In this issue, Huang et al. (J Allergy Clin Immunol 2011;127: 372-381.e3), reporting on behalf of the NHLBI’s Asthma Clinical Research Network [ACRN], report first-ever research findings associating the composition of airway flora with clinical features of asthma. They postulate that the airway supports a complex community of bacteria that may contribute to clinical features of asthma among asthmatics taking inhaled corticosteroids (ICS). The researchers use a microarra-based method that detects distinct 16S rRNA gene sequences permitting detection and identification of bacterial taxa without previous knowledge of their presence in the relevant sample. Huang et al. report that using this tool, taxa in the phylum Proteobacteria were the most abundant in the cohort of patients studied.
The study occurred in parallel with a clinical trial examining the effects of long-term clarithromycin therapy in subjects with sub-optimal asthma control. Bronchial brushings were obtained from 65 asthma subjects and 10 healthy subjects. The authors find that airway colonization is variable in both healthy and asthmatic subjects, but that asthmatic subjects had significantly greater bacterial diversity than controls. Further, subjects in the clarithromycin treatment group with the highest bacterial diversity pre-treatment, had the greatest improvement in airway hyperresponsiveness following treatment.
Huang et al. comment that finding an airway microbiota in asthma patients on ICS therapy may not be surprising, but in fact, is also consistent with the notion that disturbances in epithelial/mucosal-associated microbiomes are known to be associated with disease as is the case with intestinal inflammatory diseases. They suggest that colonization by specific bacteria may contribute to persistence of inflammation, disease presentation, and/or disease heterogeneity; in particular, they cite the example of bacteria in the family Comamonadaceae, which are known to have steroid degrading capacity, as potentially contributory to steroid-resistant asthma pathology. Further, Huang et al. propose that the effectiveness of macrolide therapy on reducing airway reactivity may be a combined effect of their anti-inflammatory and antibacterial properties.
The authors state that discerning whether increased bacterial burden and diversity is a function of having asthma or being on ICS therapy is an important research question in light of the widespread use of ICS in many airway diseases. Concluding, Huang et al. comment that their findings open new research paths on disease mechanisms in asthma.
We asked senior author Dr. Susan Lynch, PhD, from the University of California - San Francisco, to tell us a little more about the study:
JACI: Your findings have far-reaching implications for airway disease and systems biology research. In your opinion, what are the proximate priorities?
Dr. Lynch: Establishment of cross-disciplinary, integrated research efforts to define microbiota structure, function and host interplay in well defined cohorts of patients. Openness to the possibility that this field of research may dramatically change our long-held perceptions of chronic inflammatory disease genesis and progression.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Monday, January 31, 2011
Friday, January 7, 2011
Gene-environment protective effects are context-dependent in development of asthma
Recent genomic studies have begun to demonstrate that adaptive genotypes are only adaptive when expressed in their relevant context. In this month’s issue, Ege et al. and the European consortium, GABRIEL, present surprising findings from a gene-environment (G*E) interaction analysis for childhood asthma and the farming environment (J Allergy Clin Immunol 2011;127:138-144.e4).
Ege et al. report that previously identified common SNPs associated with asthma in urban populations did not interact with farming environment parameters. Previously identified interactions with farming related exposures were not confirmed despite adequate statistical power.
Among rarer SNPs, however, significant interactions were detected with farming related exposures such as
consumption of raw milk, and exposure to cow and/or straw. By this approach the authors identified new genes that differed from those reported as asthma-associated. SNPs in the GRM1 (metabotropic glutamate receptor 1) gene specifically and significantly interacted with farm exposures. The GRM1 is involved in immunological and neuronal synaptic function. The authors note that these results must be interpreted carefully as the SNPs are rare.
Ege et al. conclude that there may exist different phenotypes of asthma that are susceptible to either genetic or environmental effects, but rarely to both at the same time. They propose that genotypes which are protective for one exposed population do not carry an effect in an unexposed population.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Ege et al. report that previously identified common SNPs associated with asthma in urban populations did not interact with farming environment parameters. Previously identified interactions with farming related exposures were not confirmed despite adequate statistical power.
Among rarer SNPs, however, significant interactions were detected with farming related exposures such as
consumption of raw milk, and exposure to cow and/or straw. By this approach the authors identified new genes that differed from those reported as asthma-associated. SNPs in the GRM1 (metabotropic glutamate receptor 1) gene specifically and significantly interacted with farm exposures. The GRM1 is involved in immunological and neuronal synaptic function. The authors note that these results must be interpreted carefully as the SNPs are rare.
