High plasma IL-6 levels may enhance the adverse effects of mouse allergen exposure in urban schools on asthma morbidity in children.

BACKGROUND: Few data on the relationships between environmental exposures, asthma morbidity, and systemic IL-6 inflammation exist. OBJECTIVE: We sought to determine whether baseline plasma IL-6 level is associated with increased asthma morbidity in children exposed to mouse allergen in inner-city classrooms. METHODS: Data from the longitudinal School Inner-City Asthma Studies of 215 children with asthma, aged 4 to 14 years and recruited from urban elementary schools, were analyzed. Given the unknown threshold of IL-6 risk levels and skewness of the distribution, the children were stratified into tertiles as follows: low baseline IL-6 level (<0.013 pg/mL), moderate baseline IL-6 level (0.013-0.302 pg/mL), and high baseline IL-6 level (>0.302 pg/mL). Relationships between plasma IL-6 level and body mass index (BMI) percentile, inflammatory markers, lung function, mouse allergen exposure, and asthma outcomes were assessed. RESULTS: Cross-sectional analysis demonstrated that increasing IL-6 level was associated with higher BMI percentile (P < .0001), C-reactive protein level (P = .0006), and blood neutrophil count (P = .0024). IL-6 was not associated with type 2 inflammatory markers, including blood eosinophil count, allergic sensitization, or fractional exhaled nitric oxide level. Longitudinal analysis showed that children with high IL-6 levels had a higher number of days with asthma symptoms than did those children with moderate (incidence rate ratio = 1.74 [95% CI = 1.10-2.77]; P = .0187) or low (incidence rate ratio =1.83 [95% CI = 1.21-2.77]; P = .0043) IL-6 levels. Children with high IL-6 levels who were exposed to increasing levels of mouse allergen exhibited lower ratios of FEV1 value to forced vital capacity than did children with moderate IL-6 levels (ß = -0.0044 [95% CI = -0.0073 to -0.0015]; pairwise interaction P = .0028) or low IL-6 levels (ß = -0.0042 [95% CI = - 0.0070 to -0.0013]; pairwise interaction P = .0039). CONCLUSIONS: Inner-city children with asthma and high plasma IL-6 levels are more likely to have an increased BMI, elevated C-reactive protein level, elevated blood neutrophil count, and greater asthma symptoms. High IL-6 level appears to increase susceptibility to the effects of classroom exposure to mouse allergen on lung function in urban children.

HEPA filtration intervention in classrooms may improve some students' asthma.

OBJECTIVE: The School Inner-City Asthma Intervention Study 2 (SICAS 2) tested interventions to reduce exposures in classrooms of students with asthma. The objective of this post-hoc analysis was limited to evaluating the effect of high-efficiency particulate (HEPA) filtration interventions on mold levels as quantified using the Environmental Relative Moldiness Index (ERMI) and the possible improvement in the students' asthma, as quantified by spirometry testing. METHODS: Pre-intervention dust samples were collected at the beginning of the school year from classrooms and corresponding homes of students with asthma (n = 150). Follow-up dust samples were collected in the classrooms at the end of the HEPA or Sham intervention. For each dust sample, ERMI values and the Group 1 and Group 2 mold levels (components of the ERMI metric) were quantified. In addition, each student's lung function was evaluated by spirometry testing, specifically the percentage predicted forced expiratory volume at 1 sec (FEV1%), before and at the end of the intervention. RESULTS: For those students with a higher Group 1 mold level in their pre-intervention classroom than home (n = 94), the FEV1% results for those students was significantly (p < 0.05) inversely correlated with the Group 1 level in their classrooms. After the HEPA intervention, the average Group 1 and ERMI values were significantly lowered, and the average FEV1% test results significantly increased by an average of 4.22% for students in HEPA compared to Sham classrooms. CONCLUSIONS: HEPA intervention in classrooms reduced Group 1 and ERMI values, which corresponded to improvements in the students' FEV1% test results.

Obesity may enhance the adverse effects of NO2 exposure in urban schools on asthma symptoms in children.

