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PURPOSE OF REVIEW: Allergic disorders are the result of complex interactions between genetic predisposition and environmental exposures. Elucidating how specific environmental exposures contribute to allergic diseases in adults is crucial, especially as the world population ages in a rapidly changing environment. RECENT FINDINGS: The effects of environmental exposures on allergic diseases remain understudied in adults. While epidemiological studies suggest various environmental exposures are associated with the development and exacerbation of allergic diseases, further longitudinal studies are needed across various age groups in adults to pinpoint the exposures of concerns and the time windows of susceptibility. Mechanistic studies in adults are few. A multi-component strategy targeting several allergens has been conditionally recommended for asthma, but recent findings on mitigation strategies remain limited. SUMMARY: Further research on how environmental exposures cause and exacerbate allergic disorders is needed in adults, particularly across disease phenotypes. The effects of mitigation strategies against environmentally-induced adult allergic diseases remain large research gaps. A better understanding of how and which environmental exposures contribute to allergic disorders is necessary to identify patients who are at higher risk and would benefit from specific interventions.

The last 2 years yielded a proliferation of high-quality asthma research. These include new understandings of the incidence and natural history of asthma, findings on the effects of exposure to air pollution, allergens, and intake of acetaminophen, soy isoflavones, and polyunsaturated fatty acids, and exposure to microbial products. The past 2 years have benefited from great strides in determining potential mechanisms of asthma development and asthma exacerbations. These novel understandings led to identification and development of exciting new avenues for potential therapeutic intervention. Finally, there has been significant progress made in the development of tools to facilitate the diagnosis of asthma and measurement of airway physiology and in precision diagnostic approaches. Asthma guidelines were updated and new insights into the pharmacologic management of patients, including biologics, were reported. We review the most notable advances in the natural history of asthma, risk factors for the development of asthma, underlying mechanisms, diagnostic approaches, and treatments. Although greater knowledge of the mechanisms underlying responses and nonresponses to novel therapeutics and across asthma phenotypes would be beneficial, the progress over just the past 2 years has been immense and impactful.

Laura A Conrad,1 Natalie Buchinsky,2 Luis M Acosta,2 J David Nugent,3 Khalil W Savary,4 Rachel L Miller,5 Nurdant Emanet,6 Julie Herbstman,2 Beatrice Beebe,6 Michael M Myers,3 William P Fifer,3 Matthew S Perzanowski2 1Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, New York, NY, USA; 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; 3Division of Developmental Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4Department of Pediatrics, Rutgers University, Newark, NJ, USA; 5Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USACorrespondence: Matthew S PerzanowskiDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th St, 11th Floor, New York, NY, 10032, USATel +1 212-305-3465Fax +1 212-305-4012Email mp2217@cumc.columbia.eduIntroduction: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheeze, emergency department visits, and hospitalizations. These findings were independent of allergic sensitization, and we theorized that increased parasympathetic tone underlay the association. We also reported that increased heart-rate variability (HRV) in infants predicted wheeze in 2– 3 year-olds. In a convenience sample of children participating in a birth cohort study, we tested the hypothesis that infants with RWWC would have elevated HRV, indicating increased parasympathetic tone.Methods: RWWC symptoms since birth were queried for 3-month-old children. At 4-months, HRV was assessed (root mean square of successive differences [RMSSD]) during a standardized infant–mother still-face paradigm, which included 2 minutes of mother/child play immediately followed by 2 minutes of the mother maintaining a still-face.Results: Among participants (n=38), RWWC was common for girls (32%) and boys (21%). The children with the greatest decrease in RMSSD between play and still-face challenge (lowest tertile) had a higher prevalence of RWWC as compared with children in the higher tertiles (50% vs 16%, P=0.045). In a logistic regression model controlling for sex, age and time between HRV and RWWC assessment, children with greater decrease in HRV between play and still-face (lowest tertile) had greater odds of having RWWC (odds ratio=6.0, P=0.029).Conclusion: In this relatively small study, we demonstrated greater decreases in HRV in response to a stressor among children with reported RWWC, suggesting that these children might have increased parasympathetic tone and/or overall greater vagal reactivity.Keywords: watery eyes, still-face challenge, rhinitis, exercise-induced asthma, autonomic nervous system, heart rate variability

Background Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective. Objective Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history. Methods Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated. Results The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females. Conclusions US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.

