Factors associated with receiving CF care and use of telehealth in 2020 among persons with Cystic Fibrosis in the United States.

BACKGROUND: The COVID-19 pandemic resulted in the use of telehealth to deliver the cystic fibrosis (CF) care model, which recommends routine follow-up for monitoring of nutritional status, bacterial culture surveillance, pulmonary function testing, and screening for CF-related complications such as diabetes or osteoporosis. METHODS: The objective of this study was to use Cystic Fibrosis Foundation Patient Registry (CFFPR) data to quantify the extent to which persons with CF received the recommended components of the care model in 2019 versus 2020. A risk factor analysis was implemented to identify patient characteristics associated with attaining the recommended CF care and use of any telehealth using multivariable logistic regression. RESULTS: A total of 28,132 CFFPR participants were included in the study. The proportion of individuals meeting the recommendations for CF care was lower in 2020 for every indicator, and lower in adults compared to children. In adults, demographic, socioeconomic and CF-related disease covariates were significantly associated with both achieving an aggregate level of care and use of telehealth. In the pediatric population, minority race/ethnicity and markers of lower socioeconomic status were associated with a lower odds of telehealth use. In all analyses, having received the recommended level of care in 2019 was associated with a higher odds of both reported telehealth use and achieving the recommended elements of the CF care model in 2020. CONCLUSION: Fewer participants met recommendations for care in 2020 despite widespread use of telehealth, and use of telehealth did not equate to adherence to all aspects of CF care.

DNA methylation regulates the neonatal CD4+ T-cell response to pneumonia in mice.

Pediatric acute lung injury, usually because of pneumonia, has a mortality rate of more than 20% and an incidence that rivals that of all childhood cancers combined. CD4+ T-cells coordinate the immune response to pneumonia but fail to function robustly among the very young, who have poor outcomes from lung infection. We hypothesized that DNA methylation represses a mature CD4+ T-cell transcriptional program in neonates with pneumonia. Here, we found that neonatal mice (3-4 days old) aspirated with Escherichia coli bacteria had a higher mortality rate than juvenile mice (11-14 days old). Transcriptional profiling with an unsupervised RNA-Seq approach revealed that neonates displayed an attenuated lung CD4+ T-cell transcriptional response to pneumonia compared with juveniles. Unlike neonates, juveniles up-regulated a robust set of canonical T-cell immune response genes. DNA methylation profiling with modified reduced representation bisulfite sequencing revealed 44,119 differentially methylated CpGs, which preferentially clustered around transcriptional start sites and CpG islands. A methylation difference-filtering algorithm detected genes with a high likelihood of differential promoter methylation regulating their expression; these 731 loci encoded important immune response and tissue-protective T-cell pathway components. Disruption of DNA methylation with the hypomethylating agent decitabine induced plasticity in the lung CD4+ T-cell marker phenotype. Altogether, multidimensional profiling suggested that DNA methylation within the promoters of a core set of CD4+ T-cell pathway genes contributes to the hyporesponsive neonatal immune response to pneumonia. These findings also suggest that DNA methylation could serve as a mechanistic target for disease-modifying therapies in pediatric lung infection and injury.

The influence of small for gestational age status on outpatient bronchopulmonary dysplasia outcomes.

OBJECTIVE: To describe the characteristics of small for gestational age (SGA) and non-SGA infants with bronchopulmonary dysplasia (BPD) and to ascertain whether respiratory outcomes and health-care utilization patterns in these two populations differ. STUDY DESIGN: Three hundred and twenty-five infants with BPD born at <32 weeks gestation were recruited in the outpatient setting. Sociodemographic data and indicators of respiratory morbidity were collected via questionnaire and retrospective chart review. RESULT: SGA infants were on average 1 month older than non-SGA infants at discharge from the neonatal intensive care unit and were more likely to have a weight less than 10th percentile at first clinic visit. History of SGA was associated with increased risk of emergency department visits as well as with caregiver perception of poor weight gain. CONCLUSION: SGA status in infants with BPD is associated with increased health-care utilization, including length of initial hospitalization and emergency department visits.

Health-care utilization and respiratory morbidities in preterm infants with pulmonary hypertension.

