Pharmacogenomics of asthma: present and perspective

One main area of pharmacogenomics is the discovery of new drugs and drug targets with molecular genetic or genomic methods; the other is the study of how genomic differences influence the variability in patients responses to drugs. In this review the authors summarise the most important results of this latter issue. Despite the availability of three major classes of therapeutic agents for asthma, it has been estimated that as many as half of asthmatic patients do not respond to treatment with beta2-agonists, leukotriene modifiers or inhaled corticosteroids. Moreover, in some individuals asthma therapy has been associated with serious adverse drug reactions. An estimated 60 to 80% of variability in individual responses to therapy may have genetic bases. All of the currently available data on asthma pharmacogenomics originated from genetic variations in genes of the drug treatment target or target pathways. Results of genetic association studies that investigate responses to beta2-agonist, leukotriene modifier and corticosteroid therapy will be summarised and recent findings in the literature highlighted. Although, at present pharmacogenomics can explain only a fraction of the adverse drug responses, hopefully these results mark the clinical use of genotyping at an individual level as adjunct to pharmacotherapy for asthma and many other diseases.     

Self-reported asthma in adults and proxy-reported asthma in children--Washington, 1997-1998

Increased awareness of asthma as a public health problem reflects recent increases in asthma prevalence, asthma-related visits to hospital emergency departments, and asthma-related mortality. To assess the prevalence of asthma in Washington, the Washington State Department of Health added survey items on asthma to its 1997 and 1998 Behavioral Risk Factor Surveillance System (BRFSS) survey. This report summarizes the results of those surveys, which indicate that persons with asthma reported significantly lower health status than other respondents and that a substantial proportion of households with children reported having a child with asthma.     

Air pollution, health, and socio-economic status: the effect of outdoor air quality on childhood asthma

This paper estimates the effect of air pollution on child hospitalizations for asthma using naturally occurring seasonal variations in pollution within zip codes. Of the pollutants considered, carbon monoxide (CO) has a significant effect on asthma for children ages 1-18: if 1998 pollution levels were at their 1992 levels, there would be a 5-14% increase in asthma admissions. Also, households respond to information about pollution with avoidance behavior, suggesting it is important to account for these endogenous responses when measuring the effect of pollution on health. Finally, the effect of pollution is greater for children of lower socio-economic status (SES), indicating that pollution is one potential mechanism by which SES affects health.     

Links between multiple chemical sensitivity and asthma in a rat model of cholinergic hypersensitivity: a brief review.

Individuals with multiple chemical sensitivity (MCS) also commonly report symptoms of asthma, but, as far as we have been able to determine, no one has yet suggested that an abnormal cholinergic system may provide the link between asthma and MCS. The present brief review provides evidence for such a link by summarizing recent findings in a genetic animal model of cholinergic hyperresponsiveness. The Flinders Sensitive Line (FSL) rats were developed by selective breeding for increased responses to an anticholinesterase agent similar to commonly used organophosphate pesticides. Relative to their control line, the Flinders Resistant Line (FRL) rats, the FSL rats are more sensitive to drugs that stimulate acetylcholine receptors, alcohol, diazepam, and drugs that have a selective effect on dopamine or serotonin receptors. These findings raise the possibility that the FSL rats may resemble individuals with MCS. Hyperresponsiveness of the airways is a hallmark of asthma. The procedure known as whole-body plethysmography, where breathing can be monitored in freely moving animals, was employed to study the FSL and FRL rats. The FSL rats exhibited a greater index of bronchoconstriction than the FRL rats in response to both a cholinergic agonist and an allergen challenge. Thus, the FSL rats are more sensitive both to a variety of drugs unrelated to the cholinergic system and to cholinergic- and allergen-induced bronchoconstriction. An abnormal cholinergic system may therefore contribute to both MCS and asthma.     

Risk and incidence of asthma attributable to occupational exposure among HMO members

Occupational asthma may account for a significant proportion of adult-onset asthma, but incidence estimates from surveillance of physician reports and workers' compensation data (0.9 to 15/100,000) are lower than expected from community-based cross-sectional studies of asthma patients. We conducted a prospective cohort study of 79,204 health maintenance organization members between the ages of 15 and 55 at risk for asthma. Computerized files, medical records, and telephone interviews were used to identify and characterize asthma cases. Evidence for asthma attributable to occupational exposure was determined from work-related symptoms and workplace exposure. The annual incidence of clinically significant, new-onset asthma was 1.3/1,000, and increased to 3.7/1,000 when cases with reactivation of previously quiescent asthma were included. Criteria for onset of clinically significant asthma attributable to occupational exposure were met by 21% (95% CI 12–32%) of cases giving an incidence of 71/100,000 (95% CI 43–111). Physicians documented asking about work-related symptoms in 15% of charts, and recorded suggestive symptoms in three cases, but did not obtain occupational medicine consultation, diagnose occupational asthma, report to the state surveillance program, or bill workers' compensation for any of them. These data suggest that the incidence of asthma attributable to occupational exposures is significantly higher than previously reported, and accounts for a sizable proportion of adult-onset asthma. Am. J. Ind. Med. 33:1–10, 1998. © 1998 Wiley-Liss, Inc.     

