Prenatal exposure to metal mixtures and lung function in children from the New Hampshire birth cohort study.

Prenatal exposure to metals/metalloids, even at common US population levels, may pose risks to fetal health, and affect children's lung function. Yet, the combined effects of simultaneous prenatal exposures on children's lung function remain largely unexplored. This study analyzed 11 metals (As speciation, Cd, Co, Cu, Mo, Ni, Pb, Sb, Se, Sn, Zn) in maternal urine during weeks 24-28 of gestation and evaluated lung function, including forced vital capacity (FVC) and forced expiratory volume in the first second of expiration (FEV1), in 316 US mother-child pairs at around age 7. We used Bayesian Kernel Machine Regression (BKMR), weighted quantile sum regression (WQSR), and multiple linear regression to examine the association between metal mixture exposure and children's lung function, adjusting for maternal smoking, child age, sex, and height. In BKMR models assessing combined exposure effects, limited evidence of metal non-linearity or interactions was found. Nevertheless, Co, As species, and Pb showed a negative association, while Mo exhibited a positive association with children's FVC and FEV1, with other metals held constant at their medians. The weighted index, from WQSR analysis assessing the cumulative impact of all metals, highlighted prenatal Mo with the highest positive weight, and Co, As, and Sb with the most substantial negative weights on children's FVC and FEV1. Urinary Co and Pb were negatively associated with FVC (ß = -0.09, 95% confidence interval (CI) (-0.18; -0.01) and ß = -0.07, 95% CI (-0.13; 0.00), respectively). Co was also negatively associated with FEV1 (ß = -0.09, 95% CI (-0.18; 0.00). There was a negative association between As and FVC, and a positive association between Mo and both FVC and FEV1, though with wide confidence intervals. Our findings suggest that prenatal trace element exposures may impact children's lung function, emphasizing the importance of reducing toxic exposures and maintaining adequate nutrient levels.

Prenatal exposure to arsenic and lung function in children from the New Hampshire Birth Cohort Study.

Prenatal arsenic exposure is associated with an increased risk of lung cancer along with multiple non-carcinogenic outcomes, including respiratory diseases in arsenic-contaminated areas. Limited epidemiologic data exist on whether in utero arsenic exposure influences lung development and subsequent respiratory health. We investigated the association between gestational arsenic exposure and childhood lung function in the New Hampshire Birth Cohort Study. Urinary arsenic speciation including inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and arsenobetaine was measured in maternal urine samples collected during pregnancy and spirometry was performed in offspring at a median age of 7.4 years. Forced vital capacity (FVC), forced expiratory volume in the first second of exhalation (FEV1), and forced expiratory flow between 25% and 75% of FVC (FEF25-75) standardized z-scores were assessed in linear models as dependent variables with the log2-transformed summation of urinary arsenic species (ΣAs = iAs + MMA + DMA) corrected for specific gravity as an independent variable and with adjustment for maternal smoking status, children's age, sex and height. Among the 358 children in the study, a doubling of ΣAs was associated with a -0.08 (ß) decrease in FVC z-scores (95% confidence interval (CI) from -0.14 to -0.01) and -0.10 (ß) (95% CI from -0.18 to -0.02) decrease in FEV1 z-scores. The inverse association appeared stronger among those mothers with lower secondary methylation index (urinary DMA/MMA), especially among girls. No association was observed for FEF25-75 z-scores. Our results suggest that gestation arsenic exposure at levels relevant to the general US population during the vulnerable period of lung formation may adversely affect lung function in childhood.

Altered Stool Microbiota of Infants with Cystic Fibrosis Shows a Reduction in Genera Associated with Immune Programming from Birth.

