eMedicine Specialties > Radiology > Chest

Cystic Fibrosis, Thoracic

Author: Eleni Giannouli, MD, Consulting Staff, Assistant Professor, Section of Respirology and Critical Care, Department of Critical Care,Winnipeg Regional Health Authority Health Sciences Center
Coauthor(s): Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St. Boniface General Hospital; Bruce Maycher, MD, Director of Pulmonary Radiology, St Boniface General Hospital; Associate Professor, Department of Radiology, University of Manitoba
Contributor Information and Disclosures

Updated: Apr 13, 2009

Introduction

Background

Cystic fibrosis (CF) is a multisystemic, autosomal recessive disorder that predominantly affects infants, children, and young adults.^1,2,3 CF is the most common life-limiting genetic disorder in whites, with an incidence of 1 case per 3200-3300 newborns in the United States.

Manifestations of CF involve the lung and gastrointestinal tract, including the pancreas.⁶ Dr D. Anderson first described the disease comprehensively in 1938. The term cystic fibrosis was coined because of the microscopic appearance of the pancreas.

For excellent patient education resources, visit eMedicine's Lung and Airway Center, Pneumonia Center, Cancer and Tumors Center. Also, see eMedicine's patient education articles Bronchitis, Emphysema, Bacterial Pneumonia, and Bronchial Adenoma.

Pathophysiology

Pathology

Hyperplastic airway epithelium with areas of erosion and squamous metaplasia are seen. Hyperplasia of the submucosal glands and plugs of mucoid material and inflammatory cells are found in the lumen. Eventually, grossly dilated airways with purulent secretions and severely congested parenchyma develop. Radiologic findings reflect the pathologic changes in the airways.⁷

Pathogenesis

Malfunction of the gene coding for the CF transmembrane conductance regulator (CFTR) protein results from most of the mutations described in Genetics, below. This malfunction leads to defective cAMP-dependent chloride secretion from the epithelium of different exocrine tissues, leading to thick viscous and difficult-to-clear secretions in lungs, sinuses, pancreas, intestine, liver, and reproductive tract.^8,9,10,11 In addition, the CFTR-mediated regulation of sodium channel activity may fail, leading to increased sodium absorption from the airways, which contributes to the alteration in the rheology of airway secretions. Typically, patients with CF present with multisystemic disease involving several or all of the organs mentioned.¹²

Chronic airway obstruction due to viscous secretions is soon followed by colonization with pathogenic bacteria, including Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas aeruginosa. P aeruginosa and some other gram-negative bacteria, such as Stenotrophomonas maltophilia, Burkholderia cepacia, Burkholderia pickettii, and Burkholderia gladioli, often acquire a mucoid phenotype, which is multidrug-resistant and rare in other disease states.^13,14

CFTR protein may have additional functions beyond that of the chloride channel that can account for the frequent colonization and persistent infection by these bacteria. That CFTR protein may alter the mix of sugars in the epithelial surface in ways that favor colonization by some organisms and not others has been postulated.

Bacterial killing via neutrophils and b-defensins in the airways also appears to require normal, rather than high, levels of chloride. Endobronchial infection occurs very early in life in patients with CF. The initial microorganisms are gram-negative bacteria, such as Escherichia coli and Proteus and Klebsiella species. In addition, H influenzae and S aureus are recovered on the initial encounter in many patients. By age 15-16 years, more than 60% of patients with CF acquire a P aeruginosa infection. The mucoid variant of this infection is considered pathognomonic for CF.

Later in the course of the disease, persistent colonization and infection (especially by P aeruginosa) may provoke an increase in inflammatory responses.¹⁵ The presence of chronic inflammation promotes the viscosity of airway mucus, which is increased by the large amounts of DNA and cytosol matrix proteins released by the granulation of neutrophils. Additionally, chronic inflammation promotes tissue destruction via the excessive release of elastase by recruited neutrophils. Lung damage progresses to bronchiectasis, altered pulmonary function, and respiratory failure.¹⁶

CF is caused by mutations in a single large 250,000–base pair gene on chromosome 7 that encodes the CFTR protein.^17,18 Expression of the CF gene is restricted largely to epithelial cells. The CFTR protein is similar in structure to a family of proteins (ie, traffic adenosine triphosphatase [ATPase]) that are involved in active transport across the cell membrane.¹⁹

The CFTR protein has 2 hydrophobic domains, each involving 6 loops that span the membrane and 2 nucleotide-binding folds that cleave ATPase, providing the energy for transport. In addition, CFTR contains a highly charged central regulatory domain, with multiple phosphorylation sites. This allows CFTR to function as a regulated chloride channel, which in turn may regulate the activity of other chloride and sodium channels at the cell surface. When the regulatory domain is not phosphorylated by phosphokinase A, it acts as a gate blocking the flow of chloride. The addition of phosphates, probably through cleavage of ATPase, opens the gate, allowing chloride to flow through the pore.