BACKGROUND: Sparse data address the effects of nitrogen dioxide (NO2) exposure in inner-city schools on obese students with asthma. OBJECTIVE: We sought to evaluate relationships between classroom NO2 exposure and asthma symptoms and morbidity by body mass index (BMI) category. METHODS: The School Inner-City Asthma Study enrolled students aged 4 to 13 years with asthma from 37 inner-city schools. Students had baseline determination of BMI percentile. Asthma symptoms, morbidity, pulmonary inflammation, and lung function were monitored throughout the subsequent academic year. Classroom NO2 data, linked to enrolled students, were collected twice per year. We determined the relationship between classroom NO2 levels and asthma outcomes by BMI stratification. RESULTS: A total of 271 predominantly black (35%) or Hispanic students (35%) were included in analyses. Fifty percent were normal weight (5-84th BMI percentile), 15% overweight (≥85-94th BMI percentile), and 35% obese (≥95th BMI percentile). For each 10-parts per billion increase in NO2, obese students had a significant increase in the odds of having an asthma symptom day (odds ratio [OR], 1.86; 95% CI, 1.15-3.02) and in days caregiver changed plans (OR, 4.24; 95% CI, 2.33-7.70), which was significantly different than normal weight students who exhibited no relationship between NO2 exposure and symptom days (OR, 0.90; 95% CI, 0.57-1.42; pairwise interaction P = .03) and change in caregiver plans (OR, 1.37; 95% CI, 0.67-2.82; pairwise interaction P = .02). Relationships between NO2 levels and lung function and fractional exhaled nitric oxide did not differ by BMI category. If we applied a conservative Holm-Bonferroni correction for 16 comparisons (obese vs normal weight and overweight vs normal weight for 8 outcomes), these findings would not meet statistical significance (all P > .003). CONCLUSIONS: Obese BMI status appears to increase susceptibility to classroom NO2 exposure effects on asthma symptoms in inner-city children. Environmental interventions targeting indoor school NO2 levels may improve asthma health for obese children. Although our findings would not remain statistically significant after adjustment for multiple comparisons, the large effect sizes warrant future study of the interaction of obesity and pollution in pediatric asthma.

Effect of School Integrated Pest Management or Classroom Air Filter Purifiers on Asthma Symptoms in Students With Active Asthma: A Randomized Clinical Trial.

Importance: School and classroom allergens and particles are associated with asthma morbidity, but the benefit of environmental remediation is not known. Objective: To determine whether use of a school-wide integrated pest management (IPM) program or high-efficiency particulate air (HEPA) filter purifiers in the classrooms improve asthma symptoms in students with active asthma. Design, Setting, and Participants: Factorial randomized clinical trial of a school-wide IPM program and HEPA filter purifiers in the classrooms was conducted from 2015 to 2020 (School Inner-City Asthma Intervention Study). There were 236 students with active asthma attending 41 participating urban elementary schools located in the Northeastern US who were randomized to IPM by school and HEPA filter purifiers by classroom. The date of final follow-up was June 20, 2020. Interventions: The school-wide IPM program consisted of application of rodenticide, sealing entry points, trap placement, targeted cleaning, and brief educational handouts for school staff. Infestation was assessed every 3 months, with additional treatments as needed. Control schools received no IPM, cleaning, or education. Classroom portable HEPA filter purifiers were deployed and the filters were changed every 3 months. Control classrooms received sham HEPA filters that looked and sounded like active HEPA filter purifiers. Randomization was done independently (split-plot design), with matching by the number of enrolled students to ensure a nearly exact 1:1 student ratio for each intervention with 118 students randomized to each group. Participants, investigators, and those assessing outcomes were blinded to the interventions. Main Outcomes and Measures: The primary outcome was the number of symptom-days with asthma during a 2-week period. Symptom-days were assessed every 2 months during the 10 months after randomization. Results: Among the 236 students who were randomized (mean age, 8.1 [SD, 2.0] years; 113 [48%] female), all completed the trial. At baseline, the 2-week mean was 2.2 (SD, 3.9) symptom-days with asthma and 98% of the classrooms had detectable levels of mouse allergen. The results were pooled because there was no statistically significant difference between the 2 interventions (P = .18 for interaction). During a 2-week period, the mean was 1.5 symptom-days with asthma after use of the school-wide IPM program vs 1.9 symptom-days after no IPM across the school year (incidence rate ratio, 0.71 [95% CI, 0.38-1.33]), which was not statistically significantly different. During a 2-week period, the mean was 1.6 symptom-days with asthma after use of HEPA filter purifiers in the classrooms vs 1.8 symptom-days after use of sham HEPA filter purifiers across the school year (incidence rate ratio, 1.47 [95% CI, 0.79-2.75]), which was not statistically significantly different. There were no intervention-related adverse events. Conclusions and Relevance: Among children with active asthma, use of a school-wide IPM program or classroom HEPA filter purifiers did not significantly reduce symptom-days with asthma. However, interpretation of the study findings may need to consider allergen levels, particle exposures, and asthma symptoms at baseline. Trial Registration: ClinicalTrials.gov Identifier: NCT02291302.

