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight gain, and concentration of sweat chloride.[2] Ivacaftor was initially approved for adults and children aged 6 years or older who have at least 1 copy of the G551D mutation in the CFTR gene. In February 2014, ivacaftor gained approval for an additional 8 CFTR gene mutations.[60] In 2015, use in CF was expanded to include children as young as 2 years with the approval of an oral granule which is mixed with soft food or liquid. In 2019, the FDA approved use in children as young as 6 months old. Since its approval, ivacaftor has gradually gained approval for additional CFTR gene mutations, which total 38 as of April 2019.

Approval of lumacaftor/ivacaftor was based on data from 2 Phase III studies (TRAFFIC and TRANSPORT) that enrolled more than 1100 people with CF aged 12 years and older who had 2 copies of the F508del mutation. In September 2016, the FDA expanded this indication to include children aged 6-11 years. People with 2 copies of the F508del mutation represent the largest group of people with CF. Of the 30,000 people in the United States with CF, approximately 8,500 individuals aged 12 years or older have 2 copies of the F508del mutation. Patients treated with lumacaftor/ivacaftor experienced statistically significant improvements in lung function. Patients also experienced reductions in pulmonary exacerbations and improvements in body mass index (BMI).[56]

Another ivacaftor-containing drug, tezacaftor/ivacaftor (Symdeko) was approved in February 2018 for cystic fibrosis in patients aged 12 years or older who are homozygous for the F508del mutation or who have at least 1 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approval was based on the phase 3 studies (EVOLVE and EXPAND) that involved about 750 people with CF. In both trials, the mean absolute change in percentage of the predicted FEV1 was in favor of tezacaftor–ivacaftor over placebo. In the EVOLVE trial, the rate of pulmonary exacerbation was 35% lower in the tezacaftor–ivacaftor group than in the placebo group. The EXPAND trial showed both tezacaftor-ivacaftor or ivacaftor alone had significant benefits versus placebo in both primary and secondary endpoints.[89, 90]

In June 2019, the FDA expanded the indication to include children and adolescents aged 6 to 12 years. Approval was based on completion of the 24-week phase 3 open-label, multicenter study (n=70) to evaluate the pharmacokinetics, safety, and tolerability of tezacaftor/ivacaftor and ivacaftor in children aged 6-11 years in the U.S. and Canada. The combination therapy was generally well tolerated, and safety data were similar to what was observed in previous studies of patients aged 12 years and older.[91]

While corticosteroids have been shown to slow the progression of lung disease, they also had significant adverse effects, especially on growth.[61]

A 2012 study exploring new treatment strategies for CF assessed whether long-term treatment with inhaled mannitol improves lung function and morbidity. Results showed that adding inhaled dry powder mannitol to standard therapy for CF produced sustained improvement in lung function for up to 52 weeks.[62]

In March 2013, the FDA approved tobramycin inhalation powder for the treatment of CF patients with P aeruginosa.[63] The powder is inhaled twice daily for 28 days; treatment is then stopped for 28 days before resuming. In a study of 95 pediatric and adult CF patients infected with P aeruginosa, those treated with inhaled tobramycin powder experienced a significant increase in forced expiratory volume in 1 second (FEV1) compared with placebo-treated patients (12.5% vs 0.09%).

Bisphosphonate treatment initiated during childhood may help counter the bone mineral density (BMD) loss seen in patients with CF, according to the results of a 2013 prospective, open-label observational study of the effects of calcium and vitamin D on BMD in 171 young CF patients, which was followed by a randomized, placebo-controlled trial of the bisphosphonate alendronate.[64, 65]

In the first part of the study, calcium and vitamin D intake were monitored; patients whose BMD had not improved more than 5% within 1 year (75%) joined the second part of the study, in which 128 patients were randomly assigned to treatment with either daily oral alendronate or placebo for 1 year.[65] Among the 65 patients who received alendronate, BMD increased by 16.3%, compared with 3.1% among the 63 patients who received placebo. Among the treated patients, approximately one third attained a BMD that was normal for their ages.

