Pediatrics

Cystic fibrosis

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OVERVIEW: What every practitioner needs to know

Are you sure your patient has cystic fibrosis? What are the typical findings for this disease?

Patients with cystic fibrosis can be asymptomatic at diagnosis if diagnosed through newborn screening or secondary to a positive family history.

In symptomatic diagnosis, they can have a single or multisystem presentation including (1) chronic sinopulmonary disease, (2) gastrointestinal and nutritional abnormalities (3) salt loss syndromes and (4) genital abnormalities.

Additional details on typical findings in cystic fibrosis

Chronic sinopulmonary symptoms can include chronic cough or sputum production and persistent radiographic abnormalities such as the following:

Bronchiectasis

Atelectasis

Infiltrates

Nasal polyps

Pansinusitis on computed tomography (CT) or plain radiography

Airway obstruction with air trapping/ hyperinflation

Hemoptysis

Pneumothorax

Airway culture positive for CF-specific bacteria such as Pseudomonas aeruginosaorBurkholderia cepacia

Gastrointestinal findings may occur in one or more organs. The intestines can be involved with the following:

Meconium ileus

Rectal prolapse

Chronic constipation

Distal intestinal obstructive syndrome

Intussusception

Pancreatic abnormalities lead to steatorrhea manifested by frequent bulky, foul smelling, greasy stools; failure to thrive; or recurrent pancreatitis. Prolonged neonatal jaundice, biliary cirrhosis, and hepatic steatosis are manifestations of liver involvement. Untreated nutritional abnormalities lead to failure to thrive and linear growth stunting.

Salt loss syndromes include both hyponatremic hypochloremic dehydration from acute salt depletion and chronic metabolic alkalosis.

Genital abnormalities that can be a presenting sign of CF include congenital bilateral absence of the vas deferens, leading to obstructive azoospermia.

What other disease/condition shares some of these symptoms?

There are many respiratory and gastrointestinal illnesses that can have similar presenting signs, including the following:

Asthma

Primary ciliary dyskinesia

Immunodeficiency

Recurrent viral infections

Aspiration disorders and gastroesophageal reflux

Celiac disease

Shwachman-Diamond syndrome

Irritable bowel syndrome

Pancreatitis due to alternative causes (anatomic abnormalities, drug side effects, alcohol abuse)

What caused this disease to develop at this time?

Cystic fibrosis is a genetic disease and is present at conception. Clinical symptoms appear at various ages. In the United States and many other countries, infants undergo newborn screening for cystic fibrosis and are diagnosed shortly after birth, usually before the onset of symptoms. In 2012, 61% of US patients were diagnosed by newborn screening. Clinical signs and symptoms lead to diagnosis in the remainder of patients, most of whom were born before newborn screening was implemented in their states of birth. However, newborn screening may miss up to 5% of cases.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Diagnosis is made based on one or more characteristic clinical features, a history of cystic fibrosis in a sibling orpositive newborn screen test plus laboratory evidence of abnormality in the cystic fibrosis transmembrane conductance regulator (CFTR) gene/protein. Sweat testing indicates the latter and is the gold standard for the diagnosis of cystic fibrosis.

Newborn screening for cystic fibrosis

If the newborn screen produces positive results, sweat testing is needed for diagnosis. Newborn screening identifies patients at risk of cystic fibrosis and is not a diagnostic test. The test is based on immunoreactive trypsinogen (IRT). This is a pancreatic enzyme that is three to five times higher in infants with cystic fibrosis than in other infants. It is important to note that IRT levels are elevated in both pancreatic-sufficient and pancreatic-insufficient patients.

There are several methods to perform newborn screens in the United States; the IRT/IRT method and the IRT/DNA method are the most common. IRT/IRT methods check IRT levels on a blood spot in the newborn period and, if elevated, will check again at 2 weeks of life. The IRT/DNA methods measure IRT levels from blood spot in the newborn period and, if elevated, check DNA forCFTR mutations from same blood spot. The number of mutations analyzed varies by location. Both IRT/IRT and IRT/DNA are 90%-95% sensitive. Thus, a negative newborn screen does not exclude a CF diagnosis.

