Pediatric Annals

CME Article 

Cystic Fibrosis and CRMS Screening: What the Primary Care Pediatrician Should Know

Michael J. Rock, MD; Jack K. Sharp, MD, CM

Abstract

“Every physician’s first duty is to diagnose — accurately and promptly.”

This mantra is taught to medical students and residents and should be a guiding principle for our day-to-day practice.

In the case of cystic fibrosis (CF), diagnosis by clinical suspicion can be challenging because of the multiple and sometimes subtle ways that CF can present, presented in Sidebar 1 (see page 760). Because symptoms may be subtle, the diagnosis of CF can be delayed by months to years. Delayed diagnosis can lead to failure to thrive with permanent growth-stunting, the development and progression of lung disease, and frustration for parents undergoing the “diagnostic odyssey” before an eventual diagnosis of CF.1

Abstract

“Every physician’s first duty is to diagnose — accurately and promptly.”

This mantra is taught to medical students and residents and should be a guiding principle for our day-to-day practice.

In the case of cystic fibrosis (CF), diagnosis by clinical suspicion can be challenging because of the multiple and sometimes subtle ways that CF can present, presented in Sidebar 1 (see page 760). Because symptoms may be subtle, the diagnosis of CF can be delayed by months to years. Delayed diagnosis can lead to failure to thrive with permanent growth-stunting, the development and progression of lung disease, and frustration for parents undergoing the “diagnostic odyssey” before an eventual diagnosis of CF.1

Michael J. Rock, MD, is Professor of Pediatrics, University of Wisconsin-Madison. Jack K. Sharp, MD, CM, is Associate Professor of Pediatrics, State University of New York at Buffalo.

Dr. Rock and Dr. Sharp have disclosed no relevant financial relationships.

Address correspondence to: Michael J. Rock, MD, Professor of Pediatrics, University of Wisconsin-Madison, 600 Highland Ave., mail code 9988, Madison, WI 53792.

“Every physician’s first duty is to diagnose — accurately and promptly.”

This mantra is taught to medical students and residents and should be a guiding principle for our day-to-day practice.

In the case of cystic fibrosis (CF), diagnosis by clinical suspicion can be challenging because of the multiple and sometimes subtle ways that CF can present, presented in Sidebar 1 (see page 760). Because symptoms may be subtle, the diagnosis of CF can be delayed by months to years. Delayed diagnosis can lead to failure to thrive with permanent growth-stunting, the development and progression of lung disease, and frustration for parents undergoing the “diagnostic odyssey” before an eventual diagnosis of CF.1

Sidebar 1.

  1. Family history of CF

  2. Meconium ileus

  3. Prolonged jaundice of infancy

  4. Edema, hypoproteinemia, and anemia

  5. Steatorrhea

  6. Failure to thrive

  7. Rectal prolapse

  8. Recurrent abdominal pain

  9. Portal hypertension

  10. Distal intestinal obstruction syndrome

  11. Intussuception

  12. Hyponatremic hypochloremic dehydration

  13. Pseudotumor cerebri

  14. Chronic cough

  15. Wheezing

  16. Recurrent pneumonia

  17. Sinusitis

  18. Nasal polyps

  19. Bronchiectasis

  20. Fingernail clubbing

  21. Tastes salty when kissed

  22. Male sterility

Through research conducted in the past 25 years, newborn screening for CF has proved to be beneficial. A randomized, controlled trial conducted in Wisconsin demonstrated nutritional and cognitive benefits of newborn screening.2,3 Research in the Netherlands4 and Australia5 showed a pulmonary benefit of newborn screening, and there appears to be a survival advantage of newborn screening for CF.6

Benefits of Newborn Screening

Based on these studies, a joint conference sponsored by the Cystic Fibrosis Foundation (CFF) and the Centers for Disease Control and Prevention in November 2003 concluded that the benefits of newborn screening were sufficient enough that the implementation of CF newborn screening should be considered by each state.7 A stronger recommendation arose from the American College of Medical Genetics (commissioned by the Maternal and Child Health Bureaus of the Health Resources and Services Administration) to standardize newborn screening from state to state.8 This 2005 recommendation that every state should screen for 29 core conditions, including CF, led to rapid expansion of newborn screening for CF. In 2005, only nine states were screening for CF. As of Dec. 1, 2009, all 50 states and the District of Columbia were performing newborn screening for CF.

The methods for CF newborn screening vary from state to state. Regardless of the screening algorithm, the primary care pediatrician (PCP) is often the first provider to learn of the results and must provide these results to the family and help to facilitate follow-up of the newborn screening results. This article is meant to guide PCPs through this process.