OBJECTIVE: To assess health-care utilization and risk of respiratory morbidities in preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). STUDY DESIGN: Retrospective data were obtained from subjects (n=109) attending a BPD clinic. Subjects were stratified by the presence or absence of PH before and after 2 months of age. Analytic methods included t-tests, χ(2) tests and regression. RESULT: Subjects with BPD and PH present after 2 months of age were hospitalized for 2.2 months longer than those without PH (P=0.02). These subjects were 4.5 times more likely to receive home supplemental oxygen or mechanical ventilation (P=0.03). No difference in the risk of respiratory morbidities after initial hospital discharge was seen with PH. CONCLUSION: PH in preterm infants is associated with longer initial hospitalizations and a higher likelihood of requiring home respiratory support. This has implications for counseling families and reducing the medical, psychosocial, and economic burden of BPD and PH.

Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis.

OBJECTIVE: To quantify the relative contribution of factors other than cystic fibrosis transmembrane conductance regulator genotype and environment on the acquisition of Pseudomonas aeruginosa (Pa) by patients with cystic fibrosis. STUDY DESIGN: Lung infection with Pa and mucoid Pa was assessed using a co-twin study design of 44 monozygous (MZ) and 17 dizygous (DZ) twin pairs. Two definitions were used to establish infection: first positive culture and persistent positive culture. Genetic contribution to infection (ie, heritability) was estimated based on concordance analysis, logistic regression, and age at onset of infection through comparison of intraclass correlation coefficients. RESULTS: Concordance for persistent Pa infection was higher in MZ (0.83; 25 of 30 pairs) than DZ twins (0.45; 5 of 11 pairs), generating a heritability of 0.76. Logistic regression adjusted for age corroborated genetic control of persistent Pa infection. The correlation for age at persistent Pa infection was higher in MZ twins (0.589; 95% CI, 0.222-0.704) than in DZ twins (0.162; 95% CI, -0.352 to 0.607), generating a heritability of 0.85. CONCLUSION: Genetic modifiers play a significant role in the establishment and timing of persistent Pa infection in individuals with cystic fibrosis.

Respiratory medication adherence in chronic lung disease of prematurity.

BACKGROUND: Chronic lung disease of prematurity (CLDP) is a frequent complication of premature birth. Infants and children with CLDP are often prescribed complex medication regimens, which can be difficult for families to manage. OBJECTIVE: We sought to determine whether non-adherence was associated with increased CLDP-related morbidities and to identify predictors of adherence. METHODS: Recruited caregivers of 194 children with CLDP completed questionnaires regarding self-reported adherence, respiratory outcomes, and quality of life (January 2008-June 2010). Adherence data were available for 176 subjects, of whom 143 had self-reported data only, and 33 had prescription claims data, which were used to calculate a medication possession ratio (MPR). Participants in the Prescription Claims Sample (n = 33) were more likely to have public insurance (P < 0.001). RESULTS: Self-reported adherence substantially overestimated medication possession; the mean MPR was 38.8% (n = 33) and was not associated with self-reported adherence (P = 0.71; n = 26). In a small sample, higher MPR was associated with decreased odds ratios of visiting the emergency department (ED) (OR = 0.75 for a 10% increase in MPR [95%CI: 0.58, 0.97]; P = 0.03; n = 74 questionnaires from 28 participants), activity limitations (OR = 0.71 [95%CI: 0.53, 0.95]; P = 0.02; n = 70 questionnaires from 28 participants), and rescue medication use (OR = 0.84 [95%CI: 0.73-0.98]; P = 0.03; n = 70 questionnaires from 28 participants). Increasing caregiver worries regarding medication efficacy and side effects were associated with lower MPR (P = 0.04 and 0.02, respectively; n = 62 questionnaires from 27 participants). Socio-demographic and clinical risk factors were not predictors of MPR (n = 33). CONCLUSIONS: We found that non-adherence with respiratory medications was common in premature infants and children with CLDP. Using multiple timepoints in a small sample, non-adherence was associated with a higher likelihood of respiratory morbidities. Although self-reported adherence and demographic characteristics did not predict MPR, concerns about medications did. We suggest that addressing caregiver concerns about medications may improve adherence and ultimately decrease CLDP-related morbidities. Larger, prospective studies are needed to confirm these findings and determine which factors predict non-adherence.

