Defining and identifying early‐onset lung disease in cystic fibrosis with cumulative clinical characteristics

Abstract

Background Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early‐onset lung disease is needed. Objective To develop a CF early‐onset lung disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life. Design We studied 145 infants born during 2012–2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1–2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe. Results The most frequent manifestation of CF early lung disease was MD‐reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent‐reported cough severity was correlated with the number of respiratory hospitalizations (r = 0.48, p < 0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred threefold higher in pancreatic insufficient (PI, 49%) versus sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition‐related hospitalizations, plasma cytokines interleukin (IL)‐6 and IL‐10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores. Conclusion The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision‐making particularly in the initiation of CFTR modulator therapy.

Severe lung disease in children with cystic fibrosis missed in newborn screening

“…The IRT level can be falsely low in patients with meconium ileus as illustrated by Case 5 17 . Before the era of routine CF NBS, the onset of CF lung disease was not well characterized, 10 but it is now understood that respiratory manifestations can develop early and present as either insidious or acute/severe lung disease 19–21 . Although some reported screening missed cases due to false negative results have not manifested lung disease, 22 our observations and others 23,24 demonstrate clearly that false negative tests can result in dangerous delays in diagnosis and treatment that are potentially associated with increased mortality.…”

Impact of intrinsic and extrinsic risk factors on early‐onset lung disease in cystic fibrosis

“…However, since objective measures of lung function such as multiple breath washout are not performed in routine clinical settings for children younger than 3 years of age, the CFELD system provides a standardized approach to assess lung disease severity. In addition, it was developed with sound multiattribute methodology 7 . But, validation of the CFELD system by objective measures of lung disease is needed and is planned by the FIRST team when all subjects have completed their age 6‐years assessments.…”

“…The WGS component 19 was initiated in 2017. Of the 145 infants who completed follow-up to ≥3 years of age 7,18 thus eligible for WGS, 116 subjects' families were available to approach for consent, and 90% (N = 104) agreed.…”

“…The characteristic clinical features of CF and our unique cohort of young children in the longitudinal Feeding Infants Right… from the STart (FIRST) project 18 enabled us to develop a clinical severity scoring system for infants and toddlers that we refer to as Cystic Fibrosis Early‐onset Lung Disease (CFELD) 7 . Its first application confirmed the heterogeneity of CF lung disease, particularly in its onset between 1 and 3 years of age 7 .…”

“…1 It is known from histopathological studies on autopsied infants 2,3 and chest computed tomography (CT) observations [4][5][6] on patients diagnosed through newborn screening that lung disease develops as early as 10 weeks of age, 4,5 and nearly one-third have bronchiectasis by 2-4 months of age. 6 In addition, early development of lung disease, defined herein as during the first 3 years of life, 7 correlates with its progression in children with CF. 8,9 Yet very little attention has been given to the timing and determinants of early onset of CF lung disease, nor to the interplay of intrinsic/genetic [10][11][12] and extrinsic/environmental risk factors in young children that potentially determine prognosis as patients age.…”