All newborn screening for CF begins with measurement of immunoreactive trypsinogen (IRT). This substance, a precursor to trypsin, is elevated in the blood of babies with CF and can be measured from dried blood spots. The theory behind the elevation of IRT is that the abnormal CF gene leads to abnormal functioning of pancreatic ductule cells, causing elevated IRT in the blood. This abnormal functioning of pancreatic ductule cells occurs in babies with CF who are pancreatic insufficient and pancreatic sufficient, making measurement of IRT ideal as a screening test. Thereafter, there are two predominant CF newborn screening algorithms: IRT/IRT and IRT/DNA, with some variations, including the California IRT/DNA/gene scanning technique and the Colorado IRT/IRT/DNA technique.9

In the IRT/IRT technique, the initial IRT is measured from the dried blood spot specimen obtained in the newborn nursery. A second IRT is measured at approximately 2 weeks, if the first IRT value is elevated. Some states have mandatory rescreening, in which a second newborn screening specimen is obtained for all infants. In those states, the PCP does not need to take action on the results of the first IRT value. In states that perform IRT/IRT and do not have mandatory rescreening, the baby must be recalled for a second newborn screening specimen; this is a responsibility of the PCP.

At this point, families should be informed that their baby has a positive newborn screening test for CF and that it is possible that the baby has CF. Generalizing the likelihood of CF varies by state because IRT cutoff values are not uniform between states. IRT may also be elevated in infants who experienced stressful deliveries with low APGAR scores; infants with CF who are heterozygote carriers of a CF mutation; and black infants, who have a higher rate of elevated IRT values compared with white infants.

If the second IRT value is normal, then the baby is at lower risk for CF, and no further action is required. If the second IRT value is elevated, the infant needs to be referred to a facility that can perform a high-quality, accurate quantitative pilocarpine iontophoresis (QPIT) sweat test. In most cases, the sweat test should be performed at a CFF-accredited center; this is required in some states. The CFF requires that all care centers adhere to sweat testing guidelines and have periodic inspection of sweat testing procedures to maintain accreditation. There can be challenges in obtaining adequate quantities of sweat from 2-week-old babies.

Discussing CF with families and explaining the implications and the need for follow-up evaluation and testing can be complicated and challenging. Coordinating care between the PCP and CF specialist is especially important. The CF specialist should contact the PCP to explain the diagnosis. The PCP and family should be alert for signs and symptoms consistent with a CF diagnosis. These include poor weight gain, loose stools, flatus, abdominal pain, or chronic or prolonged respiratory symptoms, such as wheezing and chronic cough, that last for longer than 2 weeks, or if severe or rapidly progressing. The role of the PCP is crucial, especially if there are geographic, financial, or other barriers to follow-up care at the CF center.

What the Values Mean

The definition of normal, intermediate, and abnormal sweat chloride values for infants who are younger than 6 months differs from the values for infants who are older than 6 months of age.10 A normal sweat chloride value is less than 30 mEq/L; intermediate is 30 to 59 mEq/L; and abnormal, indicative of CF, is greater than or equal to 60 mEq/L.

Sweat test labs vary in the turnaround time for results and who notifies the family of the results. Some CF center sweat testing labs will have the families wait for the results (as soon as 1 hour after collecting the sweat). In this case, the CF center personnel directly inform the families of the sweat testing results and may initiate counseling and care on the same day.

Other sweat labs will not have the results available until later in the day. In this case, either the sweat testing lab personnel/interpreting physician will call the family with results or the lab personnel/interpreting physician will inform the PCP of the results. Regardless of whether the family receives the results from the CF center personnel or the PCP, there needs to be good communication among the CF center lab, the PCP, and the family.

A normal sweat chloride value likely rules out CF. In this case, the family is told that the baby does not have CF. However, there have been cases of CF in which the initial sweat chloride value has been less than 30 mEq/L. A high index of suspicion for CF should be maintained if there is the occurrence of any CF symptoms (see Sidebar 1, page 760).

An intermediate sweat chloride of 30 to 59 mEq/L could be indicative of CF or CRMS11 (CF transmembrane conductance regulator-related metabolic syndrome). These infants require further follow-up in a CF center with repeat sweat testing in the future and possible extended CF mutation analysis.

In the IRT/DNA technique, the IRT value is measured on the neonatal screening specimen that is obtained in the newborn nursery. If the value is normal, then no further testing is performed, and the infant has a normal CF newborn screening report. If the value is elevated above the cutoff, then a DNA analysis is performed on the same specimen.

What to Do Next

If the infant has one mutation on the CF newborn screening specimen, they may have CF, CRMS, or be a normal heterozygote carrier. These infants should also be referred to a qualified sweat testing laboratory. Families of infants who have CF mutations detected on newborn screening require genetic counseling. A carrier infant has an increased risk of having a subsequent sibling with CF, because one parent is clearly a carrier. Additionally, the carrier infant is at risk of having a child with CF in the distant future.

Other newborn screening disorders, such as median chain acyl-dehydrogenase deficiency, congenital hypothyroidism or phenylketonuria, require prompt diagnosis and treatment to prevent life-threatening complications or permanent mental retardation. Although making a diagnosis of CF is not as urgent as these other disorders, there should be no delay in following up on the newborn screening results and referral to a sweat testing lab.

Ideally, sweat testing should take place between 14 and 28 days. It is essential to make an early diagnosis to begin treatment and avoid failure to thrive and hyponatremic dehydration, an early-life threatening complication of CF. Prompt diagnosis and initiation of care by the CF center (with reinforcement by the PCP) will optimize nutritional and respiratory treatment.12 Another condition that can be avoided is the triad of edema, hypoproteinemia, and anemia, a rare complication of CF that occurs in a subset of pancreatic insufficient infants with CF who are breast-fed.