A school-based asthma intervention program in the Buffalo, New York, schools

This project investigated the feasibility and effectiveness of a school asthma program in reducing asthma exacerbations among school children. In 1997-1998, two schools were selected for a case control pilot study. The intervention required that students with asthma, who needed medication daily at school, must present a written plan from the health care provider. Students with asthma were identified through parent/guardian or school reports. The pilot program was expanded into five schools in 1998-1999. All schools kept records of rescue treatments for asthma episodes. The pilot intervention resulted in an 80% decrease in rescue treatments from 1996-1997 to 1997-1998. In the additional five schools, an overall decrease of 17% occurred in rescue treatments during 1998-2000. Overall, 65% of physicians provided requested Asthma Care Plans (ACP). In two schools, the number of asthma care plans that required anti-inflammatory medications tripled. Preliminary results indicate this school asthma program proved feasible and effective in reducing the frequency of asthma exacerbations at school.     

Urinary excretion of mutagens in cirrhosis: Limited evidence of an association

Although bacterial mutagenesis assays have detected mutagenic substances in urine from smokers and patients treated with certain medications, these assays have not found mutagens in body fluids of subjects without such exposures. A recent report, however, suggested that mutagenic substances were present in the urine of unexposed individuals with cirrhosis. Since this observation could have important implications for the metabolism of potentially toxic substances and might provide leads to the cause of the high incidence of hepatoma among patients with cirrhosis, the reproduction of those findings of that report was attempted. In contrast with the earlier report, no evidence of mutagenic substances in urine samples from unexposed patients with cirrhosis was observed. While differences between these studies might be attributed to the subjects tested, it seems possible that the mutagenic activity reported previously was due to technical interference with the testing procedure by nonmutagenic materials in urine rather than the presence of mutagens. These observations may help clarify the interpretation of assays for urine mutagenicity in occupational or other environmental studies.     

Fate of mutagenic activity during conventional treatment of municipal wastewater sludge

The mutagenic activity of wastewater was followed during conventional activated sludge treatment at a municipal plant. Raw wastewater was initially screened for mutagenic potential, using the AmesSalmonella/mammalian microsomal test and employer tester strains. The combined raw wastewater produced dose-related mutagenic responses in the presence of S9 metabolic activation. Raw wastewater from domestic sources alone was not mutagenic. Mutagenic activity was observed throughout the treatment process. Activated sludge prior to chlorination contained the highest specific mutagenic activity. Chlorination decreased the specific mutagenic activity at pH 11. Mutagenic activity in municipal wastewater containing industrial discharges is not removed by conventional treatment processes and can be enhanced by activated sludge treatment.     

Is the global rise of asthma an early impact of anthropogenic climate change?

The increase in asthma incidence, prevalence, and morbidity over recent decades presents a significant challenge to public health. Pollen is an important trigger of some types of asthma, and both pollen quantity and season depend on climatic and meteorologic variables. Over the same period as the global rise in asthma, there have been considerable increases in atmospheric carbon dioxide concentration and global average surface temperature. We hypothesize anthropogenic climate change as a plausible contributor to the rise in asthma. Greater concentrations of carbon dioxide and higher temperatures may increase pollen quantity and induce longer pollen seasons. Pollen allergenicity can also increase as a result of these changes in climate. Exposure in early life to a more allergenic environment may also provoke the development of other atopic conditions, such as eczema and allergic rhinitis. Although the etiology of asthma is complex, the recent global rise in asthma could be an early health effect of anthropogenic climate change.     

Comparison of parent and student responses to asthma surveys: students grades 1-4 and their parents from an urban public school setting

This study compared parent and child responses to a symptom questionnaire as a means of determining whether child and parent responses are equally valuable in case-detection procedures. We completed a study validating a multistage case-detection procedure. The case-detection procedure classified students into 3 categories based on their parents' questionnaire responses (probable asthma, possible asthma, and negative for asthma). Those who were classified as possible asthma by questionnaire underwent further testing, including spirometry and exercise challenge. The children with abnormal testing results were considered to have probable asthma. McNemar's test and kappa coefficients were used to examine parent-child agreement. Sensitivity and specificity of the case-detection procedure were compared using either the parent's or the child's responses to the questionnaire. The data indicated moderate agreement between parent and child responses to questions regarding previous diagnosis of asthma and past asthma therapy (p < .001, kappa coefficients of 0.6030 and 0.5966, respectively). Sensitivity, specificity, and predictive values in the multistage case-detection procedure were similar when using either parent or child responses to the questionnaire. Among the false negatives, the distribution of asthma severity was consistent whether using child or parent responses. Parent-child agreement did not differ significantly by gender or age of the child or whether the child had a previous diagnosis of asthma. These results suggest that the use of child responses is a viable option for case detection, particularly in identifying those with a previous diagnosis of asthma     

