James E. Gern

Role of viral respiratory infections in asthma and asthma exacerbations

Summary Viral respiratory tract infections are common and usually selflimited illnesses. For patients at risk of asthma, or with existing asthma, viral respiratory tract infections can have a profound effect on the expression of disease or loss of control. New evidence has shown that wheezing episodes early in life due to human rhinoviruses are a major risk factor for the later diagnosis of asthma at age 6 years. For those with existing asthma, exacerbations are a major cause of morbidity, can need acute care, and can, albeit rarely, result in death. Viral respiratory tract infections, predominantly those caused by human rhinoviruses, are associated with asthma exacerbations. There is also evidence that deficiencies in antiviral activity and the integrity of the airway epithelial barrier could make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation. In view of the effect of respiratory viruses on many aspects of asthma, efforts to understand the mechanisms and risk factors by which these airway infections cause changes in airway pathophysiology are a first step towards improved treatment.

Rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma.

Rhinovirus (RV) infections trigger asthma exacerbations. Genome-wide expression analysis of RV1A-infected primary bronchial epithelial cells from normal and asthmatic donors was performed to determine whether asthma is associated with a unique pattern of RV-induced gene expression. Virus replication rates were similar in cells from normal and asthmatic donors. Overall, RV downregulated 975 and upregulated 69 genes. Comparisons of transcriptional profiles generated from microarrays and confirmed by quantitative reverse transcription PCR and cluster analysis showed some up- and downregulated genes in asthma cells involved in immune responses (IL1B, IL1F9, IL24, and IFI44) and airway remodeling (LOXL2, MMP10, FN1). Notably, most of the asthma-related differences in RV-infected cells were also present in the cells before infection. These findings suggest that differences in RV-induced gene expression profiles of cells from normal and mild asthmatic subjects could affect the acute inflammatory response to RV, and subsequent airway repair and remodeling.

The ABCs of Rhinoviruses, Wheezing, and Asthma

ABSTRACT Human rhinoviruses (HRVs) were discovered as common cold pathogens over 50 years ago. Recent advances in molecular viral diagnostics have led to an appreciation of their role in more-significant respiratory illnesses, including bronchiolitis in infancy, childhood pneumonia, and acute exacerbations of chronic respiratory diseases such as asthma, chronic obstructive lung disease, and cystic fibrosis. Until a few years ago, only two groups of HRVs (A and B) had been recognized. However, full and partial sequencing of HRVs led to the discovery of a third species of HRV (HRV-C) that has distinct structural and biologic features. Risk factors and pathogenic mechanisms for more-severe HRV infections are being defined, and yet fundamental questions persist about mechanisms relating this common pathogen to allergic diseases and asthma. The close relationship between HRV infections and asthma suggests that antiviral treatments could have a major impact on the morbidity associated with this chronic respiratory disease.

Prenatal Maternal Stress and Cord Blood Innate and Adaptive Cytokine Responses in an Inner-City Cohort

RATIONALE Stress-elicited disruption of immunity begins in utero. OBJECTIVES Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families). METHODS Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). MEASUREMENTS AND MAIN RESULTS Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than

The Urban Environment and Childhood Asthma Study

15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-alpha to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-gamma. CONCLUSIONS Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.

Human monocytic cells direct the robust release of CXCL10 by bronchial epithelial cells during rhinovirus infection

Childhood asthma is not distributed evenly throughout the population, and children who grow up in crowded urban neighborhoods have higher rates of asthma and experience greater morbidity because of asthma. There are several environmental and lifestyle factors associated with urban living that are suspected to promote the development of asthma, particularly in the first few years of life. Collectively, this information suggests the hypothesis that exposure in early life to adverse environmental and lifestyle factors associated with disadvantaged urban environments modifies immune development to increase the risk for allergic diseases and asthma. The Urban Environment and Childhood Asthma (URECA) birth cohort study was initiated in 2004 to test this hypothesis. The study population was recruited prenatally and consisted of 560 families from 4 urban areas who were at high risk for allergies and/or asthma on the basis of parental histories, along with an additional 49 families without atopic parents. Immune development, respiratory illnesses, and exposure to stress, indoor pollutants, microbial products, and allergens were measured prospectively, and the major study outcomes are recurrent wheeze at 3 years of age and asthma at age 7 years. This review summarizes the study design, methods, and early findings of the URECA study.

