Cystic Fibrosis

Description

Other Names

CF
Cystic fibrosis of the pancreas
Mucoviscidosis

Diagnosis Coding

ICD-10

E84.0, Cystic fibrosis with pulmonary manifestations

E84.1, Cystic fibrosis with intestinal manifestations

E84.11, Meconium ileus in cystic fibrosis

E84.19, Cystic fibrosis with other intestinal manifestations

E84.8, Cystic fibrosis with other manifestations

E84.9, Cystic fibrosis, unspecified

ICD-10 for Cystic Fibrosis (icd10data.com) provides further coding details.

Description

Cystic fibrosis (CF) occurs when a patient carries 2 deleterious mutations for CF transmembrane conductance regulator (CFTR) function in the epithelia of various organs. CFTR mutations cause impaired chloride ion channel function resulting in abnormal secretions in sweat glands, the lungs, liver, pancreas, sinuses, digestive system, and reproductive system. The accumulation of thick, sticky secretions leads to organ-specific dysfunction. In the lungs, this results in poor mucocilliary clearance, which greatly increases the risk of infection. In addition, most individuals with CF have exocrine pancreatic insufficiency that leads to poor absorption of fat-soluble vitamins, protein, and fat, which results in malnutrition.

Dramatic improvements in outcomes for individuals with CF have been accomplished in the past couple of decades as evidence-based care has driven quality improvement in Cystic Fibrosis Care Centers. Because this care is very complex and specialized, medical home clinicians should collaborate with a CF Center for every patient with CF.

Prevalence

CF is the most common life-threatening autosomal recessive disease in the United States. It occurs in approximately 1:3,500 newborns. [Sontag: 2005] [Parad: 2003] [Comeau: 2004] However, incidence varies widely by race and ethnicity – a study of newly diagnosed cases in the US from 1990-1992, using the CF Foundation Registry, calculated incidences of 1:3,200 in whites, 1:9,200 in Hispanics, 1:10,900 in Native Americans, 1:15,000 in African Americans, and 1:31,000 in Asians. [Hamosh: 1998] Population prevalence of CF in the US has steadily increased over the past few decades as care and survival have improved; estimated prevalence in 2016 was 1:10,964. [Marshall: 2017]

Genetics

CF is inherited in an autosomal recessive fashion. More than 1,500 known mutations of the CFTR gene on chromosome 7 can cause CF; at least 70-90% of children with CF have the F508del mutation. Although this mutation is generally associated with severe disease when patients are homozygous for this mutation, the severity of lung disease is difficult to predict because of other variables (modifier genes, epigenetic factors, and environmental variables). [Dawson: 2001] [Gallati: 2003]

Classification of severe mutations is based on whether pancreatic insufficiency is associated with them. When an individual has a severe and mild mutation, the pancreatic phenotype is generally mild. Children with 2 severe mutations generally have malabsorption as newborns and into early childhood. One mild mutation in conjunction with a severe mutation may allow sufficient pancreatic function and no enzyme supplementation is required. [Mickle: 2000] Rarely, individuals with disease causing CFTR gene mutations may be asymptomatic. Many mutations in the CFTR gene have not been confirmed to be disease causing and may represent genetic variations. For more information, see Clinical & Functional Translation of CFTR for Clinicians.

Prognosis

Treatment reduces health complications and survival into middle adulthood is common (in 2017, expected median survival was 47 years). Pulmonary complications, including those secondary to transplantation, and liver disease cause the majority of CF-related deaths. If CF is not treated, patients may experience malnutrition and poor growth, fat-soluble vitamin deficiency, electrolyte depletion, pulmonary damage or bronchiectasis, diabetes; liver disease, and death in childhood. Outcomes following lung transplantation for end-stage lung disease in CF have improved but vary with existing co-morbidities, including presence of B cepacian and CF-related arthropathy. Median survival from lung transplantation is 8.3 years and 10.5 years for those who survive the first year. [Morrell: 2016]

Roles Of The Medical Home

Accredited CF Care Centers (CF Foundation) have improved outcomes for children with CF dramatically through their efforts in measurement-driven quality improvement. The medical home should refer patients to and collaborate with such centers, as well as provide routine well-child care, assuring that immunizations are current, including the 23-valent pneumococcal vaccine and annual influenza vaccines, and acute care.

The medical home can provide ongoing education about:
  • Signs, symptoms, and the need for urgent care when the child becomes ill
  • Harmful effects of second-hand smoke and other airborne irritants, such as dust
  • Importance of hand washing to prevent infections
  • Need for a high-salt, high-fat, high-calorie diet (aiming for 150%-180% of the recommended dietary allowances) and extra fluids.
The clinician may also collaborate with the CF Care Center or CF experts to manage prescriptions for pancreatic enzymes, bronchodilators, mucus thinners, antibiotics, and other medications. The medical home should also help to support families in finding and accessing community services and supports, advocating for insurance funding when necessary, and managing the numerous challenges associated with school, healthy (or not so healthy) siblings, recreation, and friends.

Practice Guidelines

Several published guidelines on various components of CF care are listed below. Additional guidelines can be found at Cystic Fibrosis Clinical Care Guidelines (CFF).
  • Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. [Farrell: 2017]
  • Evidence-based guidelines for management of infants with cystic fibrosis. [Borowitz: 2009]
  • Clinical practice guidelines for preschoolers with cystic fibrosis. [Lahiri: 2016]
  • Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. [Mogayzel: 2013]
  • Cystic fibrosis pulmonary guidelines: airway clearance therapies. [Flume: 2009]
  • Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. [Flume: 2009]
  • Management of cystic fibrosis-related diabetes in children and adolescents. [Moran: 2014]

Helpful Articles

PubMed search for cystic fibrosis in children, last 1 year

Sermet-Gaudelus I, Mayell SJ, Southern KW.
Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
J Cyst Fibros. 2010;9(5):323-9. PubMed abstract / Full Text

Schram CA.
Atypical cystic fibrosis: identification in the primary care setting.
Can Fam Physician. 2012;58(12):1341-5, e699-704. PubMed abstract / Full Text

Pittman JE, Ferkol TW.
The Evolution of Cystic Fibrosis Care.
Chest. 2015;148(2):533-542. PubMed abstract / Full Text

Morris PJ.
Physical activity recommendations for children and adolescents with chronic disease.
Curr Sports Med Rep. 2008;7(6):353-8. PubMed abstract

Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H.
Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.
J Am Diet Assoc. 2008;108(5):832-9. PubMed abstract

Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B.
Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
Diabetes Care. 2010;33(12):2697-708. PubMed abstract / Full Text

Clinical Assessment

Overview

Since cystic fibrosis (CF) is now included in routine newborn screening (see Cystic Fibrosis), the majority of affected infants will be identified in the first few weeks of life. However, since no screening system is perfect, medical home clinicians should explore CF as a possibility for infants and children presenting with suspicious findings. Ongoing assessment at well-child and acute-care visits will augment those performed at the collaborating CF Care Center and may provide early awareness of concerning complications or exacerbations.