Association between fungal spore exposure in inner-city schools and asthma morbidity.

BACKGROUND: Home fungus exposures may be associated with development or worsening of asthma. Little is known about the effects of school/classroom fungus exposures on asthma morbidity in students. OBJECTIVE: To evaluate the association of school-based fungus exposures on asthma symptoms in both fungus-sensitized and nonsensitized students with asthma. METHODS: In this prospective study, 280 children with asthma from 37 inner-city schools were phenotypically characterized at baseline and followed-up for 1 year. Fungal spores were collected by using a Burkard air sampler twice during the school year. Clinical outcomes were evaluated throughout the school year and linked to classroom-specific airborne spore sampling. The primary outcome was days with asthma symptoms per 2-week period. RESULTS: Fungal spores were present in all classroom samples. The geometric mean of the total fungi was 316.9 spores/m3 and ranged from 15.0 to 59,345.7 spores/m3. There was variability in total fungus quantity between schools and classrooms within the same school. Mitospores were the most commonly detected fungal grouping. Investigation of the individual mitospores revealed that exposure to Alternaria was significantly associated with asthma symptom days in students sensitized to Alternaria (OR = 3.61, CI = 1.34-9.76, P = .01), but not in children not sensitized to Alternaria (OR = 1.04, CI = 0.72-1.49, P = .85). Students sensitized to Alternaria and exposed to high levels (≥75th percentile exposure) had 3.2 more symptom days per 2-week period as compared with students sensitized but exposed to lower levels. CONCLUSION: Children with asthma who are sensitized to Alternaria and exposed to this fungus in their classroom may have significantly more days with asthma symptoms than those who were sensitized and not exposed. CLINICAL TRIAL REGISTRATION: Clinicaltrials.govNCT01756391.

Adam8 limits the development of allergic airway inflammation in mice.

To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyperresponsiveness (AHR), we compared AAI and AHR in wild-type (WT) versus Adam8(-/-) mice in different genetic backgrounds sensitized and challenged with OVA or house dust mite protein extract. OVA- and house dust mite-treated Adam8(-/-) mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some Th2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8's anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8(-/-) mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8(-/-) macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients, but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma.

Allergens on desktop surfaces in preschools and elementary schools of urban children with asthma.

Desktop dust has been studied as a source of food allergen, but not as a source of potential aeroallergen exposure. Thirty-six wiped samples from desktop surfaces were collected from preschools and schools. Samples were analyzed for detectable levels of common aeroallergens including Alternaria, cockroach, dog, dust mite, cat, mouse, and rat allergens by immunoassay. Mouse allergen was the most prevalent, detectable in 97.2% of samples. Cat allergen was detectable in 80.6% of samples, and dog allergen was detectable in 77.8% of samples. Other allergens were not as prevalent. Mouse was the only allergen that was highly correlated with settled floor dust collected from the same rooms (r = 0.721, P < 0.001). This is the first study to detect aeroallergens on desktop surfaces by using moist wipes. Allergens for mouse, cat, and dog were highly detectable in wipes with mouse desktop surface levels correlating with levels in vacuumed floor dust.

Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and exhaled nitric oxide.

RATIONALE: ß2-Agonists are the treatment of choice for exercise-induced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of ß2-agonists. OBJECTIVES: To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection. METHODS: A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 µg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV1, response to salmeterol, degree of EIB, and exhaled nitric oxide (FE(NO)) at baseline were examined for their association with loss of bronchoprotection (LOB). MEASUREMENTS AND MAIN RESULTS: The maximum exercise-induced FEV1 fall was 27.9 ± 1.4% during the run-in period, 8.1 ± 1.2% (70.3 ± 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 ± 3.2% (18.9 ± 11.5% bronchoprotection) after 2 weeks of salmeterol (P = 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FeNO values at baseline were significantly related to the LOB (r = 0.47; P = 0.01). Mean change was a 74 ± 13% LOB in subjects with FE(NO) levels greater than 50 ppb and a 7 ± 16% gain in bronchoprotection in those with FE(NO) levels less than 25 ppb (P = 0.01). CONCLUSIONS: The LOB that occurs with chronic long-acting ß2-agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE(NO) was associated with marked LOB. Use of long-acting ß2-agonists before achieving a reduction in FeNO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).

Exposures to molds in school classrooms of children with asthma.

BACKGROUND: Students spend a large portion of their day in classrooms which may be a source of mold exposure. We examined the diversity and concentrations of molds in inner-city schools and described differences between classrooms within the same school. METHODS: Classroom airborne mold spores, collected over a 2 day period, were measured twice during the school year by direct microscopy. RESULTS: There were 180 classroom air samples collected from 12 schools. Mold was present in 100% of classrooms. Classrooms within the same school had differing mold levels and mold diversity scores. The total mold per classroom was 176.6 ± 4.2 spores/m3 (geometric mean ± standard deviation) and ranged from 11.2 to 16,288.5 spores/m3. Mold diversity scores for classroom samples ranged from 1 to 19 (7.7 ± 3.5). The classroom accounted for the majority of variance (62%) in the total mold count, and for the majority of variance (56%) in the mold diversity score versus the school. The species with the highest concentrations and found most commonly included Cladosporium (29.3 ± 4.2 spores/m3), Penicillium/Aspergillus (15.0 ± 5.4 spores/m3), smut spores (12.6 ± 4.0 spores/m3), and basidiospores (6.6 ± 7.1 spores/m3). CONCLUSIONS: Our study found that the school is a source of mold exposure, but particularly the classroom microenvironment varies in quantity of spores and species among classrooms within the same school. We also verified that visible mold may be a predictor for higher mold spore counts. Further studies are needed to determine the clinical significance of mold exposure relative to asthma morbidity in sensitized and non-sensitized asthmatic children.

Allergens in urban schools and homes of children with asthma.

BACKGROUND: Most studies of indoor allergens have focused on the home environment. However, schools may be an important site of allergen exposure for children with asthma. We compared school allergen exposure to home exposure in a cohort of children with asthma. Correlations between settled dust and airborne allergen levels in classrooms were examined. METHODS: Settled dust and airborne samples from 12 inner-city schools were analyzed for indoor allergens using multiplex array technology (MARIA). School samples were linked to students with asthma enrolled in the School Inner-City Asthma Study (SICAS). Settled dust samples from students' bedrooms were analyzed similarly. RESULTS: From schools, 229 settled dust and 197 airborne samples were obtained. From homes, 118 settled dust samples were obtained. Linear mixed regression models of log-transformed variables showed significantly higher settled dust levels of mouse, cat and dog allergens in schools than homes (545% higher for Mus m 1, estimated absolute difference 0.55 µg/g, p < 0.0001; 198% higher for Fel d 1, estimated absolute difference 0.13 µg/g, p = 0.0033; and 144% higher for Can f 1, estimated absolute difference 0.05 µg/g, p = 0.0008). Airborne and settled dust Mus m 1 levels in classrooms were moderately correlated (r = 0.48; p < 0.0001). There were undetectable to very low levels of cockroach and dust mite allergens in both homes and schools. CONCLUSION: Mouse allergen levels in schools were substantial. In general, cat and dog allergen levels were low, but detectable, and were higher in schools. Aerosolization of mouse allergen in classrooms may be a significant exposure for students. Further studies are needed to evaluate the effect of indoor allergen exposure in schools on asthma morbidity in students with asthma.