Virus/Allergen Interactions and Exacerbations of Asthma

Background Human rhinovirus (HRV) infections are a major cause of exacerbations in chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease, but HRV‐induced immune responses of the lower airway are poorly understood. Earlier work examining cytokine release following HRV infection has focused on epithelial cells because they serve as the principal site of viral replication, and internalization and replication of viral RNA appear necessary for epithelial cell mediator release. However, during HRV infection, only a small proportion of epithelial cells become infected. As HRV‐induced cytokine levels in vivo are markedly elevated, this observation suggests that other mechanisms independent of direct viral infection may induce epithelial cell cytokine release.

Retention strategies and predictors of attrition in an urban pediatric asthma study

Clinical research findings indicate that there are synergistic interactions between allergy and viral infection that cause increased severity of asthma exacerbations. This article summarizes the current literature linking these 2 risk factors for asthma exacerbation, and reviews experimental data suggesting potential mechanisms for interactions between viral infection and allergy that cause asthma exacerbations. In addition, the authors discuss clinical evidence that treatment of allergic inflammation could help to reduce the frequency and severity of virus-induced exacerbations of asthma.

The relationships among immunoglobulin levels, allergic sensitization, and viral respiratory illnesses in early childhood.

Background The Urban Environment and Childhood Asthma (URECA) study is a multicenter prospective birth cohort study designed to examine factors related to the development of childhood asthma and allergies in an inner-city population. The retention of these participants has been challenging due to high mobility, inconsistent phone service, custody issues, and stressful life situations. Purpose In this article, we describe the specific retention challenges we encountered during the first 2 years of follow-up in URECA and the strategies we utilized to address them. We also examine how selected maternal characteristics and other factors are related to retention and missed study visits. Methods Strategies implemented to engage participants included: collecting updated and alternative contact information, after-hours phone calls to participants, culturally competent staff, flexible study event scheduling, clinic visit transportation, quarterly newsletters, retention events, drop-in home visits, and cell phone reimbursements. An internally developed web-based data management system enabled close monitoring by site teams and the coordinating center. The rate of deactivations was calculated using survival analysis. Characteristics of active and deactivated participants were compared using the chi-squared test with a Cochran—Mantel — Haenszel adjustment for study site. The proportion of missed visits of the total expected in the first 2 years was calculated and compared by family characteristics using an ANOVA model or a trend test controlling for study site. All analyses were performed using SAS version 9.1 (Cary, NC). Results The 2-year retention rate was 89%. Participation in the first study event predicted subsequent engagement in study activities. Mothers who did not complete the first visit were more likely to miss future events (46.1% vs. 8.9%, p<0.0001) and to be deactivated (38.5% vs. 4.5%, p<0.0001). Mothers under 18 years of age were more likely to leave the study compared to older mothers (22.7% vs. 10.1%, p = 0.02). Also, mothers who were married missed fewer events than those not married (8.8% vs. 15.6%, p = 0.01). In addition, deactivations were more common when the child had entered daycare by 3 months of age (10.9% vs. 3.6%, p = 0.05). Limitations The URECA population is predominantly minority, thus our findings might not be generalizable to other populations. Furthermore, we may not be able to observe the effects that might exist in a more diverse population. For example, 86% of the mothers are unmarried, making it difficult to reliably examine the effect of marital status. Conclusion In research, successfully engaging and retaining participants is essential for achieving the study objectives. Identifying factors related to missed visits and deactivations are the initial step in recognizing the potential at-risk participants and can enable the design of targeted strategies to retain participants. Clinical Trials 2010; 7: 400—410. http://ctj.sagepub.com

Expression patterns of atopic eczema and respiratory illnesses in a high-risk birth cohort

Possin ME, Morgan S, DaSilva DF, Tisler C, Pappas TE, Roberg KA, Anderson E, Evans MD, Gangnon R, Lemanske RF, Gern JE. The relationships among immunoglobulin levels, allergic sensitization, and viral respiratory illnesses in early childhood.
Pediatr Allergy Immunol 2010: 21: 990–996.
© 2010 John Wiley & Sons A/S