Background Whether concomitant home exposures modify the effectiveness of mouse allergen reduction among mouse-sensitized children with asthma is unknown. Objective To determine whether a lower baseline home mouse allergen level, lower particulate matter 10 μ or less (PM10), and the absence of sensitization and exposure to other indoor allergens are associated with greater improvements in asthma associated with mouse allergen reduction. Methods A secondary analysis of a randomized clinical trial of a home mouse allergen intervention was performed to examine the effect of 3 indoor factors on the relationship between mouse allergen reduction and a range of asthma outcomes. Results Participants (N = 297) were predominantly minority (78% African American, 22% Hispanic) and publicly insured (88%). Higher baseline mouse allergen levels were associated with a greater response to mouse allergen reduction for several symptom and exacerbation outcomes. Lower indoor PM10 levels were associated with a greater response to mouse allergen reduction for several symptom outcomes, but not exacerbation outcomes. Overall, sensitization and exposure to other indoor allergens did not appear to modify the effect of mouse allergen reduction. Conclusions In this population of predominantly low-income children with persistent asthma and mouse sensitization, mouse allergen reduction was associated with improvements in asthma, especially among those with high baseline mouse allergen exposure. Lower indoor PM10 was associated with greater improvements in asthma symptoms.

Many notable advances in drug allergy, urticaria, angioedema, and anaphylaxis were reported in 2018. Broad-spectrum antibiotic use and, consequently, antibiotic resistance are widespread, and algorithms to clarify β-lactam allergy and optimize antibiotic use were described. Meaningful data emerged on the pathogenesis of delayed drug hypersensitivity reactions. Progress not only in defining biomarkers but also in understanding the effect on quality of life and developing better treatments has been made for patients with chronic idiopathic urticaria. Patients with hereditary angioedema (HAE) have gained additional access to highly efficacious therapies, with associated improvements in quality of life, and some progress was made in our understanding of recurrent angioedema in patients with normal laboratory results. Guidelines have defined clear goals to help providers optimize therapies in patients with HAE. The epidemiology and triggers of anaphylaxis and the mechanisms underlying anaphylaxis were elucidated further. In summary, these disorders (and labels) cause substantial burdens for individual persons and even society. Fortunately, publications in 2018 have informed on advancements in diagnosis and management and have provided better understanding of mechanisms that potentially could yield new therapies. This progress should lead to better health outcomes and paths forward in patients with drug allergy, urticaria, HAE, and anaphylaxis.

Background Specific patterns of allergic sensitization to common allergens may provide relevant clinical insight into asthma risk. Objective To identify patterns of allergic sensitization based on multiple individual allergens and link these to current and persistent asthma using baseline and 3-year follow-up data. Methods Children 7 to 8 years old with (n = 196) and without (n = 136) asthma from the New York City Neighborhood Asthma and Allergy Study were studied. IgE against a panel of 112 antigens was measured using the ISAC multiplex panel array. Latent class analysis (LCA) was used to identify patterns of allergic sensitization among the 26 most common allergens against which children had measurable IgE. The association between patterns of allergic sensitization and risk of asthma and other allergic diseases was examined. Results LCA identified 4 patterns of allergic sensitization as follows: low risk of sensitization (prevalence of 53% in children with asthma and 76% in children without asthma), indoor (prevalence of 23% in children with asthma and 15% in children without asthma), pollen and indoor group 1 (prevalence of 16% in children with asthma and 5% in children without asthma), and pollen and indoor group 2 (prevalence of 9% in children with asthma and 4% in children without asthma). Compared with the low risk of sensitization pattern, children belonging to the 3 sensitized patterns had significantly higher risk of asthma at ages 7 to 8 years and 3 years later, with the highest risk for children in the pollen and indoor group 1 pattern. Conclusions LCA facilitates the study of sensitization profiles to a large number of common allergens. Analyzing patterns of allergic sensitization from multiple allergens reveals additional relevant associations with asthma than the study of a single allergen or total IgE.