Previous work from our group indicated an association between the gastrointestinal microbiota of infants with cystic fibrosis (CF) and airway disease in this population. Here we report that stool microbiota of infants with CF demonstrates an altered but largely unchanging within-individual bacterial diversity (alpha diversity) over the first year of life, in contrast to the infants without CF (control cohort), which showed the expected increase in alpha diversity over the first year. The beta diversity, or between-sample diversity, of these two cohorts was significantly different over the first year of life and was statistically significantly associated with airway exacerbations, confirming our earlier findings. Compared with control infants, infants with CF had reduced levels of Bacteroides, a bacterial genus associated with immune modulation, as early as 6 weeks of life, and this significant reduction of Bacteroides spp. in the cohort with CF persisted over the entire first year of life. Only two other genera were significantly different across the first year of life: Roseburia was significantly reduced and Veillonella was significantly increased. Other genera showed differences between the two cohorts but only at selected time points. In vitro studies demonstrated that exposure of the apical face of polarized intestinal cell lines to Bacteroides species supernatants significantly reduced production of interleukin 8 (IL-8), suggesting a mechanism whereby changes in the intestinal microbiota could impact inflammation in CF. This work further establishes an association between gastrointestinal microbiota, inflammation, and airway disease in infants with CF and presents a potential opportunity for therapeutic interventions beginning in early life.IMPORTANCE There is growing evidence for a link between gastrointestinal bacterial communities and airway disease progression in CF. We demonstrate that infants with CF ≤1 year of age show a distinct stool microbiota versus that of control infants of a comparable age. We detected associations between the gut microbiome and airway exacerbation events in the cohort of infants with CF, and in vitro studies provided one possible mechanism for this observation. These data clarify that current therapeutics do not establish in infants with CF a gastrointestinal microbiota like that in healthy infants, and we suggest that interventions that direct the gastrointestinal microbiota closer to a healthy state may provide systemic benefits to these patients during a critical window of immune programming that might have implications for lifelong health.

Use of an In-line Digestive Cartridge With Enteral Nutrition Improves the Weight Trajectory of 2 Children With Cystic Fibrosis Complicated by Another Medical Diagnosis.

This clinical observation describes the enteral nutrition (EN) management of 2 toddlers at high nutrition risk due to cystic fibrosis (CF), exocrine pancreatic insufficiency, and comorbid medical conditions. The first case report describes a boy with severe malabsorption after intestinal resection. The second case report reviews a boy with CF and neuroblastoma. When pancreatic enzyme replacement therapy with EN was not effective or appropriate, use of an in-line digestive cartridge was initiated. While using the digestive cartridge, both children showed improvements in their anthropometric measures. This observation reviews the nutrition management throughout their clinical course and describes the use of a digestive cartridge with EN.

Cystic Fibrosis Foundation Pulmonary Guidelines. Use of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy in Patients with Cystic Fibrosis.

RATIONALE: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are a new class of medications targeting the underlying defect in CF. Ivacaftor (IVA) and IVA combined with lumacaftor (LUM; IVA/LUM) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with CF. However, the FDA label for these medications encompasses patient groups that were not studied as part of the drug approval process. CF clinicians, patients, and their families have recognized a need for recommendations to guide the use of these medications. OBJECTIVE: Develop evidence-based guidelines for CFTR modulator therapy in patients with CF. METHODS: A multidisciplinary committee of CF caregivers and patient representatives was assembled. A methodologist, an epidemiologist, a medical librarian, and a biostatistician were recruited to assist with the literature search, evidence grading, and generation of recommendations. The committee developed clinical questions using the Patient-Intervention-Comparison-Outcome format. A systematic review was conducted to find relevant publications. The evidence was then evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach, and recommendations were made based on this analysis. RESULTS: For adults and children aged 6 years and older with CF due to gating mutations other than G551D or R117H, the guideline panel made a conditional recommendation for treatment with IVA. For those with the R117H mutation, the guideline panel made a conditional recommendation for treatment with IVA for 1) adults aged 18 years or older, and 2) children aged 6-17 years with a forced expiratory volume in 1 second (FEV1) less than 90% predicted. For those with the R117H mutation, the guideline panel made a conditional recommendation against treatment with IVA for 1) children aged 12-17 years with an FEV1 greater than 90% predicted, and 2) children less than 6 years of age. Among those with two copies of F508del, the guideline panel made a strong recommendation for treatment with IVA/LUM for adults and children aged 12 years and older with an FEV1 less than 90% predicted; and made a conditional recommendation for treatment with IVA/LUM for 1) adults and children aged 12 years or older with an FEV1 greater than 90% predicted, and 2) children aged 6-11 years. CONCLUSIONS: Using the GRADE approach, we have made recommendations for the use of CFTR modulators in patients with CF. These recommendations will be of help to CF clinicians, patients, and their families in guiding decisions regarding use of these medications.

