Edward M. Zoratti

House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection

Significance Early-life exposure to dogs is protective against allergic disease development, and dog ownership is associated with a distinct milieu of house dust microbial exposures. Here, we show that mice exposed to dog-associated house dust are protected against airway allergen challenge. These animals exhibit reduced Th2 cytokine production, fewer activated T cells, and a distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii, which itself can confer airway protection when orally supplemented as a single species. This study supports the possibility that host–environment interactions that govern allergic or infectious airway disease may be mediated, at least in part, by the impact of environmental exposures on the gastrointestinal microbiome composition and, by extension, its impact on the host immune response. Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c+/CD11b+ and CD11c+/CD8+ cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults.

Man’s best friend? The effect of pet ownership on house dust microbial communities

Pet-ownership, which has been shown to be protective against allergic disease development, is associated with increased house dust bacterial diversity and fewer fungal species, suggesting a potentially microbial-based mechanism for this protective effect.

Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations

BACKGROUND Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure. OBJECTIVE We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school. METHODS A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations (clincaltrials.gov #NCT01430403). Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined. RESULTS Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; 95% CI, 0.25-0.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33-1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02-0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002-0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88). Adverse events were rare and similar among arms. CONCLUSIONS Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.

Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation

Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma. We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1–11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1–3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4+ cells producing interleukin (IL)-4 and reduced the relative abundance of CD4+CD25+FOXP3+ cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4+CD25+FOXP3+ cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4+ T cell dysfunction associated with childhood atopy.

Cat shedding of Fel d I is not reduced by washings, Allerpet-C spray, or acepromazine ☆ ☆☆ ★ ★★

BACKGROUND No published studies have compared the effectiveness of several treatments proposed to reduce cat allergenicity. Cat washing studies demonstrating efficacy involved very small sample sizes or infrequent washings. Allerpet-C (Allerpet, Inc., New York, N.Y.), a widely advertised topical spray, and acepromazine, a tranquilizer advocated as efficacious in subsedating doses, have never been scientifically studied. OBJECTIVE We compared the effects of cat washing, Allerpet-C spray, and acepromazine with that of no treatment on the shedding of the primary cat allergen, Felis domesticus I by cats. METHODS In a blinded, comparative, controlled study, we measured the amounts of Fel d I shed during an 8-week treatment period with a sample of 24 female mongrel cats randomly assigned to four groups; one group received weekly distilled water washings, one received weekly Allerpet-C spray applications, one received daily oral acepromazine, and one had no treatment (control). Thirty-minute, twice-weekly air samples were collected from each cat with a laminated plastic-acrylic chamber and air sampler. RESULTS One-sample, two-sided t tests comparing baseline to final-week measurements revealed no significant change in Fel d I within each group (mean change +/- SD: washing; 487.6 +/- 1896.4 mU per 30 minutes, p = 0.63; Allerpet-C spray, 429.2 +/- 871.6 mU per 30 minutes, p = 0.46 acepromazine; -620.6 +/- 1031.2, p = 0.52 per 30 minutes). Furthermore, analysis of covariance revealed no significant change in Fel d I levels between groups (p = 0.72). CONCLUSIONS Out data do not show significant reductions in Fel d I shedding as a result of any of these treatments. Therefore we cannot recommend them to patients allergic to cats.

Lifetime dog and cat exposure and dog‐ and cat‐specific sensitization at age 18 years

Background Prior research about whether keeping a dog or cat at home causes allergies to that pet has been limited to outcomes in early childhood.

Prenatal exposure to household pets influences fetal immunoglobulin E production

Background Early life pet exposure may protect against allergic sensitization during childhood. Few studies have evaluated the effect of prenatal pet exposure on potential neonatal markers of allergic risk.

Relationship of house-dust mite allergen exposure in children's bedrooms in infancy to bronchial hyperresponsiveness and asthma diagnosis by age 6 to 7

BACKGROUND Several studies have suggested that exposure to house-dust mite (HDM) allergen in infancy increases the risk of developing asthma. OBJECTIVE To determine whether exposure to higher levels of dust mite in infants increased the risk of developing bronchial hyperresponsiveness (BHR) or physician-diagnosed asthma by age 6 to 7 years. METHODS A health maintenance organization-based cohort of 97 middle class suburban children born from 1987 to 1989 with a high cord blood immunoglobulin E, defined as > or = 0.56 IU/mL, was followed as a part of the Childhood Allergy Study. During the first 2 years of life, monthly bedroom dust samples were collected and analyzed for Der f 1 and Der p 1. Between 6 and 7 years of age, 64 of the original cohort answered a questionnaire used to determine the presence of physician-diagnosed asthma, underwent clinical examination, skin prick testing, and methacholine inhalation challenge. Mann-Whitney tests were used to compare Der f 1 and Der p 1 levels in homes of children with and without BHR, and those with and without physician-diagnosed asthma. RESULTS In all, 1,421 dust samples were collected and assayed. No significant differences were seen in either the mean, maximum, or minimum dust mite allergen levels in homes of children with versus without BHR, or children with versus without asthma. However, sensitization to HDM was associated with physician-diagnosed asthma (P < 0.05). CONCLUSIONS When compared with other studies, we were able to more accurately estimate the level of dust mite allergen exposure through repeated sampling over a relatively long period, incorporating seasonal variations. Although HDM sensitization and asthma were concurrently related, we were unable to find any relationship between level of HDM allergen exposure in childrens bedrooms in early childhood and development of BHR or physician-diagnosed asthma by age 6 to 7 years.

Development of cockroach immunotherapy by the Inner-City Asthma Consortium

BACKGROUND Cockroach allergy is a key contributor to asthma morbidity in children living in urban environments. OBJECTIVE We sought to document immune responses to cockroach allergen and provide direction for the development of immunotherapy for cockroach allergy. METHODS Four pilot studies were conducted: (1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults. RESULTS The adult SLIT trial (n = 54; age, 18-54 years) found a significantly greater increase in cockroach-specific IgE levels between the active and placebo groups (geometric mean ratio, 1.92; P < .0001) and a trend toward increased cockroach-specific IgG4 levels in actively treated subjects (P = .09) but no evidence of functional blocking antibody response. The pediatric SLIT trial (n = 99; age, 5-17 years) found significant differences in IgE, IgG, and IgG4 responses between both active groups and the placebo group but no consistent differences between the high- and low-dose groups. In the SCIT study the treatment resulted in significant changes from baseline in cockroach IgE, IgG4, and blocking antibody levels. The safety profile of cockroach immunotherapy was reassuring in all studies. CONCLUSIONS The administration of cockroach allergen by means of SCIT is immunologically more active than SLIT, especially with regard to IgG4 levels and blocking antibody responses. No safety concerns were raised in any age group. These pilot studies suggest that immunotherapy with cockroach allergen is more likely to be effective with SCIT.

Racial Disparities in Allergic Outcomes in African Americans Emerge as Early as Age 2 Years

Racial disparities in allergic disease outcomes have been reported with African Americans suffering disproportionately compared to White individuals.