BACKGROUND: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheezing, emergency department visits, and respiratory-related hospitalizations for asthma. These findings appeared independent of infant wheezing and allergy. Overall, we theorize that prenatal material hardship and psychosocial distress can induce infant dysregulation in the autonomic nervous system leading to infant RWWC and school age exercise-induced wheezing. OBJECTIVE: To test the hypotheses that indicators of prenatal stress and measures of maternal demoralization, which can alter infant autonomic nervous system responses, would predict infant RWWC. METHODS: In a prospective birth cohort of urban children (n = 578), pregnant women were queried in the third trimester about material hardship and maternal demoralization using validated instruments. Child RWWC was queried every 3 months in infancy. RESULTS: Notably, 44% of the mothers reported not being able to afford at least one of the basic needs of daily living during pregnancy, and children of those mothers were more likely to have infant RWWC (P < .001). The children had an increased risk of RWWC with increasing maternal demoralization during pregnancy (P < .001). In models controlling for sex, race/ethnicity, maternal asthma, maternal allergy, smoker in the home (pre- or postnatal), prenatal pesticide exposure, and older siblings, RWWC was predicted by mother’s report of material hardship (relative risk, 1.22; P = .021) and maternal demoralization (relative risk, 1.14; P = .030). CONCLUSION: These results suggest an association between material hardship and psychological distress during pregnancy and RWWC in infancy, further supporting a link between infant autonomic dysregulation and RWWC.

Exposome research can improve the understanding of the mechanistic connections between exposures and health to help mitigate adverse health outcomes across the life span. The exposomic approach provides a risk profile instead of single predictors and thus is particularly applicable to allergic diseases and asthma. Under the PRACTALL collaboration between the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy, Asthma, and Immunology (AAAAI), we evaluated the current concepts and the unmet needs on the role of the exposome in allergic diseases and asthma. ispartof: ALLERGY vol:74 issue:3 pages:449-463 ispartof: location:Denmark status: published

Background Rhinitis and conjunctivitis are often linked to asthma development through an allergic pathway. However, runny nose and watery eyes can result from nonallergic mechanisms. These mechanisms can also underlie exercise-induced wheeze (EIW), which has been associated with urgent medical visits for asthma, independent of other indicators of asthma severity or control. Objective To test the hypothesis that rhinitis or watery eyes without cold symptoms (RWWC) in infancy predict development of EIW and urgent respiratory-related medical visits at school age, independent of seroatopy. Methods Within a prospective birth cohort of low-income, urban children (n = 332), RWWC was queried during the first year of life. Relative risks (RRs) for EIW, emergency department (ED) visits, and hospitalizations for asthma and other breathing difficulties at 5 to 7 years of age were estimated with multivariable models. Seroatopy was determined at 7 years of age. Results Infant RWWC was common (49% of children) and predicted school-age EIW (RR, 2.8; P P = .001), and hospitalizations (RR, 9.8; P = .002). These associations were independent of infant wheeze. They were also independent of birth order, an indicator of increased risk of exposure to viruses in infancy, and infant ear infections, an indicator of sequelae of upper airway infections. The association between infant RWWC and ED visits at 5 to 7 years of age was attenuated (RR, 1.2; P = .23) when EIW at 5 to 7 years of age was included in the model, suggesting EIW mediates the association. Adjustment for seroatopy did not diminish the magnitudes of any of these associations. Conclusion These findings suggest a nonallergic connection between infant nonwheeze symptoms and important consequences of urban respiratory health by school age through EIW.

Despite attempts and some successes to improve air quality over the decades, current U.S. national trends suggest that exposure to outdoor and indoor air pollution remains a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Emerging science also suggests that environmental exposures during the prenatal period and early childhood years increase the risk of developing asthma. Multiple mechanisms mediate this risk as a wide range of deleterious air pollutants contribute to the pathogenesis of asthma, across a variety of complex asthma phenotypes. In this review, we will consider the role of altered innate and adaptive immune responses, gene by environment interactions, epigenetic regulation, and possibly gene by environment by epigene interactions. Gaining a greater understanding of the mechanisms that underlie the impact of exposure to air pollution on asthma, allergies, and other airway diseases can identify targets for therapy. Such interventions will include pollutant source reduction amongst those most exposed and most vulnerable, and novel pharmaceutical strategies to reduce asthma morbidity.

Asthma definitions vary widely across research studies and feature a trade-off between inclusivity and precision. Harmonizing definitions across multiple asthma birth cohort studies highlights these challenges.