Pearls & Alerts

Risk of diabetes

Diabetes occurs in about 10% of adolescents with CF. Beginning at age 10, children should be tested annually with an oral glucose tolerance test to monitor for impaired glucose tolerance and CF-related diabetes; hemoglobin A1C testing is not recommended as a primary screening tool.

Small bowel obstruction

Small bowel obstruction should be suspected anytime an individual with CF presents with abdominal pain. CF patients with history of meconium ileus at birth are at higher risk of distal intestinal obstruction syndrome (DIOS) and should be promptly evaluated for abdominal pain and constipation. Delay in management of DIOS can lead to perforation and gut necrosis.

Screening

For The Condition

All states screen newborns for CF, but some use 1 screen IRT/DNA) and others use 2 screens (IRT/IRT or IRT/IRT/DNA). All positive screens should be followed by sweat chloride testing, which is the gold standard for diagnosis. The Portal’s Cystic Fibrosis has more details about immediate follow-up after a positive newborn screen.

Of Family Members

Each full sibling of an affected individual with CF has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Screening for carriers in families with CF allows carriers to understand their chances of having a child with CF, make informed decisions in family planning, and better plan for the birth of their child.

Couples who are sure they would not terminate a pregnancy no matter the diagnosis and they do not want to take the risks associated with prenatal diagnosis should be counseled about the extreme importance of completing the screening panel once the baby is born.

For Complications

Routine screening with spirometry, chest X-ray, chest CT, oropharyngeal/respiratory cultures, and annual blood work is recommended, but it should be performed by a CF Care Center to assure best specimen collection and most reliable test performance and interpretation. The CF Foundation recommends that all patients 12 years and older receive annual screening for depression and anxiety; see Screening & Treating Depression & Anxiety Guidelines (CF Foundation).

About 25% of individuals with CF develop diabetes by the age of 20. Annual screening for diabetes with OGTT should begin by approximately age 10 years. [Moran: 2010]

Presentations

Children with mild disease or atypical mutations may occasionally be missed by newborn screening, which has only been in place since January 2010. Primary care clinicians should suspect CF when the following are observed:
  • Meconium ileus (present in 15-20% of newborns diagnosed with CF)
  • Salty sweat or sweat crystals on the skin
  • Poor weight gain
  • Smelly, greasy, bulky, and bright green stools (even in breastfed infants)
  • Diarrhea, constipation, or persistent abdominal pain
  • Rectal prolapse
  • Persistent coughing or wheezing
  • Thick phlegm and mucus
  • Recurrent lung and sinus infections
  • Nasal polyps
  • Infertility or congenital bilateral absence of the vas deferens in males
The most common complaints that lead to diagnosis are persistent respiratory infections, failure to thrive, and meconium ileus. However, many patients demonstrate mild or atypical symptoms, and clinicians should remain alert to the possibility of CF even when only a few features are present, including chronic diarrhea, failure to thrive, or infertility.

Diagnostic Criteria

Sweat chloride testing is necessary to demonstrate CFTR dysfunction even if 2 disease-causing mutations have been identified. Genetic testing may be helpful in some cases where sweat chloride testing is indeterminate. The following recommendations are from [Farrell: 2017] where more detail is available.

In individuals with a normal newborn screen who present with symptoms of CF, with or without positive family history, sweat chloride testing is the first step:
  • If the result is ≤29 mmol/L, CF is unlikely but repeat testing should be considered if clinical suspicion persists.
  • If the result is between 30 and 59 mmol/L, CF is possible and further testing (repeat sweat test, CFTR gene analysis and/or CFTR functional analysis) are indicated and should be performed by an accredited CF center.
  • If the result is ≥60 mmol/L, CF is diagnosed.
Individuals with clinical findings suggestive of CFTR dysfunction (obstructive azoospermia, bronchiectasis, or acute, recurrent, or chronic pancreatitis) but who have fewer than 2 CF-causing mutations may be diagnosed with a CFTR-related disorder, depending on their clinical picture or family history, and are at risk for CF. Repeat sweat testing and extensive evaluation may be indicated.

Significant clinical signs/symptoms of CF, laboratory indication of pancreatic insufficiency, or a positive culture for a CF-associated pathogen (especially P. aeruginosa), is strongly suggestive of CF. Individuals who have sweat chloride values in the intermediate range (30-59 mmol/L) and exhibit no significant signs of CF should be monitored periodically in an accredited CF center for the appearance of symptoms.

Clinical Classification

CF can be classified by the genetic mutation, but clinical outcomes can vary widely within genetic groupings. General clinical classification includes:
  • Cystic fibrosis: Two disease--causing mutations and an abnormal sweat chloride test result
  • CFTR-related disease: More than 1 mutation of which at least 1 is disease causing and an intermediate sweat chloride test result. Patients can’t be detected through the newborn screen for this diagnosis.
  • CFTR-Related Metabolic Syndrome (CRMS) or Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID): Asymptomatic infants with positive newborn screening results and either
    • Intermediate sweat chloride results (at least twice) and less than 2 CF-causing mutations
    • Normal sweat chloride results and 2 CFTR mutations, at least 1 of which is known to be CF-causing

Differential Diagnosis

The differential diagnosis for CF depends on whether lung or pancreatic symptoms are the focus. Lung problems that may be confused with CF, but would not be accompanied by a positive sweat chloride test, include:
  • Cough due to airway abnormalities
  • Reactive airway disease
  • Primary ciliary dyskinesia
  • Indolent infections, such as tuberculosis or those associated with HIV infection
  • Immunologic disorders
  • Gastroesophageal Reflux Disease/aspiration
Pancreatic problems may be due to:
  • Disease caused by mutations in genes other than those encoding for CFTR
  • Biliary atresia
  • Congenital abnormalities
  • Shwachman Diamond syndrome

Comorbid Conditions

Pancreatic insufficiency: Most CF patients have pancreatic insufficiency and if undertreated or untreated poor fat absorption by 1 year of age may manifest with frequent, bulky, foul-smelling stools, poor weight gain, and failure to thrive.

