HuiChuan J. Lai

Background: Genetic modifiers have been identified that increase the risks of lung disease and other complications, such as diabetes in people with cystic fibrosis (CF). Variants in the hemochromatosis gene (HFE) were reported in a study of adults to be associated with worse lung disease.Objectives: To ascertain the frequency of HFE variants, particularly C282Y (c.845G > A) and H63D (c.187C > G) and to determine if they are associated with variations in the onset and early severity of CF lung disease as well as abnormalities in iron status.Design: We studied with whole genome sequencing and clinical outcome measures in a cohort of 104 children with CF at 5–6 years old who were previously found to show an association between aggregated genetic modifiers and an earlier onset and a more severe lung disease phenotype.Results: In our cohort, 23% have H63D and 11% have C282Y. Lung function at age 6 years and Pseudomonas aeruginosa infections did not differ by HFE variants, but having C282Y was associated with more pulmonary exacerbations in the first 6 years of life. Three patients have H63D/C282Y genotype, and all showed phenotypic expression of hemochromatosis with abnormal iron indices.Conclusion: Our study revealed that the presence of HFE variant C282Y in people with CF may lead to more severe lung disease manifestations beginning in early childhood. There is a risk of hemochromatosis in CF patients with two HFE variants, and thus they should be followed for evidence of iron overload.

Objective: Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early‐onset lung disease in young children with CF.Methods: One hundred and forty‐five infants with CF born during 2012–2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early‐onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology.Results: ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α‐diversity at 3 years of age was significantly lower and early‐onset lung disease more severe, in persistent ABT users compared to nonusers of ABT.Conclusion: In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early‐onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk–benefit analysis of ABT to ensure proper guidelines for children with CF.

Background: Although respiratory pathology is known to develop in young children with cystic fibrosis (CF), the determinants of early‐onset lung disease have not been elucidated.Objective: We aimed to determine the impact of potential intrinsic and extrinsic risk factors during the first 3 years of life, testing the hypothesis that both contribute significantly to early‐onset CF lung disease.Design: We studied 104 infants born during 2012–2017, diagnosed through newborn screening by age 3 months, and evaluated comprehensively to 36 months of age. Lung disease manifestations were quantified with a new scoring system known as CFELD for Cystic Fibrosis Early‐onset Lung Disease. The variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were determined and categorized. Whole genome sequencing was performed on each subject and the data transformed to polygenic risk scores (PRS) that aggregate variants associated with lung function. Extrinsic factors included socioeconomic status (SES) indicators and environmental experiences such as exposures to smoking, pets, and daycare.Results: We found by univariate analysis that CFTR genotype and genetic modifiers aggregated by the PRS method were significantly associated with early‐onset CF lung disease. Ordinal logistic regression analysis demonstrated that high and stable SES (maternal education ≥community college, stable 2‐parent home, and not receiving Medicaid) and better growth (weight‐for‐age and height‐for‐age z‐scores) reduced risks, while exposure to smoking and daycare ≥20 h/week increased the risk of CFELD severity.Conclusions: Extrinsic, modifiable determinants are influential early and potentially as important as the intrinsic risk factors in the onset of CF lung disease.

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.