Background Mouse sensitization and exposure are associated with uncontrolled asthma, but whether they are associated with asthma severity, an intrinsic disease characteristic and long-term outcome predictor, is unclear. Objective To examine relationships between mouse sensitization and/or exposure and asthma severity in urban children. Methods A total of 645 children (5-17 years) with uncontrolled asthma underwent mouse sensitization evaluation. Sensitized children had mouse allergen measured in bedroom dust. Relationships between mouse sensitization, allergen levels, and asthma severity measures (treatment step and Composite Asthma Severity Index [CASI]) were examined using regression models adjusted for age, sex, atopy, study site, race, ethnicity, and insurance. Results The study population was predominantly minority (69.6% black, 20.8% Hispanic), low income (61.8%), and mouse sensitized (54.4%). Mean ± SD treatment step was 3.2 ± 1.6, equivalent to medium-dose inhaled corticosteroid. Mean ± SD CASI was 6.5 ± 3.4, reflecting moderate persistent asthma. Mouse sensitization was associated with higher treatment step (3.5 vs 2.9, mouse-sensitized vs nonsensitized, P β [95% CI], 0.36 [0.07-0.64]; P = .01). Mouse sensitization was associated independently with CASI ( β [95% CI], 0.82 [0.16-1.47]; P = .02). Among mouse-sensitized participants, higher bedroom floor and bed Mus m 1 were independently associated with treatment step ( β [95% CI], 0.26 [0.09-0.43]; P = .002 and β [95% CI], 0.22 [0.01-0.43]; P = .04), respectively. Higher bedroom floor Mus m 1 was independently associated with CASI ( β [95% CI], 0.43 [0.05-0.81]; P = .03). Conclusions Mouse sensitization and exposure are associated with asthma severity, among low-income, minority children. Further studies are needed to determine whether reducing allergen exposure among mouse-sensitized patients with asthma can reduce severity, ultimately altering childhood asthma natural history.

Cow’s milk is a major component of most of our diets, but concerns about its ingestion have been in and out of public health dialogues for decades. Raw milk has long been associated with numerous foodborne illnesses and outbreaks due to enteric and opportunistic bacteria such as Brucella, Salmonella, Listeria monocytogenes, Yersinia, Campylobactor species, Staphylococcus aureus, and Escherichia coli species.1,2 Mycobacterium bovis infection was transmitted to humans following drinking unpasteurized milk from infected cows, causing tuberculosis and scrofula.3 Pasteurization, in which milk is heated to 161°F for at least 15 seconds and then cooled, was intended to reduce or eliminate the microbial content, thus decreasing the risk for serious bacterial infections and prolonging the shelf life.4 Since the 1920s, universal pasteurization of milk and milk products has lessened significantly the incidence of these serious infections.3,5 At the start of the obesity epidemic in the United States in the 1980s, milk was drawn into the public spotlight when the fat in whole milk was considered partly responsible for weight gain and the associated metabolic and cardiovascular complications. When the 1995 US Department of Agriculture guidelines recommended switching from whole milk to reduced-fat milk,6 consumption of whole milk plummeted in favor of low-fat varieties.

Environmental epigenetic regulation in asthma and allergic disease is an exciting area that has gained a great deal of scientific momentum in recent years. Environmental exposures, including prenatal maternal smoking, have been associated with asthma-related outcomes that may be explained by epigenetic regulation. In addition, several known allergy and asthma genes have been found to be susceptible to epigenetic regulation. We review the latest experimental and translational studies that have been published this past year in several areas, including 1) characterization of environmental asthma triggers that induce epigenetic changes, 2) characterization of allergic immune and regulatory pathways important to asthma that undergo epigenetic regulation, 3) evidence of active epigenetic regulation in asthma experimental models and the production of asthma biomarkers, 4) evidence of transmission of an asthma-related phenotype across multiple generations, and 5) “pharmaco-epigenetics.” The field has certainly advanced significantly in the past year.

Significant strides in the understanding of the role of epigenetic regulation in asthma and allergy using both epidemiological approaches as well as experimental ones have been made. This review focuses on new research within the last 2 years. These include advances in determining how environmental agents implicated in airway disease can induce epigenetic changes, how epigenetic regulation can influence T helper cell differentiation and T regulatory cell production, and new discoveries of epigenetic regulation associated with clinical outcomes.

Phthalates, pesticides, and bisphenol-A (BPA) are three groups of chemicals, implicated in endocrine disruption and commonly found in the local environment, that have been implicated in the pathogenesis of asthma and allergies [1-3]. Multiple observational studies have demonstrated an association between exposure to phthalates and the development of asthma and allergies in humans. Associations with exposure to pesticides and BPA and the development of respiratory disease are less clear. However, recent evidence suggests that prenatal or early postnatal exposure to BPA may be deleterious to the developing immune system. Future cohort-driven epidemiological or translational research should focus on determining whether these ubiquitous chemicals contribute to the development of asthma and allergies in humans, and attempt to establish the routes and mechanisms by which they operate. Determining dose-response relationships will be important to establishing safe levels of these chemicals in the environment and in consumer products. Attempts to reduce exposures to chemicals such as phthalates, pesticides, and BPA may have environmental repercussions as well as public health impact for the developing child.

