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Cystic Fibrosis

Overview

Cystic fibrosis (CF) occurs when a patient carries 2 deleterious mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to CFTR protein malfunction in the epithelia of various organs. The CFTR protein is an ion channel, whose malfunction causes impaired chloride ion channel movement, resulting in abnormal secretions in the sweat glands, 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 occurred in the past couple of decades as evidence-based care has driven quality improvement in CF care centers. Because this care is very complex and specialized, medical home clinicians should collaborate with an Accredited CF Care Centers (CF Foundation) for every patient with CF.

Other Names & Coding

CF Cystic fibrosis of the pancreas Mucoviscidosis
ICD-10 coding

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.

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. [Marshall: 2017] [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] There are now more adults than children living with CF in the US. [Marshall: 2017]

Genetics

CF is inherited in an autosomal recessive fashion. More than 1,500 known mutations of the CFTR gene on chromosome 7 are described, but not all are CF causing. Many mutations in the CFTR gene have not been confirmed to be disease causing and may represent genetic variations. At least 70-90% of children with CF have the F508del mutation. Although F508del is generally associated with severe disease when patients are homozygous for this mutation (45% of the CF population), the severity of lung disease is difficult to predict because of other variables, such as modifier genes, epigenetic factors, and environmental variables. [Dawson: 2001] [Gallati: 2003]
Severe mutations are associated with pancreatic insufficiency, whereas mild mutations are not. Children with 2 severe mutations generally have malabsorption throughout their lives, detectable in infancy. 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. For more information, see Clinical & Functional Translation of CFTR for Clinicians.

Prognosis

Treatment reduces health complications, and survival into middle adulthood is possible. 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, bronchiectasis (pulmonary damage), 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 chronic growth of organisms such as B. cepacia and CF-related arthropathy. Median survival from lung transplantation is 8.3 years and 10.5 years for those in the first year. [Morrell: 2016]

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]

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

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

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

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

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

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

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

Roles of the Medical Home

Accredited CF Care Centers (CF Foundation) have improved outcomes for children with CF dramatically through measurement-driven quality improvement. The medical home should refer patients to and collaborate with such centers, as well as provide routine well-child care, ensure that immunizations are current, including the 23-valent pneumococcal vaccine and annual influenza vaccines, and provide 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
  • Need for a high-salt, high-fat, high-calorie diet (aiming for 150%-180% of the recommended dietary allowances) and extra fluids, especially in hot weather to prevent dehydration
  • Importance of infection control practices, such as:
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 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. Each CF center should have a social worker who is knowledgeable about the Cystic Fibrosis Foundation and other CF-specific resources for families.

Clinical Assessment

Overview

Since cystic fibrosis (CF) is now included in routine newborn screening for all US states, 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. See Cystic Fibrosis (CF).

Pearls & Alerts for Assessment

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 due to increased RBC turnover in CF which may falsely lower the hemoglobin A1C level.

Small bowel obstruction

Small bowel obstruction should be suspected anytime an individual with CF presents with abdominal pain. CF patients with a 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. DIOS should be managed in coordination with a CF physician with bowel cleanout; surgery is generally avoided.

Aquatic wrinkling

People with CF may have early aquagenic wrinkling of the skin, in which the palms wrinkle in less than 3 minutes of exposure to water, compared to 7 minutes in carriers and 11 minutes in controls.

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 (CF) has more details about immediate follow-up after a positive newborn screen. Genetic counseling should be available for screen positive babies and their families.

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. 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
  • Hemoptysis
  • Positive sputum culture for a CF-related pathogen (Pseudomonas )
  • Nasal polyps
  • Infertility or congenital bilateral absence of the vas deferens in males
  • Hyponatremic, hypochloremic dehydration
  • Recurrent pancreatitis
  • Small bowel obstruction
  • Digital clubbing
  • Liver disease
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 is helpful in some cases when 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 cannot 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 & Secondary 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 in 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

Current & 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.

Family History

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

Pregnancy/Perinatal History

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

Developmental & 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.

Maturationalprogress

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 & 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. Other skin findings may be due to vitamin or micro-nutrient deficiencies. Vitamin A deficiency can cause dry skin. Zinc deficiency may result in xerosis (dry, scaling skin) or alopecia, as well as acrodermatitis enteropathica (inflammatory rash around the mouth or anus), diarrhea, and hair loss. People with CF may have early aquagenic wrinkling of the skin, in which the palms wrinkle in less than 3 minutes of exposure to water, compared to 7 minutes in carriers and 11 minutes in controls. [Gild: 2010]

HEENT/Oral

Sinusitis and nasal polys are common. The incidence of polyps increases with age. Assess oral mucous 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 is characterized by a focal bulbous enlargement of the terminal segments of the fingers due to proliferation of connective tissue between the nail matrix and the distal phalanx. It may occur in CF patients who are not hypoxemic or in those who have liver disease. The exact cause is unknown but may be related to platelet-derived or vascular endothelial growth factor released into the circulation. [Rutherford: 2013] 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; an added complication could be vitamin D deficiency).

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, 36 weeks corrected gestation. Because reliable sweat testing requires expertise, it should only be performed in laboratories that have considerable ongoing experience and quality control.
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 (pancreatic) 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. Deep throat cultures are obtained in children who cannot expectorate.
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. Fecal elastase is a reliable measure of pancreatic insufficiency or sufficiency status regardless if the patient is taking exogenous pancreatic enzymes.

