Indeterminate cystic fibrosis newborn screening results

We wish to praise Drs. Massie and Gillam for their thoughtful approach to the clinical dilemma of uncertain diagnosis after newborn screening forCF, emphasizing the importance of beneficence and non-maleficence as well as respect for autonomy and justice and avoidance of harm. The authors propose three options for “management” of these infants: Option 1. Manage as CF (initiating CF therapies), Option 2. Manage as CF carrier (not initiating CF therapies), or Option 3. Manage with surveillance (monitoring for treatable symptoms). We would like to point out that the author’s use of the term management does not distinguish between “treatment” and “monitoring. ” While monitoring may be considered to do harm in terms of cost and impact on family dynamics, we believe that in the absence of solid natural history data on the entity defined as CFTR-Related Metabolic Syndrome (CRMS), this safety net is a reasonable intervention. The greatest harm is initiating therapywithout specific clinical indications. Although not all of the infants may have been diagnosed by NBS, 80% of the 160 patients under 5 years of age with the R117H mutation reported as having CF in the most recent year of full data in the US CFRegistry had sweat chloride concentrations in the intermediate or normal range (most with unknown poly T status). Of these infants, 24% were being treated with pancreatic enzyme replacement therapy. Although, ductal bicarbonate flow may be decreased in these infants as it is in thosewith CF and pancreatic sufficiency, need for pancreatic enzyme replacement therapy is unlikely. We also reiterate that in the current era of infection protection and control, it is important to implement for CRMS patients the same clinical protocols in place for CF patients to minimize the risk of potential harm from exposure to pathogens. With regards to infants with one CF causing mutation and R117H-7T, we disagree that this genotype should be ignored in the newborn screening setting. We acknowledge that many individuals with this genotype may be entirely asymptomatic. However, in a cohort of 27 infants identified through CF NBS in Massachusetts and New York with one CF causing mutation and one R117H allele (all but one 7T), prospectively followed over the first 3 years of life, 6 of 15 cultured grew Pseudomonas aeruginosa, 5 had chronic respiratory symptoms and 5 had abnormal chest X-rays. Thus in spite of inconsistent arguments around the world regarding this genotype, there is evidence that some infants identified through CF newborn screening to have CRMS develop symptoms and signs that should prompt intervention and ultimately may be consistent with a diagnosis of CF. Drs. Massie and Gillam’s rationale in option 2 is to treat infants with an uncertain diagnosis as healthy carriers because “the available evidence suggests that most of the childrenwith anuncertaindiagnosis donotgoon todevelop clinical CF.” This option requires a high level of understanding on the part of the family and the child’s primary careprovider that in this case there is somehealth risk that is greater than the health riskof a healthy carrier. Themessage from theCF clinician is to put all of the responsibility in the hands of individuals who do not have CF experience and thus are least likely to recognize subtle changes. In the parlance of US football, this is “punting,” meaning “we’re stymied—you take charge and be responsible. ” For the third option, managing infants with uncertain diagnosis with some surveillance, the authors state “A simple approachmight include annual reviewwith further testing only based on clinical demand,” essentially the approach outlined by The US CF Foundation. This document includes an explanation for parents as well as an explanation for primary care providers, supporting the principles of beneficence, non-maleficence, autonomy, and justice. The experience in Rochester, NY illustrates this evolution of care. In the initial years after CF NBS was launched in New York State infants with an indeterminate CF diagnosis were followed closely, in a manner similar to infants with a clear-cut CF diagnosis.