Background Cat ownership is inversely associated with atopy and asthma in some areas of the world, but the relevance of cat ownership to allergic disease in the inner city is less known. Objective We sought to evaluate the relationship between cat ownership and the development of early sensitization and wheeze. Methods By using a prospective birth cohort study, Dominican and African American mothers living in New York City underwent repeated questionnaires about their child from birth to age 5 years. Sera collected from children at ages 2 (n = 323), 3 (n = 336), and 5 (n = 242) years were assayed for anti-cat IgE and anti–Fel d 1 IgG antibodies. Results Cat ownership was a significant risk factor for the development of anti-cat IgE by age 2 years (risk ratio [RR], 6.4; 95% CI, 1.9-22) but not for anti-cat IgE development between the ages of 2 and 5 years (RR, 0.88; 95% CI, 0.24-2.3). Current wheeze was significantly more common among those children with anti-cat IgE at ages 3 (RR, 3.5; 95% CI, 2.1-6.0) and 5 (RR, 3.4; 95% CI, 2.3-4.9) years. Cat ownership was inversely associated with current wheeze at age 5 years among children without anti-cat IgE (RR, 0.26; 95% CI, 0.083-0.81). Among children with anti-cat IgE, a similar trend was observed (RR, 0.57; P = .044, Fisher exact test), although one with borderline statistical significance. Conclusions Despite a positive association with sensitization, cat ownership in this inner-city cohort was inversely associated with wheeze, potentially suggesting an IgE-independent protective mechanism in this community.

Background Environmental exposures to indoor allergens are major contributors to asthma symptoms, particularly in inner cities. The effectiveness of household allergen reduction as an adjunct to National Asthma Education Prevention Program guideline–based pharmacologic therapy in asthma has not been prospectively studied. Objective To study the effect of individualized allergen reduction on ability to reduce asthma pharmacologic therapy over 40 weeks. Methods We performed a randomized controlled trial to determine the effect of multifaceted indoor allergen avoidance measures on the ability to reduce asthma controller therapy in adults and children residing in New York City who were both sensitized and exposed to at least 1 indoor allergen. Asthma treatment and control were optimized in all subjects before randomization. Results A total of 125 subjects were randomized to receive individualized household allergen reduction and 122 received a sham intervention. Subjects in the intervention group significantly reduced all measured allergen levels (cat, dog, dust mite allergens in the bedroom, cockroach and mouse allergens in the kitchen and bedroom); those in the control group reduced only dust mite and mouse allergens in the bedroom and cockroach allergen in the kitchen. Participants in the intervention arm reduced National Asthma Education Prevention Program–based therapy from step 4.4 at randomization to 3.50 postintervention (range, 0-6); participants in the control arm reduced medication from step 4.4 to 3.4 ( P = .76). There were no differences in other measured asthma outcomes. Conclusions Targeted allergen avoidance measures do not allow for reduction in asthma pharmacologic therapy compared with usual care in patients already receiving optimal controller therapy.

Background Although mouse and cockroach allergy is known to be important in urban children with asthma, the independent association of mouse and cockroach sensitization with rhinitis in these children is unknown. Objective To determine the association of mouse and cockroach sensitization with rhinitis in urban children with asthma. Methods As part of the Mouse Allergen and Asthma Intervention Trial, 499 urban children (5-17 years) with persistent asthma underwent spirometry, skin prick testing to 14 common environmental allergens, and serology for mouse-specific IgE. In 269 subjects, cockroach-specific IgE serology was also obtained. Patient/parent-reported rhinitis in the last 2 weeks and the last 1 year was the primary outcome measure. Mouse/cockroach exposure was measured by reported frequency of sightings. Mouse allergen–settled bedroom dust samples were also measured in mouse-sensitized children. Results Rhinitis was reported in 49.9% and 70.2% of the participants within the last 2 weeks and the last 1 year, respectively. Serum mouse IgE level of 0.35 IU/mL or more was associated with rhinitis in the past 2 weeks (adjusted odds ratio, 2.15; 95% CI, 1.02-4.54; P = .04) and the past 1 year (adjusted odds ratio, 2.40; 95% CI, 1.12-5.1; P = .02) after controlling for age, race, sex, the presence of any smokers at home, primary caregiver education level, number of allergen sensitivities, cockroach IgE level of 0.35 IU/mL or more, and study site (Boston or Baltimore). Measures of home mouse exposure were not associated with rhinitis, regardless of mouse sensitivity. Cockroach sensitivity was not associated with rhinitis regardless of sensitization to other allergens. Conclusions In urban children with asthma, increased mouse IgE, but not cockroach IgE, in the sera (mouse IgE ≥ 0.35 IU/mL) may be associated independently with rhinitis.