Diet and Exercise

In general, a normal diet with additional energy and unrestricted fat intake is recommended. A high-energy and high-fat diet, in addition to supplemental vitamins (especially fat soluble) and minerals, is recommended to compensate for malabsorption and the increased energy demand of chronic inflammation.

In children, because of various physical activities and eating habits, assessment and modification of energy requirements is based on growth and weight gain. Special consideration is given to female patients with a potential for delayed puberty because of malnutrition, patients with diabetes mellitus, and patients with liver disease.

Additional salt intake is recommended for patients living in hot climates, especially during exercise or activities that cause excessive sweating.

Nutritional supplements in the form of either high-energy oral preparations (eg, Scandishake) or enteral feeds (eg, elemental formulas, high-fat mixtures) via nasogastric tube or gastrostomy may be indicated in some patients. In one study, gastrostomy tube placement has been shown to significantly improve percentile body mass index and percent-predicted FEV1 in male patients and female pediatric patients. Lung function changes after placement did not depend on the level of lung function at placement.[66] . The Cystic Fibrosis Foundation published evidence-informed guidelines on enteral tube feeding in cystic fibrosis which include indications, evaluation and investigations before the procedure, as well as timing in relation to pulmonary status.[67]

Regular exercise increases physical fitness in patients with cystic fibrosis. Upper body exercises, such as canoe paddling, may increase respiratory muscle endurance.

Surgical Management of Complications

Surgical therapy may be required for the treatment of the following respiratory complications:

  • Pneumothorax

  • Massive recurrent or persistent hemoptysis

  • Nasal polyps

  • Persistent and chronic sinusitis

GI tract complications requiring surgical therapy are as follows:

  • Meconium ileus

  • Intussusception

  • Gastrostomy tube placement for supplemental feeding

  • Rectal prolapse

Lung transplantation is indicated for the treatment of end-stage lung disease.[3] Studies suggest that, although lung transplantation may improve quality of life, it may not lengthen survival.[68, 69]

Special Populations

Pregnant patients

CF patients and their partners should attend counseling, including genetic counseling, when planning for pregnancy. Women with CF can have successful pregnancies provided that special care is taken with the following:

  • Nutrition (vitamin and energy supplements)

  • Airway clearance

  • Treatment of respiratory infections

Patients with diabetes

Pancreatic tissue damage leads to diabetes mellitus in 8-12% of CF patients older than 25 years. In the Cystic Fibrosis-Related Diabetes Therapy (CFRDT) Trial, Moran et al found that among patients with CF-–related diabetes without fasting hyperglycemia, insulin therapy improved and sustained body mass index (BMI).[50] Patients treated with repaglinide had an initial significant BMI gain; however, after 6 months, it declined, and no difference was noticed at 1 year.

Consultations and Long-Term Monitoring

In addition to the specialists available at CF centers (usually pulmonologists and/or gastroenterologists), other specialists may need to be consulted when other systems are involved or complications involve other organs, including the following:

  • Surgeon

  • Otolaryngologist

  • Endocrinologist

  • Cardiologist

  • Transplant surgeon

Patients are monitored in the CF clinic every 2-3 months to achieve the following goals:

  • Maintenance of growth and development

  • Maintenance of as nearly normal lung function as possible using clinical assessment, pulmonary function testing, and oxyhemoglobin saturation

  • Intervention and retardation of the progression of lung disease via appropriate use of antibiotics, bronchodilators, and airway clearance techniques

  • Clinical assessment to monitor gastrointestinal tract involvement and presence of malabsorption and to provide enzyme and nutrition supplementation

  • Monitoring for complications and their treatment

  • Addressing psychosocial issues

Respiratory cultures should be obtained during each clinic visit. Common practice is to obtain expectorated sputum for this purpose. In young patients who cannot expectorate, deep throat swab cultures are obtained.

A recent study suggests that induced sputum using increasing concentrations of saline has a higher microbiological yield compared with conventional samples.[70] Although sputum induction is safe and may provide additional information to guide antimicrobial therapy, related extra time and expenses may warrant its use only in special situations.