CF-related diabetes: Insulin deficiency is due to the thick mucus buildup in the pancreas. About 25% of individuals with CF develop insulin-dependent diabetes by the age of 20, and the incidence continues to increase in adulthood.

Liver disease: CF-related liver disease is diagnosed when 2 of the following 3 are present:
  1. Elevated liver enzymes (AST, ALT, and GGT)
  2. Abnormal liver imaging on ultrasound
  3. Hepatosplenomegaly on physical exam

Meconium ileus and distal ileal obstruction: Almost all full-term infants with meconium ileus have CF. Small bowel obstruction can occur in children and adults. This should be suspected anytime an individual with CF presents with abdominal pain or worsening constipation with decreased oral intake.

Anemia: Individuals with CF are at risk for anemia, which is present in about 10 percent of children and is more common with advancing age and declining pulmonary function.

Gastrointestinal disease: The GI system is greatly affected with CF. Common findings are malnutrition, malabsorption, constipation/diarrhea, reflux, and cirrhosis.

Osteoporosis: This problem occurs due to poor absorption of vitamin D, decreased physical activity, steroid treatments, and delayed puberty (causing decreased sex hormone production). [Sparks: 2009] [Sermet-Gaudelus: 2009]

Depression and anxiety: Depression and anxiety are common in patients with CF (19% and 32% respectively) and their parents. [Quittner: 2014]

History & Examination

Family History

Family history of CF can guide important discussions about expectations, course, care, support from other family members, and more.

Pregnancy Or Perinatal History

History is not likely relevant unless the family is worried about CF because of family history or genetic testing.

Current And Past Medical History

Pulmonary infections, diarrhea, greasy, foul-smelling stools, and wheezing are relatively common findings in children, but may not be present in infants. Ask about these symptoms and treatment protocol.

Developmental And Educational Progress

Ask about frequency of school absences due to illness, and ask about concerns related to meeting growth and developmental milestones. Ask if families have a 504 plan or IED for medical accommodations. Ask if there is a history of vitamin deficiencies that may have had cognitive impacts.

Maturational Progress

Assess pubertal progress and understanding of sexuality, as with all maturing patients. Though male fertility is low, education about sexuality and avoiding pregnancy and sexually transmitted infections is important. Addressing transition to adult care should begin no later than age 14; pediatric CF Care Centers generally transition patients to adult care by 18-21 years of age.

Social And Family Functioning

Ask about the family's emotional and financial supports, such as how they are managing the manifestations of CF and the financial and insurance impacts of clinic visits and medications. Be aware that families often experience a grief process with a child’s chronic illness. Additionally, parents of children with CF report rates of depression and anxiety that are 2-3 times higher than the general population. This may impact the care the child receives.

Physical Exam

Vital Signs

RR | SpO2: Elevation of respiratory rate and lower pulse oximetry than usual may be the only signs of pulmonary infection in some children.

Growth Parameters

Ht | Wt | BMI: Infants with CF may have poor weight gain. Weight gain and BMI are frequently affected, but height may not be affected initially.

Skin

Assess for pale skin and other signs of dehydration.

HEENT

Sinusitis and nasal polys are common. The incidence of polyps increases with age. Assess oral mucous membranes for pallor, inflammation.

Mouth/Teeth

Assess mucus membranes for pallor, inflammation.

Chest

Chest findings with crackles and/or consolidation, as well as chronic complications such as bronchiectasis with coarser rales and rhonchi, generally reflect current infection.

Abdomen

Careful examination and measurement of the liver and spleen by palpation and percussion should be performed at each clinic visit. A panel of liver blood tests should be obtained annually. Mobile masses may suggest constipation. Rectal prolapse is very rare in CF since the implementation of pancreatic enzymes and decreased rates of constipation, although it is still possible.

Extremities/Musculoskeletal

Clubbing of fingers and toes reflects chronic hypoxia associated with pulmonary complications. Patients with CF also have decreased bone density and exhibit a higher rate of fractures than the general population (not usually seen in the pediatric age group).

Testing

Laboratory Testing

Sweat testing, reflective of chloride channel function in sweat glands, is the gold standard for diagnosis of CF. The minimum age for sweat chloride testing is 48 hours of age. Because reliable sweat testing requires expertise, it should only be performed in laboratories that have considerable ongoing experience and quality control (see Accredited CF Care Centers (CF Foundation)).

After the diagnosis is confirmed, the patient should be evaluated in a CF Center where additional testing may be performed to establish the extent of the disease, including CBC, comprehensive metabolic profile, fat-soluble vitamin concentrations (A, D, and E), fecal elastase, pulmonary function testing (over age 3), CXR, and sputum culture.

Sputum cultures should be performed a minimum of 4 times a year in all individuals with CF to monitor respiratory flora and guide treatment of pulmonary infection. More frequent testing may be needed.

At age 10, children are tested annually with an oral glucose tolerance test to monitor for impaired glucose tolerance and CF-related diabetes.

Stool analysis may be indicated periodically.

Imaging

Dexa scans to measure bone mineral density may be ordered in adolescents since individuals with CF have a high risk of osteoporosis. Liver function testing may show elevated transaminases due to hepatobiliary disease, which, in a minority of individuals (approximately 5%) may progress to focal biliary cirrhosis with portal hypertension and ultimately require liver transplantation. Additional testing may include CXR and lung CT.

