Management of CRMS in First 2 Years and Beyond Clinical Care Guidelines

These guidelines were developed by consensus based on expert opinion and a medical literature review to guide the monitoring and care of infants who have an abnormal cystic fibrosis newborn screening result, but do not meet the full criteria for a CF diagnosis.

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Management of CRMS in First 2 Years and Beyond Clinical Care Guidelines

Borowitz D, Parad RB, Sharp JK, Sabadosa KA, Robinson KA, Rock MJ, Farrell PM, Sontag MK, Rosenfeld M, Davis SD, Marshall BC. 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(6 Suppl):S106-16

In 2008, the Cystic Fibrosis Foundation published guidelines for the diagnosis of cystic fibrosis in newborns through adulthood. However, a group of infants identified through newborn screening (NBS) programs posed a diagnostic and management dilemma. They showed:

  • Elevated trypsinogen.
  • A sweat chloride (SC) value that was not in the defining range of CF.
  • Or, fewer than two CF disease-causing mutations in the CF transmembrane conductance regulator (CFTR) gene.

Furthermore, these infants were often asymptomatic.

A committee of experts was therefore established to propose diagnostic and management guidelines to guide the monitoring and care of these individuals. The term CFTR-related metabolic syndrome (CRMS) was proposed to:

  • Provide families with a name that does not imply a diagnosis of CF.
  • Include mutations of unclear or unproved clinical relevance.
  • Become associated with an ICD billing code.

Since the publication of the original guideline in 2009, there have been a significant number of new publications relevant to this subject. These are listed at the end of this summary.

Purpose and Background

CF NBS programs work by detecting elevated levels of immunoreactive trypsinogen (IRT) in a blood sample collected at birth. Most programs also perform mutation analysis on the CFTR gene on select samples with an elevated IRT value.

An increasing number of infants are identified to have hypertrypsinogenemia by NBS, but with subsequent SC values that are less than 60 millimoles per liter (mmol/L) and with fewer than two CF-disease causing mutations. Therefore, these individuals do not meet the CF Foundation guidelines for the diagnosis of CF, and there is a paucity of evidence upon which to base management decisions for this group of individuals. This guideline was developed to guide the monitoring and management of these individuals in a quickly evolving field of science.

Methodology

An expert committee, using the Delphi methodology, reached systematic consensus on proposed recommendations. Committee members rated their level of agreement with each statement on a scale from zero to nine, with values between seven and nine considered good agreement. Consensus was defined as at least 80 percent in good agreement in two separate rounds of revision.

Recommendations

DIAGNOSIS

Recommendations Evaluation of the Evidence
1. Infants with an initial SC concentration in the intermediate range (30-59 mmol/L) should have a repeat sweat test by 2 months of age.  
2. If an infant is found to have a persistently elevated SC concentration in the intermediate range, extended CFTR mutation analysis should be conducted.  
3. A third sweat test should be performed at approximately 6 months of age.  
4. Based on the 2009 consensus guidelines, infants should be considered to have CRMS if they have either:
  1. Intermediate SC concentrations on at least two occasions and fewer than two CF-causing CFTR mutations, or
  2. A normal SC and two CFTR mutations, of which no more than one is known to be CF-causing.
 
5. Updated guidelines for diagnosis of CRMS are available. These guidelines define an infant to have CRMS if he or she is asymptomatic with a positive NBS test and has either:
  1. An SC level of 30-59 mmol/L or at least two occasions and fewer than two CF disease-causing mutations, or
  2. A normal SC level ( <30 mmol/L) and two CFTR mutations of which no more than one is known to be CF disease-causing.
 
6. Access to genetic counseling and evaluation by a CF specialist should be made available to infants with CRMS.  
7. A genetic counselor should be present if possible during discussion of genetic findings in patients with CRMS. Delphi Method: Consensus
8. Infants with CRMS should be monitored by their primary care provider (PCP) and a CF clinician.  
9. Monitoring of infants with CRMS is recommended due to increased risk for development of CF-like symptoms. In some individuals, evolving signs and symptoms, new information about disease-causing CFTR mutations, or changes in SC concentrations may ultimately lead to a diagnosis of CF.  

COMMUNICATION

Recommendations Evaluation of the Evidence
10. The CF specialist should communicate directly with the PCP to discuss implication of CRMS immediately after the initial assessment. Delphi Method: Consensus
11. The PCP should contact the CF specialist for any symptoms that are not resolving in two weeks, including weight loss, loose stool or flatus, abdominal pain, and respiratory symptoms that may be concerning for CF-like symptoms. Delphi Method: Consensus