More than 70% of patients with CF have deletion of 3 contiguous base pairs resulting in the loss of a single amino acid (phenylalanine at codon 508), hence its designation as DF508. However, more than 300 additional CFTR gene defects have been identified, of which at least 230 are known to be associated with clinical disease.²⁰

CFTR mutations have been grouped in 5 classes as follows:

• Class I: The defective synthesis of CFTR is a result of unstable messenger RNA and leads to the complete absence of CFTR protein and its function. Abnormal transcription is caused by non-sense, frameshift, or splice-site mutations (genotype example [GE], W1282X).
• Class II: Protein processing is defective. A typical example of this mutation involves DF508. In this example, the CFTR protein fails to undergo the appropriate folding required for its trafficking to the correct position in the cell membrane, and as a result, it is degraded and entrapped in the endoplasmic reticulum.
• Class III: Regulation and activation of CFTR are defective. Abnormal CFTR proteins arrive at the site of function, but they are unable to activate or function normally as ion channels (GE, G551D).
• Class IV: Defective conduction in the chloride channel results in a reduction of ion flow and induces changes while the ion channel remains open (GE, R117H).
• Class V: Some authors have described a class V mutation, in which decreased attenuated production of CFTR and attenuated conductance occur.

Different cell lines may vary in their ability to process varying defective proteins. The phenotypic presentation of the disease is probably related to the underlying genetic abnormality. The common clinical presentation of the disease is in a child with respiratory distress and malabsorption; this presentation is typical of patients who are homozygous for DF508. Patients with less-severe variations of the disease or those with typical CF and sweat test results that are borderline normal have other haplotypes.²¹

Mutations in CFTR have been identified in adults with idiopathic chronic pancreatitis without other evidence of an increased prevalence of CF.²² Results of several studies suggest that CFTR mutations may play an important role in the pathogenesis of chronic pancreatitis. In addition, some individuals in the general population who have chronic rhinosinusitis may have mutations in the CFTR gene. The most common polymorphism is M470V.²³

CFTR plays a significant role in the organogenesis of wolffian structures and the vas deferens. Incompletely developed wolffian structures and, most commonly, an absent vas deferens are found almost universally in patients with CF. These abnormalities, as well as defects in sperm transport related to malfunction of the CFTR protein, account for the infertility seen in more than 95% of male patients with CF.^24,25

No known specific CFTR mutation predisposes patients to the development of meconium ileus or hepatobiliary disease.

Frequency

United States

CF is the most common autosomal recessive disease among whites, with an occurrence of 1 case per 3200-3300 live births in whites. The carrier rate in whites is 1 in 29.

International

Inheritance varies in persons in European countries, following a geographic gradient. The incidence is higher in northwestern countries and lower in southeastern countries. The highest rate occurs in Scotland, with an incidence of 1 case per 500 population. Overall, the incidence of CF is estimated to be 1 case per 2000-4000 population in whites.

Several isolated populations have an unusually high incidence of CF. The Hutterite population in Alberta has a rate of 1 case per 313 population; Afrikaners in southwestern Africa, 1 case per 622; and French Canadians from the Saguenay-Lac St Jean region, 1 case per 895.

Mortality/Morbidity

At one time, the disease killed affected patients during infancy, but advances in therapy have brightened the outlook. Pulmonary complications account for most of the mortality and morbidity.²⁶ Socioeconomic factors and the availability of resources play an important role in mortality and morbidity.

• Although the median survival was less than 1 year for patients in 1940, it had increased to 14 years by the 1970s, and it is now 29-31 years. Although previously, CF was a childhood disease, it has become an adult pulmonary condition.²⁷
• Currently, one third of the population with this pediatric disease is adult, and patients as old as 60 years are seen in CF clinics.
• In South America, the median survival age remains at 9 years.

Race

CF occurs infrequently in native Africans and Asians. In the US, incidence of CF differs by race and ethnicity, ie, 1 case per 15,000 African Americans, 1 case per 9500 Hispanics, 1 case per 11,200 American Indians, and 1 case per 32,000 in individuals of Asian origin.

• The carrier rate varies similarly, ie, 1 per 62 in African Americans; 1 per 90 in Asian Americans; and 1 per 49 in Hispanics. The high carrier rate may infer a heterozygote advantage related to disease resistance or fecundity, but the mechanism is unclear.
• In most patients, the family history is negative for CF. CF should be considered in patients with diverse racial and ethnic backgrounds, especially those from multiracial countries.

Sex

Overall, the male-to-female ratio of CF is balanced.