Occupational respiratory allergy in bakery workers: A review of the literature

Baker's asthma has long been recognized as a serious disease among workers in the bakery industry and the number of cases with baker's asthma is steadily increasing. This paper presents a review of the available literature on baker's allergy with a special focus on the allergens involved, the epidemiologic research and issues on exposure assessment, evidence of exposure-response-relationships, and possible prevention strategies. A large number of potential allergens have been identified and are described here. At present little is known about the incidence of baker's allergy. On the other hand, a large number of cross-sectional studies have been performed, showing that sensitization and work-related symptoms are common among bakery workers. Only atopy and exposure level have consistently been reported as determinants of this occupational disease. Age, gender, and smoking habits do not seem to be associated with sensitization or work-related respiratory symptoms. Recently, immunochemical methods have been developed to measure specific allergens in the bakery industry, which have been used to unravel the role of allergen exposure in the development of baker's asthma. Clear exposure-response-relationships have been found. The implications of these recent findings for prevention strategies and standard setting are discussed. Am. J. Ind. Med. 34:529–546, 1998. © 1998 Wiley-Liss, Inc.     

空气致敏花粉污染与支气管哮喘的研究进展

花粉是一种重要的空气致敏原,可引起支气管哮喘等一系列过敏性疾病,严重困扰了人们的日常生活。目前,对致敏花粉污染与过敏性疾病的研究日趋深入。本文综述了花粉飘散规律及其预报,致敏原的确定方法,以及支气管哮喘的预防控制和免疫治疗的最新进展,并提出了展望。     

TLR4 and LPS hyporesponsiveness in humans

Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and allow scientists to investigate unique gene-environment interactions that are involved in the development of biologically specific forms of asthma.     

IgE-blocking therapy for difficult-to-treat asthma: a brief review

PURPOSE: To review the characteristics of difficult-to-treat asthma and describe patients who may benefit from therapy with the recently approved humanized monoclonal antiimmunoglobulin E (IgE) antibody, omalizumab. PRINCIPAL FINDINGS: Up to 20 percent of patients have difficult-to-treat asthma. These patients consume a disproportionate share of asthma care resources. Clinical and economic outcomes can be improved via improved self-management, increased adherence to prescribed therapy, and better compliance to national asthma treatment guidelines. These patients also may benefit from therapies that directly target mechanisms responsible for persistent airway inflammation and elicit favorable clinical responses. CONCLUSIONS: Effective asthma control remains difficult in a small cohort of patients with persistent, severe airway inflammation. Management strategies that improve asthma control and reduce exacerbations can improve clinical outcomes and minimize health care resource utilization.     

Previous maternal oral contraception and the risk among subsequent offspring of asthma diagnosis in early childhood

Previous maternal use of the oral contraceptive pill (OCP) has been linked with asthma in subsequent offspring and has been implicated in the increased prevalence of childhood asthma in recent decades. We conducted a matched case–control study to test the hypothesis that maternal OCP used close to conception is associated with asthma in the offspring, particularly in children with coexistent eczema. We examined maternal OCP exposure in relation to asthma in the offspring ( n  = 6730) compared with offspring with no asthma ( n  = 6730) further stratifying by eczema, age group, treatment category and gender of the offspring. Maternal use of OCP was classified as: no OCP use in the 2 years prior to conception; past OCP use within 2 years but >6 months before conception; and recent OCP use within 6 months of conception.
The adjusted odds ratio (OR) for asthma in the offspring was 1.16 [95% confidence interval 1.06, 1.27] among mothers who were recent users of the OCP when compared with mothers who had not used the OCP. Past OCP use was not associated with asthma in the offspring. In the stratified analyses, we observed weak but statistically significant associations between recent maternal OCP use and asthma in the offspring among children: without a history of eczema (adjusted OR 1.22 [1.09, 1.36]), those aged ≤3 years (adjusted OR 1.24 [1.12, 1.37]), those not on treatment for their asthma (adjusted OR 1.33 [1.12, 1.58]) and among females (adjusted OR 1.34 [1.13, 1.51]). We did not find convincing evidence for a causal relationship between maternal OCP used close to conception and asthma in the offspring. The small statistically significant associations were not among children with characteristic features of asthma such as those with eczema and may be due to bias, uncontrolled confounding or chance.     