Asthma is a heterogeneous airway inflammatory disease, which is associated with Th2 cytokine-driven inflammation and non-Th2, TNF-α mediated inflammation. Unlike Th2 mediated inflammation, TNF-α mediated asthma inflammation is generally insensitive to inhaled corticosteroids (ICS). ASHMITM, aqueous extract of three medicinal herbs-Ganoderma lucidum (G. lucidum), Sophora flavescens Ait (S. flavescens) and Glycyrrhiza uralensis Fischer (G. uralensis), showed a high safety profile and was clinically beneficial in asthma patients. It also suppresses both Th2 and TNF-α associated inflammation in murine asthma models. We previously determined that G. uralensis flavonoids are the key active compounds responsible for ASHMITM suppression of Th2 mediated inflammation. Until now, there are limited studies on anti-TNF-α compounds presented in ASHMITM. The objective of this study was to isolate and identify TNF-α inhibitory compounds in ASHMITM. Here we report that G. lucidum, but not the other two herbal extracts, S. flavescens or G. uralensis inhibited TNF-α production by murine macrophages; and that the methylene chloride (MC)-triterpenoid-enriched fraction, but not the polysaccharide-enriched fraction, contained the inhibitory compounds. Of the 15 triterpenoids isolated from the MC fraction, only ganoderic acid C1 (GAC1) significantly reduced TNF-α production by murine macrophages (RAW 264.7 cells) and peripheral blood mononuclear cells (PBMCs) from asthma patients. Inhibition was associated with down-regulation of NF-κB expression, and partial suppression of MAPK and AP-1 signaling pathways. Ganoderic acid C1 may have potential for treating TNF-α mediated inflammation in asthma and other inflammatory diseases.

[Background]: Maternal asthma is a risk factor for asthma in offspring; however, transmission of the risk for allergic asthma without direct offspring sensitization has not been explored. [Objective]: To determine whether offspring from mothers with ovalbumin (OVA)-sensitized asthma would develop airway disease at first-ever exposure to OVA and whether preconception maternal treatment with the Antiasthma Simplified Herbal Medicine Intervention (ASHMI) or dexamethasone (DEX) could modify this risk in offspring [Methods]: Female BALB/c mice (F0) with OVA-induced asthma were generated using established protocols. Mice with asthma were treated with ASHMI, DEX, or water for 6 to 7 weeks. Naive mice served as controls. Subsequently, mice were mated. Twelve-day-old F1 offspring received 3 consecutive intranasal low- or high-dose OVA exposures without sensitization. Forty-eight hours later, airway inflammation, mucus hypersecretion, serum antibodies, and cytokines were evaluated. [Results]: Offspring from OVA-sensitized mothers, but not naive mothers, showed eosinophilic and neutrophilic airway inflammation, and mucus hyperplasia after OVA exposure and he presence of OVA-specific IgG1 and IgG2a. Offspring of ASHMI- and DEX-treated mothers showed decreased airway inflammation and mucus hypersecretion after low-dose OVA (P, Dr López-Expósito acknowledges financial support from the Consejo Superior de Investigaciones Científicas through a JAE-Doc grant. Dr Srivastava was supported by a KL2 Faculty Scholar Award (KL2TR000069) from the Mount Sinai Clinical and Translational Science Award. Dr Li received grants from the National Institutes of Health, the FAI, the Chris Burch Fund, the Sean Parker Foundation, and Winston Wolkoff Integrative Medicine for Allergies and Wellness. Dr. Li holds US Patent PCT/US05/08600 for ASHMI™ and is shareholder of Herb Springs LLC. Funding: This study was supported from the National Center for Complementary and Alternative Medicine, National Institutes of Health (grant 1P01 AT002644725-01); the Center for Chinese Herbal Therapy for Asthma; the Sean Parker Foundation (Antiasthma Simplified Herbal Medicine Intervention active compounds for asthma therapy); and Winston Wolkoff Integrative Medicine for Allergies and Wellness.