Age

In 70% of patients, diagnosis is established prior to age 1 year, usually within the first several months of life. However, more recent statistics from the US Cystic Fibrosis Foundation database report a mean age of 3 years at diagnosis. In 8% of patients, the diagnosis is not established until after the age of 10 years, and the diagnosis is being made in an increasing number of adults.^28,29

Presentation

In most patients, CF is suggested by the presence of 1 or more typical clinical features as follows:

• Chronic sinopulmonary disease - Persistent colonization and infection by typical CF pathogens (ie, S aureus, H influenzae, mucoid and nonmucoid P aeruginosa, and Burkholderia species)
  • Chronic cough and sputum production
  • Airway obstruction manifested by wheezing and airtrapping
  • Nasal polyps
  • Digital clubbing
• Gastrointestinal and nutritional abnormalities
  • Intestinal - Meconium ileus, distal intestinal obstruction syndrome (DIOS), rectal prolapse, pancreatic insufficiency, and recurrent pancreatitis
  • Hepatic - Chronic hepatic disease resulting from focal or multilobular cirrhosis
  • Nutritional - Failure to thrive (protein calorie malnutrition), hypoproteinemia and edema, and complications secondary to fat-soluble vitamin deficiency³⁰
• Salt loss syndrome - Acute salt depletion and chronic metabolic alkalosis
• Male urogenital abnormalities - Resulting in obstructive azoospermia (congenital bilateral absence or atresia of the vas deferens)

The clinical presentations can vary by age group: prenatal, neonatal, infancy and childhood, and adolescence and adulthood. Findings are as follows:

• Prenatal
  • High-risk pregnancy
    • If the genotype status of the parents is known, the diagnosis of CF can be excluded or confirmed with a high degree of accuracy by means of direct mutation analysis performed on fetal cells. These cells are obtained from chorionic villus sampling at 10 weeks or from cultured amniotic fluid cells collected at 15-18 weeks.
    • Postnatal sweat testing should also be performed in all patients in whom CF is confirmed or excluded on the basis of prenatal DNA results.
  • Fetal intestinal obstruction
    • In fetuses not known to be at increased risk for CF, the diagnosis is occasionally suspected because of prenatal sonographic findings suggestive of intestinal obstruction, such as a hyperechoic fetal bowel pattern.³¹ A hyperechoic bowel may be a benign variant. If it is benign, it is usually resolved before the third trimester. In pregnancies with evidence of fetal intestinal obstruction, carrier testing for CF gene mutations can be performed. If both parents are carriers for the mutation, CF in the fetus is highly likely. This can be confirmed by means of direct mutation analysis of amniotic fluid cells.
    • Prenatal ultrasonography can also demonstrate meconium peritonitis secondary to small-bowel perforation in utero; however, this is associated with CF in only a minority of patients. The presence of abdominal calcifications suggests causes of meconium peritonitis other than CF. Conversely, the absence of calcifications suggests a diagnosis of CF. Parental CF carrier testing with fetal mutation analysis in at-risk couples is useful in such cases.
• Neonatal³²
  • Meconium ileus may be present. Of patients with CF, 18% present with intestinal obstruction in the immediate postnatal period. The condition is secondary to inspissation of tenacious meconium in the ileum. In these patients, 50% experience complications such as peritonitis, volvulus, atresia, necrosis, perforation, or pseudocyst formation. In full-term neonates with meconium ileus, CF is confirmed in 98%.
  • Meconium plug syndrome can be the presenting manifestation of CF in the neonatal period.
    • Meconium plug syndrome is characterized by transient distal colonic obstruction relieved by the passage of a meconium plug. Meconium plug syndrome is not specific to CF because it can occur either by itself or in association with premature birth, sepsis, infant of diabetic mother and Hirschsprung disease, but its presence raises the possibility of CF.
    • Meconium ileus and meconium plug syndrome should be distinguished from meconium disease or inspissated meconium syndrome seen in infants with low birth weight. Inspissated meconium syndrome is seen in patients several days of age, after the initial passage of meconium. In this condition, meconium plugs are found in the distal ileum and colon; respiratory distress syndrome, unrelated to CF, is commonly present.
  • Jejunal atresia can also be the presenting feature of CF, often in association with volvulus and meconium peritonitis.
  • Liver disease may be present. Neonates with CF may present with prolonged obstructive jaundice resulting from intrahepatic and extrahepatic bile stasis, due to thick bile. Meconium ileus or delayed passage of meconium is associated with 50% of cases. Clinical and laboratory features may mimic biliary atresia. The frequency at which cases progress to liver failure or early cirrhosis is unknown.
  • Pulmonary manifestations may be observed. Although histologic findings are normal at birth, pulmonary changes beginning with obstruction of the peripheral airways from retained secretions may be seen within weeks. Respiratory symptoms may begin during the first month of life, eg, cough, wheezing, tachypnea, and retractions. Other infants may have severe respiratory distress associated with a bronchiolitis-like syndrome.
  • Growth failure may occur. Failure to regain birth weight within 2 weeks or inadequate weight gain at age 4-6 weeks is common in neonates with CF.
• Infancy and childhood
  • Upper respiratory tract: The presence of nasal polyps in a child is an indication for a sweat test. Nasal polyps occur in 10-32% of patients with CF. More than 90% of patients older than age 8 months have recurrent sinusitis that is refractory to antibiotic therapy. Rarely, a patient with CF presents with unilateral proptosis secondary to mucocele of the underlying sinus.
  • Lower respiratory tract: In 50% of patients with CF, the diagnosis is first considered because of pulmonary symptoms. Although the lower respiratory tract is involved almost invariably, manifestations may not appear until months or years after birth. Manifestations of lower respiratory tract involvement include the following:
    • Prolonged/recurrent pneumonia and bronchitis
    • Atelectasis
    • Airway hyperreactivity: One study documented wheezing in 50% of young children with CF and mild pulmonary disease (mean age, 16 mo). Of children with wheezing, 43% were responsive to bronchodilator therapy. However, this response does not always persist with increasing age, and some patients have worsening expiratory airflow in the form of refractory asthma or a deterioration in response to treatment with beta-adrenergic agents. The latter is due to floppy airways secondary to loss of cartilaginous support related to progressive airway damage.
    • Bronchiolitis
    • Bronchiectasis
    • Chronic cough: The clinical picture associated with most of the above conditions is characterized by chronic cough, which can be dry at first. This is often paroxysmal, worse at night, and progressively productive.
    • An increase in sputum production and changes in its color and quality are found. Also noted is the occasional low-grade fever, increased fatigue, shortness of breath, tachypnea, wheezing, and suprasternal or intercostal retractions characterized by periodic flare-ups.
    • Colonization by pathogenic bacteria is a hallmark of the disease. S aureus and H influenzae are pathogens commonly found in early childhood, with an incidence of isolation in respiratory cultures of 38% for S aureus and approximately 16% for H influenzae, although prevalence of the latter may vary in different regions. P aeruginosa is the most prevalent of the pathogens found in patients with CF; ultimately, it is isolated in approximately 60-80% of children, while B cepacia and S maltophilia are isolated with increasing frequency (4%). Aspergillus fumigatus and other fungi are recovered frequently from the respiratory tracts of patients with CF. The significance of this is unclear, but on occasion, allergic bronchopulmonary aspergillosis (ABPA), extensive mucus plugging, or development of a mycetoma in a preexisting bronchiectatic space can be seen.³³ Mycobacterial species are documented in 2-20% of patients, and in some patients, the microorganisms may be pathogenic.
    • Initially, pulmonary function abnormalities include airway obstruction with hyperinflation and gas trapping, which result in an elevated ratio of the residual volume to the total lung capacity. In more advanced disease states, the total lung capacity may decline because interstitial fibrosis and restrictive components are manifested. Hypoxemia occurs, initially during sleep or exercise; this results from an extensive ventilation and perfusion mismatch. The severity of hypoxemia parallels the status of the lung. Hypercapnia occurs as a late event in CF disease progression and generally portends a poor prognosis.
    • Pulmonary abnormalities include the following:
      • Hemoptysis
      • Pneumothorax (This is believed to be the result of rupture of subpleural blebs and is generally seen in more-severe disease.)
      • Clubbing is a universal finding in symptomatic patients older than 4 years. Often, digital clubbing is present early in the course of pulmonary manifestations. The severity appears to be correlated with a degree of pulmonary dysfunction, but this is not universal. Clubbing can also be seen in patients with mild pulmonary disease accompanied by liver disease.
  • Gastrointestinal tract