A potential immunotherapy approach: mucosal immunization with an IL-13 peptide-based virus-like particle vaccine in a mouse asthma model

Interleukin (IL)-13 is critical in asthma pathogenesis. Previously, we have developed an IL-13 peptide-based vaccine and confirmed that subcutaneous immunization with the vaccine suppressed airway allergic inflammatory responses in a mouse asthma model. In the present study, we sought to test if mucosal immunization with the vaccine could be a potential approach, by inducing specific autoantibodies of both local IgA in the airway and systemic IgG in serum, to provide an overall suppression of redundant IL-13 effects. The results show that intranasal vaccination induces IL-13-specific IgA responses in multiple mucosal tissues and higher titers of IgG in serum than subcutaneous vaccination. This approach leads to a more effective suppression of ovalbumin-driven Th2 patterns of antibody responses and airway IL-13 and eosinophil accumulation than subcutaneous immunization, even when the induced IL-13 IgG responses were at a similar level. In conclusion, mucosal vaccination may be an innovative potential approach in the treatment of asthma.     

The relationship of health insurance to the diagnosis and management of asthma and respiratory problems in children in a predominantly Hispanic urban community

OBJECTIVES: As part of an asthma screening study, we evaluated the relationship of health care insurance coverage to the diagnosis and treatment of elementary school children for asthma and related respiratory problems from 1998 through 2001. METHODS: A bilingual questionnaire assessing health care coverage, asthma diagnosis, respiratory symptoms, and use of medications was distributed to parents of 6235 public and private school children in grades 2 through 5 in Passaic, NJ. RESULTS: Responses for 4380 children (70%) revealed disparities in health care coverage and asthma diagnosis among racial and ethnic groups. Mexican and Dominican children had significant increases in health care coverage over the 4 years. CONCLUSIONS: The percentage of children with health insurance grew from 67% in 1998 to 81% in 2001, and the increase was related to NJ KidCare. Diagnosis of asthma and treatment were related to health care coverage.     

Measuring childhood asthma prevalence before and after the 1997 redesign of the National Health Interview Survey--United States

Asthma is the most common chronic disease of childhood and a leading cause of disability among children (1,2). Since 1980, asthma prevalence has increased dramatically in children (3,4). The National Health Interview Survey (NHIS), the principal source of asthma prevalence data for the United States, was redesigned in 1997. This report presents NHIS data from 1980-1998 to examine the effect of the redesign on measuring trends in asthma prevalence overall and among age and racial subgroups of children. The findings indicate that although asthma prevalence estimates for 1997-1998 are lower than those preceding changes in the survey design, estimates after 1997 are not comparable to previous estimates. Additional data are needed to establish a new trend after 1997.     

Unifying concepts underlying the effects of organic dust exposures

Defense mechanisms protect the lung very well from inhaled organic dusts. With sufficient exposure to certain dusts, however, susceptible individuals develop hypersensitivity pneumonitis (HP), the organic dust toxic syndrome (ODTS), or asthma. Mucous membrane irritation (MMI) bothers some individuals inhaling grain dust. Allergic asthma is caused by IgE-mediated immunologic responses to allergenic dust contaminants. ODTS can be explained by a nonimmunologic release of interleukin 1 (IL-1) and perhaps other endogenous pyrogens from alveolar macrophages by endotoxin or other ingredients of dusts. The pathogenesis of HP may involve IL-1 release combined with a specific immunological response by effector T-lymphocytes. MMI may be the result of an irritant effect not involving immune responses or mediators.     

Agreement between responses to a standardized asthma questionnaire and a questionnaire following a demonstration of asthma symptoms in adults

Asthma epidemiology relies heavily on standardized questionnaires, but little is known about the understanding of asthma symptoms among adults in the community. In 2004, the authors assessed the level of agreement between responses to a standardized questionnaire and responses to a questionnaire completed by participants after viewing a demonstration of asthma symptoms. The study involved 601 young adults from Chile. The field-workers were trained to explain and demonstrate the asthma symptoms to the participants. The symptoms were wheeze, waking at night with breathlessness, breathlessness following exercise, and waking with cough. The kappa statistic did not exceed 0.4, and the recorded prevalence of asthma symptoms following the demonstration was 30-60% lower than that for the standardized questionnaire. Using bronchial responsiveness as the proxy gold standard, the positive likelihood ratios for wheeze and waking short of breath were higher following symptom demonstration. The low agreement between the standardized questionnaire and the postdemonstration questionnaire and the likelihood ratios' closeness to 1 for the standardized questionnaire decreases the authors' confidence in the appropriateness of this tool for estimating the prevalence of asthma in the community. For etiologic studies of asthma, it may contribute to the lack of consistency between different studies analyzing the same etiologic exposures.