Sweat tests for cystic fibrosis

Sweat tests are acceptable if done by the quantitative pilocarpine iontopheresis method. This procedure involves a small quantity of pilocarpine to be driven into the sweat glands of the skin through a low-voltage electrical current (iontophoresis). The sweat is collected in a coil or on gauze or filter paper and is analyzed for chloride content. Sweat tests should be performed at a Cystic Fibrosis Foundation accredited center and quality control should be ensured, with less than 10% of tests in newborns and less than 5% in older children having a "quantity not sufficient" result.

Timing of testing is as early as 48 hours of life in symptomatic patients; however, in asymptomatic patients with a positive newborn screening result, it is recommended that the sweat test be performed once the patient weighs more than 2 kg and is older than 14 days and greater than 39 weeks' gestation. This reduces the risk of obtaining a "quantity not sufficient" result.

For all groups, a positive test is a result of greater than 60 mmol/L of chloride. In infants younger than 6 months of age, an intermediate test result is within the range of 30-60 mmol/L of chloride, with a negative test result defined as less than 30 mmol/L of chloride. In patients older than 6 months of age, intermediate test results are 40-60 mmol/L of chloride and negative test results are less than 40 mmol/L of chloride.

False-positive sweat tests can be caused by the following:

Atopic dermatitis (eczema)

Malnutrition

Congenital adrenal hyperplasia

Mauriac syndrome

Fucosidosis

Ectodermal dysplasia

Klinefelter syndrome

Nephrogenic diabetes insipidus

Adrenal insufficiency

Hypothyroidism

Environmental deprivation

Munchausen syndrome by proxy

Causes of false-negative sweat tests include the following:

Dilution of sample

Malnutrition

Peripheral edema

Low sweat rate, which is reported as "quantity not sufficient"

Hypoproteinemia

Dehydration

Mutations with reserved sweat duct function

Genetics of cystic fibrosis

More than 1800 mutations in theCFTR gene have been reported; however, the functional significance of many remains unknown. Delta F508 is most common mutation, with one copy present in up to 50% of patients and two copies in up to 90%.

There are multiple methods of assessing mutations. Specific mutation probes assess for a limited number of mutations that are most clinically relevant. Full gene sequencing analyzes the entire gene for mutations and is thus more comprehensive, allowing for assessment of the majority of existing mutations and the ability to discover novel mutations. Full gene sequencing might also find polymorphisms or mutations of unknown or unclear significance. Deletion and duplication analysis looks for large deletions or duplications in theCFTR gene that can be missed on gene sequencing and can identify the genetic defect in patients diagnosed with cystic fibrosis in whom neither mutation is found by otherCFTR testing methods.

Would imaging studies be helpful? If so, which ones?

Early pulmonary disease can be seen radiograpically before it appears on pulmonary function tests. Early lung disease can affect any lobe and is not evenly distributed throughout the lungs.

A chest radiograph is the most commonly used imaging study. In a cohort of patients diagnosed through newborn screening, 50% showed evidence of irreversible abnormality on chest radiography by age 2 years, whereas airway obstruction on pulmonary function testing was not evident in 50% of the patients until the age of 15 years. In the same study, 85% of the patients had irreversible lung disease on the chest radiograph by 5 years of age.

CT of the chest is extremely effective at providing the most information on changes in lung disease in patients with cystic fibrosis; however, routine testing is not recommended because of concern for radiation exposure. Scans show evidence of bronchiectasis, peribronchial wall thickening, mucous plugging, and parenchymal opacities, and may also show air trapping, mosaicism, nodules, and sacculations.

Sinus evaluation through either sinus radiographs or CT will show evidence of pansinusitis and possibly nasal polyps. Virtually all patients with cystic fibrosis have abnormalities on sinus studies, which are performed only in patients with specific sinopulmonary symptoms.

Confirming the diagnosis

The diagnosis of cystic fibrosis in newborns through older adults, Cystic Fibrosis Foundation Consensus Report algorithm is an excellent evidence-based guideline for the diagnosis of cystic fibrosis (Figure 1).

Figure 1.

Diagnosis of cystic fibrosis in newborns through older adults. Cystic Fibrosis Foundation Consensus Report.

If you are able to confirm that the patient has cystic fibrosis, what treatment should be initiated?

First and foremost, consult a cystic fibrosis specialist at a Cystic Fibrosis Foundation accredited center.