If CF Is Missed

Although newborn screening for CF diagnoses most cases, it is not perfect. A CF diagnosis may be missed by any of the following possibilities.

If a newborn screening specimen is not obtained or is mislabeled, the IRT is below the cutoff value, miscommunication between the newborn screening lab and the PCP or between the PCP and the family (eg, “the IRT levels were higher than the cutoff value and were determined to be abnormal, but the family was not contacted.”).13 Regardless of the newborn screening result, the PCP should maintain an index of suspicion for CF if there are any suggestive symptoms.

Once the diagnosis of CF is made, the infant should be referred to a US Cystic Fibrosis Foundation (US-CFF) accredited CF care center (CFCC) within 1 to 3 days. Frequently, this is the responsibility of the pediatrician. In most cases, the CFCC team is aware of the diagnosis, as most sweat tests are performed in either an accredited CFCC or one of its affiliates, which then contact PCPs and families to notify them of the diagnosis and to set up the initial visit with the CFCC team. The US-CFF has recently revised the criteria for diagnosis of CF10 and developed a consensus statement on the care of newborns and toddlers with CF up to 2 years of age12 to assist CF caregivers and PCPs in making informed decisions about diagnosis and treatment plans.

The diagnosis of CF in a screened infant is often unexpected because the infant usually appears healthy. The psychosocial effect must be accounted for at the first visit. Extended family members should be invited to participate to lend support to the parents of the affected child.

At the initial visit, a comprehensive discussion about the diagnosis may take place; however, some families need time to adjust to this news and may not process the amount of information often provided to them at the initial visit. The length of the visit and the amount of information must be customized for each family; additional visits may need to be scheduled to allow each family time to process the information. A summary of issues to be discussed by the PCP and the CFCC team at the first visit are shown in Sidebar 2 (see page 761) and Sidebar 3.

Sidebar 2.

  • Infants with CF need supplemental salt; older children with CF should be taught to salt their food.
  • The goal for infants with CF is to be at or above the 50th percentile weight-for-length (“slightly chubby”). A high-fat diet is encouraged, including the use of whole milk. Inform the CF center if there is any lack of weight gain or weight loss.
  • Early symptoms can be subtle; call the CF Center for any pulmonary or gastrointestinal symptoms, such as cough or wheezing, or loose stools or abdominal pain.
  • Antibiotics are used with a lower threshold in patients with CF and for a longer period of time than in other children.
  • Life expectancy is steadily increasing, but this depends on daily preventive care. Practitioners should:
    • -- Convey hope that we expect these infants to lead full, adult lives.

    • -- Inquire about adherence to the prescribed CF regimen at each primary care visit.

    • -- Reinforce limit-setting (especially important in children who require daily treatments but may be perceived as vulnerable).

  • The diagnosis creates psychosocial challenges.:
    • -- We strongly discourage children with CF from person-to-person interactions with others with CF to prevent cross-infection.

    • -- CF places the entire family under stress.

  • Ask how unaffected siblings feel about CF.
  • Share insights on family functioning with CF Center team.

Modified from: Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009;155:S73–S93.

Sidebar 3.

  • Assess emotional and educational status of the family.
  • Explain how we know the infant has CF.
  • Explain basic genetic concepts.
  • Convey the most difficult facts about the disease:
    • -- Currently CF is a life-limiting disorder.

    • -- Most males are infertile.

    • -- CF is a chronic condition requiring ongoing daily care.

  • Provide a general description of CF symptoms and what causes them.
  • Introduce the CF Center care team concept.
    • -- Parents and primary care providers are part of the care team.

    • -- CF Foundation is part of the team.

  • Emphasize the need to get CF information from reliable sources:
    • -- CF Care team.

    • -- CF Foundation’s website ( www.cff.org).

    • -- Explain that incorrect and outdated information about CF is common (eg, from friends and family, in books, and on the Web).

  • Give the family hope.
    • -- Life expectancy has been steadily increasing.

    • -- Many new treatments are actively being studied, which are likely to be of direct benefit to your child in his or her life.

    • -- Prevention is especially important.

    • -- Follow-up in the clinic is critical; consider giving the family a copy of the Monitoring and Care Recommendations.

    • -- Describe how to contact the CF care center with questions or concerns; schedule the next visit before the family leaves.

Modified from: Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009;155:S73–93.

In states with IRT/DNA screening programs, one or two CF transmembrane conductance regulator (CFTR) mutations often will have been identified. These mutations may assist in the diagnosis of CF. However, some mutations on state or commercial screening panels are not clearly associated with the diagnosis of CF, adding further potential confusion and anxiety when they are identified. There is a strong association between CFTR genotype and pancreatic function phenotype,12 as some CF-causing mutations are classified as being associated (pancreatic insufficient — PI); not associated (pancreatic sufficient – PS); or variably associated (could be PI or PS) with malnutrition.