Genetic Testing

Children who are positive for CF by sweat testing should have genetic testing to identify specific mutations, which may help confirm the diagnosis and inform the extended family about risk of CF in subsequent pregnancies. [Farrell: 2017]

Maternal carrier genetic testing is offered to women of childbearing age. This testing may not be covered by insurance. See  Carrier Screening for Cystic Fibrosis (ACOG) for more information. Preimplantation genetic diagnosis (PGD) followed by implantation of unaffected embryos offers carrier parents the option to avoid having an offspring with CF.

Other Testing

Bone densitometry to monitor for osteoporosis will often be performed in adolescents, in individuals of any age with malnutrition and low vitamin D levels, and in those who have sustained fractures.

Transepithelial nasal potential difference testing is used to diagnose indeterminate cases in some individuals. It is available in few CF Centers and is generally used in children over 6 years of age. [Schüler: 2004]

Prenatal testing is available if there is a known family history of CF. DNA testing of samples obtained by amniocentesis or chorionic villus sampling should target known family mutations. Most routine screens look for 30+ mutations, whereas >1,500 known mutations have been identified. Comprehensive prenatal testing, which requires sequencing or sequence analysis of the whole CFTR gene and evaluation for duplications and deletions, is not routinely offered to patients unless there is a clinical indication.

Spirometry or pulmonary function testing is recommended quarterly for children 6 years of age and older, preferably by a CF Care Center. Children as young as 3-4 years of age might be able to perform acceptable spirometry. Patients with coexisting autism, developmental delay, or cerebral palsy might not be able to perform spirometry.

Subspecialist Collaborations & Other Resources

Newborn Screening Programs (see Services below for relevant providers)

Depending on the state, the primary care provider may need to work with the newborn screening program to arrange diagnostic testing.

Cystic Fibrosis Clinics (see Services below for relevant providers)

If available, all children with CF should receive care from an accredited CF Center. Collaboration between CF Centers and primary care clinicians can improve the care and outcomes for patients and their families.

Pediatric Pulmonology (see Services below for relevant providers)

Once a CF diagnosis is confirmed, the initiation of treatment at a CF Center should start within 24-48 hours. Early treatment, nutritional interventions, and prevention of lung damage is key to survival.

Treatment & Management

Overview

Patients between 0-6 months are seen monthly in Cystic Fibrosis (CF) Centers. Patients between 6-12 months are seen every other month in CF Centers. Patients >1 year of age are seen quarterly in CF Centers. These centers have a specialized, comprehensive interdisciplinary medical team to address the multiple needs of the patient. CF Centers use pulmonary function tests, sputum cultures, and blood tests at each visit to monitor patients’ health and treat problems early. Patient survival rates have significantly improved since the implementation of CF Centers.

Pearls & Alerts

Encourage exercise

Exercise is a great form of lung clearance and should be encouraged.

Dehydration risk

Dehydration occurs easily in individuals with CF due to salt losses through perspiration. Extra salt intake is necessary. Avoid dehydrating circumstances.

Hand hygiene

Hand hygiene is critical to the prevention of respiratory and enteric infections.

Prevent RSV infections

Infants with CF are particularly prone to serious RSV infections. Consider immunization with the anti-RSV monoclonal antibody (Synagis) if Red Book (AAP) criteria are met.

Provide flu vaccine

Prevent influenza with yearly vaccines for the individual with CF and the family. Also, mention that they should receive all other routine vaccinations.

Cross contamination

Patients with CF are at high risk for sharing infections with each other, and the consequences can be very serious. Two non-sibling children with CF should not be placed in the same classroom at school. When in the same location, they should always maintain a distance of at least 6 feet. Siblings who have CF are allowed to be in the same room/house, but do not perform airway clearance treatments in the same room. Patients with CF should also maintain 6 feet distance from any person with tracheostomy. Patients with cystic fibrosis are discouraged from using hot tubs, jacuzzis, and hot springs due to the risk of inhaling Pseudomonas.

Increased thrombophilic tendency in pediatric cystic fibrosis

CF appears to be a risk factor for recurrent venous thrombosis, in part due to frequent use of central venous catheters (CVC). In a review of 120 children and young adults with acute venous thromboembolism, recurrent thrombosis occurred in 19. [Raffini: 2006] [Williams: 2010]

How should common problems be managed differently in children with Cystic Fibrosis?

Growth Or Weight Gain

Children with CF have better outcomes when they have higher BMIs (above the 50th percentile), and high-calorie foods are encouraged. Pancreatic enzyme supplementation is also crucial for nutrient absorption. Calories may need to be supplemented with enteral tube feedings overnight. It is important to work closely with a CF nutrition specialist and address quickly any drop in BMI.

Development (cognitive, motor, language, social-emotional)

Developmental milestones should be assessed carefully in patients with CF. Children may be behind due to vitamin deficiencies, chronic illness, hospitalizations, missed school, anxiety, depression, or other psychosocial issues. If so, refer to supportive therapies as soon as possible.

Viral Infections

Collaboration with the CF Center is extremely important when a CF patient has a pulmonary exacerbation during episodes of viral and bacterial infections. Treatment is determined by past medication use and sputum or throat culture results. It is important to assess and treat symptoms of cough, sputum change, or weight loss early. Waiting to treat exacerbations can lead to hospitalization and permanent lung damage. It is recommended that patients increase the frequency of their airway clearance during an exacerbation and continue with all chronic medications.

Over The Counter Medications

It is important to ask about all medications or supplements being used, due to the possibility of interactions. Use of cough syrups are discouraged, and the use of guaifenesin (in Mucinex and others) is pointless in the face of the much more effective mucolytics used in treating CF.

Prescription Medications

Given the myriad and increasing numbers of medications used in CF, there is substantial potential for adverse interactions, particularly with medications that affect metabolism by cytochrome P-450 enzymes – see [Jordan: 2016] and [Nichols: 2015] for reviews. CFTR modulators, especially lumacaftor/ivacaftor, interact with numerous medications, including azole antifungals, rifampin, oral contraceptives, seizure medications, oral steroids, and proton pump inhibitors (see Drug Interactions with Lumacaftor/Ivacaftor (Vertex) for detailed information). CF-specific vitamins (calcium, zinc, and iron) interact with Cipro/levofloxacin; the latter should be taken at least 2 hours after/before the vitamins and dairy products.