Nutritional management of cystic fibrosis

One of the first things to determine is if the patient is pancreatic-sufficient or -insufficient, which can be assessed with a fecal pancreatic elastase test. While awaiting the results, pancreatic enzyme replacement therapy should be initiated unless the patient has identifiedCFTR mutations reliably associated with pancreatic sufficiency. There is a benefit of improving absorption and facilitating optimal growth that outweighs minimal risk of side effects, especially in infants with known pancreatic-insufficientCFTR gene mutations.

Next, the patient should be given salt replacement therapy to compensate for loss through the sweat glands. In general, from birth to 6 months of age, infants need 1/8 teaspoon daily, whereas those older than 6 months of age require 1/4 teaspoon daily. Older children and adults require liberal salt intake by eating salty foods and using a salt shaker.

Patients are encouraged to eat a high-calorie, high-protein, well-balanced diet, as they require 120%-200% of the recommended daily allowance of calories to achieve the goal of normal growth. Liberal fat intake is the easiest way to achieve increased calories in the diet.

Patients also require fat-soluble vitamin therapy with vitamins A, D, E, and K. There are commercially available prescription medications specifically formulated for cystic fibrosis that provide these vitamins.

Patients should be monitored very closely for growth through frequent assessment of height, weight, and weight for height (infants <2 years old) or body mass index (BMI). The goal is normal growth. Higher weight for age and body mass index percentiles are associated with better long-term outcomes in cystic fibrosis; the US national goal is that patients achieve a BMI greater than or equal to the 50th percentile by 2 years of age and thereafter.

Respiratory management of cystic fibrosis

Airway clearance should be initiated in order to facilitate clearance of pulmonary secretions. This can be done with manual chest physical therapy in infants and toddlers and additional devices in older children. Albuterol is given before airway clearance beginning in infancy. This modality should be prescribed at least once daily.

A chest radiograph should be obtained by 6 months of age and at least every 2-4 years for ongoing evaluation.

Respiratory culture for cystic fibrosis–specific pathogens should be performed at least four times per year, but are often obtained at every visit. Oropharyngeal swabs are used for patients who are unable to expectorate sputum.

Additional therapies to facilitate mucociliary clearance and reduce infectious burden are often prescribed in infants but have a stronger evidence base in older children. These include dornase alfa, hypertonic saline, inhaled antibiotics, macrolides, and ibuprofen; specific guidelines for use have been published. Dornase alfa cleaves DNA in respiratory mucus to help thin secretions. Hypertonic saline helps hydrate the airway and induce cough. Inhaled antibiotics help treat bacterial infections. Macrolides have been shown to possibly decrease inflammation, whereas ibuprofen does decrease inflammation. See Table I.

Table 1.

Mutation directed therapy for cystic fibrosis

A novel medication, ivacaftor, treats the basic defect and has been approved by the FDA for using in patients with specific mutations (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R). In clinical trials, ivacaftor was shown to decrease sweat chloride tests to less than 60 mmol/L, improved lung function and weight.

Additional medications directed at the basic defect are in clinical trials. For the most common mutation, deltaF508, combination of another novel drug, lumacaftor and ivacaftor improved sweat chloride and FEV1 in CF patients homozygous for deltaF508. Additional trials are ongoing.

For patients who have a stop mutation, ataluren has shown some promising effect. In those patients enrolled in the study who were not on inhaled tobramycin, there was an increase in FEV1 and fewer pulmonary exacerbations. Further studies are planned.

Additional management of cystic fibrosis

Genetic counseling is important to help family understand the genetic mechanisms of cystic fibrosis and the risk in future pregnancies. It is also important to support family in understanding this life-altering illness.

What about longer term treatment?

There are numerous current and evolving treatments for cystic fibrosis over the long term. Patients are best served by being treated in coordination with a Cystic Fibrosis Foundation accredited center where they can be treated with the most efficacious therapies to support their long-term health.

What are the adverse effects associated with each treatment option?

Patients initially started on pancreatic enzyme replacement therapy will have changes in their bowel habits. They may experience some mild constipation that can be treated with mild laxatives. A rare disorder called fibrosing colonopathy is associated with very high doses of pancreatic enzymes.

Symptomatic patients generally have decreased cough after initiating airway clearance; however, some of the inhaled medications lead to transient increases in cough (generally immediately after administration) and voice alterations (such as hoarse voice).