    • Steatorrhea/pancreatic insufficiency is present from birth in most patients with CF and results in malabsorption of fat and protein. Clinical features include abdominal protuberance; cramping abdominal pain; flatulence; frequent, bulky, oily, malodorous stools; and poor weight gain. Associated rectal prolapse may occur.
    • Acute pancreatitis may be present.
    • Intussusception may be noted.
    • Mucoid impaction of the appendix (asymptomatic right lower quadrant mass) may occur. The diagnosis of CF is occasionally suggested by the histologic appearance of an appendix removed from a patient with acute or recurrent/chronic abdominal pain, which is characterized by an increased number of goblet cells distended with mucus and eosinophilic cast of the crypts extruding into the lumen.
    • Recurrent DIOS or meconium ileus equivalent (MIE) occurs as a result of stools that adhere to the intestinal wall. Clinically, DIOS and MIE are characterized by recurrent cramping abdominal pain, a palpable mass in the right lower quadrant, and signs of complete or partial intestinal obstruction. The prevalence is usually higher during the second or third decades of life. DIOS and MIE are uncommon in patients younger than 5 years, and the prevalence in that age group is approximately 2%. Fibrosing colonopathy is described in young children ( <10 y) but not adults, especially among those treated with high daily doses of pancreatic enzyme supplements. Affected patients may have evidence of obstruction and bloody diarrhea, and biopsy findings include submucosal and lamina propria fibrosis combined with inflammatory changes.
    • Gastroesophageal reflux
  • Focal multilobular biliary cirrhosis of the liver and/or cholestasis may occur. Cholestasis is commonly associated with CF. Approximately 30% of patients have elevation of liver enzymes and alkaline phosphatase levels only. Focal biliary cirrhosis is usually clinically insignificant and can be seen in 25% of patients with CF. However, in a small number of patients, multilobular biliary cirrhosis may develop (5%), and disease in 2% of patients progresses to cirrhosis, portal hypertension, splenomegaly, esophageal varices, and liver failure. Severely malnourished infants may present with a fat liver.
  • Absence of the vas deferens is an incidental finding at the time of orchiopexy or herniography. This may provide the initial clue to the diagnosis of CF in this patient population.
  • Deficiency of vitamins, electrolytes, and protein
    • Bulging fontanel and pseudotumor cerebri result from vitamin A deficiency.
    • Hemolytic anemia results from vitamin E deficiency.
    • Hemorrhagic complications can result from vitamin K deficiency from liver failure or malabsorption.
    • Rickets is seen only rarely, resulting from vitamin D deficiency.
    • Edema and hypoproteinemia usually occur in association with breast milk or soya protein feedings. Associated findings include anemia, hepatomegaly, elevated concentration of liver enzymes, and rash (acrodermatitis enteropathica).
    • Failure to thrive may occur.
    • Hyponatremic/hypochloremic dehydration is secondary to salt depletion from sweat (salty skin).
    • Hypokalemic metabolic alkalosis is secondary to chronic salt loss. Always consider CF in an infant with profound hypoelectrolytemia that is not accounted for by gastrointestinal losses.
• Adolescence and adulthood³⁴
  • Upper and lower respiratory tract
    • Many patients have a history of typical, although somewhat mild, respiratory tract features of CF, with an onset in childhood. This is often associated with a poor growth pattern.
    • In some patients, pulmonary symptoms may first appear after age 13 years and sometimes after the second or third decade of life. In older patients, respiratory symptoms are occasionally absent.
    • Respiratory manifestations usually are similar to those found in children. The severity may progress with time, with the deterioration of bronchiectasis and the development of large cystic airspaces and fibrosis.
    • Hemoptysis occurs in as many as 60% of patients over their lifetime. Hemoptysis, pneumothorax (5-20%), allergic pulmonary aspergillosis, or poorly controlled asthma is more common in adults than in children, whereas the incidences of nasal polyps/sinusitis are similar in adults and children.
    • P aeruginosa and B cepacia are recovered more frequently in adults than children, with rates of 90% and 6%, respectively.
    • Pulmonary hypertension/cor pulmonale developing with advanced pulmonary parenchymal disease is a poor prognostic sign and, in adults, is associated with a mean survival of 8 months.
  • Pancreatic or gastrointestinal involvement³⁵
    • Manifestations are similar to those found in children.
    • The incidences of DIOS are similar in adults and children. However, some reports state that the incidence of DIOS increases with age, with a peak incidence of 27% in patients with CF older than 30 years.
    • Episodes of acute pancreatitis and peptic ulcer disease are more common in adults than children.
    • The incidence of gastrointestinal cancer increases in association with CF, and more cases are anticipated as patients live longer.
    • Cancer of the esophagus, stomach, small intestine, liver or biliary tract, pancreas, and retroperitoneum have been reported.
    • The colon is the most common site of cancer in CF with cancer of the colon accounting for 37.5% of malignancies.
    • Possible carcinogenic factors include abnormal CFTR protein function and an antioxidant deficiency related to malabsorption.
    • Glucose intolerance is observed in 30-60% of patients, with overt diabetes occurring in 10%. Diabetes is more common in adults than children. Unlike usual juvenile onset diabetes mellitus, adolescents with CF rarely exhibit ketoacidosis and ketonuria.
  • Hepatobiliary disease³⁶
    • Cholelithiasis, usually with cholesterol stones, is seen in approximately 10-12% of patients and may result from excessive loss of bile acids in the stool, with consequent reduction of lithogenic bile.
    • Older patients may present with cirrhosis in the absence of pulmonary symptoms. Consider CF in any patient with obscure liver disease.
  • Reproductive system
    • Infertility is a nearly universal feature in males with CF because of congenital bilateral absence of the vas deferens and, less commonly, atresia of the vas deferens resulting in obstructive azoospermia. Approximately 1% of males with CF are fertile, and these individuals usually have very mild disease manifestations. Spermatogenesis is normal in men with CF; however, incidence of abnormal spermatozoa is higher than observed in men without CF. Surgical retrieval of sperm from the epididymis and endocystic reproductive techniques can facilitate biologic fatherhood for a small number of men with CF.
    • The incidence of female infertility may be as high as 20%. It may result both from secondary amenorrhea (resulting from malnutrition or chronic lung disease) and the production of abnormally tenacious cervical mucus. When patients with CF become pregnant, the maternal and fetal outcomes are usually favorable. Before pregnancy, the following findings contribute to a good prognosis: forced expiratory volume in 1 second (FEV₁) exceeds 50-60% of predicted values, an excellent nutritional status, intact pancreatic function, and an older age.³⁷
  • Musculoskeletal disorders
    • Hypertrophic osteoarthropathy (HBOA) is a syndrome characterized by abnormal proliferation of the skin and osseous tissue at the distal parts of the extremities. HBOA occurs in association with radiographically confirmed periosteal formation in newborns. Clubbing and HBOA are different manifestations of the same disease process; however, unlike clubbing, HBOA is less frequent, seen in approximately 5% of patients. HBOA is usually rare in children and appears with increased age and increased disease severity.
    • CF arthropathy occurs in 2-9% of patients and is characterized by short episodes of arthritis. This is occasionally accompanied by painful nodular skin lesions and purpura.
    • Osteoporosis and pathologic fractures may occur. Mineralization of the bones is 20% less common in patients with CF than in age- and sex-matched control subjects. This mineralization results in a higher fracture risk.^38,39