Ege et al. conclude that there may exist different phenotypes of asthma that are susceptible to either genetic or environmental effects, but rarely to both at the same time. They propose that genotypes which are protective for one exposed population do not carry an effect in an unexposed population.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Thursday, January 6, 2011
Advances in immunotherapy for allergies have increased safety and effectiveness
Casale and Stokes take a look at new technologies and experimental therapies developed to improve on the standard approach of subcutaneous injection of increasing concentrations of allergens (SCIT) in this month’s issue (J Allergy Clin Immunol 2011;127:8-15). They discuss omalizumab add-on therapy to conventional SCIT and report on studies in which omalizumab was administered concurrently and prior to initiation of SCIT. Omalizumab plus SCIT showed significant reduction in allergic rhinitis symptoms, and less use of rescue medication compared to SCIT alone. When omalizumab was given as pre-treatment to SCIT, both allergic rhinitis and allergic asthma subjects had fewer severe reactions and more subjects were able to achieve target maintenance dose than subjects receiving placebo plus SCIT.
The authors continue with recent efforts to mobilize mitigating Th1 responses through Toll-like receptor (TLR) agonists and CpG immunostimulatory responses. Combined allergen and TLR therapy is reported to provide significant improvements in rhinitis symptoms and medication use in both adults and children. They also discuss effectiveness associated with bonding immunostimulatory CpG sequences with ragweed allergen to influence T cell responses toward Th1 dominance and reduced eosinophilia; however, clinical impact was minimal. Engineering the allergen and CpG sequences, as well as CpG sequences alone, into virus-like particles provided significantly greater improvements in symptoms and immunologic markers.
Casale and Stokes cover the use of T-cell derived peptides in the treatment of allergies including cat allergy and bee venom allergy. They describe increased benefit and safety of SCIT therapy with newer preparations of Fel d 1 peptides, and early impressive results with Api m 1 and phospholipase A2.
Different routes of administration are also reviewed by the authors such as intranasal and intrabronchial, focusing on escalating oral and sublingual (SLIT) therapies. They report encouraging results from oral desensitization/tolerance studies for subjects with food allergies, which included decreased inflammation markers, decreased specific IgE, increased specific IgG, and achievement of tolerance in a majority of subjects. Results from SLIT therapy trials have been positive as well. SLIT clinical trials for grass and ragweed allergies have shown efficacy in subjects with seasonal allergic rhinitis, and there are positive results noted for other allergens in seasonal allergic rhinitis and allergic asthma.
In conclusion, the authors comment that adjunct omalizumab therapy clearly improves safety and TLR agonists are more effective for shifting to Th1 response. They are optimistic about the future of immunotherapy, although they feel that with the rapid evolution in new technology and increased knowledge of the immune system, how immunotherapy will be used in the future will be substantially different than what is occurring today.
The authors continue with recent efforts to mobilize mitigating Th1 responses through Toll-like receptor (TLR) agonists and CpG immunostimulatory responses. Combined allergen and TLR therapy is reported to provide significant improvements in rhinitis symptoms and medication use in both adults and children. They also discuss effectiveness associated with bonding immunostimulatory CpG sequences with ragweed allergen to influence T cell responses toward Th1 dominance and reduced eosinophilia; however, clinical impact was minimal. Engineering the allergen and CpG sequences, as well as CpG sequences alone, into virus-like particles provided significantly greater improvements in symptoms and immunologic markers.
Casale and Stokes cover the use of T-cell derived peptides in the treatment of allergies including cat allergy and bee venom allergy. They describe increased benefit and safety of SCIT therapy with newer preparations of Fel d 1 peptides, and early impressive results with Api m 1 and phospholipase A2.
Different routes of administration are also reviewed by the authors such as intranasal and intrabronchial, focusing on escalating oral and sublingual (SLIT) therapies. They report encouraging results from oral desensitization/tolerance studies for subjects with food allergies, which included decreased inflammation markers, decreased specific IgE, increased specific IgG, and achievement of tolerance in a majority of subjects. Results from SLIT therapy trials have been positive as well. SLIT clinical trials for grass and ragweed allergies have shown efficacy in subjects with seasonal allergic rhinitis, and there are positive results noted for other allergens in seasonal allergic rhinitis and allergic asthma.
In conclusion, the authors comment that adjunct omalizumab therapy clearly improves safety and TLR agonists are more effective for shifting to Th1 response. They are optimistic about the future of immunotherapy, although they feel that with the rapid evolution in new technology and increased knowledge of the immune system, how immunotherapy will be used in the future will be substantially different than what is occurring today.