What are the possible outcomes of cystic fibrosis?

The median age of survival iin 2012 was 41.1 years and has steadily increased. A model in the United Kingdom predicts that a child born today with cystic fibrosis will typically live to 50 years of age. Death is most commonly secondary to respiratory insufficiency. Patients with significant pulmonary morbidity may consider lung transplantation. Cystic fibrosis is currently the main indication for lung transplantation, with about 60% of all transplants going to patients with cystic fibrosis; however, only about 70 transplantations per year in the United States are in children. Survival after transplantation at 1, 4, and 10 years is 83%, 50%, and 40% respectively.

What causes this disease and how frequent is it?

Cystic fibrosis is an autosomal recessive genetic illness caused by mutations in the cystic fibrosis transmembrane regulatory (CFTR) conductance gene. It is found in approximately 1/3000 newborns, although frequency is variable depending on the racial and ethnic background of the patient. Cystic fibrosis affects approximately 1/3000 non-Hispanic white Americans, 1/4-10,000 Hispanic Americans, and 1/15-20,000 African Americans.

What is known about the genetics?

Cystic fibrosis is caused by a mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulatory protein (CFTR) found on chromosome 7. Inheritance is autosomal recessive with more than 1800 mutations reported. The most common mutation is F508del, which is more common in non-Hispanic whites than in racial and ethnic minorities.

How do these pathogens/genes/exposures cause the disease?

TheCFTR gene codes for a chloride channel in the apical membrane of the cell. A functioning gene allows the chloride channel to transport chloride across the cell membrane. The chloride helps to attract water to the cell surface. This creates a normal airway surface liquid volume, facilitating optimal mucus clearance. A nonfunctioning gene does not allow chloride to exit the cell, thus decreasing the hydrating airway surface liquid. The result leads to a dehydrated, sticky, thick airway surface that prevents adequate mucociliary clearance. A nonfunctioning gene in other organs (liver, reproductive organs, pancreas) leads to accumulation of thick mucus that block ducts, preventing normal function of these organs.

Different classes of mutations in cystic fibrosis

There are six classes of mutations that lead to cystic fibrosis. Class I mutations lead to the absence of synthesis of the chloride channel protein. Class II mutations result in premature degradation of the mature chloride channel protein. The most common mutation, F508del, which causes protein misfolding, is in this class. Class III mutations cause abnormal regulation (or gating) of the chloride channel protein. Class IV mutations result in structural defects in the chloride channel, reducing conductance. Class V mutations lead to a reduced number of chloride channel transcripts secondary to promoter or splicing abnormality. Class VI mutations lead to accelerated turnover of the chloride channel from the cell surface.

What complications might you expect from the disease or treatment of the disease?

Pulmonary complications include hemoptysis, pneumothorax, and respiratory failure; other relatively common complications are liver disease, cystic fibrosis–related diabetes, failure to thrive, and distal intestinal obstruction syndrome. Treatment is multifaceted and each individual treatment has potential side effects. Partnership with a cystic fibrosis specialist will facilitate prevention or early and prompt recognition and treatment of complications of the disease or its treatment.

Cystic fibrosis–related diabetes

Cystic fibrosis–related diabetes most commonly begins in teenage or adult years, with an incidence of 3% per year; about 20% of adolescents and 40%-50% of adults having cystic fibrosis–related diabetes. Screening is performed by annual random glucose determinations at all ages; after 10 years of age, annual oral glucose tolerance testing is added. Treatment is with insulin. A high-calorie, liberal-fat diet should be continued.

Cystic fibrosis liver disease

The prevalence of cystic fibrosis–related liver disease is 13-17% of patients, with no significant increase in prevalence after mid-adolescence. No more than about one third of patients will have clinically significant disease. Testing for screening consists of annual serum liver enzyme determinations (aspartate aminotransferase/gamma glutamyl transpeptidase). The most common liver diseases are focal or multilobular biliary cirrhosis, cholelithiasis, and microgallbladder. Portal hypertension precedes liver synthetic dysfunction. Treatment varies from medical to surgical options, including liver transplantation.