Systems

Respiratory

The goals of respiratory treatment are to slow the development of lung damage and improve breathing by reducing infection and decreasing lung mucus. A variety of therapies, such as anti-inflammatory agents, bronchodilators, dornase alfa, and inhaled 7% hypertonic saline, may be useful. Antibiotics, delivered by oral, IV, or inhaled routes are used to both prevent and treat infection. A combination of postural drainage and percussion, deep breathing exercises, and other respiratory techniques are also used. The overall treatment plan, particularly for bacterial and fungal pathogens, is likely best directed by CF-Center specialists.

Frequent or severe sinus infections may require treatment with medications or surgery. Lung or heart/lung transplantation may be indicated for individuals with severe advanced lung disease.

Respiratory Care Guidelines (CFF) provides clinical care guidelines for airway clearance and lung transplants and recommendations for treatment of pulmonary exacerbation and complications such as pneumothorax and hemoptysis.

Subspecialist Collaborations & Other Resources

Cystic Fibrosis Clinics (see Services below for relevant providers)

Improved outcomes occur when care of children with CF are directed by CF Centers in collaboration with the primary care clinician.

Pediatric Pulmonology (see Services below for relevant providers)

Optimally, this care will be available through a CF Center; if not, refer for ongoing management of children with CF.

Gastro-Intestinal & Bowel Function

Treatment for pancreatic insufficiency involves replacing digestive enzymes, monitoring growth and nutrition, and preventing intestinal blockage. Proprietary digestive enzyme formulations currently available include Creon, Zenpep, Pancreaze, and Pertzye. Even with digestive enzymes, malabsorption may remain a problem. In children who have a BMI less than the 50th percentile, additional therapies may include specialized elemental formulas and tube feedings.

All individuals with CF require high-caloric dietary intake and fat-soluble vitamin supplementation. Individuals with symptoms of biliary obstruction, including elevation of hepatic enzymes, may require further evaluation for evidence of focal biliary cirrhosis. Monitoring of hepatic function in these individuals includes annual liver and spleen ultrasounds with Doppler flow studies.

Subspecialist Collaborations & Other Resources

Pediatric Gastroenterology (see Services below for relevant providers)

Referral may be helpful in individuals with malabsorption, distal intestinal obstruction syndrome, focal biliary cirrhosis, and growth failure.

Nutrition/Growth/Bone

Nutrition is extremely important in children with CF. A nutritionist should be involved at diagnosis and with ongoing management. If not managed carefully by an experienced nutritionist, children may not receive enough calories and may exhibit deficiencies in growth and vitamins A, D, E, and K. Vitamin E deficiency may exhibit as anemia and neurocognitive delay. Virtually all children with CF need to be on a high-calorie, high-fat diet, and they may also need nutritional drinks, tube feeding supplementation, and vitamin supplementation. Appetite stimulants are occasionally used as well. See Calcium and Vitamin D and Power Packing.

In some children, despite receiving adequate nutrition, growth may still be suboptimal and an endocrinologist might decide that growth hormone is helpful. [Culhane: 2013] Growth hormone may increase glucose intolerance and emergence of CF-related diabetes must be carefully monitored for while on this therapy.

Nutrition and GI Care (CFF) provides guidelines for nutrition in infants and children, enteral tube feeding, vitamin D screening and supplementation, pancreatic enzyme replacement therapy, and use of antioxidant supplementation.

Subspecialist Collaborations & Other Resources

Nutrition Assessment Services (see Services below for relevant providers)

Nutritional management should begin with diagnosis. Children with a BMI under the 50th percentile require nutritional supplementation. A BMI lower than 50% is associated with poorer outcomes. A dietitian can help ensure intake of calories and nutrients. Optimally, this care will be available through a CF Center.

Endocrine/Metabolism

Approximately 10% of individuals will develop diabetes in adolescence; this proportion increases through adulthood. Screening for diabetes should begin around 10 years of age. Presentation could include worsening lung function or weight loss. Patients with CF-related diabetes will require insulin therapy and dietary therapy can be challenging because of the need to not restrict calories. Close follow up with endocrinology is required. Optimized control of blood glucose levels will positively impact lung health. [Moran: 2010]. For a summary of care from [Moran: 2010], see Cystic Fibrosis-Related Diabetes Clinical Care Guidelines (CF Foundation).

Subspecialist Collaborations & Other Resources

Pediatric Endocrinology (see Services below for relevant providers)

Co-management of diabetes with an endocrinologist is recommended for children with CF.

Pharmacy & Medications

Children with CF will use multiple medications that generally fall into the categories that follow. Clinical pharmacists, who may be available for consultation through a children’s hospital, are very helpful in managing these medications and avoiding interactions among them.

CFTR Function Restoration
Historically, CF treatments addressed the downstream consequences of chloride channel malfunction (infection, mucus impaction, etc.). Medications that directly target the cystic fibrosis transmembrane conductance regulator (also known as the chloride channel) are now available. Ivacafotr (Kalydeco) was FDA approved in 2012, Ivacaftor/Lumacaftor (Orkambi) was FDA approved in 2015, and Ivacaftor/Tezacaftor (Symdeko) was FDA approved in 2018. These medications, collectively CFTR modulators, only should be initiated by CF Centers as they are mutation-specific and require interval testing. Potential for drug-drug interactions is high – see Drug Interactions with Lumacaftor/Ivacaftor (Vertex) for detailed information.

Mucociliary Clearance
Mucus in the CF lung is known to be sticky and thick. Dornase alfa (Pulmozyme) is a mucolytic drug that breaks down the extracellular DNA making mucus thinner, looser, and easier to expectorate. Hypertonic saline (Pulmosal and HyperSal) are hyperosmolar sodium chloride solutions that function as mucolytics by drawing water into the lumen of the airway and also by triggering cough.

Anti-Inflammatory
Chronic azithromycin is used in small doses primarily in patients who are chronically colonized with Pseudomonas aeruginosa as an anti-inflammatory agent. High-dose ibuprofen is used in selected centers, but its use is limited nationally due to lack of specialized laboratories and expertise.

