Discussion:
In this study we performed a retrospective analysis of children reported to have CRMS in the CFFPR. Our results show that for the first 9-10 years of life, the large majority of infants with CRMS remain healthy and do not convert to CF. In contrast to children with CF, their ppFEV1 and nutritional indices are normal. However, a small percentage of children do develop clinical features concerning for CF, such as a respiratory culture positive for Pa.
Although several studies of prevalence and outcomes of CRMS/CFSPID, most studies have been limited to children ≤3 years old [7, 8]. Grove, et al performed a retrospective study of 29 infants with CRMS who were followed for 2-10 years and reported that 48% converted to CF [15]. However, many of these children were diagnosed on the basis of non-specific clinical signs, such as cough. More recently, Muncket al reported the results of a prospective matched cohort study of infants with CF and CFSPID [16]. Comparison of their results to ours is difficult because a large percentage (32%) of the CFSPID infants were later diagnosed with CF due to reclassification of their CFTR mutations as CF-causing. With that caveat in mind, their cohort also demonstrated normal nutritional and FEV1 indices. However, chest computed tomography revealed the presence of bronchiectasis in 8% of the cohort, highlighting the potential for lung disease in CRMS/CFSPID infants. Terlizzi et al reported that 10% of CFSPID infants followed for up to 6 years converted to CF, based on an elevation of sweat chloride ≥60 mmol/L [17]. However, they did not report on any clinical features of these infants. Gonska, et al prospectively followed a cohort of infants with CRMS/CFSPID in Canada and Verona up to age 7 years [9]. Similar to our study, they found that nutritional indices and lung function were normal at age 7 years. Our study complements that of Gonska, et al and other by analyzing a larger, more diverse cohort of infants with CRMS/CFSPID followed at >100 CF Care Centers across the USA. We also analyzed microbiologic outcomes at different ages and showed that in contrast to infants/children with CF, Pa prevalence in CRMS/CFSPID declined with age. Taken together, the studies cited above and our results indicate that infants who meet a CFF guideline definition of CRMS may still present with clinical features concerning for CF even in childhood, and they support the need for continued close monitoring of this infants.
There are several limitations of our study, but also some strengths. Not all CRMS infants are entered into the CFFPR, either because their care teams or the families do not wish to enroll them. This may have resulted in underreporting of the true prevalence of CRMS. There were also many patients with incomplete genetic or sweat chloride data, which precluded us from being able to assign a guideline diagnosis of CF or CRMS. The CFFPR collects only limited clinical symptom and physical exam findings, such as cough or wheeze; having such data may have provided more insight into why some children were classified as CF despite not meeting sweat chloride or CFTR mutation criteria for this diagnosis. There is also variation in care amongst CF Centers, such as frequency of respiratory cultures and follow up sweat testing, which may have affected the consistency of some of our outcome measures. The loss to follow up rate was higher in the CRMSc/CRMSg compared to the other groups (Tables S3, S4, and S5). This may have resulted in selection bias towards retaining only those infants with more symptoms or concerns for CF. Thus we need to be circumspect in comparing clinical outcomes between the CRMSc/CRMSg and CFc/CRMSg groups. Since follow up sweat testing was performed at the discretion of clinical care teams, we could not perform any analysis of serial sweat testing. Strengths of our study include the large number of patients in our study cohort followed at a large number of different CF Centers and the long follow up time.
In summary, this large registry-based analysis of CRMS infants up to ages 9-10 years shows that the large majority remain well, do not convert to a CF diagnosis, and have normal nutritional and pulmonary indices. However, a small proportion do develop clinical features concerning for CF. These results support continued close monitoring of these infants at least into early childhood. Future research should include longer follow up to ascertain the risk of CFTR-related disorder in these children and to identify any other risk factors for development of CF other than initial sweat chloride concentration.
Acknowledgements
The authors would like to thank the Cystic Fibrosis Foundation for the use of CF Foundation Patient Registry data to conduct this study. Additionally, we would like to thank the patients, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CF Foundation Patient Registry. We also thank Ase Sewall for her assistance with data preparation.