Various techniques used to clear airways may include the following:

  • Chest physical therapy by hands

  • Forced expiratory technique and autogenic drainage

  • Positive expiratory pressure (PEP) using a PEP mask

  • High-frequency oscillation using a Flutter device

  • High-frequency chest compression using a ThAIRapy Vest

These techniques can be combined with bronchodilator therapy via a nebulizer.

Routine vaccinations are indicated in patients with cystic fibrosis, including seasonal influenza vaccination. A recent attempt by a Cochrane review to study the palivizumab vaccine for prevention of respiratory syncytial virus infection in patients with cystic fibrosis identified one randomized control trial, which reported no increase in the adverse events in the treatment versus placebo groups and that the vaccine made no difference.[71]

A study by Kazmerski et al that explored the attitudes, preferences, and experiences of patients with CF and CF providers toward sexual and reproductive health care for young women with CF found that both CF providers and patients agree that the CF provider has a fundamental role in providing CF-specific sexual and reproductive health care.[72]

 

Medication

Medication Summary

Medications used to treat patients with cystic fibrosis may include pancreatic enzyme supplements, multivitamins (particularly fat-soluble vitamins), mucolytics, antibiotics (including inhaled, oral, or parenteral), bronchodilators, anti-inflammatory agents, and CFTR potentiators (eg, ivacaftor) and correctors (eg, lumacaftor, tezacaftor).

Enzymes, Pancreatic

Class Summary

These agents aid digestion when the pancreas is malfunctioning. Current pancreatic enzyme preparations are derived from porcine extracts and contain various proportions of lipase, amylase, and protease. Most of the preparations are available in multiple strengths.

A particular dose is prescribed based on clinical symptoms and age and weight and then modified according to the clinical response. Usually, the dose of pancreatic enzymes should not exceed 2000 U/kg/meal of lipase. The novel preparation TheraCLEC-Total, a highly purified microbiologically-derived enzyme preparation, is under investigation in clinical trials.

Pancrelipase (Creon, Pancreaze, Ultresa, Zenpep)

These enteric-coated pancreatic enzyme microspheres contain various amounts of lipase, protease, and amylase. Pancrelipase assists in the digestion of protein, starch, and fat.

Vitamins

Class Summary

Vitamins are organic substances required by the body in small amounts for various metabolic processes. They may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation. They are classified as fat or water soluble. Vitamins A, D, E, and K are fat soluble while biotin, folic acid, niacin, pantothenic acid, B vitamins (ie, B-1, B-2, B-6, B-12), and vitamin C are generally water soluble.

Vitamin deficiency may result from an inadequate diet, increased requirements (eg, pregnancy, lactation), or secondary to disease or drug use. Vitamins are clinically used for the prevention and treatment of specific vitamin deficiency states. Supplementation of fat-soluble vitamins is routine in cystic fibrosis because of chronic malabsorption.

Vitamin A (Aquasol A)

Vitamin A is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.

Vitamin D (1,25-Dihydroxycholecalciferol, Calciferol, Cholecalciferol)

Vitamin D is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.

Vitamin E (Alpha-tocopherol, Aquasol E, Tocopherol)

Vitamin E is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.

Vitamin K1 (phytonadione) (AquaMephyton, Mephyton)

Vitamin K is a fat-soluble vitamin and is essential for antioxidant effects and as coenzymes for biological pathways, neurodevelopment, bone development, and coagulation. Typical multivitamin preparations formulated especially for patients with CF are referred to as ADEKs. Doses vary by patient age.

Bronchodilators

Class Summary

Albuterol provides selective agonistic action on beta2-adrenoceptors. Stimulation of adenyl cyclase results in smooth muscle relaxation of the bronchi, uterus, and skeletal muscle.

Inhaled beta2-agonists are often administered before chest physical therapy for airway clearance. They also are indicated when clinical evidence of bronchial hyperresponsiveness exists. In children with CF, the use of bronchodilators must be evaluated. Children with bronchiectasis may have a paradoxic bronchodilatation in response to beta-adrenergic agents. Pulmonary function testing before and after bronchodilators is suggested to avoid these counterproductive effects.