CLINICAL CARE

Recommendations Evaluation of the Evidence
12. An infant with CRMS should be assessed by a CF specialist by no later than 2 months of age. Delphi Method: Consensus
13. Infants with CRMS should be assessed in a clinic adherent to CF Foundation guidelines for patients with CF or in a clinic separate from patients with CF. Delphi Method: Consensus
14. Care for an infant with CRMS may be provided by a CF specialist alone, outside the context of a full CF team, while ancillary personnel may need to see the individual with CRMS on an as-needed basis. Delphi Method: Consensus
15. At the initial visit, a complete history and physical exam should be performed in addition to an objective measure of pancreatic function and oropharyngeal culture. Delphi Method: Consensus
16. A chest X-ray should only be obtained if respiratory symptoms are present. Delphi Method: Consensus
17. Consensus was not achieved as to whether laboratory tests should be obtained at the time of the initial visit. Delphi Method: No Consensus
18. Routine use of more extensive testing, such as chest computer tomography, nasal potential difference (NPD), and bronchoscopy with bronchoalveolar lavage (BAL), is not recommended. Delphi Method: Consensus
19. Individuals with CRMS may be treated per CF protocol if Pseudomonas aeruginosa is found on an oropharyngeal swab, even if a definitive diagnosis of CF has not been established. Delphi Method: Consensus
20. Asymptomatic infants with CRMS should be seen by a CF specialist at least twice in the first year of life and yearly thereafter if they remain symptom free. Delphi Method: Consensus
21. Oropharyngeal swabs should be obtained at each visit and processed in the same manner as CF sputum. Delphi Method: Consensus

INITIAL THERAPY

Recommendations Evaluation of the Evidence
22. Consensus was not achieved in regard to recommendations for salt supplementation or the need to check fat-soluble vitamin levels.
  1. However, if levels are found to be low, supplementation with vitamins designed for patients with CF, as opposed to standard multivitamins, is recommended.

Delphi Method: No Consensus

  1. Delphi Method: Consensus
23. In the absence of clinical or radiologic evidence of lung disease, routine airway clearance therapy should not be prescribed. Delphi Method: Consensus
24. Airway clearance therapy may be considered if individuals with CRMS have recurrent or prolonged respiratory symptoms or have chest X-ray findings suggestive of lower airway disease. Delphi Method: Consensus
25. Individuals with CRMS should not be exposed to cigarette smoke. Delphi Method: Consensus
26. Individuals with CRMS should receive an annual influenza vaccine. Delphi Method: Consensus
27. Pancreatic function status, such as fecal elastase, may be rechecked in individuals with CRMS who show signs of malabsorption such as poor weight gain, loose stools, and increased abdominal flatus. Delphi Method: Consensus

Unanswered Questions

  • Should infants with recurrent Pseudomonas growth from oropharyngeal cultures be placed on chronic inhaled antipseudomonal coverage?
  • How often, and for how long, should individuals with CRMS be followed in a CF specialist center?

Further Reading

Relevant manuscripts published after the original guidelines are listed below. These manuscripts have not been reviewed or endorsed by the guidelines committee.

  • Ren CL, Desai H, Platt M, Dixon M. Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome. Pediatric Pulmonology. 2011;46(11):1079-84. Epub 2011 Apr 29.PMID: 21538969
  • Ren CL, Fink AK, Petren K, Borowitz DS, McColley SA, Sanders DB, Rosenfeld M, Marshall BC. Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening. J Pediatr. 2015;135(6):e1386-92. Epub 2015 May 11.PMID: 25963008
  • Salinas DB, Sosnay PR, Azen C, Young S, Raraigh KS, Keens TG, Kharrazi M. Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants. J Cyst Fibros. 2015;14(6):714-9. Epub 2015 Mar 29. PMID25824995
  • Groves T, Robinson P, Wiley V, Fitzgerald DA. Long-term outcomes of children with intermediate sweat chloride values in infancy. J Pediatr. 2015;166(6):1469-74 e1-3. Epub 2015 Mar 23.PMID: 25812778
  • Levy H, Nugent M, Schneck K, Stachiw-Hietpas D, Laxova A, Lakser O, Rock M, Dahmer MK, Biller J, Nasr SZ, Baker M, McColley SA, Simpson P, Farrell PM. Refining the continuum of CFTR-associated disorders in the era of newborn screening. Clin Genet. 2016 May;89(5):539-49. Epub 2016 Jan 20.PMID: 26671754.
  • Ooi CY, Castellani C, Keenan K, Avolio J, Volpi S, Boland M, Kovesi T, Bjornson C, Chilvers MA, Morgan L, van Wylick R, Kent S, Price A, Solomon M, Tam K, Taylor L, Malitt KA, Ratjen F, Durie PR, Gonska T. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015;135(6):e1377-85.
  • Kharrazi M, Yang J, Bishop T, Lessing S, Young S, Graham S, Pearl M, Chow H, Ho T, Currier R, Gaffney L, Feuchtbaum L. California Cystic Fibrosis Newborn Screening Consortium. Newborn Screening for Cystic Fibrosis in California. Pediatrics. 2015;136(6):1062-72. Epub 2015 Nov 16.PMID: 26574590
  • Munck A, Mayell SJ, Winters V, Shawcross A, Derichs N, Parad R, Barben J, Southern KW, ECFS Neonatal Screening Working Group. Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening. J Cyst Fibros. 2015;14(6):706-13. Epub 2015 Jan 24.PMID: 25630966
  • 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;S4-S15e.1. PMID: 28129811
  • Ren CL, Borowitz DS, Gonska T, Howenstine MS, Levy H, Massie J, Milla C, Munck A, Southern KW. Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis. J Pediatr. 2017;S45-S51.e1.PMID: 28129812

This executive summary was prepared by:

  • Evans Machogu, MBChB, MS, (Indiana University School of Medicine, Riley Hospital for Children, Indianapolis) and Clement L. Ren, MS, MD, (Indiana University School of Medicine, Riley Hospital for Children, Indianapolis)

The guidelines were published in December 2009, they were reviewed in April 2019 and it was determined that no update is needed at this time.

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