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis.

Cystic fibrosis (CF) clinical care guidelines exist for the care of infants up to age 2 years and for individuals ≥6 years of age. An important gap exists for preschool children between the ages of 2 and 5 years. This period marks a time of growth and development that is critical to achieve optimal nutritional status and maintain lung health. Given that disease often progresses in a clinically silent manner, objective and sensitive tools that detect and track early disease are important in this age group. Several challenges exist that may impede the delivery of care for these children, including adherence to therapies. A multidisciplinary committee was convened by the CF Foundation to develop comprehensive evidence-based and consensus recommendations for the care of preschool children, ages 2 to 5 years, with CF. This document includes recommendations in the following areas: routine surveillance for pulmonary disease, therapeutics, and nutritional and gastrointestinal care.

Associations between Gut Microbial Colonization in Early Life and Respiratory Outcomes in Cystic Fibrosis.

OBJECTIVE: To examine patterns of microbial colonization of the respiratory and intestinal tracts in early life in infants with cystic fibrosis (CF) and their associations with breastfeeding and clinical outcomes. STUDY DESIGN: A comprehensive, prospective longitudinal analysis of the upper respiratory and intestinal microbiota in a cohort of infants and young children with CF followed from birth was performed. Genus-level microbial community composition was characterized using 16S-targeted pyrosequencing, and relationships with exposures and outcomes were assessed using linear mixed-effects models, time-to-event analysis, and principal components analysis. RESULTS: Sequencing of 120 samples from 13 subjects collected from birth to 34 months revealed relationships between breastfeeding, microbial diversity in the respiratory and intestinal tracts, and the timing of onset of respiratory complications, including exacerbations and colonization with Pseudomonas aeruginosa. Fluctuations in the abundance of specific bacterial taxa preceded clinical outcomes, including a significant decrease in bacteria of the genus Parabacteroides within the intestinal tract prior to the onset of chronic P aeruginosa colonization. Specific assemblages of bacteria in intestinal samples, but not respiratory samples, were associated with CF exacerbation in early life, indicating that the intestinal microbiome may play a role in lung health. CONCLUSIONS: Our findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions. Further studies in larger cohorts validating these findings are needed.

Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection.

DESCRIPTION: The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF. METHODS: A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).

Atypical presentation of chronic granulomatous disease with Burkholderia cepacia.

Chronic granulomatous disease (CGD) is a rare inherited disorder of neutrophil oxidative burst. In patients with CGD, phagocyte destruction of catalase-producing organisms is impaired, resulting in recurrent and potentially fatal infections. Burkholderia cepacia, a catalase-producing organism, is known to infect patients with dysfunctional immune systems. We report a case of a 3-year-old boy with this rare infection that unravelled the diagnosis of CGD.

Paraneoplastic autoimmune multiorgan syndrome (paraneoplastic pemphigus) in a child: case report and review of the literature.

Paraneoplastic autoimmune multiorgan syndrome, also known as paraneoplastic pemphigus, has been observed only rarely among children. We describe a 10-year-old boy with typical clinical and histologic findings of paraneoplastic pemphigus associated with Castleman's disease. His disease was refractory to resection of the tumor and aggressive combination immunosuppressive therapies. The patient died 1 year after presentation, as a result of complications of bronchiolitis obliterans. This case is unusual because of the young age of the patient.