Endotoxin exposure in inner-city schools and homes of children with asthma.

BACKGROUND: Endotoxins are stimulators of the immune system and, despite their potential to protect against allergy, have been associated with early wheezing and asthma morbidity. OBJECTIVE: To compare inner-city school endotoxin exposure with home endotoxin exposure in children with asthma. METHODS: Students with asthma were recruited from 12 urban elementary schools. Settled and airborne dust samples, linked to enrolled students, were collected from school classrooms, gymnasiums, and cafeterias twice during the academic year. For comparison, settled dust was collected once from the bedrooms of students with asthma. RESULTS: Two hundred twenty-nine school settled dust samples and 118 bedroom settled dust samples were collected and analyzed for endotoxin. The median endotoxin concentration for school samples was 13.4 EU/mg (range, 0.7-360.7 EU/mg) and for home samples was 7.0 EU/mg (range = LLOD-843.0 EU/mg). The median concentration within each individual school varied from 6.6 EU/mg to 24.0 EU/mg. One hundred four students with asthma had matched classroom and bedroom endotoxin exposure measurements performed in the same season and demonstrated significantly higher concentrations of endotoxin in the students' classrooms (mean log value, 1.13 vs 0.99, P = .04). The median of the classrooms was 12.5 EU/mg compared with their bedrooms, with a median of 7.0 EU/mg. Within the school environment, no significant difference was seen between the fall and spring samples (mean log value 1.14 vs 1.09; P = .35). CONCLUSION: Inner-city children with asthma were exposed to higher concentrations of endotoxin in their classrooms as compared with their bedrooms. Further studies are needed to evaluate school endotoxin exposure as a factor in asthma morbidity.

Predicting food challenge outcomes for baked milk: role of specific IgE and skin prick testing.

BACKGROUND: Cow's milk allergy is the most common food allergy in childhood. Many children with IgE-mediated cow's milk allergy may tolerate baked milk products, but few data exist on predictors of outcomes of baked milk challenges. OBJECTIVE: To determine the relation of milk protein allergen specific IgE (sIgE) levels and skin prick test (SPT) wheal size with baked milk challenge outcomes. METHODS: A retrospective medical record review was conducted of 35 baked milk challenges. SPT results, sIgE levels, demographic characteristics, and food challenge results were analyzed. RESULTS: Thirty-five children underwent open challenges to baked milk and 29 (83%) passed. Of those who failed, 3 (50%) passed the initial clinic challenge but developed symptoms to ongoing exposure at home, days to months later. One child who ultimately failed at home required epinephrine. Compared with those who passed, children who failed were younger (median age, 8.9 and 3.7 years, respectively; P = .02). Children with a milk SPT wheal less than 12 mm were more than 90% likely to pass a baked milk challenge, and no child with a milk SPT wheal less than 7 mm failed a baked milk challenge. We were also able to establish more than 90% predictive values for passing baked milk challenges with a casein SPT wheal of 9 mm, a milk sIgE level of 1.0 kU/L, and a casein sIgE level of 0.9 kU/L. CONCLUSION: Most children allergic to cow's milk tolerated baked milk. Milk protein SPT wheal may be more reliable than sIgE level in predicting outcomes of baked milk challenges. It is important to be aware of the possibility of late reactions to ongoing baked milk exposure.

Role of specific IgE and skin-prick testing in predicting food challenge results to baked egg.