Anti-Infective
Multiple inhaled/nebulized antibiotics for Pseudomonas aeruginosa are available (tobramycin: Kitabis Pak, Bethkis, Tobi Podhaler, aztreonam: Cayston). Recently inhaled amikacin became available for use in patients with non-tuberculous mycobacterium. Inhaled vancomycin is currently being developed for use in patients who are chronically colonized with methicillin-resistant Staphylococcus aureus.

Maturation/Sexual/Reproductive

Puberty can be delayed in individuals with CF, and yearly physical exams in adolescents should include Tanner staging. Delayed puberty is defined as no signs of secondary sexual characteristics by 13 years in girls and 14 years in boys. Although delays were thought to be due to malnutrition, this problem can persist despite good nutritional management. Sex hormone replacement therapy is prescribed, as necessary, to achieve secondary sexual characteristics.

The majority of males with CF are infertile due to azoospermia caused by absence or atrophy of Wolffian duct structures. In some genetic variants of CF, men have congenital absence of the vas deferens but lack other manifestations of CF. The majority of males with CF are infertile due to azoospermia caused by absence or atrophy of Wolffian duct structures. In some genetic variants of CF, men have congenital absence of the vas deferens but lack other manifestations of CF. Women with CF are able to become pregnant, although they may be less fertile than the general population. Pregnancy carries increased risks for complications, but women generally do well if they have good nutritional and pulmonary status before and during the pregnancy. [Cheng: 2006] [Gilljam: 2000] Carrier screening can be offered.

Subspecialist Collaborations & Other Resources

Pediatric Endocrinology (see Services below for relevant providers)

Consider referral for CF-related diabetes, delayed puberty, bone disease, or height and weight deficiency.

Mental Health/Behavior

Living with CF is difficult for the patient and their family. The medical home clinician should be alert to psychosocial issues during all encounters with the family. Since direct contact among individuals with CF poses risk for acquisition of potentially life-threatening infections, it limits opportunities to interact with peers who share their experiences and challenges. Otherwise, individuals with CF are encouraged to participate in normal childhood activities. Depression and anxiety are relatively common among children with CF (citations) and their parents. Refer for family support (Cystic Fibrosis Foundation) and counseling as needed for mental health or behavior issues as they arise.

Subspecialist Collaborations & Other Resources

Psychologist, Child-18 (PhD, PsyD) (see Services below for relevant providers)

Refer as needed, preferably to a provider familiar with pediatric chronic illnesses, for mental health/behavior issues.

Mental Health Counselor (LPC, LCPC, CMHC) (see Services below for relevant providers)

Refer as needed for family support and functioning.

Social Workers (see Services below for relevant providers)

Refer as needed for advocacy, family support, and transitions.

Complementary & Alternative Medicine

Although many patients with CF use alternative medicine modalities, they may infrequently discuss this with their physicians. Commonly used are probiotics, air purifiers, humidifiers, and omega-3 fatty acids; less commonly used are body-mind medicine and manipulations. [Tanase: 2008] [Giangioppo: 2016] Herbal products present particular concerns because of the potential for adverse interactions with the myriad medications used to treat CF – see Use of Herbal Products in Cystic Fibrosis (CFF) (PDF Document) for guidance in use and warnings for avoidance of alternative medicines.

Questions from Clinicians

How often should an individual with CF be seen by their primary care provider? How often by the CF specialty clinic?

Patients should be seen by their primary care clinician at the same frequency as any other patient and may require more visits when sick. Collaboration with the CF Center can optimize care at both sites. Recommended minimum frequency of visits to the CF Center, per CF Foundation guidelines:

  • 0-6 months: monthly
  • 7-12 months: every other month
  • 1 year-end of life: every 3 months

Can a patient with a normal newborn screen have cystic fibrosis?

Yes, the newborn screen is just a screen, and it will be miss cases. When symptoms are suggestive of CF, please obtain sweat chloride testing at a CF-accredited lab; do not obtain genetic testing because multiple testing panels exist and it is usually done by the CF center if sweat test is intermediate or positive (> 30 mmol/L).

What medications should be used for common bacterial infections (e.g., acute otitis media) in children with CF?

Discussion of medications and dosages with the CF Center should be helpful. Choice of medication is often based on relevant recent culture results; higher dosages and longer durations are generally employed.

Issues Related to Cystic Fibrosis

Funding & Access to Care

Writing Letters of Medical Necessity

Resources

Information for Clinicians

Cystic Fibrosis (Medical Home Portal)
Information about immediate clinical follow-up after a positive newborn screen.

Cystic Fibrosis (OMIM)
Extensive review of literature that provides technical information on genetic disorders; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Respiratory Care Guidelines (CFF)
Clinical care guidelines for airway clearance, lung transplants, and pulmonary exacerbation such as pneumothorax and hemoptysis; Cystic Fibrosis Foundation.

Nutrition and GI Care (CFF)
Clinical guidelines related to nutrition in infants and children, enteral tube feeding, vitamin D screening and supplementation, pancreatic enzyme replacement therapy, and use of antioxidant supplementation; Cystic Fibrosis Foundation.

Clinical & Functional Translation of CFTR for Clinicians
Information about specific and combined mutations. Also contains data about the sweat chloride, lung function, pancreatic status, and pseudomonas infection rates in patients in the CFTR2 database, which includes data for more than 88,000 patients from 41 countries; Cystic Fibrosis Foundation, Johns Hopkins University, The Hospital for Sick Children.

Helpful Articles

PubMed search for cystic fibrosis in children, last 1 year

Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B.
Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
Diabetes Care. 2010;33(12):2697-708. PubMed abstract / Full Text

Morris PJ.
Physical activity recommendations for children and adolescents with chronic disease.
Curr Sports Med Rep. 2008;7(6):353-8. PubMed abstract

Pittman JE, Ferkol TW.
The Evolution of Cystic Fibrosis Care.
Chest. 2015;148(2):533-542. PubMed abstract / Full Text

Schram CA.
Atypical cystic fibrosis: identification in the primary care setting.
Can Fam Physician. 2012;58(12):1341-5, e699-704. PubMed abstract / Full Text

Sermet-Gaudelus I, Mayell SJ, Southern KW.
Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
J Cyst Fibros. 2010;9(5):323-9. PubMed abstract / Full Text

Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H.
Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.
J Am Diet Assoc. 2008;108(5):832-9. PubMed abstract

Clinical Tools

Care/Action Plans

Cystic Fibrosis Clinical Care Guidelines (CFF)
Access to numerous guidelines for the care of individuals with CF; Cystic Fibrosis Foundation.