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 or gamma glutamyl transferase (GGT) 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 and is not full gene sequencing so may miss some CF mutations. 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.

Specialty Collaborations & Other Services

Newborn Screening Services (see RI providers [2])

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 RI providers [2])

All children with CF should receive care from an accredited CF Center. This may require travel. Collaboration between the CF Center and primary care clinician can improve the care and outcomes for patients and their families.

Pediatric Pulmonology (see RI providers [6])

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 0-6 months old are seen at least monthly; those 6-12 months old are seen at least every other month in CF Centers. Patients >1 year of age are seen at least quarterly in CF Centers. These centers have a specialized, comprehensive interdisciplinary medical team including dieticians, respiratory therapists, social workers, nursing or advanced provider coordinators, physicians, psychologists, and pharmacists 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 Accredited CF Care Centers (CF Foundation).

Pearls & Alerts for Treatment & Management

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) in the first year of life if Red Book (AAP) criteria are met.

Provide influenza vaccine

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

Infection control

Patients with CF are at high risk for passing infections to 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 CF 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 weight for length (<24 months) or BMIs (≥2 years); the Cystic Fibrosis Foundation recommends these be maintained ≥50th percentile. High-calorie foods are encouraged. Pancreatic enzyme supplementation is also crucial for nutrient absorption. Calories may need to be supplemented with oral or enteral tube feedings. It is important to work closely with a CF nutrition specialist and address quickly any drop in weight or 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. Patients with CF will require more frequent antibiotics than non-CF patients, even with a viral illness, due to the chronic growth of bacteria and the thick mucus in their airways. 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; guaifenesin (in Mucinex and others) is not very effective when compared with the 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 (drugs that correct the CFTR protein function), 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 treatments are to slow the development of lung damage and improve breathing by reducing infection and decreasing lung mucus to prevent bronchiectasis (lung damage). A variety of therapies, such as anti-inflammatory agents, bronchodilators, dornase alfa (DNAse), 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 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.

Specialty Collaborations & Other Services

Cystic Fibrosis Clinics (see RI providers [2])

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

Pediatric Pulmonology (see RI providers [6])

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, Pancrease, 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.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see RI providers [18])

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 oral supplementation, tube feeding supplementation, and vitamin supplementation. Appetite stimulants, such as Periactin and Megace, are occasionally used as well. See Calcium and Vitamin D and Boosting Calories for Babies, Toddlers, and Older Children.
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 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.

Specialty Collaborations & Other Services

Dieticians and Nutritionists (see RI providers [3])

Nutritional management should begin with diagnosis. Children with a weight for length or BMI under the 50th percentile require nutritional supplementation. 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).

Specialty Collaborations & Other Services

Pediatric Endocrinology (see RI providers [12])

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. Ivacaftor (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 called CFTR modulators, should only be initiated by CF Centers as they are mutation-specific and require interval testing such as yearly eye exams for lens abnormalities and liver function 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 sticky and thick. Dornase alfa (Pulmozyme) is a mucolytic drug that breaks down the extracellular DNA found in neutrophilic inflammation, 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: Tobi nebulized, Kitabis Pak, Bethkis, Tobi Podhaler, aztreonam: Cayston). Recently, inhaled amikacin (Arikayce) 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. 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.

Specialty Collaborations & Other Services

Pediatric Endocrinology (see RI providers [12])

Consider referral for CF-related diabetes, delayed puberty, vitamin D deficiency, 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 connect with peers and share experiences and challenges. Individuals with CF may interact with others on online forums, such as CF Peer Connect (CF Foundation), and other video conferences. Otherwise, individuals with CF are encouraged to participate in normal childhood activities, including sports or athletics. Depression and anxiety are relatively common among children with CF and their parents. Refer for family support (Cystic Fibrosis Foundation) and counseling as needed for mental health or behavior issues as they arise.

Specialty Collaborations & Other Services

General Counseling Services (see RI providers [30])

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

Social Workers (see RI providers [13])

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

Complementary & Alternative Medicine

Although many patients with CF use alternative medicines, 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 medications used to treat CF.
No Related Issues were found for this diagnosis.

Ask the Specialist

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 miss cases. When symptoms are suggestive of CF, obtain sweat chloride testing at a CF-accredited laboratory; do not obtain genetic testing because multiple testing panels exist and it is usually done by the CF center if sweat test is intermediate (>30 mmol/L) or positive (> 60 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.

Resources for Clinicians

On the Web

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

Cystic Fibrosis (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Respiratory Care Guidelines (CFF)
Clinical care guidelines for airway clearance, lung transplants, and pulmonary exacerbations, 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 and 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

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

Goetz D, Ren CL.
Review of Cystic Fibrosis.
Pediatr Ann. 2019;48(4):e154-e161. 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

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 Tools

Care, Action, & Self-Care 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.

Patient Education & Instructions

Managing 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.

Resources for Patients & Families

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.

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 (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the 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.

Studies/Registries

Cystic Fibrosis, Children or Adolescents (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Rhode Island (RI)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: December 2018; last update/revision: July 2019
Current Authors and Reviewers:
Author: Fadi Asfour, MD, MBBS
Contributing Author: Camille Walker, MSN, CPNP
Reviewer: Danielle Goetz, MD
Authoring history
2014: first version: Barbara Chatfield, MDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

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