A complete history and physical examination, review of the family history (including pedigree) and environmental exposures, a review of the newborn screen, sweat test results and any additional laboratory assessment should be obtained in the first visit(s) and reviewed with the family. The evaluation should focus particularly on assessing growth and nutritional status and respiratory symptoms. Although many infants may appear completely “healthy,” a careful history may identify subtle symptoms consistent with the CF diagnosis.

Growth

The first 2 years of life are a time of extraordinary metabolic needs, when infants normally double their birth weights by 4 months and triple them by 1 year. The US-CFF recommends that children should reach the 50th percentile of weight-for-length status by 2 years of age, because better early nutrition is associated with better lung function and later respiratory outcomes.14 Nutritional status assessment should include assessment of growth-weight, height, and head circumference.

In infants with PI-associated CFTR mutations, pancreatic dysfunction may evolve over the first year of life, initially present at birth in about 60% of infants with CF, and in about 90% by 1 year of age.15 Because initial pancreatic function cannot be fully predicted by genotype, an objective measure of pancreatic function is important to guide therapy. The measurement of fecal elastase is an easily performed, noninvasive, and highly predictive measure of PI status. If the initial fecal elastase test is normal, it should be repeated if symptoms of malnutrition (change in stool pattern, weight loss, or poor weight gain) occur, or by 1 year of age at the latest.

Deficiencies

Biochemical micronutrient deficiencies may be detectable16 in the CF infant in the first month of life, including deficiencies in fat-soluble vitamins and essential minerals, such as zinc and sodium. Up to two-thirds of newly diagnosed infants with CF have low vitamin levels at diagnosis,16 particularly those with hypoalbuminemia and a low alkaline phosphatase, or those homozygous for the F508del mutation.16 Vitamin deficiencies may also be seen in CF-PS infants.

Visual and cognitive impairment may be seen respectively in association with vitamin A and vitamin E deficiencies. All infants with CF should receive supplementation with a standard age-appropriate multivitamin and supplements with the fat-soluble vitamins A, D, E, and K.12 Initial measurement of vitamin levels should be performed in the first months of life, preferably 1 to 2 months after initiating pancreatic enzyme replacement therapy (PERT) and vitamin replacement therapy, and periodic monitoring for vitamin deficiency should be a part of routine care in all CF patients.12

Deficiencies in sodium, zinc, and fluoride are also seen in infants with CF. Poor growth can be seen in association with sodium and zinc deficiencies, whereas anorexia, fever, vomiting, weakness, and dehydration with hyponatremic hypochloremic metabolic alkalosis can be seen in extreme cases of salt depletion. Sodium deficiency comes from excessive sweat losses, which can be prevented in most cases by oral salt supplementation; standard infant formulas and toddler foods do not provide adequate salt for the typical CF infant.

Daily dosages of one-eighth teaspoon (12.5 mEq elemental sodium) for infants younger than 6 months; one-quarter teaspoon between 6 to 12 months (up to 4 mEq/kg/d); and one-half teaspoon for those infants older than 12 months have been recommended until children are taking a regular diet. Additional sodium supplementation may be necessary, particularly in hot climates, living conditions, or with overbundling.

Zinc deficiency is caused by poor absorption and enterohepatic recirculation, which correlates with the degree of fecal fat malabsorption and often improve with PERT therapy. An empiric trial of zinc supplementation with 1 mg/kg/day of elemental zinc for 6 months for infants with growth deficiency is recommended for infants with adequate calorie intake and PERT.

Fluoride deficiency is possible in CF infants and toddlers living in communities where the water supply content of fluoride is less than 0.3 ppm. These individuals should have supplements of 0.25 mg/d of fluoride.

For infants with documented pancreatic insufficiency, supplemental PERT should begin immediately to prevent nutritional deficiencies and potential for adverse behavioral consequences from abdominal symptoms associated with feedings. PERT should be given with any type of feeding, including breast milk, infant formulas, and all (semisolid) foods. Although an optimal dose of PERT for infants has not been established, historic recommendations of 2,000 to 5,000 lipase units/feeding remain acceptable for initial dosing,17 with adjustment for growth so dosing is maintained less than 2,500 lipase units/kg/feeding (10,000 lipase units/kg/day).

Infants will often exceed the daily limits of PERT therapy because of frequent smaller feedings (particularly if breast-fed). Frequent assessment of growth in relation to intake and enzyme dose during the first years is important. Infants may be at higher risk for fibrosing colonopathy (strictures of the ascending colon) with excessive PERT dosing because of increased intestinal permeability. Parents should not adjust enzyme dosing without consultation with the CFCC.

Infants with CF should be able to grow and thrive using standard formulas and infant foods. No optimal feeding regimen is available because no consistent differences in growth have been seen between infants who are fed breast milk, cow’s-milk formulas,18,19 or other types of formulas (standard, hydrolyzed, or semielemental).20–22 Although older patients with CF usually require high-calorie diets, there are no data for the proactive use of fortified human milk, high-calorie formulas, or complementary foods in infants who are growing well, except in infants with inadequate growth, where these foods should be used to improve growth and nutrition. Both interventional measures to correct the deficiency and investigations to identify the cause of poor growth should be considered.