Although maternal atopy is a risk factor for the development of peanut allergy, this phenomenon has not been well characterized experimentally, and the mechanisms underlying offspring risk are unclear.We sought to determine whether offspring of mothers with peanut allergy (O-PAM mice) are more susceptible to peanut allergy than offspring of naive mothers (O-NM mice) in a murine model and, if so, whether the susceptibility is linked to TH2-biased epigenetic alterations.Five-week-old O-PAM and O-NM mice were intragastrically sensitized to and challenged with peanut. Serum peanut-specific IgE levels, plasma histamine levels, anaphylactic reactions, and splenocyte and MLN cell cytokine production were measured. DNA methylation levels of the Il4 gene promoter from splenocytes and MLN cells from sensitized offspring and splenocytes from unsensitized neonatal offspring were determined by means of pyrosequencing.O-PAM mice exhibited 3-fold higher peanut-specific IgE levels after peanut sensitization, as well as 5-fold higher histamine levels and significantly higher anaphylactic symptom scores after challenge than O-NM mice (P .05-.01). Cultured splenocytes and MLNs from O-PAM mice produced significantly more TH2 cytokines than cells from O-NM mice (P .05-.01). Cells from O-PAM mice exhibited significantly reduced DNA methylation at CpG sites of the Il4 gene promoter than cells from O-NM mice. DNA methylation levels were inversely correlated with IL-4 and IgE production. O-PAM neonatal splenocyte hypomethylation of the Il4 gene promoter was also present.This study is the first to demonstrate that increased susceptibility to peanut allergy in O-PAM mice is associated with epigenetic alteration of the Il4 gene promoter. This finding might provide insight into preventing the development of early-life allergy.

Ann Marie Reardon, MAa,b, Matthew S. Perzanowski, PhDa,b, Robin M. Whyatt, DrPHa,b, Ginger L. Chew, ScDa,b, Frederica P. Perera, DrPHa,b, and Rachel. L. Miller, MDa,b,c Ann Marie Reardon: ; Matthew S. Perzanowski: ; Robin M. Whyatt: ; Ginger L. Chew: ; Frederica P. Perera: ; Rachel. L. Miller: rlm14@columbia.edu a Mailman School of Public Health, Columbia University b Columbia Center for Children’s Environmental Health c Columbia University College of Physicians and Surgeons, Division of Pulmonary, Allergy and Critical Care Medicine, New York, NY

Background: Recent data suggest that the regulation of class switching to IgE by cytokines is mediated by STAT transcription factors. The induction of IgE by IL-4 and IL-13 occurs through the activation of the intracellular signal-transducing protein Stat6, whereas the inhibition of IgE class switching by interferon-γ (IFN-γ) occurs through the activation of Stat1. Objective: We hypothesized that in extrinsic asthma or in cases of markedly elevated IgE (ie, hyperimmunoglobulin E [HIE]) increased levels of IgE may be associated with alterations in the cytokine levels or the activation of Stat6. Methods: PBMCs and sera from 8 patients with extrinsic asthma (mean IgE, 285 ± 100 IU/mL), 3 patients with HIE (mean IgE, 7050 ± 1122 IU/mL), and 14 nonatopic control subjects (mean IgE, 112 ± 28 IU/mL) were analyzed. Results: The mean IL-4 level detected by ELISA was much greater in patients with HIE than control subjects (88.6 ± 11.5 pg/mL vs 11.5 ± 7.1 pg/mL, P = .005), and increased IL-4 levels among patients with both asthma and HIE correlated with the increased IgE levels. In contrast, IL-13 levels were not elevated. Levels of Stat6 protein present in PBMCs did not differ in the patients and control subjects. Examination of Stat6 DNA-binding activity demonstrated no activation of IL-4 signaling in patients with either HIE or acute asthma. Interestingly, evidence for the presence of B cells that have already switched to IgE was seen in PBMCs of several patients with asthma or HIE. Conclusion: These results indicate that (1) IgE production in asthma and HIE usually is associated with elevated levels of IL-4, but not IL-13, in the peripheral blood; (2) the increased sera IL-4 levels in asthma and HIE are not sufficient to induce Stat6 activation in PBMCs; and (3) evidence of switch recombination to ϵ may be detected in isolated cases of elevated IgE. This implies that high levels of IgE in these patients either results from B cells that have already undergone class switching, from Ig class switching that is localized to target tissues, or both. (J Allergy Clin Immunol 1998;102:503-11.)