Diagnostic criteria for CF

• One of the following:
  • Two elevated sweat chloride levels (60 mEq/L)
  • Two CF mutations
  • Abnormal transepithelial potential readings

• Plus one of the following:
  • One or more clinical phenotype features (eg, chronic suppurative pulmonary disease and/or pancreatic insufficiency)
  • History of CF in a first-degree relative

Preferred Examination

The diagnosis of CF is based on compatible clinical findings, with biochemical or genetic confirmation. So far, the sweat chloride test is the mainstay of laboratory confirmation. However, CF is a complex syndrome, and the clinical manifestations are sometimes subtle. Also, the family history is not always straightforward. Therefore, a battery of clinical or genetic tests and a high index of suspicion are often required to establish the diagnosis, especially in adolescents and young adults.

Commonly performed tests are described below. Radiologic modalities used to diagnose or follow up thoracic CF invariably include chest radiography and CT of thorax.^40,41,42 CT of sinuses or abdomen is occasionally used, as are nuclear medicine studies, ultrasonography, and angiography.^43,44,45

Laboratory tests⁴⁶

Sweat chloride test

The sweat chloride test remains the criterion standard for the diagnosis of CF. Most diagnostic laboratories in the US screen for 20-30% of the most common mutations, identifying approximately 90% of chromosomes affected in CF. The remaining 10% of affected chromosomes comprise more than 400 different pathologic mutations of CFTR. As a result, more-extensive screening is impractical. A sweat chloride value greater than 60 mEq/L distinguishes CF from other forms of chronic pulmonary disease. However, normal sweat chloride concentrations may be observed in approximately 1% of patients with CF, who have unusual genotypes (ie, 3849+10kb CT or poly T defects).

The test is performed by collecting sweat with pilocarpine iontophoresis on 2 or more occasions and by chemically determining the chloride concentration. Conditions other than CF that are associated with elevated sweat electrolyte concentrations include adrenal insufficiency, anorexia nervosa, celiac disease, malnutrition, hypothyroidism, and congenital metabolic diseases.

The incidence of erroneous sweat test results is probably in the range of 10-15%, and most errors represent false-positive results. Most errors are caused by the use of unreliable methodology, inadequate sweat collection, technical mistakes, and misinterpretation of results; therefore, the test should be performed in a laboratory that regularly uses extreme care with assays. False-negative results can be seen in hypoproteinemic edema and with the concurrent administration of steroids.

Nasal potential-difference measurements

Abnormalities in epithelial chloride secretions can be demonstrated in most patients with CF by evaluating the nasal transepithelial potential difference in the basal state. This test is performed after nasal perfusion with amiloride and after nasal perfusion with a chloride-free solution.

Three features distinguish CF: (1) increased basal potential difference, which reflects enhanced Na⁺ transport across a relatively chloride-impermeable barrier; (2) greater inhibition of potential difference after nasal perfusion with the Na⁺ channel inhibitor amiloride, which reflects inhibition of accelerated Na⁺ transport; and (3) little or no change in potential difference in response to perfusion of the nasal epithelial surface with a chloride-free solution in conjunction with isoproterenol, which reflects an absence of CFTR- mediated chloride secretion.