Behavioral Issues

Behavioral issues related to mealtimes are common in infants and toddlers with CF. Newborn screening provides the opportunity to provide anticipatory guidance and to assess for and manage these difficulties before they become severe. Adverse feeding behaviors, such as prolonged meal times with inadequate intake and neophobia23 are increased in CF infants and toddlers. Interventions may include a structured behavior program and reviewing and documenting energy intake goals.

Infants with CF diagnosed through newborn screening are often without clinical respiratory symptoms at the time of diagnosis. However, significant chronic respiratory disease often develops in the first year of life. CXR, chest CT, BAL, and infant PFT studies have shown CF lung disease often begins early.24,25 A goal of early diagnosis and intervention in CF is to prevent establishment of early chronic progressive lung disease, although little evidence exists to support guidelines for therapies to accomplish these goals. Preventing environmental tobacco smoke exposure is one exception, as it hastens the progression of lung disease in CF patients.

Pathogenic Factors

Pathogens commonly identified from the respiratory tracts of infants with CF include E. coli, S. aureus, H. influenzae, and P. aeruginosa. Treatment of asymptomatic colonization has not proved to be beneficial and may be harmful, except in the case of P. aeruginosa. Prophylactic treatment of S. aureus has resulted in decreased isolation of this organism from cultures but has been associated with increased risk of P. aeruginosa acquisition, 26 without the benefit of significant changes in lung function, nutritional status, hospitalization rates, or additional use of antibiotics.27

Early acquisition of P. aeruginosa is associated with increased pulmonary disease and reduced survival; therefore, new acquisition of P. aeruginosa (or reinfection of infants previously cleared by treatment) should be treated, even in the absence of symptoms. Serial identification of P. aeruginosa in respiratory cultures has been associated with increased cough, lower CXR scores, and higher levels of circulating immunoglobulins, suggesting chronic inflammation. Eradication can be achieved with 1 to 2 months of inhaled tobramycin.28 If cultures remain positive after two attempts at eradication, chronic, alternate-month administration of inhaled tobramycin is recommended. Success in treatment of older individuals without symptoms and mild to severe disease29 with prophylactic inhaled tobramycin for chronic infection with P. aeruginosa suggests the benefits of this therapy could extend to infants.

Infants with symptomatic respiratory disease should be treated based on clinical condition, as well as results of previous cultures. Intravenous antibiotics are often required.

More significant findings of atelectasis or infiltrates should be further evaluated or treated. Baseline CXR should be obtained by 3 to 6 months of age, and annually thereafter, particularly with symptomatic infants not responsive to basic treatment interventions. Computed tomography (CT) of the chest, by controlled-ventilation method, is more sensitive in detecting pulmonary parenchymal abnormalities in CF infants,30 but routine use is not recommended because of the need for sedation to achieve high-quality imaging and because of the risks of exposure to higher doses of radiation. However, these studies may be useful in selected infants with clinical disease that is not responsive to basic interventions.

Pulmonary function testing is an essential part of the management of respiratory disease in older children and adults with CF. Infant pulmonary function testing (iPFTs) by the raised-volume rapid thoracoabdominal compression (RVRTC) and infant plethysmography to measure fractional lung volumes is sensitive enough to be able to detect early changes in airflow and lung volumes, even in the absence of symptoms.31

Widespread use of these techniques has been limited by the need for specialized equipment, extensive training that is needed to perform the technique satisfactorily, and the need for sedation to perform testing. Routine measurement of lung function in asymptomatic infants is recommended only in centers with expertise in this area.

For the first few visits, newly diagnosed infants with CF should be segregated from other CF patients until adequate infection control education has been provided to caregivers.32 Person-to-person transmission of respiratory pathogens between individuals, especially between older individuals and younger individuals with CF, has been documented in crowded clinic settings, occasionally with severe consequences. Family education should include appropriate hand hygiene, cough etiquette, and the importance of using these techniques in other settings, such as the home and daycare, with periodic reinforcement. Appropriate cleaning and disinfecting of devices used for respiratory medications should also be implemented.

Immunizations

All standard immunizations recommended by the AAP should be administered to CF infants, including annual influenza vaccinations after 6 months. Communication between primary health care providers and the CF center regarding immunizations is essential to avoid missed or duplicated immunizations. Vaccination of all household members, contacts, out-of-home caregivers, and health care providers is also recommended. For infants with CF younger than 2 years of age, the CFF recommends that use of palivizumab be considered for prophylaxis of respiratory syncytial virus.12

Airway clearance techniques are recommended for all infants with CF because the potential for benefit is likely, although there is minimal evidence supporting the use of bronchodilators and percussion and postural drainage (P&PD) in infants.

Positioning

The use of head-down positioning is not recommended in infants because of an increased incidence of GERD, URTI, antibiotic use, worse pulmonary function, and CXR scores.33 Other chronic respiratory therapies for infants with CF are primarily based on positive results of studies in older children and adults. Dornase alfa,34 7% hypertonic saline, and azithromycin29 have shown benefit in controlling symptoms, reducing exacerbations, and improving lung function in limited studies in children aged older than 6 years and adults with CF. Small studies in infants have shown improved lung function, oxygenation, and growth in infants treated with dornase alfa and good tolerance of the use of 7% inhaled saline.35 Inhaled corticosteroids are recommended for use only in individuals with CF in which airway hyperreactivity has been demonstrated.

