Michael J. Abramson

Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials

Abstract Objective: To determine whether intranasal corticosteroids are superior to oral H1 receptor antagonists (antihistamines) in the treatment of allergic rhinitis. Design: Meta-analysis of randomised controlled trials comparing intranasal corticosteroids with oral antihistamines. Setting: Randomised controlled trials conducted worldwide and published between 1966 and 1997. Subjects: 2267 subjects with allergic rhinitis in 16 randomised controlled trials. Main outcome measures: Nasal blockage, nasal discharge, sneezing, nasal itch, postnasal drip, nasal discomfort, total nasal symptoms, nasal resistance, and eye symptoms and global ratings. Outcomes measured on different scales were combined to determine pooled odds ratios (categorical outcomes) or standardised mean differences (continuous outcomes). Assessment of heterogeneity between studies, and subgroup analyses of eye symptoms, were undertaken. Results: Intranasal corticosteroids produced significantly greater relief than oral antihistamines of nasal blockage (standardised mean difference −0.63, 95% confidence interval −0.73 to −0.53), nasal discharge (−0.5, −0.6 to −0.4), sneezing (−0.49, −0.59 to −0.39), nasal itch (−0.38, −0.49 to −0.21), postnasal drip (−0.24, −0.42 to −0.06), and total nasal symptoms (−0.42, −0.53 to −0.32), and global ratings gave an odds ratio for deterioration of symptoms of 0.26 (0.08 to 0.8). There were no significant differences between treatments for nasal discomfort, nasal resistance, or eye symptoms. The effects on sneezing, total nasal symptoms, and eye symptoms were significantly heterogeneous between studies. Other combined outcomes were homogeneous between studies. Subgroup analysis of the outcome of eye symptoms suggested that the duration of assessment (averaged mean score over the study period versus mean score at end of study period) might have accounted for the heterogeneity. Conclusion: The results of this systematic review, together with data on safety and cost effectiveness, support the use of intranasal corticosteroids over oral antihistamines as first line treatment for allergic rhinitis.

Indoor airborne fungal spores, house dampness and associations with environmental factors and respiratory health in children

Children living in a damp house are more likely to suffer from respiratory symptoms and it has been suggested that exposure to fungi is an important contributing factor. However, more knowledge about underlying mechanisms for the association are needed.

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

BACKGROUND We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. METHODS We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. FINDINGS Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. INTERPRETATION The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. FUNDING National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.

Increased risk of allergy in children due to formaldehyde exposure in homes

Background: Formaldehyde levels were measured in 80 houses in the Latrobe Valley, Victoria, Australia. An association between exposure to formaldehyde and sensitization to common aeroallergens has been suggested from animal trials, but no epidemiologic studies have tested this hypothesis.

Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Although the main risk factor is smoking, 15–19% of COPD even in smokers has been attributed to occupational exposures. The aim of this study was to investigate the association between occupational exposure and risk of COPD. Methods: Participants were part of a cross sectional study of risk factors for COPD. A total of 1232 completed a detailed respiratory questionnaire, spirometric testsing and measurement of gas transfer. Job histories were coded according to the International Standard Classification of Occupations. These codes were then used to establish occupational exposures using the ALOHA job exposure matrix. Results: The prevalence of emphysema was 2.4%, chronic obstructive bronchitis 1.8%, and COPD 3.4%. Subjects ever exposed to biological dusts had an increased risk of chronic obstructive bronchitis (OR 3.19; 95% CI 1.27 to 7.97), emphysema (OR 3.18; 95% CI 1.41 to 7.13), and COPD (OR 2.70, 95% CI 1.39 to 5.23). These risks were higher in women than in men. For biological dust, the risk of emphysema and COPD was also significantly increased in both the duration of exposure categories, again in women but not in men. No significant increased risks for COPD were found for mineral dust (OR 1.13; 95% CI 0.57 to 2.27) or gases/fumes (OR 1.63; 95% CI 0.83 to 3.22). Conclusion: In this general population sample of adults, occupational exposures to biological dusts were associated with an increased risk of COPD which was higher in women. Preventive strategies should be aimed at reducing exposure to these agents in the workplace.

Airway Smooth Muscle Hypertrophy and Hyperplasia in Asthma

RATIONALE Increased thickness of the airway smooth muscle (ASM) layer in asthma may result from hyperplasia or hypertrophy of muscle cells or increased extracellular matrix (ECM). OBJECTIVES To relate ASM hypertrophy, ASM hyperplasia, and deposition of ECM to the severity and duration of asthma. METHODS Airways from control subjects (n = 51) and from cases of nonfatal (n = 49) and fatal (n = 55) asthma were examined postmortem. Mean ASM cell volume (V(C)), the number of ASM cells per length of airway (N(L)), and the volume fraction of extracellular matrix (f(ECM)) within the ASM layer were estimated. Comparisons between subject groups were made on the basis of general linear regression models. MEASUREMENTS AND MAIN RESULTS Mean V(C) was increased in the large airways of cases of nonfatal asthma (P = 0.015) and fatal asthma (P < 0.001) compared with control subjects. N(L) was similar in nonfatal cases and control subjects but increased in large (P < 0.001), medium (P < 0.001), and small (P = 0.034) airways of cases of fatal asthma compared with control subjects and with nonfatal cases (large and medium airways, P ≤ 0.003). The f(ECM) was similar in cases of asthma and control subjects. Duration of asthma was associated with a small increase in N(L). CONCLUSIONS Hypertrophy of ASM cells occurs in the large airways in both nonfatal and fatal cases of asthma, but hyperplasia of ASM cells is present in the large and small airways in fatal asthma cases only. Both are associated with an absolute increase in ECM. Duration of asthma has little or no effect on ASM hypertrophy or hyperplasia or f(ECM).