Background Bisphenol A (BPA) is used widely to manufacture food container linings. Mouse models suggest exposure to BPA might increase allergic inflammation. Objectives We hypothesized that BPA exposure, as assessed based on urinary BPA concentrations, would be associated with increased odds of wheeze and asthma and increased fraction of exhaled nitric oxide (Feno) values in children. Methods The Columbia Center for Children's Environmental Health recruited pregnant women for a prospective birth cohort study (n = 568). Mothers during the third trimester and children at ages 3, 5, and 7 years provided spot urine samples. Total urinary BPA concentrations were measured by using online solid-phase extraction, high-performance liquid chromatography, isotope-dilution tandem mass spectrometry. Wheeze in the last 12 months was measured by using questionnaires at ages 5, 6, and 7 years. Asthma was determined by a physician once between ages 5 and 12 years. Feno values were measured at ages 7 to 11 years. Results Prenatal urinary BPA concentrations were associated inversely with wheeze at age 5 years (odds ratio [OR], 0.7; 95% CI, 0.5-0.9; P = .02). Urinary BPA concentrations at age 3 years were associated positively with wheeze at ages 5 years (OR, 1.4; 95% CI, 1.1-1.8; P = .02) and 6 years (OR, 1.4; 95% CI, 1.0-1.9; P = .03). BPA concentrations at age 7 years were associated with wheeze at age 7 years (OR, 1.4; 95% CI, 1.0-1.9; P = .04) and Feno values (β = 0.1; 95% CI, 0.02-0.2; P = .02). BPA concentrations at ages 3, 5, and 7 years were associated with asthma (OR, 1.5 [95% CI, 1.1-2.0], P = .005; OR, 1.4 [95% CI, 1.0-1.9], P = .03; and OR, 1.5 [95% CI, 1.0-2.1], P = .04, respectively). Conclusions This is the first report of an association between postnatal urinary BPA concentrations and asthma in children.

Background The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) reported that the inactivated influenza vaccine is safe for patients with asthma and recommended its use to reduce the morbidity associated with infection. Objective Because the ALA-ACRC's recommendation would include vaccination of all patients with asthma, including those with severe asthma and first-time vaccinees, we conducted a parallel study to address whether patients with asthma who report bronchospasm after vaccination might be demonstrating a hypersensitivity response to the vaccine. Methods Thirty-two adult patients with asthma from the ALA-ACRC cohort were recruited. Subjects were randomly assigned to receive influenza vaccine or placebo and then recorded asthma symptoms and peak expiratory flow rates for 14 days. On day 14, influenza vaccine and egg antigen–induced mononuclear cell proliferation and IFN-γ, IL-5, and IL-4 production were measured and compared with symptoms. Results Increased influenza but not egg antigen–induced mononuclear cell proliferation was present among vaccinated subjects. These responses were unrelated to asthma exacerbations after vaccine. There were no differences in cytokine production in response to either influenza or egg antigen in association with asthma exacerbations. Conclusions Episodes of bronchospasm after influenza vaccination do not seem related to hypersensitivity to the vaccine.

Background Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs), can induce asthma. However, the effects of early repeated PAH exposure over time on different asthma phenotypes have not been examined. Objective To assess associations between repeated PAH exposure, measured from prenatal personal and residential indoor monitors in children's homes, and asthma in an inner-city cohort. Methods Prenatal exposure was assessed by personal air monitoring during 48 hours and exposure at 5 to 6 years of age by 2-week residential monitoring in the Columbia Center for Children's Environmental Health cohort. PAH was dichotomized into pyrene (representative semivolatile PAH) and the sum of 8 nonvolatile PAHs. High exposure to each was defined as measures above the median at both repeated time points. Asthma and wheeze were determined by validated questionnaires at ages 5 to 6 years. Children with specific IgE levels greater than 0.35 IU/mL to any of 5 indoor allergens were considered seroatopic. Results Among all 354 children, repeated high exposure to pyrene was associated with asthma (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.13-3.20). Among 242 nonatopic children, but not those sensitized to indoor allergens (n = 87) or with elevated total IgE levels (n = 171), high pyrene levels were associated positively with asthma (OR, 2.89; 95% CI, 1.77-5.69), asthma medication use (OR, 2.28; 95% CI, 1.13-4.59), and emergency department visits for asthma (OR, 2.43; 95% CI, 1.20-4.91). Associations between the levels of the 8 nonvolatile PAHs and asthma were not observed, even when stratifying by seroatopy. Conclusion Nonatopic children may be more susceptible to the respiratory consequences of early pyrene exposures.