Process of Diagnosis

The implementation of CF newborn screening (NBS) programs has resulted in the detection of asymptomatic infants with hypertrypsinogenemia and either sweat chloride value in the intermediate range (30 to 59 mmol/L), and/or one or two mutations in the CFTR gene that are not clearly identified with CF disease, or both. This group of infants is different from older symptomatic individuals with these laboratory findings, which are classified as CFTR-related disorders, in that they are asymptomatic. To better define this group, the diagnostic term CFTR-related metabolic syndrome (CRMS) was proposed.

Because of inadequate knowledge of the implications and natural history of this heterogenous group of individuals, monitoring for signs and symptoms of CF-like diseases, the CFF convened an expert panel to provide detailed care guidelines, which were recently published.11 A summary of issues to be discussed by the PCP and the CFC team at the first visit are shown in Sidebar 4 (see page 764) and Sidebar 5 (page 765).

Sidebar 4.

  • Phenotype is more important than genotype.
    • -- Many infants with CRMS will continue to be healthy and will thrive.

    • -- Males with CRMS may be at higher risk of infertility.

  • Early symptoms can be subtle; open communication with the CF specialist is important if there are concerning symptoms, such as:
    • -- Lack of weight gain or unresolved acute weight loss.

    • -- Persistent loose stools or excessive flatus.

    • -- Abdominal pain.

    • -- Coughing or wheezing.

    Contact the CF specialist if these symptoms persist > 2 weeks.
  • If individuals with CRMS develop symptoms they may benefit from currentand new treatments.
  • The CF Center is a resource for:
    • -- Medical advice.

    • -- Psychosocial support for families who have difficulty coping with the uncertainty of this diagnosis.

    • -- Information about new developments as they become available.

Modified from: Borowitz D, Parad RB, Sharp JK, et al. Cystic Fibrosis Foundation Practice Guidelines for the Management of Infants with Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome During the First Two Years of Life and Beyond. J Pediatr 2009;155:S106–S116.

Sidebar 5.

  • Assess emotional and educational status of the family.
  • Explain basic genetic concepts.
    • -- Be sure that formal genetic counseling has been provided or is scheduled.

  • Provide a general description of CF symptoms and what causes them.
  • Explain that there is a lot of incorrect and outdated information about CF (eg, from friends and family, in books, and on the Web).
    • -- Explain why we think the infant likely does not have CF.

    • -- Explain how we know the infant has CRMS.

  • What was the process that led to this diagnosis.
  • What does it mean if a child has CRMS.
  • Convey the news that we are uncertain about the prognosis:
    • --“We expect this child to lead a full life.”

    • --“Some, but not all individuals with CRMS may develop symptoms that should be treated.”

  • Some individuals with CRMS are at high risk for male infertility:
    • --“This is why we need to establish the current baseline and follow this child in our clinic.“

    • --“We may not have all the answers right now, but new information becomes avail-able all the time.“

  • If individuals with CRMS cannot be seen separately from patients with CF, discuss infection control.
  • Describe the monitoring plan, how to contact the CF Care Center with questions or concerns; schedule the next visit before the family leaves.

Modified from: Borowitz D, Parad RB, Sharp JK, et al. Cystic Fibrosis Foundation Practice Guidelines for the Management of Infants with Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome During the First Two Years of Life and Beyond. J Pediatr 2009;155:S106–S116.

The process of CRMS diagnosis begins when an individual having hypertrypsinogenemia is identified through a newborn screening program (with or without specific mutation testing), and subsequently has an initial sweat test in the intermediate range (sweat chloride value greater than/equal to 30 and less than 60 mmol/L), usually at 2 to 4 weeks. An intermediate sweat chloride value should prompt repeat testing by 2 months, which may result in resolution of the intermediate value to either a normal (less than 30 mmol/L) or abnormal (greater than/equal to 60 mmol/L) value.

If the result remains persistently intermediate, expanded genetic testing should then be done (in states with IRT/DNA methods, these results are an extension of testing done in the state NBS lab). An extended mutation panel or DNA sequencing can also be done in coordination with genetic counseling for the infant’s family.

A diagnosis of CRMS is made if, after a complete assessment, the infant continues to have 1) intermediate sweat chloride concentrations on at least two occasions and fewer than two CF-causing CFTR mutations; or 2) a normal sweat chloride and two CFTR mutations, of which one or fewer are known to be disease-causing. Infants with suspected or confirmed CRMS should be monitored by family, their PCP, and a CF specialist for signs and/or symptoms of CF, as they are at risk for development of CF-like symptoms. Some individuals who develop signs or symptoms may eventually have increases in sweat chloride concentrations, leading to a CF diagnosis.

Care of Patient and Family

Clinical care for the infant with CRMS depends on the presentation of clinical symptoms. Early assessment by the CF specialist is important to discuss the diagnosis with the family and to establish a baseline evaluation. Infection control guidelines should be followed as for an infant with CF to prevent the spread of respiratory pathogens.32 Care may be provided by the CF specialist with or without the rest of the full CF care team.