Background: The variable response to fat‐soluble vitamin supplementation in young children with cystic fibrosis (CF), and factors contributing to this variability, remain under‐investigated.Objective: To determine if recommended supplement doses normalize serum vitamins A (retinol), D (25‐hydroxy‐vitamin D, 25OHD), and E (α‐tocopherol), and identify factors predictive of achieving sufficiency, in children with CF in the first 3 years of life.Design: We studied 144 infants born during 2012–2017 and diagnosed with CF through newborn screening. Serum retinol, 25OHD, α‐tocopherol and plasma cytokines interleukin (IL)‐6, IL‐8, IL‐10, and tumor necrosis factor (TNF)‐α were measured in early infancy and yearly thereafter. Vitamin supplement intakes and respiratory microbiology were assessed every 1–2 months in infancy and quarterly thereafter.Results: The prevalence of vitamin D insufficiency (<30 ng/ml) at all ages combined was significantly higher (22%) compared to vitamin A (<200 ng/ml, 3%) and vitamin E (<5 µg/ml, 5%). All children were vitamin A sufficient by age 2 years. Vitamin E insufficiency was rare. Only 42% were early responders of vitamin D and 17% remain insufficient despite high supplement intakes. IL‐6 was positively correlated, while IL‐8, IL‐10, and TNF‐α were negatively correlated, with retinol and 25OHD. Multiple regression analysis revealed that supplement dose, season, α‐tocopherol, pancreatic insufficiency, respiratory infections and IL‐10 were significant predictors of 25OHD.Conclusion: Diagnosis through newborn screening coupled with supplementation normalized serum retinol and α‐tocopherol in almost all infants with CF by age 3 years. However, response to vitamin D supplements in young children with CF occurred later and variably despite early and sustained supplementation.

Background: Zinc deficiency is associated with poor growth in children without cystic fibrosis (CF), but its impact on growth in children with CF is unknown.Objective: To determine the prevalence of low serum Zn (sZn) and its relationship with growth in the first 3 years of life in children with CF.Methods: We utilized data from infants with CF who were enrolled in a longitudinal study of nutrition and lung health and had sZn measured as part of clinical care. Cross‐sectional correlations between sZn levels and growth z scores were assessed by Pearson's correlation coefficient. To identify factors associated with sZn status and its association to longitudinal growth patterns, multiple regression analysis with repeated measures were performed using generalized estimating equations.Results: A total of 106 sZn measurements from 53 infants were identified. Seventeen infants (32%) had intermittent Zn insufficiency, defined as at least one sZn z scores. However, analysis of longitudinal growth patterns revealed that weight‐ and length‐for‐age z scores in children with intermittent Zn insufficiency were lower during early infancy and their weight‐for‐length z scores at age 3 years were also lower compared to those who were always Zn sufficient.Conclusion: Low sZn occurs in one‐third of children with CF in the first 3 years of life. Cross‐sectional and longitudinal analyses revealed discrepant associations between sZn and growth. Therefore, prospective studies are needed to understand the role of Zn in growth in CF.

BACKGROUND: Exocrine pancreatic insufficiency causes fat malabsorption in patients with cystic fibrosis (CF) and increases risks of vitamin D deficiency. Serum 25‐hydroxy vitamin D [25(OH)D] is the recommended biomarker for monitoring vitamin D status. The CF Foundation (CFF) recommends daily vitamin D supplementation, starting at 400–500IU/day of vitamin D ₃ after diagnosis and 800–1000IU/day for children above 1 year old. The current Recommended Dietary Allowances (RDA) for vitamin D is 400IU/day for infants and 600IU/day for toddlers between 1 to 3 years old. The reported prevalence of suboptimal vitamin D status ( FIRST (Feeding Infants Right… from the STart), a multicenter prospective observational study initiated in 2012 at 6 CF centers (Madison, Milwaukee, Indianapolis, Salt Lake City, Boston, and Chicago) to identify optimal feeding for infants with CF. A total of 221 sera from 22 infants who have reached 1 year of age and 74 toddlers who have reached 2 years of age by 06/30/16 and were analyzed. Serum total 25(OH)D was measured at approximately age 4 months (n=73, 3.7 ± 0.2 months), 12 months (n=74, 12.6 ± 0.2 months), and 24 months (n=74, 22.9 ± 0.3 months). Vitamin D supplementation was assessed monthly prior to 6 months of age, bi‐monthly from 6–12 months, and every 3 months in the second year of life. RESULTS: At around 4 months of age, only 5% had vitamin D deficiency (Support or Funding Information NIH R01DK072126, UL1TR000427, CFFT‐LAI140A0