Polysomnography in preterm infants and children with chronic lung disease.

OBJECTIVE: To determine the utility of overnight polysomnography (PSG) in assessing pulmonary reserve in stable preterm children with chronic lung disease (CLD). STUDY DESIGN: A retrospective review and descriptive study of overnight PSGs and clinic visits of preterm infants/children less than 3 years of age who were diagnosed with bronchopulmonary dysplasia at discharge from the hospital and enrolled in the Johns Hopkins CLD patient registry between 2008 and 2010. RESULTS: Sixty-two clinically stable patients underwent at least one overnight polysomnogram for clinical indications. The majority of patients were referred for oxygen titration (71%). PSGs from first studies revealed a mean respiratory disturbance index (RDI) of 8.2 ± 10.1 events/hr and a mean O(2) saturation (SaO(2) ) nadir of 86.2 ± 5.7%. In patients who underwent more than one PSG (n = 23), a significant decrease in RDI (P < 0.001) was found between the first study (mean age: 8.0 ± 3.3 months) and second study (mean age: 13.4 ± 5.2 months). Outpatient clinical measures of mean room air SaO(2) and respiratory rate were not predictive of PSG measures of RDI and SaO(2) nadir. CONCLUSION: Mean RDI was higher in stable preterm infants/children with CLD compared to previously published controls. RDI decreased with age in stable preterm infants/children with CLD suggesting improved pulmonary reserve with age. Outpatient clinical measures (respiratory rate and room air SaO(2) ) did not correlate with RDI and SaO(2) nadir indicating that overnight PSG is more sensitive in assessing pulmonary reserve than outpatient clinical measures.

Exposure to neonatal cigarette smoke causes durable lung changes but does not potentiate cigarette smoke-induced chronic obstructive pulmonary disease in adult mice.

The impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung structure, function, and gene expression in adult mice. To model a childhood CS exposure, neonatal C57/B6 mice were exposed to 14 days of CS (Neo CS). At 10 weeks of age, Neo CS and control mice were exposed to 4 months of CS. Pulmonary function tests, bronchoalveolar lavage, and lung morphometry were measured and gene expression profiling was performed on lung tissue. Mean chord lengths and lung volumes were increased in neonatal and/or adult CS-exposed mice. Differences in immune, cornified envelope protein, muscle, and erythrocyte genes were found in CS-exposed lung. Neonatal CS exposure caused durable structural and functional changes in the adult lung but did not potentiate CS-induced COPD changes. Cornified envelope protein gene expression was decreased in all CS-exposed mice, whereas myosin and erythrocyte gene expression was increased in mice exposed to both neonatal and adult CS, suggesting an adaptive response. Additional studies may be warranted to determine the utility of these genes as biomarkers of respiratory outcomes.

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2.

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.

Socio-economic factors and outcomes in chronic lung disease of prematurity.

RATIONALE: Infants and children with chronic lung disease of prematurity (CLDP) are at increased risk for respiratory morbidities. We sought to determine (1) whether socio-economic status, race/ethnicity, and/or sex are risk factors for respiratory morbidities and (2) whether disparities in care existed for major therapy decisions such as home supplemental oxygen and gastrostomy tubes as well as initial length of stay in the neonatal intensive care unit. METHODS: Between January 2008 and February 2010 sociodemographic and respiratory morbidity data were collected on premature (<32 weeks gestation) infants and children (<3 years old) with CLDP. Associations between risk factors and respiratory morbidities and treatment parameters were examined using adjusted regression models. RESULTS: Data were collected on 135 subjects (gestational age: 26.2±2.0 weeks). Self-reported non-Whites were more likely to report rescue medication use in the past 7 days [adjusted OR: 2.87 (1.28-6.45), P=0.011] and the use of systemic steroids for respiratory symptoms since the last clinic visit [adjusted OR: 2.12 (1.02-4.43), P=0.045]. Lower median household income was associated with increased activity limitations [adjusted OR: 2.79 (1.16-6.70), P=0.022] and public insurance coverage was associated with a decreased risk for hospitalizations [adjusted OR: 0.36 (0.13-0.98), P=0.045]. Major therapy decisions were not associated with disparities of care. CONCLUSIONS: A key finding was that non-Whites were more likely to report rescue medication and systemic steroid use than Whites, but there was no difference in the frequency of respiratory symptoms or preventative inhaled corticosteroid use. Etiologies for these findings remain unclear and require further research.