Pulmonary complications: pneumothorax and hemoptysis

Pneumothorax occurs with an annual incidence of less than 1%; however, 3.4% of patients will experience it during their lifetime. If small and clinically stable, the pneumothorax can be monitored on an outpatient basis. If large or clinically unstable, recommended treatment includes admission, insertion of chest tube, continuation of nebulized medication, and modification of airway clearance modalities to not include positive pressure. Surgical pleurodesis is recommended if pneumothorax is recurrent. Postpneumothorax precautions include no air flight, no lifting weights greater than 5 pounds and no spirometry for 2 weeks after resolution.

Massive hemoptysis occurs with an annual incidence of less than 1%; however, up to 4% of patients will have it in a lifetime. If the patient has scant hemoptysis (<5 mL or "streaks"), there is no need for additional interventions, although it may be a sign of exacerbation, and antibiotic therapy may be administered.

If the patient has more than mild hemoptysis (>5 mL), the following are recommended: initiate antibiotics (since the most common cause is infection) and stop nonsteroidal antiinflammatory drugs.

If the patient has massive hemoptysis (>240 mL in a 24-hour period), the following recommendations should be followed: admit to hospital, withhold positive airway pressure if clinically feasible, withhold airway clearance therapies, withhold hypertonic saline (but not other nebulized therapies) and perform bronchial artery embolization. Bronchoscopy is not necessary.

Are additional laboratory studies available; even some that are not widely available?

Nasal potential difference is a diagnostic test that evaluates the difference in charge on the respiratory epithelium in the inferior turbinate of the nose. In cystic fibrosis, the nasal potential difference will show a high potential difference at baseline and a low voltage response to zero chloride solution and isoproterenol. The test is available through specialized research centers.

How can cystic fibrosis be prevented?

Cystic fibrosis is a genetic illness. Prenatal screening for mutations will help to inform families of their risk for having a child with cystic fibrosis. Screening prenatally is limited in that the screens primarily look at the most common genetic mutations that account for the majority of disease. There are mutations that are missed because of low frequency in the general population. If prospective parents are both carriers of mutations for cystic fibrosis, they can also undergo preimplantation screening through in vitro fertilization.

What is the evidence?

Davies, JC, Wainwright, CE, Canny, GJ. "Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation". Am J Respir Crit Care Med. vol. 187. 2013. pp. 1219-25.

(This article exemplifies the strong clinical benefit of ivacaftor in children aged 6 to 11 years of age, demonstrating decline in sweat chloride levels, improvement in lung function and weight.)

Boyle, MP, Bell, MB, Konstan, MW. "A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial". Lancet Respir Med. vol. 2. 2014. pp. 527-38.

(Demonstrates the benefit of lumacaftor combined with ivacaftor in patients homozygous for deltaF508 through improved sweat chloride and FEV1.)

De Boeck, KM, Wilschanski, N, Castellani, C. "Cystic fibrosis: terminology and diagnostic algorithms". Thorax. vol. 61. 2006. pp. 627-35.

(This is an article that discusses the heterogeneity of the clinical manifestations of cystic fibrosis, further defining typical and atypical cystic fibrosis. Diagnostic terminology and algorithms for the diagnosis cystic fibrosis are outlined as defined by the European Diagnostic Working Group. Also discusses genetic and nasal potential difference testing for diagnosis.)

Farrell, PM, Rosenstein, BJ, White, TB. "Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report". J Pediatr. vol. 153. 2008. pp. S4-S14.

(This article discusses the guidelines from the Cystic Fibrosis Foundation for diagnosis in the United States, covering newborn screening to adult diagnosis. Also includes a diagnostic algorithim for patients who had newborn screening. Discusses specifics for newborn screening, sweat testing, genetics, and ancillary test for diagnosis.)

Flume, PA, Mogayzel, PJ, Robinson, KA. "Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax ". Am J Respir Crit Care Med. vol. 182. 2010. pp. 298-306.

(A review of the pulmonary complications of cystic fibrosis, providing guidelines for the care of both pneumothorax and hemoptysis as put forth by the Cystic Fibrosis Foundation. Recommendations for care are based on consensus using the Delphi method.)

Flume, PA, O' Sullivan, BP, Robinson, KA. "Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health". Am J Respir Crit Care Med. vol. 176. 2007. pp. 957-69.

(A review of the evidence and guidelines for use of chronic medications for maintenance of lung health as put forth by the Cystic Fibrosis Foundation. There is strong research evidence for the majority of chronic medications discussed in this guideline.)