Monday, December 6, 2010
SARP reports differences in asthma genotypes & phenotypes are race-associated
In this month’s issue, the Severe Asthma Research Program [SARP] presents their findings from a cross-sectional study of the SARP database, which holds clinical, immunological, and physiological data for over 1300 subjects with asthma (Gamble C, Talbott E, Youk A, Holguin F, Pitt B, Silveira L, et al. Racial differences in biologic predictors of severe asthma: Data from the Severe Asthma Research Program. J Allergy Clin Immunol 126;1149-1156.e1). Gamble et al. partition the severe asthma subjects into two categories, “blacks” and “whites” 40 years of age and older, to evaluate variability in asthma presentation. The authors employ a univariable model and a multivariate model to detect in- and between-group differences.
In univariable analyses, higher BMI, reported GERD, and current employment are associated with severe asthma in blacks. Additionally, the presence of 2 or more family members with asthma is positively associated with severe asthma; however, the presence of atopy and 5 or more positive prick skin tests are negatively associated. Whites are more likely to report additional co-morbidities, such as hypertension and diabetes, as well as GERD, and a positive family history of asthma was not significant in whites. Interestingly, owning a pet decreased the risk of severe asthma in whites. Unlike blacks, current employment is not significant in whites with severe asthma. In both blacks and whites, second-hand smoke exposure and serum IgE are not risk factors.
Multivariate models reveal that, unlike the univariable modeling, IgE was strongly associated with severe asthma and a family history of asthma doubled the risk of severe asthma in blacks. Current employment drops out as a risk factor for blacks in this model. Blacks with GERD, high serum IgE, baseline % predicted FEV1, and 2 or more family members with asthma strongly associate with severe asthma. While whites share GERD and baseline % predicted FEV1 as risk factors with blacks, not having a pet, and no family history of asthma predict risk for severe asthma in whites.
Gamble et al. conclude that biologic/genetic factors and family history are equally or more important than socioeconomic factors as in accounting for risk of severe asthma in blacks. We asked the authors about the implications for their study. According to first author, Christy Gamble, DrPHc, MPH, and senior author, Sally Wenzel, MD, “the different predictors for blacks and whites suggest the mechanisms for severe asthma could be different and thus, approaches to treatment of severe asthma in blacks may very well differ from those in whites.”
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
In univariable analyses, higher BMI, reported GERD, and current employment are associated with severe asthma in blacks. Additionally, the presence of 2 or more family members with asthma is positively associated with severe asthma; however, the presence of atopy and 5 or more positive prick skin tests are negatively associated. Whites are more likely to report additional co-morbidities, such as hypertension and diabetes, as well as GERD, and a positive family history of asthma was not significant in whites. Interestingly, owning a pet decreased the risk of severe asthma in whites. Unlike blacks, current employment is not significant in whites with severe asthma. In both blacks and whites, second-hand smoke exposure and serum IgE are not risk factors.
Multivariate models reveal that, unlike the univariable modeling, IgE was strongly associated with severe asthma and a family history of asthma doubled the risk of severe asthma in blacks. Current employment drops out as a risk factor for blacks in this model. Blacks with GERD, high serum IgE, baseline % predicted FEV1, and 2 or more family members with asthma strongly associate with severe asthma. While whites share GERD and baseline % predicted FEV1 as risk factors with blacks, not having a pet, and no family history of asthma predict risk for severe asthma in whites.
Gamble et al. conclude that biologic/genetic factors and family history are equally or more important than socioeconomic factors as in accounting for risk of severe asthma in blacks. We asked the authors about the implications for their study. According to first author, Christy Gamble, DrPHc, MPH, and senior author, Sally Wenzel, MD, “the different predictors for blacks and whites suggest the mechanisms for severe asthma could be different and thus, approaches to treatment of severe asthma in blacks may very well differ from those in whites.”
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Maternal antioxidant SNPs modify link between acetaminophen exposure in utero and childhood asthma
Shaheen and colleagues report their findings from studies on acetaminophen and childhood asthma from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in this month’s issue (Shaheen SO, Newson RB, Rose-Zerilli MJ, Holloway JW, Henderson AJ. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin Immunol 2010;126:1141-1148.e7). The authors follow up on their previous studies demonstrating association of childhood asthma with acetaminophen use in pregnancy by investigating possible causality between the two.
Shaheen et al. reason that prenatal acetaminophen exposure may increase the risk of childhood asthma by increasing oxidative stress and glutathione depletion and that polymorphisms in antioxidant genes may influence acetaminophen toxicity in the womb. They genotyped transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), a primary regulator of antioxidant genes, and the glutathione-S-transferases GSTM1, -P1, and T1, which protect the lung from oxidative stress. Previous research has shown that Nrf2-negative mice readily develop liver toxicity in response to acetaminophen exposure.