Neonatal hyperoxia contributes additively to cigarette smoke-induced chronic obstructive pulmonary disease changes in adult mice.

The extent by which early postnatal lung injury contributes to the development of chronic obstructive pulmonary disease (COPD) in the adult is unclear. We hypothesized that exposure to hyperoxia during early postnatal life can augment lung changes caused by adult chronic cigarette smoke (CS) exposure. C57BL/6J mice (1 d old) were exposed to hyperoxia (O(2)) for 5 days. At 1 month of age, half of the O(2)-exposed mice and half of the control mice were placed in a CS chamber for 6 months. After exposure to CS, mice underwent quasi-static pressure-volume curve and mean chord length measurements; quantification of pro-Sp-c expression; and measurement of lung IL-8/ KC, CXCR2/IL8Rα, TNF-α, and IL-6 mRNA by real-time PCR. Adult mice exposed to O(2)+CS had significantly larger chord length measurements (P < 0.02) and lung volumes at 35 cm H(2)O (P < 0.05) compared with all other groups. They also had significantly less pro-Sp-c protein and surfactant protein C mRNA expression (P < 0.003). Mice exposed to O(2)+CS and CS-only mice had significantly higher lung resistance and longer mean time constants (P < 0.01), significantly more inflammatory cells in the bronchoalveolar lavage fluid (P < 0.03), and significantly higher levels of lung CXCR2/IL8Rα mRNA compared with mice not exposed to smoke (P < 0.02). We conclude that exposure to early postnatal hyperoxia contributed additively to CS-induced COPD changes in adult mice. These results may be relevant to a growing population of preterm children who sustained lung injury in the newborn period and may be exposed to CS in later life.

Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients.

BACKGROUND: Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF. METHODS: Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories. RESULTS: Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile). CONCLUSIONS: Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.

Day care increases the risk of respiratory morbidity in chronic lung disease of prematurity.

OBJECTIVES: Infants and children with chronic lung disease of prematurity (CLDP) are at increased risk for morbidity and mortality from respiratory viral infections. Exposure to respiratory viruses may be increased in the day care environment. The risk of respiratory morbidity from day care attendance in the CLDP population is unknown. We therefore sought to determine if day care attendance is a significant risk factor for increased respiratory morbidity and symptoms in infants and children with CLDP. METHODS: Between January 2008 and October 2009, parents of infants and children with CLDP were surveyed. Information on perinatal history, sociodemographic information, day care attendance, and indicators of respiratory morbidity, including emergency department (ED) visits, hospitalizations, systemic corticosteroid use, antibiotic use, and respiratory symptoms, was collected on children<3 years of age. Logistic regression models were constructed to examine associations between exposure to day care and respiratory morbidities. RESULTS: Data were collected from 111 patients with CLDP. The average gestational age was 26.2±2.0 weeks. Day care attendance was associated with significantly higher adjusted odds for ED visits (odds ratio [OR]: 3.74 [95% confidence interval (CI): 1.41-9.91]; P<.008), systemic corticosteroid use (OR: 2.22 [CI: 1.10-4.49]; P<.026), antibiotic use (OR: 2.40 [CI: 1.08-5.30]; P<.031), and days with trouble breathing (OR: 2.72 [CI: 1.30-5.69]; P<.008). Although there was an increased OR for hospitalization (OR: 3.22 [CI: 0.97-10.72]; P<.057), this did not reach statistical significance. CONCLUSIONS: We found that day care attendance is associated with increased respiratory morbidities in young children with CLDP. Physicians should consider screening for and educating caregivers about the risks of day care attendance by young children with CLDP.

Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes.