An increased, ie, more negative, basal nasal potential difference is strong evidence of CF. The presence of nasal polyps or inflamed mucosa may yield a false-negative result. The presence of a large response to chloride-free perfusion is strong evidence against CF. The test should be performed only by experienced CF centers because standardization of the location of measurement is critical.

Immunoreactive trypsin test

Infants with CF have elevated blood levels of immunoreactive trypsin (IRT), which can be quantitated by means of radioimmunoassay or enzyme-linked immunoassay. A negative result is not informative in patients older than 8 weeks. The test may be particularly useful for small or malnourished infants in whom the sweat chloride test cannot be performed successfully. Overall, false-positive and false-negative rates are relatively high.

Stool fecal fat and pancreatic-enzyme secretion tests

Stool fecal fat and pancreatic-enzyme secretion can be measured by collecting duodenal fluids after simulation with secretin and pancreatozymin. Decreased levels of pancreatic enzymes or elevated stool fat are expressed as the percentage of ingested fat in a 72-h stool collection and can be indicative of CF, respectively.

Molecular diagnostic tests

The molecular diagnosis is usually based on a direct mutation analysis.⁴⁷ A variety of techniques are used to identify specific known mutations in the nuclear type sequence of the CFTR gene. A list of testing laboratories is available through the Genetic Testing Resource. These technologies enable clinicians to identify and confirm the diagnosis, especially in patients with an atypical presentation. For example, patients may have borderline or normal sweat chloride concentrations in the presence of several characteristic phenotypic manifestations, or the suspicion may be high in the absence of clinical features. Other circumstances, such as in prenatal screening, may also warrant these tests.⁴⁸

Early diagnosis is important because early aggressive therapeutic intervention is associated with improved nutritional status, decreased morbidity, and decreased deterioration in lung function. However, screening programs have not been adopted widely.

A 5-year randomized study in Wisconsin did not identify any clear health benefits from routine screening.^32,49 Nevertheless, the identification of patients with CF in the newborn period provides a population for studying the mechanism of early lung injury and the effectiveness of no therapeutic delay in preventing the onset of lung damage.

Radiologic tests

Radiography

Chest radiography is not considered an essential technique to use in the diagnosis of CF; however, it may play a strong corroborative role in diagnosis of the disease.⁵⁰ Chest radiography has also been the mainstay in the longitudinal assessment of patients with CF.^51,52

Thoracic CT scanning

High-resolution CT (HRCT) improves spatial resolution, and it may be useful in the evaluation of minimally affected individuals. Multiple studies have shown that CT is more sensitive and specific than chest radiography in demonstrating bronchiectasis and other abnormalities in patients with normal chest radiographic results.⁵³ HRCT can demonstrate bronchiectasis and mucous plugging to the level of the fifth- or sixth-order bronchi. With expiratory imaging, focal areas of air trapping can be identified as an indication of small-airway disease.^{54,55,56,57,58,59}

The sensitivity and specificity of regular CT (with 10-mm sections) for bronchiectasis is 60-80% and 90-100%, respectively. Use of 1.5- to 5-mm resolution improves the sensitivity and specificity to 87% and 90%, respectively.

Santamaria et al addressed the role of HRCT in assessing CF, comparing HRCT scores, chest radiographic findings, pulmonary function test (PFT) results, and clinical scores.⁶⁰ They found that HRCT of the chest is most useful in the identification of early lung abnormalities in patients with CF with mild respiratory symptoms, whereas in established disease, chest radiography is still the first-line imaging technique. In patients with advanced disease, HRCT may be useful in the evaluation of specific lung changes, when more aggressive treatment, such as chest surgical interventions, is indicated.

HRCT of the chest is useful and sensitive in studying responses to therapy in patients with CF lung disease, even in patients younger than 5 years.^61,62,63 The clinical utility and practicality of this technique is unclear, but HRCT could be used to assess the effectiveness of the therapeutic modality, and its results could be a useful outcome surrogate in CF.⁶⁴

Compared with other findings, total reversible HRCT scores are better correlated with PFT results and acute changes in clinical scores during exacerbations of CF. The greatest change is seen in the mucous-plugging subcomponent of the HRCT score and then in the peribronchial thickening.

Serial CT scans allow assessment of the evolution of pulmonary abnormalities in CF patients. Helbich et al suggest that CT seems to have advantages over PFT and clinical scoring in the evaluation of pulmonary changes over time.⁶⁵ Therefore, some have suggested that HRCT scoring may provide a sensitive method of monitoring pulmonary disease status; this could possibly be helpful in follow-up of small children who are too young to cooperate with spirometry. Some studies have also found a correlation of CT findings and scores with serum immunoglobulin levels, but no relationship to genotypes has been observed.