Albuterol (AccuNeb, ProAir, Proventil HFA, VoSpire ER, Ventolin HFA)

Albuterol is the most commonly used bronchodilating agent. It is available in multiple dosage forms (eg, solution for nebulization, metered-dose inhaler, PO solution). Typically, 2.5 mg of albuterol nebulizer solution is used either in premixed solution with isotonic sodium chloride solution or 0.5 mL of albuterol solution is mixed with 3 mL of 0.9% NaCl and administered before chest physical therapy.

Mucolytic Agents

Class Summary

Large amounts of neutrophil-derived DNA released from dead neutrophils increase sputum viscosity. Mucolytics, such as dornase alfa, an enzyme that hydrolyses the DNA, are used in patients with CF to improve airway clearance.

The Pulmonary Therapies Committee of Cystic Fibrosis Foundation recommends long-term use of hypertonic saline for patients with cystic fibrosis aged 6 years or older to improve lung function and to reduce the number of exacerbations.[59]

Dornase alfa (Pulmozyme)

Dornase alfa is a recombinant human DNase (rhDNase) that cleaves and depolymerizes extracellular DNA and separates DNA from proteins. This allows endogenous proteolytic enzymes to break down the proteins, thus decreasing viscoelasticity and surface tension of purulent sputum.

CFTR Potentiators and Correctors

Class Summary

Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis.

CFTR correctors (eg, lumacaftor, tezacaftor) corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein.

A recently published phase 3 extension study reported 42% slower rate of decline in percent predicted FEV1 in patients receiving long term treatment with lumacaftor and ivacaftor than in matched CF registry controls.[73]

Similarly, phase 3 trials with tezacaftor/ivacaftor and ivacaftor measured improvements across multiple disease measures, including lung function and pulmonary exacerbations compared with ivacaftor monotherapy.[80, 81]

Ivacaftor (Kalydeco)

Ivacaftor potentiates the CFTR protein, a chloride channel present at the surface of epithelial cells in multiple organs. This facilitates increased chloride transport by potentiating the channel-open probability (or gating) of certain CFTR gene mutations. It is indicated for cystic fibrosis in adults and children aged 6 months or older who have one mutation in the CFTR gene. It is not effective when used without a CFTR corrector (eg, lumacaftor) if the patient is homozygous for the F508del mutation in the CFTR gene.

Lumacaftor/ivacaftor (Orkambi)

This combination product contains lumacaftor, a CFTR corrector. Lumacaftor corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR proteins. The combination is indicated for cystic fibrosis (CF) in patients aged 6 y or older who are homozygous for the F508del mutation in the CFTR gene. This combination is well tolerated in young children. 

Tezacaftor/ivacaftor (Symdeko)

CFTR corrector and potentiator combination regimen. It is indicated for cystic fibrosis (CF) in patients aged ≥6 yr who are homozygous for the F508del mutation or who have at least 1 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.

Antibiotics

Class Summary

Antibiotic treatment may vary from a short course of one antibiotic agent to a continuous course with multiple antibiotics administered via various routes, including oral, intravenous, or inhalation. Antibiotic therapy has been found to be related to the greater likelihood of recovery after acute decline in FEV1.[74]  Because patients with cystic fibrosis have a larger lean body mass, they often have a higher clearance rate for many antibiotics. Achieving effective levels in respiratory secretions is difficult; higher doses of antibiotics and monitoring of aminoglycoside levels are required.

A Cochrane review included four studies (total 328 patients) comparing once-daily dosing of aminoglycosides in the treatment of acute pulmonary exacerbation with thrice-daily dose. There were no significant differences in lung function, weight for height, and body mass index. The creatinine changes significantly favored once-daily treatment in children but not in adults. These findings support the recent trend to use once-daily intravenous aminoglycosides.[75]

Administer aerosolized antibiotics when the airway pathogens are resistant to oral antibiotics or when the infection is difficult to control at home. Aerosolized antibiotics may reduce symptoms by reducing the organism density in the airways. Other advantages include prevention of infection or delay of chronic colonization, treatment of acute infection, and treatment of bacterial colonization in patients following transplantation to prevent infection in the transplanted lungs.