However, it is advisable for the nurse or social worker to be introduced to the family to be able to assist with coping with the diagnosis, handling phone calls, and dealing with financial issues related to the diagnosis.

Assessment and Evaluation of a Child with Crms

The initial assessment (history and physical examination, measure of pancreatic function, and respiratory culture) of the infant with CRMS is similar to that of a newly diagnosed CF infant. Additional assessments are warranted only in the presence of respiratory or gastrointestinal symptoms and may include a CXR, serologic evaluation of chemistry, liver function, and fa-tsoluble vitamin (A and E) levels.

Further evaluation of infants with CRMS should continue periodically, until resolution into a CF diagnosis can be made or excluded. A repeat sweat test should be conducted after 6 months, at which time a sweat chloride value of less than 40 mmol/L is not consistent with the diagnosis of CF. Follow-up visits with the CF specialist should occur at least twice during the first year and at least yearly thereafter. More frequent visits to evaluate new symptoms or for familial reassurance are warranted. Oropharyngeal swabs should be performed at each visit.

Treatment Recommendations for CRMS

Definitive treatment recommendations about nutritional and respiratory therapies for asymptomatic CRMS infants are difficult to make. Although these infants are at less risk for salt depletion than CF infants, there is no consensus about salt supplementation. Patients with CRMS are also likely to be at low risk for fat-soluble vitamin (A, D, E, and K deficiency), but there is no consensus on testing CRMS infants for vitamin deficiencies. As with PS-CF infants, individuals with CRMS may be at risk of intermittent pancreatitis. Evaluation of fecal elastase should be made if symptoms of poor weight gain, loose stools, excessive flatus, or abdominal pain are noted.

Because enteropathy may cause secondary pancreatic insufficiency, repeat elastase testing is warranted with symptomatic improvement in these cases. Constipation from loss of intraluminal fluid volume may also be present, which may contribute to poor appetite and weight gain.

Prolonged cough after a respiratory virus may be seen in all infants but is especially concerning in infants with CRMS. Further evaluation by the PCP, including chest radiography, may be warranted in such cases. Therapy with bronchodilators or airway clearance therapy, with more frequent follow-up by the PCP and/or CF specialist, may be considered.

Because it is uncertain whether infants with CRMS will develop CF-like respiratory symptoms, routine airway clearance therapies should not be prescribed. However, routine immunizations, including annual influenza immunization after 6 months and avoidance of exposure to environmental sources of tobacco smoke, are recommended. Discussion of male infertility may be warranted in association with certain CFTR mutations, although detailed discussions of infertility and further evaluation may not be necessary until adolescence or later.

As with many newly defined disorders, much more information, collected in a central registry, is needed to provide better prognostic information as to who is at risk for developing CF-related disorders and to guide specific therapies for individuals with CRMS. Until that time, cautious observation and close follow-up to assess for early signs of CF-related disease remain the best approach to these individuals, balancing communication with the importance of long-term follow-up.

Conclusion

Newborn screening for CF is now universal in the US. All programs screen infants for hypertrypsinogenemia, although most employ molecular genetic testing to look for disease-causing mutations in the CFTR gene. Early diagnosis and intervention in CF is key to improving survival and decreasing respiratory morbidity and nutritional deficiencies seen early in this disease. Many nutritional and respiratory therapies for older children with CF can be used in infants, although the data supporting the use of many of these therapies are limited.

CRMS is a new condition created by the diagnosis of asymptomatic infants with hypertrypsinogenemia and intermediately elevated sweat chlorides and/or CFTR mutations that are potentially abnormal yet not clearly CF-causing. Further monitoring of this group of individuals is warranted to provide prognostic and therapeutic information for improved care.

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CME Educational Objectives

  1. Learn of the contrast between the immunoreactive trypsinogen (IRT) IRT/IRT and IRT/DNA newborn screening techniques.

  2. Become familiar with the categorization of sweat chloride results as normal, intermediate, and abnormal.

  3. Learn the evaluation and management of nutritional complications in CF infants diagnosed by newborn screening.

Sidebar 1.

  1. Family history of CF

  2. Meconium ileus

  3. Prolonged jaundice of infancy

  4. Edema, hypoproteinemia, and anemia

  5. Steatorrhea

  6. Failure to thrive

  7. Rectal prolapse

  8. Recurrent abdominal pain

  9. Portal hypertension

  10. Distal intestinal obstruction syndrome

  11. Intussuception

  12. Hyponatremic hypochloremic dehydration

  13. Pseudotumor cerebri

  14. Chronic cough

  15. Wheezing

  16. Recurrent pneumonia

  17. Sinusitis

  18. Nasal polyps

  19. Bronchiectasis

  20. Fingernail clubbing

  21. Tastes salty when kissed

  22. Male sterility

Sidebar 2.