The authors find that early [≤20 weeks gestation] and late [≥20 weeks gestation] acetaminophen exposure in utero is associated with increased risk for wheezing and asthma in childhood. Late gestation acetaminophen exposure has a more profound effect on wheezing and, in addition, is associated with increased serum IgE.
They also find that effects of prenatal acetaminophen exposure on asthma risk are modified by Nrf2 and GST variants in the mother, but not in the child, strengthening evidence that the link between acetaminophen use in pregnancy and childhood asthma may be causal.
Shaheen et al. reason that prenatal acetaminophen exposure may increase the risk of childhood asthma by increasing oxidative stress and glutathione depletion and that polymorphisms in antioxidant genes may influence acetaminophen toxicity in the womb. They genotyped transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), a primary regulator of antioxidant genes, and the glutathione-S-transferases GSTM1, -P1, and T1, which protect the lung from oxidative stress. Previous research has shown that Nrf2-negative mice readily develop liver toxicity in response to acetaminophen exposure.
The authors find that early [≤20 weeks gestation] and late [≥20 weeks gestation] acetaminophen exposure in utero is associated with increased risk for wheezing and asthma in childhood. Late gestation acetaminophen exposure has a more profound effect on wheezing and, in addition, is associated with increased serum IgE.
They also find that effects of prenatal acetaminophen exposure on asthma risk are modified by Nrf2 and GST variants in the mother, but not in the child, strengthening evidence that the link between acetaminophen use in pregnancy and childhood asthma may be causal.
Wednesday, November 3, 2010
New definitions for severe asthma recommended to WHO
We are highlighting a report in this month’s issue from the WHO consulting asthma experts that addresses the lack of universality in the diagnosis of severe asthma. Bousquet et al. present syncretic definitions of asthma severity, control, and exacerbations, and then further characterize severe asthma according to responsiveness to therapy.
Bousquet et al. propose uniformity of definitions of asthma severity based on 1) the components of asthma severity, which include intrinsic severity, clinical control, and attendant health and drug risks associated with the disease, 2) exacerbations, and 3) responsiveness to therapy. Current guidelines employ severity definitions that are tied to treatment response; however, the authors make a good case for the inclusion of severity assessment prior to therapy as well as during therapy, based on the more global issues associated with access to care and medicines in developing countries.
Bousquet et al. then propose a uniform definition of severe asthma as: “Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children).” Framing the definition in light of public health impact and challenges, they divide severe asthma into three groups: untreated severe, difficult-to-treat severe and treatment-resistant severe asthma. The last group comprises the current concept of refractory and steroid-resistant asthma and asthma that can be controlled only at the highest doses of treatment. Importantly, Bousquet et al. includes wheezing disorders in pre-school children in an effort to encourage research on differential clinical and phenotypic characteristics of early childhood asthma from adult asthma.
The authors conclude with comment on the global public health impact of severe asthma and the pressing need for interventions directed at reduction of healthcare utilization and optimization of quality of life. They also issue a call-to-arms for future asthma research programs to reduce the burden of severe childhood asthma and embrace a zero-tolerance philosophy for asthma-related death.
Dr. Stanley Szefler, Deputy Editor, contributes an editorial on the positive impact of Bousquet et al. recommendations.
We asked Dr. Bousquet to tell us about translating these recommendations into practice:
JACI: You have pointed out the difficulties associated with consistent asthma management in developing countries, such as access to and viability of appropriate medications. Will the difficulties faced by these countries make it hard for their practitioners to apply the uniform definitions you propose?
Jean Bousquet: A specific effort has been placed for developing countries. A large number of experts are from developing countries and the definition can be easily used in these countries. The definition also has a public health impact and it is hoped that this proposal will help all patients with asthma in the world (to) be able to get affordable asthma treatment.”
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Bousquet et al. propose uniformity of definitions of asthma severity based on 1) the components of asthma severity, which include intrinsic severity, clinical control, and attendant health and drug risks associated with the disease, 2) exacerbations, and 3) responsiveness to therapy. Current guidelines employ severity definitions that are tied to treatment response; however, the authors make a good case for the inclusion of severity assessment prior to therapy as well as during therapy, based on the more global issues associated with access to care and medicines in developing countries.
Bousquet et al. then propose a uniform definition of severe asthma as: “Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children).” Framing the definition in light of public health impact and challenges, they divide severe asthma into three groups: untreated severe, difficult-to-treat severe and treatment-resistant severe asthma. The last group comprises the current concept of refractory and steroid-resistant asthma and asthma that can be controlled only at the highest doses of treatment. Importantly, Bousquet et al. includes wheezing disorders in pre-school children in an effort to encourage research on differential clinical and phenotypic characteristics of early childhood asthma from adult asthma.