Agents used in the aerosolized form include gentamicin, aztreonam, colistin, and preservative-free high-dose tobramycin especially formulated for inhalation (ie, TOBI). Currently, clinical trials using a powder form of tobramycin and colistin are under way. These preparations use novel delivery devices and shorten the time required for dosage administration. A European study comparing lung function in 380 patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection reported that colistimethate sodium dry powder inhalation was as effective as nebulized tobramycin.[76]

Cephalosporins are effective against staphylococci and Haemophilus influenzae. A small subset of third-generation cephalosporins is effective against Pseudomonas aeruginosa. Generally speaking, moving from first-generation to third-generation cephalosporins gives increasing gram-negative coverage and less gram-positive coverage.

Fluoroquinolones are effective against most gram-positive and gram-negative organisms. They are the only class of oral antibiotics effective against P aeruginosa. The most commonly used medication in this class is ciprofloxacin. No fluoroquinolones are approved for children because of concern regarding their effects on deposition in the cartilage. However, studies from Europe have reported substantial evidence of their safety in patients with CF.

In patients with colonization with P aeruginosa, azithromycin administered orally 3 times per week on a long-term basis has been shown to improve lung function and nutritional status and to reduce acute pulmonary exacerbations.[77] . However, one study reported that azithromycin may interfere with the P aeruginosa, killing the action of inhaled tobramycin in these patients.[78]

Because colonization with P aeruginosa is considered to be an unfavorable event in the clinical course of patients with cystic fibrosis, various regimens have been studied in an attempt to eradicate the organism. A group in Italy compared inhaled tobramycin plus oral ciprofloxacin with inhaled colistin plus oral ciprofloxacin. They reported 62.8% and 65.2% eradication, respectively, thus showing no superiority for either treatment.[79]

Tobramycin inhaled (TOBI, Bethkis, TOBI Podhaler)

Preservative-free high-dose tobramycin especially formulated for oral inhalation (ie, TOBI, Bethkis) has been reported to be safe and effective in patients older than 6 months. The usual dose is 300 mg inhaled via nebulization twice daily administered during alternate months. A dry powder inhaler device is also available (TOBI Podhaler) with a different dosage regimen of 4 capsules (28 mg/cap) inhaled orally BID. Long-term intermittent administration in patients with P aeruginosa infection improves pulmonary function and nutritional status and reduces symptomatic pulmonary exacerbation.

Systemic tobramycin is usually combined with one of the penicillins used to treat pseudomonad infections in patients with CF. It is administered intravenously.

Aztreonam inhalation (Azactam, Cayston)

Aztreonam is a monobactam antibiotic that elicits activity in vitro against gram-negative aerobic pathogens, including P aeruginosa. This agent binds to penicillin-binding proteins of susceptible bacteria, thereby inhibiting bacterial cell wall synthesis, resulting in cell death. Activity is not decreased in the presence of cystic fibrosis lung secretions.

Aztreonam is indicated to improve respiratory symptoms in patients with CF who are infected with P aeruginosa.

Gentamicin

Gentamicin is usually combined with one of the penicillins used to treat pseudomonad infections in patients with CF.

Piperacillin

Piperacillin is effective against most strains of P aeruginosa and H influenzae. It is usually not effective against staphylococci. It is administered intravenously.

Cephalexin (Keflex)

Cephalexin is a first-generation cephalosporin that arrests bacterial growth by inhibiting bacterial cell wall synthesis. It has bactericidal activity against rapidly growing organisms. Its primary activity is against skin flora.

Ceftazidime (Fortaz, Tazicef)

Ceftazidime is a third-generation cephalosporin with broad-spectrum gram-negative activity. It has lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. It arrests bacterial growth by binding to one or more penicillin-binding proteins.

Ciprofloxacin (Cipro XR, Proquin XR)

Ciprofloxacin is a fluoroquinolone with activity against Pseudomonas organisms, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, and most gram-negative organisms, but with no activity against anaerobes. This agent inhibits bacterial DNA synthesis and, consequently, growth. Oral bioavailability is lower in younger patients with CF (65%) than in those older than 13 years (95%).