Medication Guides

Drug Interactions with Lumacaftor/Ivacaftor (Vertex)
An online search tool to find possible interactions with lumacaftor/ivacaftor (ORKAMBI) and other medications, as well as a downloadable PDF drug-drug interaction guide; from the manufacturer of ORKAMBI.

Use of Herbal Products in Cystic Fibrosis (CFF) (PDF Document)
Uses and risks of herbal preparations in those with cystic fibrosis; Cystic Fibrosis Foundation (2010).

Patient Education & Instructions

Life with Cystic Fibrosis (CFF)
Numerous pages of information about caring for a child with CF, treatments, and the transition to adult care; Cystic Fibrosis Foundation.

Anxiety and Cystic Fibrosis (CFF)
Information about symptoms, getting help, and treatment for those with anxiety and CF; Cystic Fibrosis Foundation.

Depression and Cystic Fibrosis (CFF)
Information about symptoms, getting help, and treatment for those with depression and CF; Cystic Fibrosis Foundation.

Airway Clearance (CFF)
Many articles about the aspects of lung care, including high-frequency chest wall oscillation (the Vest), chest physical therapy, fitness, and more; Cystic Fibrosis Foundation.

Huff Coughing (CFF)
Information for patients and families about the "Huff Coughing Technique" for moving mucus from the lungs; Cystic Fibrosis Foundation.

Information & Support for Families

Family Diagnosis Page

Information on the Web

Cystic Fibrosis Foundation
A nonprofit organization that offers extensive support services (local chapters) and information about testing, treatments, insurance options, pharmacy services, and much more.

What Is Cystic Fibrosis? (NHLBI, NIH)
Information about the causes, prevalence, signs and symptoms, diagnostic tests, and treatments for CF; National Heart Lung and Blood Institute and National Institutes of Health.

Cystic Fibrosis (Intermountain Healthcare)
A resource list for parents with links to many nutritious recipes and discussions about CF-related issues such as sweat testing, school, learning, and the respiratory and digestive systems.

CFTR: The Gene Associated with Cystic Fibrosis (NHGRI)
Condition-specific information focused on the future of genomics research and genomic medicine; National Human Genome Research Institute.

CFTR Gene (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

National & Local Support

CF Foundation Compass (CFF)
A personalized service to help patients and families with CF with the insurance, financial, legal, and other issues they are facing; through the Cystic Fibrosis Foundation.

Utah/Idaho Chapter, CF Foundation
Offers opportunities for volunteers, events, accessing resources, and connecting with chapter members.

Services for Patients & Families in Idaho

Select services for a different state: MT, NM, NV, RI, UT

Cystic Fibrosis Clinics

See all Cystic Fibrosis Clinics services providers (2) in our database.

Mental Health Counselor (LPC, LCPC, CMHC)

See all Mental Health Counselor (LPC, LCPC, CMHC) services providers (283) in our database.

Newborn Screening Programs

See all Newborn Screening Programs services providers (22) in our database.

Nutrition Assessment Services

See all Nutrition Assessment Services services providers (104) in our database.

Pediatric Endocrinology

See all Pediatric Endocrinology services providers (1) in our database.

Pediatric Gastroenterology

See all Pediatric Gastroenterology services providers (2) in our database.

Pediatric Pulmonology

See all Pediatric Pulmonology services providers (1) in our database.

Psychologist, Child-18 (PhD, PsyD)

See all Psychologist, Child-18 (PhD, PsyD) services providers (7) in our database.

Social Workers

See all Social Workers services providers (1) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors & Reviewers

Initial Publication: January 2014; Last Update: December 2018
Current Authors and Reviewers (click on name for bio):
Author: Fadi Asfour, MD, MBBS
Contributing Author: Camille Walker, MSN, CPNP
Authoring history
(Limited detail is available on authoring dates before 2014.)
2014: first version: Barbara Chatfield, MDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Borowitz D, Robinson KA, Rosenfeld M, Davis SD, Sabadosa KA, Spear SL, Michel SH, Parad RB, White TB, Farrell PM, Marshall BC, Accurso FJ.
Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
J Pediatr. 2009;155(6 Suppl):S73-93. PubMed abstract

Cheng EY, Goss CH, McKone EF, Galic V, Debley CK, Tonelli MR, Aitken ML.
Aggressive prenatal care results in successful fetal outcomes in CF women.
J Cyst Fibros. 2006;5(2):85-91. PubMed abstract

Comeau AM, Parad RB, Dorkin HL, Dovey M, Gerstle R, Haver K, Lapey A, O'Sullivan BP, Waltz DA, Zwerdling RG, Eaton RB.
Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections.
Pediatrics. 2004;113(6):1573-81. PubMed abstract

Culhane S, George C, Pearo B, Spoede E.
Malnutrition in cystic fibrosis: a review.
Nutr Clin Pract. 2013;28(6):676-83. PubMed abstract

Dawson KP, Frossard PM, Al-Awar B.
Disease severity associated with cystic fibrosis mutations deltaF508 and S549R(T-->G).
East Mediterr Health J. 2001;7(6):975-80. PubMed abstract

Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, Howenstine M, McColley SA, Rock M, Rosenfeld M, Sermet-Gaudelus I, Southern KW, Marshall BC, Sosnay PR.
Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation.
J Pediatr. 2017;181S:S4-S15.e1. PubMed abstract

Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC.
Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.
Am J Respir Crit Care Med. 2009;180(9):802-8. PubMed abstract / Full Text

Flume PA, Robinson KA, O'Sullivan BP, Finder JD, Vender RL, Willey-Courand DB, White TB, Marshall BC.
Cystic fibrosis pulmonary guidelines: airway clearance therapies.
Respir Care. 2009;54(4):522-37. PubMed abstract / Full Text