Previous studies suggest that children with egg allergy may be able to tolerate baked egg. Reliable predictors of a successful baked egg challenge are not well established. We examined egg white-specific IgE levels, skin-prick test (SPT) results, and age as predictors of baked egg oral food challenge (OFC) outcomes. We conducted a retrospective chart review of children, aged 2-18 years, receiving an egg white-specific IgE level, SPT, and OFC to baked egg from 2008 to 2010. Fifty-two oral baked egg challenges were conducted. Of the 52 challenges, 83% (n = 43) passed and 17% (n = 9) failed, including 2 having anaphylaxis. Median SPT wheal size was 12 mm (range, 0-35 mm) for passed challenges and 17 mm (range, 10-30 mm) for failed challenges (p = 0.091). The negative predictive value for passing the OFC was 100% (9 of 9) if SPT wheal size was <10 mm. Median egg white-specific IgE was 2.02 kU/L (range, <0.35-13.00 kU/L) for passed challenges and 1.52 kU/L (range, 0.51-6.10 kU/L) for failed challenges (p = 0.660). Receiver operating characteristic (ROC) curve analysis for SPT revealed an area under the curve (AUC) of 0.64. ROC curve analysis for egg white-specific IgE revealed an AUC of 0.63. There was no significant difference in age between patients who failed and those who passed (median = 8.8 years versus 7.0 years; p = 0.721). Based on our sample, SPT, egg white-specific IgE and age are not good predictors of passing a baked egg challenge. However, there was a trend for more predictability with SPT wheal size.

Dietary long-chain omega 3 fatty acids modify sphingolipid metabolism to facilitate airway hyperreactivity.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential nutrients that can affect inflammatory responses. While n-3 PUFAs are generally considered beneficial for cardiovascular disease and obesity, the effects on asthma, the most common inflammatory lung disease are unclear. While prenatal dietary n-3 PUFAs decrease the risk for childhood wheezing, postnatal dietary n-3 PUFAs can worsen allergic airway inflammation. Sphingolipid metabolism is also affected by dietary n-3 PUFAs. Decreased sphingolipid synthesis leads to airway hyperreactivity, besides inflammation, a cardinal feature of asthma, and common genetic asthma risk alleles lead to lower sphingolipid synthesis. We investigated the effect of dietary n-3 PUFAs on sphingolipid metabolism and airway reactivity. Comparing a fish-oil diet with a high n-3 PUFA content (FO) to an isocaloric coconut oil-enriched diet (CO), we found an n-3 PUFA-dependent effect on increased airway reactivity, that was not accompanied by inflammation. Lung and whole blood content of dihydroceramides, ceramides, sphingomyelins, and glucosylceramides were lower in mice fed the n-3 PUFA enriched diet consistent with lower sphingolipid synthesis. In contrast, phosphorylated long chain bases such as sphingosine 1-phosphate were increased. These findings suggest that dietary n-3 PUFAs affect pulmonary sphingolipid composition to favor innate airway hyperreactivity, independent of inflammation, and point to an important role of n-3 PUFAs in sphingolipid metabolism.

The school inner-city asthma study: design, methods, and lessons learned.

BACKGROUND: Children spend a significant amount of time in school. Little is known about the role of allergen exposure in school environments and asthma morbidity. OBJECTIVES: The School Inner-City Asthma Study (SICAS) is a National Institutes of Health (NIH)-funded prospective study evaluating the school/classroom-specific risk factors and asthma morbidity among urban children. METHODS/RESULTS: This article describes the design, methods, and important lessons learned from this extensive investigation. A single center is recruiting 500 elementary school-aged children, all of whom attend inner-city metropolitan schools. The primary hypothesis is that exposure to common indoor allergens in the classroom will increase the risk of asthma morbidity in children with asthma, even after controlling for home allergen exposures. The protocol includes screening surveys of entire schools and baseline eligibility assessments obtained in the spring prior to the academic year. Extensive baseline clinical visits are being conducted among eligible children with asthma during the summer prior to the academic school year. Environmental classroom/school assessments including settled dust and air sampling for allergen, mold, air pollution, and inspection data are collected twice during the academic school year and one home dust sample linked to the enrolled student. Clinical outcomes are measured every 3 months during the academic school year. CONCLUSION: The overall goal of SICAS is to complete the first study of its kind to better understand school-specific urban environmental factors on childhood asthma morbidity. We also discuss the unique challenges related to school-based urban research and lessons being learned from recruiting such a cohort.

Associations of Snoring and Asthma Morbidity in the School Inner-City Asthma Study.