Trimethoprim/sulfamethoxazole (Bactrim DS, Septra DS)

The broad spectrum and action of trimethoprim and sulfamethoxazole (TMP-SMZ) against organisms found in patients with CF and the convenience of oral administration make this combination useful for treatment of milder infections on an outpatient basis.

Chloramphenicol

Chloramphenicol is effective against H influenzae and staphylococcal species. It may help treat P aeruginosa infection, for unclear reasons. Oral chloramphenicol is no longer available in the United States.

 

Questions & Answers

Overview

What is cystic fibrosis (CF)?

What are the GI symptoms of cystic fibrosis (CF)?

What are respiratory symptoms of cystic fibrosis (CF)?

What are genitourinary symptoms of cystic fibrosis (CF)?

What are the possible physical findings of cystic fibrosis (CF)?

What are the diagnostic criteria for cystic fibrosis (CF)?

Which imaging studies may be performed in the workup of cystic fibrosis (CF)?

Which supplemental tests may be indicated in the workup of cystic fibrosis (CF)?

What are the primary treatment goals of cystic fibrosis (CF)?

What is the treatment for mild symptoms of cystic fibrosis (CF)?

Which medications are used to treat cystic fibrosis (CF)?

When is surgical therapy indicated for cystic fibrosis (CF)?

What is cystic fibrosis (CF)?

What is the cause of cystic fibrosis (CF)?

What is the role of CFTR mutations in the pathogenesis of cystic fibrosis (CF)?

What are manifestations of cystic fibrosis (CF)?

What causes sinus disease in the pathogenesis of cystic fibrosis (CF)?

How does lung disease originate in the pathogenesis of cystic fibrosis (CF)?

How does cystic fibrosis (CF) affect intestinal functioning?

What is the role of meconium ileus in the pathogenesis of cystic fibrosis (CF)?

How does cystic fibrosis (CF) affect pancreatic functioning?

How does cystic fibrosis (CF) affect liver functioning?

How does cystic fibrosis (CF) affect fertility?

Where is the genetic etiology of cystic fibrosis (CF)?

Which ethnicities carry genetic mutations that can cause cystic fibrosis (CF)?

How do CFTR mutations cause cystic fibrosis (CF)?

What is the role of genetic modifiers in the etiology of cystic fibrosis (CF)?

What is the prevalence of cystic fibrosis (CF) in the US?

How does the prevalence and clinical presentation of cystic fibrosis (CF) vary by race?

How does the prevalence of cystic fibrosis (CF) vary by sex?

What is the prognosis of cystic fibrosis (CF)?

Which complications can affect the prognosis of cystic fibrosis (CF)?

What are negative prognostic factors in cystic fibrosis (CF)?

What education about cystic fibrosis (CF) should patients and families receive?

Presentation

At what age is cystic fibrosis (CF) typically diagnosed?

What are GI symptoms of cystic fibrosis (CF)?

What are respiratory symptoms of cystic fibrosis (CF)?

What are urogenital symptoms of cystic fibrosis (CF)?

Which nasal findings suggest cystic fibrosis (CF)?

Which pulmonary findings suggest cystic fibrosis (CF)?

Which GI findings suggest cystic fibrosis (CF)?

What are possible physical findings suggestive of cystic fibrosis (CF)?

What cystic fibrosis (CF) etiology is suggested by a finding of aquagenic wrinkling of the palms (AWP)?

How is bone health affected by cystic fibrosis (CF)?

What are signs of peritonitis in cystic fibrosis (CF)?

What are atypical manifestations of cystic fibrosis (CF)?

What are potential complications of cystic fibrosis (CF)?

DDX

What are the differential diagnoses for Cystic Fibrosis?

Workup

What are the criteria for the diagnosis of cystic fibrosis (CF)?

How is prenatal diagnosis of cystic fibrosis (CF) made?

How are neonates screened for cystic fibrosis (CF)?

How is cystic fibrosis (CF) diagnosed?

Which sweat test is performed for diagnosis of cystic fibrosis (CF)?