Herrmann, U, Dockter, G, Lammert, F. "Cystic fibrosis-associated liver disease ". Best Pract Res Clin Gastroenterol. vol. 24. 2010. pp. 585-92.

(A review of the liver disease complications due to cystic fibrosis. Covers topics from the pathophysiologic features to the diagnosis and clinical course and therapy for liver complications of cystic fibrosis.)

Kerem, E, Konstan, MW, De Boeck, K. "Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial". Lancet Respir Med. vol. 2. 2014. pp. 539-47.

(Demonstrates the effect of ataluren on patients who have a stop mutation as the cause of their cystic fibrosis.)

Kleyn, M, Korzeniewski, S, Grigorescu, V. "Predictors of insufficient sweat production during confirmatory testing for cystic fibrosis". Pediatr Pulmonol. vol. 46. 2011. pp. 23-30.

(An article that discusses the predictive characteristics of patients who have insufficient sweat production during sweat testing. The study was a review of newborn screening cases in the state of Michigan.)

Moran, A, Becker, D, Casella, SJ. "Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review". Diabetes Care. vol. 33. 2010. pp. 2677-83.

(A technical review published by the cystic fibrosis–related diabetes consensus conference committee. Discusses the epidemiology, pathophysiology and prognostic implications in cystic fibrosis–related diabetes.)

O'Sullivan, BP, Freedman, SD. "Cystic fibrosis". Lancet. vol. 373. 2009. pp. 1891-904.

(Excellent review article of cystic fibrosis covering aspects from the genetic basis of disease, pathogenesis, clinical manifestations, treatments, and new horizons in therapy.)

Oermann, CM, Retsch-Boagart, CZ, Quittner, AL. "An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis". Pediatr Pulmonol. vol. 45. 2010. pp. 1121-34.

(Evidence for use of inhaled aztreonam in patients with evidence of airway infection with Pseudomonas aeruginosa.)

Ramsey, BW, Davies, J, McElvaney, NG, Tullis, E, Bell, SC, Drevinek, P. "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation". N Engl J Med. vol. 365. 2011. pp. 1663-72.

(Evidence for use of ivacaftor, demonstrating improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.)

Robinson, TE. "Imaging of the chest in cystic fibrosis". Clin Chest Med. vol. 28. 2007. pp. 405-21.

(Review of chest imaging modalities used to assess cystic fibrosis lung disease. It discusses chest radiography and CT. CT is the research modality most commonly used to assess lung disease in cystic fibrosis. The article also discusses new insights regarding imaging of cystic fibrosis lung disease and future directions in research and clinical care.)

Rowe, SM, Miller, S, Sorscher, EJ. "Cystic fibrosis". N Engl J Med. vol. 352. 2005. pp. 1992-2001.

(Excellent review of cystic fibrosis discussing the historical background, structure and function of the chloride channel, and underlying abnormalities leading to disease in cystic fibrosis.)

Saiman, L, Anstead, M, Mayer-Hamblett, N. "Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial". JAMA. vol. 303. 2010. pp. 1707-15.

(Evidence for use of azithromycin in children and adolescents with cystic fibrosis uninfected with Pseudomonas aeruginosa.)

Solomon, M, Grasemann, H, Keshavjee, S. "Pediatric lung transplantation". Pediatr Clin North Am. vol. 57. 2010. pp. 375-91.

(This article describes the current status of pediatric lung transplantation, indications for listing, evaluation of recipient and donor, updates on the operative procedure, graft dysfunction, and the risk factors, outcomes, and future directions.)

Sweet, SC. "Pediatric lung transplantation". Proc Am Thorac Soc. vol. 6. 2009. pp. 122-7.

(This is a review discussing pediatric lung transplantation in children. Discusses indications, allocation, surgical procedure and complications, management challenges, and outcomes.)

Ongoing controversies regarding etiology, diagnosis, treatment

There are cases of patients with an unclear diagnosis of cystic fibrosis, for example, two mutations with a normal sweat test, borderline sweat tests, with variable symptoms, and so on. Asymptomatic cases are classified as “cystic fibrosis metabolic syndrome” and symptomatic cases are considered CFTR-related disorders. This new designation is currently in its infancy and the clinical outcomes are still being elucidated.

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