Anna Faino

Patterns of adaptation to children's food allergies

Families with food allergy (FA) are at risk of reduced quality of life and elevated anxiety. A moderate level of anxiety may be beneficial to sustain vigilance for food avoidance; however, excessive anxiety may increase risk for burden and maladjustment. The current study presents a framework for understanding the patterns of adaptation to FA across families and to identify typologies of families that would benefit from intervention.

Experimentally manipulated sleep duration in adolescents with asthma: Feasibility and preliminary findings

To examine the impact of sleep duration on lung function and asthma symptoms in adolescents.

Extremes of Interferon-Stimulated Gene Expression Associate with Worse Outcomes in the Acute Respiratory Distress Syndrome.

Acute Respiratory Distress Syndrome (ARDS) severity may be influenced by heterogeneity of neutrophil activation. Interferon-stimulated genes (ISG) are a broad gene family induced by Type I interferons, often as a response to viral infections, which evokes extensive immunomodulation. We tested the hypothesis that over- or under-expression of immunomodulatory ISG by neutrophils is associated with worse clinical outcomes in patients with ARDS. Genome-wide transcriptional profiles of circulating neutrophils isolated from patients with sepsis-induced ARDS (n = 31) and healthy controls (n = 19) were used to characterize ISG expression. Hierarchical clustering of expression identified 3 distinct subject groups with Low, Mid and High ISG expression. ISG accounting for the greatest variability in expression were identified (MX1, IFIT1, and ISG15) and used to analyze a prospective cohort at the Colorado ARDS Network site. One hundred twenty ARDS patients from four urban hospitals were enrolled within 72 hours of initiation of mechanical ventilation. Circulating neutrophils were isolated from patients and expression of ISG determined by PCR. Samples were stratified by standard deviation from the mean into High (n = 21), Mid, (n = 82) or Low (n = 17) ISG expression. Clinical outcomes were compared between patients with High or Low ISG expression to those with Mid-range expression. At enrollment, there were no differences in age, gender, co-existing medical conditions, or type of physiologic injury between cohorts. After adjusting for age, race, gender and BMI, patients with either High or Low ISG expression had significantly worse clinical outcomes than those in the Mid for number of 28-day ventilator- and ICU-free days (P = 0.0006 and 0.0004), as well as 90-day mortality and 90-day home with unassisted breathing (P = 0.02 and 0.004). These findings suggest extremes of ISG expression by circulating neutrophils from ARDS patients recovered early in the syndrome are associated with poorer clinical outcomes.

A retrospective study of acute mountain sickness on Mt. Kilimanjaro using trekking company data.

BACKGROUND High altitude illnesses (HAI) are a risk factor for any individual who is exposed to a significant increase in altitude. To learn more about the epidemiology of HAI, we sought to determine if health records from a commercial trekking company could provide novel data on the prevalence of HAI, as well as efficacy data regarding common HAI therapeutics. METHODS Health parameters from 917 tourists ascending Mt. Kilimanjaro over a 10-yr period were analyzed for meaningful data. RESULTS Of all subjects, 70% experienced at least one instance of a symptom related to HAI (headache, nausea, vomiting, diarrhea, or loss of appetite) during the trek. Acetazolamide was used at least once by 90% of subjects and, of those who used acetazolamide, 92% began taking it on day 1 of the ascent. Acetazolamide was found to improve oxygen saturation 1.2% above 9842.5 ft (3000 m). Dexamethasone use 12 h prior to ascending above 18,996 ft (5790 m) decreased the probability of a subject exhibiting at least one AMS symptom at that altitude. DISCUSSION The prevalence of AMS symptoms was not reduced by taking 2 extra days to reach the summit of Mt. Kilimanjaro. Prophylactic acetazolamide modestly improved oxygen saturation; however, it did not reduce symptoms. Therapeutic dexamethasone, especially at higher altitudes, was effective at reducing symptoms. We conclude that meaningful high altitude physiological data can be obtained from private trekking companies.

Identifying rare variants associated with hypertension using the C-alpha test

Important rare variants may be near significantly associated common variants based on genetic distance. For this reason, we conducted an analysis of rare variants informed by tests of single-marker association at loci with common variants. We identified highly significant common variants within chromosome 3, as well as rare variants around these locations. Based on a predetermined window size, we then analyzed these rare variants with the C-alpha test to determine significant associations with hypertension. We found significant rare variants around common variants; however, the C-alpha test was sensitive to the specified window size. When comparing markers in genes to markers not in genes, we found that markers not in genes had more significant C-alpha test p values than markers in genes.