Gallati S.
Genetics of cystic fibrosis.
Semin Respir Crit Care Med. 2003;24(6):629-38. PubMed abstract

Giangioppo S, Kalaci O, Radhakrishnan A, Fleischer E, Itterman J, Lyttle B, Price A, Radhakrishnan D.
Complementary and alternative medicine use in children with cystic fibrosis.
Complement Ther Clin Pract. 2016;25:68-74. PubMed abstract

Gilljam M, Antoniou M, Shin J, Dupuis A, Corey M, Tullis DE.
Pregnancy in cystic fibrosis. Fetal and maternal outcome.
Chest. 2000;118(1):85-91. PubMed abstract

Hamosh A, FitzSimmons SC, Macek M Jr, Knowles MR, Rosenstein BJ, Cutting GR.
Comparison of the clinical manifestations of cystic fibrosis in black and white patients.
J Pediatr. 1998;132(2):255-9. PubMed abstract

Jordan CL, Noah TL, Henry MM.
Therapeutic challenges posed by critical drug-drug interactions in cystic fibrosis.
Pediatr Pulmonol. 2016;51(S44):S61-S70. PubMed abstract

Lahiri T, Hempstead SE, Brady C, Cannon CL, Clark K, Condren ME, Guill MF, Guillerman RP, Leone CG, Maguiness K, Monchil L, Powers SW, Rosenfeld M, Schwarzenberg SJ, Tompkins CL, Zemanick ET, Davis SD.
Clinical practice guidelines From the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis.
Pediatrics. 2016. PubMed abstract / Full Text

Marshall BC.
Cystic Fibrosis Foundation 2016 Annual Data Report.
Cystic Fibrosis Foundation Patient Registry. Bethesda, Maryland. 2017. / https://www.cff.org/Research/Researcher-Resources/Patient-Registry/201...

Mickle JE, Cutting GR.
Genotype-phenotype relationships in cystic fibrosis.
Med Clin North Am. 2000;84(3):597-607. PubMed abstract

Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B.
Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health.
Am J Respir Crit Care Med. 2013;187(7):680-9. PubMed abstract

Moran A, Becker D, Casella SJ, Gottlieb PA, Kirkman MS, Marshall BC, Slovis B.
Epidemiology, pathophysiology, and prognostic implications of cystic fibrosis-related diabetes: a technical review.
Diabetes Care. 2010;33(12):2677-83. PubMed abstract / Full Text

Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B.
Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
Diabetes Care. 2010;33(12):2697-708. PubMed abstract / Full Text

Moran A, Pillay K, Becker DJ, Acerini CL.
ISPAD clinical practice consensus guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
Pediatr Diabetes. 2014;15 Suppl 20:65-76. PubMed abstract

Morrell MR, Pilewski JM.
Lung Transplantation for Cystic Fibrosis.
Clin Chest Med. 2016;37(1):127-38. PubMed abstract

Morris PJ.
Physical activity recommendations for children and adolescents with chronic disease.
Curr Sports Med Rep. 2008;7(6):353-8. PubMed abstract

Nichols DP, Kuk KN, Nick JA.
Drug interactions and treatment burden as survival improves.
Curr Opin Pulm Med. 2015;21(6):617-25. PubMed abstract

Parad RB, Comeau AM.
Newborn screening for cystic fibrosis.
Pediatr Ann. 2003;32(8):528-35. PubMed abstract

Pittman JE, Ferkol TW.
The Evolution of Cystic Fibrosis Care.
Chest. 2015;148(2):533-542. PubMed abstract / Full Text

Quittner AL, Goldbeck L, Abbott J, Duff A, Lambrecht P, Solé A, Tibosch MM, Bergsten Brucefors A, Yüksel H, Catastini P, Blackwell L, Barker D.
Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries.
Thorax. 2014;69(12):1090-7. PubMed abstract

Raffini LJ, Raybagkar D, Blumenstein MS, Rubenstein RC, Manno CS.
Cystic fibrosis as a risk factor for recurrent venous thrombosis at a pediatric tertiary care hospital.
J Pediatr. 2006;148(5):659-64. PubMed abstract

Schram CA.
Atypical cystic fibrosis: identification in the primary care setting.
Can Fam Physician. 2012;58(12):1341-5, e699-704. PubMed abstract / Full Text

Schüler D, Sermet-Gaudelus I, Wilschanski M, Ballmann M, Dechaux M, Edelman A, Hug M, Leal T, Lebacq J, Lebecque P, Lenoir G, Stanke F, Wallemacq P, Tümmler B, Knowles MR.
Basic protocol for transepithelial nasal potential difference measurements.
J Cyst Fibros. 2004;3 Suppl 2:151-5. PubMed abstract

Sermet-Gaudelus I, Castanet M, Retsch-Bogart G, Aris RM.
Update on cystic fibrosis-related bone disease: a special focus on children.
Paediatr Respir Rev. 2009;10(3):134-42. PubMed abstract

Sermet-Gaudelus I, Mayell SJ, Southern KW.
Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
J Cyst Fibros. 2010;9(5):323-9. PubMed abstract / Full Text

Sontag MK, Hammond KB, Zielenski J, Wagener JS, Accurso FJ.
Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes.
J Pediatr. 2005;147(3 Suppl):S83-8. PubMed abstract

Sparks AA, McGee SJ, Boone CE, Neuringer IP, Jones SK, Aris RM.
'Old' bones in young bodies: the tale of cystic fibrosis.
Curr Opin Endocrinol Diabetes Obes. 2009;16(6):407-14. PubMed abstract

Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H.
Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.
J Am Diet Assoc. 2008;108(5):832-9. PubMed abstract

Tanase A, Zanni R.
The use of complementary and alternative medicine among pediatric cystic fibrosis patients.
J Altern Complement Med. 2008;14(10):1271-3. PubMed abstract

Williams V, Griffiths AB, Yap ZL, Martin J, Smith G, Couper R, Revesz T.
Increased thrombophilic tendency in pediatric cystic fibrosis patients.
Clin Appl Thromb Hemost. 2010;16(1):71-6. PubMed abstract