Characteristic CT findings occasionally suggest a specific diagnosis, which may not have been under clinical consideration in the differential diagnosis of CF. The pattern and distribution of abnormalities revealed by HRCT in patients with bronchiectasis are influenced by the underlying cause. For example, bilateral bronchiectasis predominantly in upper lobe is most common in patients with CF and ABPA, unilateral upper-lobe predominance is seen in patients with tuberculosis, and lower-lobe predominance is seen in patients after a childhood viral infection.⁶⁶

Adult CF and ABPA involve disease that is more extensive than idiopathic bronchiectasis, independent of other CT features (5 or 6 lobes involved). Central bronchiectasis is more commonly reported with ABPA, although the sensitivity of this finding as a diagnostic feature is only 37%. In syndromes with impaired mucociliary clearance, a lower-lobe involvement is more predominant, and bronchiectasis in hypogammaglobulinemia is characterized by less dilatation of the bronchial lumen compared with that seen in idiopathic bronchiectasis.

CT of the thorax can also greatly facilitate the diagnosis and management of pneumothorax in patients with complex cystic disease.

Magnetic resonance imaging

The role of MRI in the evaluation of patients with CF is still being defined, and the use of MRI remains limited.⁶⁷

Ultrasonography

Abdominal ultrasonography is commonly used to diagnose the complications of CF and its pancreatic and hepatobiliary manifestations.

Nuclear medicine study

The usefulness and role of lung scintigraphy in CF remain limited. Hepatobiliary scans may have a role in evaluating hepatobiliary disease in neonates and children.⁶⁸

Decreased bone density is common among patients with CF; this finding usually reflects a lack of control of the illness, and it often remains unfound with the usual investigations. If possible, dual x-ray absorptiometry should be part of the investigations in these patients.^69,70

Angiography

Bronchial arteriography is the preferred diagnostic and therapeutic examination in patients with CF and significant hemoptysis.⁷¹

Limitations of Techniques

Chest radiography

Chest radiographic findings are not specific or diagnostic because they overlap with other disorders, particularly those characterized by inflammatory or destructive changes of the airways. Early in the course of disease, chest radiographs may be normal, or they may show minor manifestations such as mild hyperinflation and minimal bronchial thickening.

Normal chest radiographic findings may be seen in infancy and even in older children with mild pulmonary involvement, though this is uncommon. The usefulness of a chest radiograph during an exacerbation of CF in adult patients is also debated. Some study results support the lack of a precise correlation between the radiographic picture and the clinical manifestations of exacerbation, with a reported sensitivity and specificity of 56% and 78%, respectively. Chest radiograph is predominantly used to exclude pneumothorax or airspace disease such as pneumonia or atelectasis.

Regardless of the radiologic findings, CF is less commonly considered in the adult patient, because of the traditional belief that CF is a childhood disease. Amorosa et al reviewed radiographs in pediatric and adult cases that showed disease of similar extent and severity.⁷ They found that radiologists made the correct diagnosis in 40% of the pediatric cases, compared with 14% in the adult cases.

Chest CT

Despite the capabilities of HRCT, clear guidelines for its use in the care of children with CF are still lacking. The advantage of detecting early changes on CT images awaits additional confirmation. Whether the early introduction of therapeutic interventions significantly affects the final outcome of the disease is yet to be demonstrated.

HRCT does not provide sufficient additional information to justify the additional cost and radiation exposure in routine follow up. With the advent of new therapies and with gene treatment raising the possibility of a cure, the need for a detailed evaluation of the lungs is great, and outcome measures for the new interventions and HRCT scanning should be considered. The value of HRCT in following up patients with CF is not yet clarified.

With regard to its value as a diagnostic tool, CT findings are of limited value in discriminating between bronchiectasis of CF and other causes in individual patients. However, differences in the distribution and morphology of bronchiectasis may be seen on CT scans in groups of patients with bronchiectasis due to different causes. Generally, the causes of bronchiectasis cannot be reliably identified on the basis of CT appearances alone.

Magnetic resonance imaging

In the depiction of bronchial wall thickening, bronchial dilatation, and mucous plugging, the resolution of MRI does not compare favorably with that of CT. MRI is a developing technology that does not involve ionizing radiation. With further refinement, it may prove to be useful in imaging the lung pathology in CF.

Nuclear medicine study

The usefulness of lung scintigraphy is limited. The main problem is the correct clinical use of a test with such a high sensitivity and a high percentage of false-positive results.

Angiography

Although hemoptysis is correlated with bronchial artery hypertrophy and a bronchopulmonary anastomosis within the bronchial walls, the role of prophylactic angiography for further interventions has not been studied. Angiography is invasive and usually performed in the setting of acute significant hemoptysis.

Differential Diagnoses

Bronchiectasis
Meconium Ileus
Meconium Plug Syndrome
Pancreatitis, Chronic

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