RATIONALE: Individuals with cystic fibrosis (CF) are subject to recurrent respiratory infections (exacerbations) that often require intravenous antibiotic treatment and may result in permanent loss of lung function. The optimal means of delivering therapy remains unclear. OBJECTIVES: To determine whether duration or venue of intravenous antibiotic administration affect lung function. METHODS: Data were retrospectively collected on 1,535 subjects recruited by the US CF Twin and Sibling Study from US CF care centers between 2000 and 2007. MEASUREMENTS AND MAIN RESULTS: Long-term decline in FEV1 after exacerbation was observed regardless of whether antibiotics were administered in the hospital (mean, -3.3 percentage points [95% confidence interval, -3.9 to -2.6]; n = 602 courses of therapy) or at home (mean, -3.5 percentage points [95% confidence interval, -4.5 to -2.5]; n = 232 courses of therapy); this decline was not different by venue using t tests (P = 0.69) or regression (P = 0.91). No difference in intervals between courses of antibiotics was observed between hospital (median, 119 d [interquartile range, 166]; n = 602) and home (median, 98 d [interquartile range, 155]; n = 232) (P = 0.29). Patients with greater drops in FEV1 with exacerbations had worse long-term decline even if lung function initially recovered with treatment (P < 0.001). Examination of FEV1 measures obtained during treatment for exacerbations indicated that improvement in FEV1 plateaus after 7-10 days of therapy. CONCLUSIONS: Intravenous antibiotic therapy for CF respiratory exacerbations administered in the hospital and in the home was found to be equivalent in terms of long-term FEV1 change and interval between courses of antibiotics. Optimal duration of therapy (7-10 d) may be shorter than current practice. Large prospective studies are needed to answer these essential questions for CF respiratory management.

Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function.

OBJECTIVE: To assess the relative contributions of environmental and genetic factors to variation in cystic fibrosis (CF) lung disease. STUDY DESIGN: Genetic and environmental contributions were quantified by use of intrapair correlations and differences in CF-specific forced expiratory volume in 1 second measures from 134 monozygous twins and 272 dizygous twins and siblings while in different living environments (ie, living with parents vs living alone), as well as by use of intraindividual differences in pulmonary function from a separate group of 80 siblings. RESULTS: Pulmonary function among monozygous twins was more similar than among dizygous twin and sibling pairs, regardless of living environment, affirming the role of genetic modifiers in CF pulmonary function. Regression modeling revealed that genetic factors account for 50% of pulmonary function variation, unique environmental or stochastic factors (36%), and shared environmental factors (14%; P < .0001). The intraindividual analysis produced similar estimates for the contributions of the unique and shared environment. The shared environment effects appeared primarily because of living with a sibling with CF (P = .003), rather than factors within the parental household (P = .310). CONCLUSIONS: Genetic and environmental factors contribute equally to pulmonary function variation in CF. Environmental effects are dominated by unique and stochastic effects rather than common exposures.

Lung function and late pulmonary complications among survivors of hematopoietic stem cell transplantation during childhood.

Hematopoietic stem cell transplantation (HSCT) is used to treat an expanding array of malignant and non-malignant disorders. Pulmonary complications represent a significant source of morbidity and mortality in HSCT recipients. Young children, whose lungs are still developing and growing, may be especially susceptible to the insults of irradiation, drug toxicities, and recurrent infections associated with immunosuppression. Late pulmonary complications, those occurring more than three months after transplantation, are often noninfectious and present with nonspecific symptomatology. Pulmonary function testing (PFT) is a mainstay of monitoring pulmonary health in HSCT recipients. The pulmonologist should be familiar with common patterns seen on PFT in recipients of HSCT during childhood. In this review, we describe the findings in studies which have examined lung function over time in patients who underwent HSCT during childhood. We discuss patterns of PFT abnormalities, associated noninfectious syndromes and their clinical implications, as well as directions for future research.

Elevated serum IL-8 levels in ataxia telangiectasia.

Serum interleukin (IL)-8 levels were measured in 50 patients with ataxia telangiectasia (A-T) and 22 without A-T. In a cross-sectional study, the geometric mean of IL-8 level was significantly higher in the patients with A-T (P <.0001). Elevated serum IL-8 levels in patients with A-T suggest that systemic inflammation may contribute to the disease phenotype.

Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis.

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.