  • Infants with CF need supplemental salt; older children with CF should be taught to salt their food.
  • The goal for infants with CF is to be at or above the 50th percentile weight-for-length (“slightly chubby”). A high-fat diet is encouraged, including the use of whole milk. Inform the CF center if there is any lack of weight gain or weight loss.
  • Early symptoms can be subtle; call the CF Center for any pulmonary or gastrointestinal symptoms, such as cough or wheezing, or loose stools or abdominal pain.
  • Antibiotics are used with a lower threshold in patients with CF and for a longer period of time than in other children.
  • Life expectancy is steadily increasing, but this depends on daily preventive care. Practitioners should:
    • -- Convey hope that we expect these infants to lead full, adult lives.

    • -- Inquire about adherence to the prescribed CF regimen at each primary care visit.

    • -- Reinforce limit-setting (especially important in children who require daily treatments but may be perceived as vulnerable).

  • The diagnosis creates psychosocial challenges.:
    • -- We strongly discourage children with CF from person-to-person interactions with others with CF to prevent cross-infection.

    • -- CF places the entire family under stress.

  • Ask how unaffected siblings feel about CF.
  • Share insights on family functioning with CF Center team.

Modified from: Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009;155:S73–S93.

Sidebar 3.

  • Assess emotional and educational status of the family.
  • Explain how we know the infant has CF.
  • Explain basic genetic concepts.
  • Convey the most difficult facts about the disease:
    • -- Currently CF is a life-limiting disorder.

    • -- Most males are infertile.

    • -- CF is a chronic condition requiring ongoing daily care.

  • Provide a general description of CF symptoms and what causes them.
  • Introduce the CF Center care team concept.
    • -- Parents and primary care providers are part of the care team.

    • -- CF Foundation is part of the team.

  • Emphasize the need to get CF information from reliable sources:
    • -- CF Care team.

    • -- CF Foundation’s website ( www.cff.org).

    • -- Explain that incorrect and outdated information about CF is common (eg, from friends and family, in books, and on the Web).

  • Give the family hope.
    • -- Life expectancy has been steadily increasing.

    • -- Many new treatments are actively being studied, which are likely to be of direct benefit to your child in his or her life.

    • -- Prevention is especially important.

    • -- Follow-up in the clinic is critical; consider giving the family a copy of the Monitoring and Care Recommendations.

    • -- Describe how to contact the CF care center with questions or concerns; schedule the next visit before the family leaves.

Modified from: Borowitz D, Robinson KA, Rosenfeld M, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr 2009;155:S73–93.

Sidebar 4.

  • Phenotype is more important than genotype.
    • -- Many infants with CRMS will continue to be healthy and will thrive.

    • -- Males with CRMS may be at higher risk of infertility.

  • Early symptoms can be subtle; open communication with the CF specialist is important if there are concerning symptoms, such as:
    • -- Lack of weight gain or unresolved acute weight loss.

    • -- Persistent loose stools or excessive flatus.

    • -- Abdominal pain.

    • -- Coughing or wheezing.

    Contact the CF specialist if these symptoms persist > 2 weeks.
  • If individuals with CRMS develop symptoms they may benefit from currentand new treatments.
  • The CF Center is a resource for:
    • -- Medical advice.

    • -- Psychosocial support for families who have difficulty coping with the uncertainty of this diagnosis.

    • -- Information about new developments as they become available.

Modified from: Borowitz D, Parad RB, Sharp JK, et al. Cystic Fibrosis Foundation Practice Guidelines for the Management of Infants with Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome During the First Two Years of Life and Beyond. J Pediatr 2009;155:S106–S116.

Sidebar 5.

  • Assess emotional and educational status of the family.
  • Explain basic genetic concepts.
    • -- Be sure that formal genetic counseling has been provided or is scheduled.

  • Provide a general description of CF symptoms and what causes them.
  • Explain that there is a lot of incorrect and outdated information about CF (eg, from friends and family, in books, and on the Web).
    • -- Explain why we think the infant likely does not have CF.

    • -- Explain how we know the infant has CRMS.

  • What was the process that led to this diagnosis.
  • What does it mean if a child has CRMS.
  • Convey the news that we are uncertain about the prognosis:
    • --“We expect this child to lead a full life.”

    • --“Some, but not all individuals with CRMS may develop symptoms that should be treated.”

  • Some individuals with CRMS are at high risk for male infertility:
    • --“This is why we need to establish the current baseline and follow this child in our clinic.“

    • --“We may not have all the answers right now, but new information becomes avail-able all the time.“

  • If individuals with CRMS cannot be seen separately from patients with CF, discuss infection control.
  • Describe the monitoring plan, how to contact the CF Care Center with questions or concerns; schedule the next visit before the family leaves.

Modified from: Borowitz D, Parad RB, Sharp JK, et al. Cystic Fibrosis Foundation Practice Guidelines for the Management of Infants with Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome During the First Two Years of Life and Beyond. J Pediatr 2009;155:S106–S116.

Authors

Michael J. Rock, MD, is Professor of Pediatrics, University of Wisconsin-Madison. Jack K. Sharp, MD, CM, is Associate Professor of Pediatrics, State University of New York at Buffalo.

Dr. Rock and Dr. Sharp have disclosed no relevant financial relationships.

Address correspondence to: Michael J. Rock, MD, Professor of Pediatrics, University of Wisconsin-Madison, 600 Highland Ave., mail code 9988, Madison, WI 53792.

10.3928/00485713-20101117-06

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