Whole Blood Gene Expression Profiling Predicts Severe Morbidity and Mortality in Cystic Fibrosis: A 5-Year Follow-Up Study

Rationale: Cystic fibrosis pulmonary exacerbations accelerate pulmonary decline and increase mortality. Previously, we identified a 10‐gene leukocyte panel measured directly from whole blood, which indicates response to exacerbation treatment. We hypothesized that molecular characteristics of exacerbations could also predict future disease severity. Objectives: We tested whether a 10‐gene panel measured from whole blood could identify patient cohorts at increased risk for severe morbidity and mortality, beyond standard clinical measures. Methods: Transcript abundance for the 10‐gene panel was measured from whole blood at the beginning of exacerbation treatment (n = 57). A hierarchical cluster analysis of subjects based on their gene expression was performed, yielding four molecular clusters. An analysis of cluster membership and outcomes incorporating an independent cohort (n = 21) was completed to evaluate robustness of cluster partitioning of genes to predict severe morbidity and mortality. Results: The four molecular clusters were analyzed for differences in forced expiratory volume in 1 second, C‐reactive protein, return to baseline forced expiratory volume in 1 second after treatment, time to next exacerbation, and time to morbidity or mortality events (defined as lung transplant referral, lung transplant, intensive care unit admission for respiratory insufficiency, or death). Clustering based on gene expression discriminated between patient groups with significant differences in forced expiratory volume in 1 second, admission frequency, and overall morbidity and mortality. At 5 years, all subjects in cluster 1 (very low risk) were alive and well, whereas 90% of subjects in cluster 4 (high risk) had suffered a major event (P = 0.0001). In multivariable analysis, the ability of gene expression to predict clinical outcomes remained significant, despite adjustment for forced expiratory volume in 1 second, sex, and admission frequency. The robustness of gene clustering to categorize patients appropriately in terms of clinical characteristics, and short‐ and long‐term clinical outcomes, remained consistent, even when adding in a secondary population with significantly different clinical outcomes. Conclusions: Whole blood gene expression profiling allows molecular classification of acute pulmonary exacerbations, beyond standard clinical measures, providing a predictive tool for identifying subjects at increased risk for mortality and disease progression.

Cysteinyl Leukotriene Receptor 1 and Health Effects of Particulate Exposure in Asthma

RATIONALE Acute exposure to ambient particle matter is associated with increased levels of the cysteinyl leukotriene (CysLT) biomarker, urinary leukotriene E4 (uLTE4), in subjects with asthma. OBJECTIVES The role of CysLTs in mediating asthma worsening after particulate matter exposures was explored. METHODS Daily concentrations of particulate matter of 2.5 μm and smaller diameter (PM2.5) and repeated measurements of albuterol use over a 5-month period were collected in 44 urban school children with persistent asthma. DNA was analyzed for gene polymorphisms on genes involved in the CysLT pathway to identify gene-environment interactions. An experimental challenge study in 16 adults with mild, nonpersistent asthma was performed to define biological pathways explaining these gene-environment interactions. Subjects in the challenge study were exposed on two different days to filtered air or diesel exhaust (300 μg PM2.5/m3). FEV1 and CysLT-related gene DNA methylation and messenger RNA expression changes were measured before and 6 hours after exposure challenges. RESULTS In school children with asthma, associations between PM2.5 and school-time albuterol usage were significantly greater in those with the variant C allele in the CysLT receptor 1 (CysLTR1) rs320995 locus (5.4% increase per interquartile range PM2.5 increase) compared with those homozygous for the wild-type T allele (1.6% decrease; P = 0.005 for allele × PM2.5 interaction). In the challenge study, declines in forced expiratory volume in 1 second after diesel exhaust exposure were associated with lower CysLTR1 expression (r2 = 0.52; P = 0.01), which, in turn, was associated with decreased leukotriene C4 synthase cg1631890 (P = 0.02) and increased CysLTR1 cg26848126 (P = 0.01) methylation, as assessed in a multivariable model (r2 = 0.69). CONCLUSIONS Health effects of acute particulate exposure on asthma are associated with changes in CysLTR1 expression and methylation of CpG sites on CysLTR1 and leukotriene C4 synthase genes.

Clinical tool for disease phenotyping in granulomatous lung disease

Background Exposure to beryllium may lead to granuloma formation and fibrosis in those who develop chronic beryllium disease (CBD). Although disease presentation varies from mild to severe, little is known about CBD phenotypes. This study characterized CBD disease phenotypes using longitudinal measures of lung function. Methods Using a case-only study of 207 CBD subjects, subject-specific trajectories over time were estimated from longitudinal pulmonary function and exercise-tolerance tests. To estimate linear combinations of the 30-year values that define underlying patterns of lung function, we conducted factor analysis. Cluster analysis was then performed on all the predicted lung function values at 30 years. These estimates were used to identify underlying features and subgroups of CBD. Results Two factors, or composite measures, explained nearly 70% of the co-variation among the tests; one factor represented pulmonary function in addition to oxygen consumption and workload during exercise, while the second factor represented exercise tests related to gas exchange. Factors were associated with granulomas on biopsy, exposure, steroid use and lung inflammation. Three clusters of patients (n = 53, n = 59 and, n = 95) were identified based on the collection of test values. Lower levels of each of the factor composite scores and cluster membership were associated with baseline characteristics of patients. Conclusions Using factor analysis and cluster analysis, we identified disease phenotypes that were associated with baseline patient characteristics, suggesting that CBD is a heterogeneous disease with varying severity. These clinical tools may be used in future basic and clinical studies to help define the mechanisms and risk factors for disease severity.