BACKGROUND: Inner-city children are disproportionately affected by asthma and sleep-disordered breathing (SDB). However, little is known about the association of SDB symptoms with asthma morbidity in this vulnerable population. OBJECTIVE: Assess the relationship between snoring frequency and asthma morbidity. METHODS: This study was part of the School Inner-City Asthma Study, a longitudinal prospective cohort study of children with persistent asthma who attended schools in the Northeast United States from 2008 to 2013. Participants had baseline assessments of asthma symptoms, snoring, and allergy status. Caregivers completed quarterly surveys for 12 months on symptoms of asthma, snoring, and health care outcomes. Snoring frequency (non-, rare-, sometimes-, habitual-snoring) and its relationship with asthma symptoms and asthma morbidity were assessed by mixed-effects models. RESULTS: There were 1186 observations from 339 subjects. Mean age was 7.9 years; roughly half were male, and most were of minority race. Half were overweight or obese, and 65.5% had atopy. At initial snoring assessment, 24.8% reported habitual snoring, but report of snoring frequency varied over the study period. Multivariate analyses revealed increased odds of maximum asthma symptom days for habitual snoring compared with nonsnoring (1.58; 95% CI, 1.19-2.10; P < .002) and all other snoring categories. Habitual snoring was associated with greater odds of health care utilization (incidence rate ratio, 1.72; 95% CI, 1.10-2.69; P = .02) and worse asthma control (odds ratio, 1.49; 95% CI, 1.05-2.11; P = .03) compared with nonsnoring. CONCLUSIONS: Snoring is common among inner-city school-age children with asthma, and habitual snoring is associated with increased asthma symptom burden and health care utilization.

Asthma Prevalence and Mold Levels in US Northeastern Schools.

BACKGROUND: Asthma is among the most common chronic diseases of children in the United States (US). Mold exposures have been linked to asthma development and exacerbation. In homes, mold exposures have been quantified using the Environmental Relative Moldiness Index (ERMI), and higher home ERMI values have been linked to occupant asthma. OBJECTIVE: In this analysis of the School Inner-City Asthma Study (SICAS), we aimed to evaluate the ERMI's applicability to measuring mold in schools compared with homes and to examine the prevalence of asthma in relationship to students' demographics and the physical characteristics of school buildings. METHODS: Northeastern US schools (n = 32) and homes (n = 33) were selected, and the 36 ERMI molds were quantified in a dust sample from each classroom (n = 114) or home. School building characteristics data were collected from SICAS. Asthma prevalence and student demographics data were obtained from government websites. Linear regression and mixed models were fit to assess the association of the current asthma prevalence and physical characteristics of the school, make-up of the student body, and the ERMI metric. RESULTS: Levels of outdoor group 2 molds were significantly (P < .01) greater in schools compared with homes. The presence of air-conditioning in school buildings correlated significantly (P = .02) with lower asthma prevalence. CONCLUSION: The prevalence of asthma in student bodies is associated with many factors in schools and homes.

Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.

BACKGROUND: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967. FINDINGS: After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures. INTERPRETATION: In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine. FUNDING: National Institutes of Health.

Allogeneic hematopoietic stem cell transplantation for X-linked ectodermal dysplasia and immunodeficiency: case report and review of outcomes.

Hypomorphic mutations in nuclear factor kappa B essential modulator (NEMO) cause X-linked ectodermal dysplasia with immunodeficiency (X-ED-ID). Clinical manifestations in boys with X-ED-ID apart from ectodermal dysplasia and immunodeficiency include osteopetrosis, lymphedema, and colitis. Further description of atypical findings in this disorder is needed. Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is in its infancy, and how or whether non-immune manifestations of defective NEMO function are impacted by HSCT is poorly described. We report an interesting case of a boy with NEMO mutation who had symptoms reminiscent of Omenn's syndrome and small intestinal villous atrophy with features reminiscent of tufting enteropathy. We describe his treatment course as well as reconstitution of immune function and correction of osteopetrosis post-HSCT, and review the cases of allogeneic HSCT reported to date in the literature.