International prevalences of reported food allergies and intolerances. Comparisons arising from the European Community Respiratory Health Survey (ECRHS) 1991-1994

Objective: The aim of this study was to report the prevalence, type and reported symptoms associated with food intolerance.Design: A cross-sectional epidemiological study involving 15 countries using standardized methodology. Participants answered a detailed interviewer-administered questionnaire and took part in blood, lung function and skin prick tests to common aeroallergens.Setting: Randomly selected adults who took part in the second phase of the European Community Respiratory Health Survey (ECRHS).Subjects: The subjects were 17280 adults aged 20–44 y.Results: Twelve percent of respondents reported food allergy/intolerance (range 4.6% in Spain to 19.1% in Australia). Atopic females who had wheezed in the past 12 months, ever had asthma or were currently taking oral asthma medications were significantly more likely to report food allergy/intolerance. Participants from Scandinavia or Germany were significantly more likely than those from Spain to report food allergy/intolerance. Respondents who reported breathlessness as a food-related symptom were more likely to have wheezed in the past 12 months, to have asthma, use oral asthma medications, be atopic, have bronchial hyperreactivity, be older and reside in Scandinavia.Conclusion: Self-reported food allergy/intolerance differed significantly across multiple countries. The reasons for these differences were not explored in this study, but are likely to be largely due to cultural differences.Sponsorship: Rosalie Woods holds a postdoctoral research fellowship from the National Health and Medical Research Council of Australia (no. 9797/0883).European Journal of Clinical Nutrition (2001) 55, 298–304

Immunotherapy in asthma: an updated systematic review

Allergen-specific immunotherapy (hyposensitization or desensitization) has long been a controversial treatment for asthma. Although beneficial effects upon clinically relevant outcomes have been demonstrated in randomized controlled trials, there remains a risk of severe and sometimes fatal anaphylaxis. The recommendations of professional bodies have ranged from cautious acceptance (1) to outright dismissal (2). A recent WHO position paper, which has been endorsed by eight other intemational and national bodies, concluded that allergen immunotherapy was an effective treatment for patients with allergic asthma (3). We have previously conducted a meta-analysis of 20 randomized controlled trials of allergen immunotherapy for asthma published between 1954 and 1990 (4). We subsequently conducted a systematic review for the Cochrane Collaboration, including a further 34 trials published between 1957 and 1997 (5). Both reviews concluded that subjects randomized to immunotherapy reported significantly fewer asthma symptoms, required significantly less asthma medication, and demonstrated both reduced nonspecific and reduced allergen-specific bronchial hyperreactivity (BHR) compared to those randomized to placebo. During recent years, there has been increasing interest in new allergen vaccines and new methods of delivery including oral, sublingual, and inhaled immunotherapy. Recombinant peptides containing the relevant epitopes, but lacking the ability to cross-link IgE bound to mast cells, have been evaluated in clinical trials. Finally, the Cochrane Collaboration has standardized protocols for systematic reviews and improved the statistical software for performing meta-analysis. Thus, it was again opportune to update our systematic review of allergen-specific immunotherapy for asthma.

Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P Stage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P Stage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.

Linkage of high-affinity IgE receptor gene with bronchial hyperreactivity, even in absence of atopy

Asthma is a manifestation of bronchial hyperreactivity (BHR) and forms part of the spectrum of atopic disease. Some pedigree studies of atopy have suggested linkage with the high-affinity IgE receptor (Fc epsilon RI beta) gene on chromosome 11q13, but others find no linkage. The molecular genetics of asthma and BHR have not been studied in the general population. We examined the genetic linkage of the Fc epsilon RI beta gene with clinical asthma and the underlying phenotypes of BHR (to methacholine) and atopy (defined by skinprick testing) in 123 affected sibling-pairs recruited from the general population. We found evidence of significant linkage of a highly polymorphic microsatellite marker in the fifth intron of the Fc epsilon RI beta gene to a diagnosis of asthma (18.0% excess of shared alleles, p = 0.002) and to BHR (21.7% excess of shared alleles, p = 0.001). Significant linkage was also observed in siblings sharing BHR when those with atopy were excluded (32.8% excess of shared alleles, p = 0.004). Atopy in the absence of BHR did not show significant linkage to the Fc epsilon RI beta gene (7.2% excess of shared alleles, p = 0.124). These findings suggest that mutations in the Fc epsilon RI beta gene or a closely linked gene influence the BHR underlying asthma, even in the absence of atopy.