How much sweat is needed for an accurate diagnosis of cystic fibrosis (CF)?

What sweat chloride reference value is required for a positive diagnosis of cystic fibrosis (CF)?

Which conditions that cause elevated levels of sweat chloride should be included in the differential diagnoses of cystic fibrosis (CF)?

What is the role of chest radiography in the workup of cystic fibrosis (CF)?

What is the role of sinus radiography in the workup of cystic fibrosis (CF)?

What is the role of abdominal radiography in the workup of cystic fibrosis (CF)?

What is the role of CT scanning in the workup of cystic fibrosis (CF)?

What is the role of ultrasonography in the workup of cystic fibrosis (CF)?

Which conditions that cause hyperechoic bowel should be considered in the differential diagnoses of cystic fibrosis (CF)?

Which GI conditions should be included in the differential diagnoses of cystic fibrosis (CF)?

What is the role of lung clearance index (LCI) in the workup of cystic fibrosis (CF)?

What is the role of ventilation MRI in the workup of cystic fibrosis (CF)?

When is genotype testing indicated in the workup of cystic fibrosis (CF)?

How is genotype testing performed in the workup of cystic fibrosis (CF)?

What is the role of nasal potential difference testing in the workup of cystic fibrosis (CF)?

Which pulmonary function tests are used in the workup of cystic fibrosis (CF)?

What is the role of pulmonary function testing in the workup of cystic fibrosis (CF)?

What is the role of BAL in the workup of cystic fibrosis (CF)?

What are the most common bacterial agents found in the sputum of patients with cystic fibrosis (CF)?

What is the role of immunoreactive trypsinogen (IRT) measurement in the workup of cystic fibrosis (CF)?

What is the role of contrast barium enema in the workup of cystic fibrosis (CF)?

Treatment

What are the initial steps in the management of cystic fibrosis?

What are the primary goals of treatment for cystic fibrosis (CF)?

How are mild pulmonary symptoms of cystic fibrosis (CF) treated?

What are medications used to treat cystic fibrosis (CF)?

What is the role of hypertonic saline inhalation in the treatment of cystic fibrosis (CF)?

What is the treatment for prenatally diagnosed meconium ileus in cystic fibrosis (CF)?

What is the role of ivacaftor (Kalydeco) in the treatment of cystic fibrosis (CF)?

What are the risks and benefits of corticosteroids for the treatment of cystic fibrosis (CF)?

What is the role of mannitol or tobramycin in the treatment of cystic fibrosis (CF)?

What is the treatment for bone mineral density (BMD) loss in cystic fibrosis (CF)?

What are the dietary restrictions for patients with cystic fibrosis (CF)?

What is the role of exercise in the management of cystic fibrosis (CF)?

Which respiratory complications of cystic fibrosis (CF) are treated surgically?

Which GI complications of cystic fibrosis (CF) are treated surgically?

When is a full lung transplant indicated in the treatment of cystic fibrosis (CF)?

How is cystic fibrosis (CF) treated during pregnancy?

What are the treatment options for cystic fibrosis (CF) comorbid with diabetes?

Which specialists should be consulted for the treatment of cystic fibrosis (CF)?

What monitoring is needed the management of cystic fibrosis (CF)?

What lab testing should be performed at each clinic visit for cystic fibrosis (CF)?

Which techniques are used for clearing airways in cystic fibrosis (CF)?

What is the role of immunizations in the management of cystic fibrosis (CF)?

Medications

What are common medications used for the treatment of cystic fibrosis (CF)?

Which medications in the drug class Antibiotics are used in the treatment of Cystic Fibrosis?

Which medications in the drug class CFTR Potentiators and Correctors are used in the treatment of Cystic Fibrosis?

Which medications in the drug class Mucolytic Agents are used in the treatment of Cystic Fibrosis?

Which medications in the drug class Bronchodilators are used in the treatment of Cystic Fibrosis?

Which medications in the drug class Vitamins are used in the treatment of Cystic Fibrosis?

Which medications in the drug class Enzymes, Pancreatic are used in the treatment of Cystic Fibrosis?