The authors conclude with comment on the global public health impact of severe asthma and the pressing need for interventions directed at reduction of healthcare utilization and optimization of quality of life. They also issue a call-to-arms for future asthma research programs to reduce the burden of severe childhood asthma and embrace a zero-tolerance philosophy for asthma-related death.
Dr. Stanley Szefler, Deputy Editor, contributes an editorial on the positive impact of Bousquet et al. recommendations.
We asked Dr. Bousquet to tell us about translating these recommendations into practice:
JACI: You have pointed out the difficulties associated with consistent asthma management in developing countries, such as access to and viability of appropriate medications. Will the difficulties faced by these countries make it hard for their practitioners to apply the uniform definitions you propose?
Jean Bousquet: A specific effort has been placed for developing countries. A large number of experts are from developing countries and the definition can be easily used in these countries. The definition also has a public health impact and it is hoped that this proposal will help all patients with asthma in the world (to) be able to get affordable asthma treatment.”
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Friday, October 1, 2010
New evidence relates prebiotics to reduced occurrence of AD
The jury is still out on whether supplementation with active prebiotics favorably affects atopic conditions, in particular, atopic dermatitis (AD) and food allergies, in children and adults. This question is becoming increasingly relevant as more and more research is showing that our gut microbiota differs significantly from what is considered to be the primitive state.
Noting that more cases of atopy are associated with children who have little or no familial risk, Grüber et al in this issue investigate the effects of immunoactive, pre-biotic oligosaccharides (OS) added to formula on weaned infants with low atopic risk. The authors created a cow’s milk formula with OS that was very similar to breast milk. Three groups were followed: a group of infants receiving pre-biotic formula (PG), a group receiving formula with no added OS (CG), and an exclusively breastfed group (BG).
The authors report that the incidence of AD in PG infants at the first birthday was reduced 44% as compared to CG infants. This rate was much closer to that of the breastfed group. Severity as measured by TARC levels did not differ between the three groups at the first birthday. Grüber et al. also report that milk and egg specific IgE was not affected, implying that pre-biotic supplementation did not alter sensitization.
Finally, Grüber et al. comment that it would be an important public health issue to know if this effect is persistent. They suggest that it does and could result in reduced respiratory allergy in later life.
We asked Dr. Grüber about the implications of this study:
JACI: Given your results on serum levels of TARC in infants that remained free of AD at their first birthday, please comment about the usefulness of TARC as a biomarker of severity in atopic dermatitis.
Dr. Christoph Grüber: TARC (Thymus- and activation-regulated chemokine) is a Th2-type chemotactic messenger which is upregulated during eczema exacerbation in the blood and which recruits inflammatory cells to the eczematous skin. TARC has been found useful as a biomarker for moderate to severe inflamed skin. Most affected infants in our study had mild eczema. TARC may discriminate non-afflicted and mildly afflicted cases less well.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Noting that more cases of atopy are associated with children who have little or no familial risk, Grüber et al in this issue investigate the effects of immunoactive, pre-biotic oligosaccharides (OS) added to formula on weaned infants with low atopic risk. The authors created a cow’s milk formula with OS that was very similar to breast milk. Three groups were followed: a group of infants receiving pre-biotic formula (PG), a group receiving formula with no added OS (CG), and an exclusively breastfed group (BG).
The authors report that the incidence of AD in PG infants at the first birthday was reduced 44% as compared to CG infants. This rate was much closer to that of the breastfed group. Severity as measured by TARC levels did not differ between the three groups at the first birthday. Grüber et al. also report that milk and egg specific IgE was not affected, implying that pre-biotic supplementation did not alter sensitization.
Finally, Grüber et al. comment that it would be an important public health issue to know if this effect is persistent. They suggest that it does and could result in reduced respiratory allergy in later life.
We asked Dr. Grüber about the implications of this study:
JACI: Given your results on serum levels of TARC in infants that remained free of AD at their first birthday, please comment about the usefulness of TARC as a biomarker of severity in atopic dermatitis.
Dr. Christoph Grüber: TARC (Thymus- and activation-regulated chemokine) is a Th2-type chemotactic messenger which is upregulated during eczema exacerbation in the blood and which recruits inflammatory cells to the eczematous skin. TARC has been found useful as a biomarker for moderate to severe inflamed skin. Most affected infants in our study had mild eczema. TARC may discriminate non-afflicted and mildly afflicted cases less well.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
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