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.
Monday, December 6, 2010
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.
Review of asthma care in the elderly
This month’s issue includes a clinical review of asthma diagnosis and management in geriatric patients by Charles Reed, MD. Dr. Reed discusses the NAEPP Expert Panel Report 3 (2007) guidelines for diagnosing and managing asthma in the context of the different presentation of late-in-life asthma.
The author points out that clinicians have additional considerations trying to diagnose asthma in geriatric patients. These confounders include decrease in lung function that results from structural compromise associated with aging, comorbid lung disease such as COPD and bronchiectasis, and increased IgE levels that are not allergen specific. Structural changes associated with aging negatively affect pulmonary function testing and often manifest as irreversibility with bronchodilators and increased residual volume.
NAEPP asthma management guidelines can be complicated by a number of characteristics associated with the elderly asthma patients. Drug therapy may be less effective in light of structural changes to the lungs, thus bronchodilators may not be fully effective. Short-acting bronchodilators have the risk of increasing cardiac symptoms and should be avoided, especially in patients with heart disease. Corticosteroid therapy may be effective, but comes with significant side effects such as osteoporosis and hyperglycemia, which are of particular concern in the elderly asthma patient. Furthermore, Dr Reed points out that elderly patients often have difficulty using inhalers effectively, and their inhalation technique needs to be checked at every visit. It may be necessary to switch to old-fashioned pressure nebulizers or oral medications.
Careful assessment of the home environment also remains an important part of management. Dr. Reed emphasizes that, even though elderly patients may not have IgE antibody to aeroallergens, mites, molds and bacteria can cause airway inflammation through innate immune pathways. He notes, “In many elderly asthmatic patients' records, information about the environment is the major omission” (unpublished correspondence). Additionally, anti-fungal medications should be considered if sputum cultures are positive for fungi.
In summary, Dr. Reed revisits the importance of following the guidelines by assessment and control of environmental triggers, effective use of inhaled corticosteroids and oral medications, close evaluation of drug side-effects, and management of comorbid lung disease.
Do you have any questions for Dr. Reed, 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.
The author points out that clinicians have additional considerations trying to diagnose asthma in geriatric patients. These confounders include decrease in lung function that results from structural compromise associated with aging, comorbid lung disease such as COPD and bronchiectasis, and increased IgE levels that are not allergen specific. Structural changes associated with aging negatively affect pulmonary function testing and often manifest as irreversibility with bronchodilators and increased residual volume.
NAEPP asthma management guidelines can be complicated by a number of characteristics associated with the elderly asthma patients. Drug therapy may be less effective in light of structural changes to the lungs, thus bronchodilators may not be fully effective. Short-acting bronchodilators have the risk of increasing cardiac symptoms and should be avoided, especially in patients with heart disease. Corticosteroid therapy may be effective, but comes with significant side effects such as osteoporosis and hyperglycemia, which are of particular concern in the elderly asthma patient. Furthermore, Dr Reed points out that elderly patients often have difficulty using inhalers effectively, and their inhalation technique needs to be checked at every visit. It may be necessary to switch to old-fashioned pressure nebulizers or oral medications.
Careful assessment of the home environment also remains an important part of management. Dr. Reed emphasizes that, even though elderly patients may not have IgE antibody to aeroallergens, mites, molds and bacteria can cause airway inflammation through innate immune pathways. He notes, “In many elderly asthmatic patients' records, information about the environment is the major omission” (unpublished correspondence). Additionally, anti-fungal medications should be considered if sputum cultures are positive for fungi.
In summary, Dr. Reed revisits the importance of following the guidelines by assessment and control of environmental triggers, effective use of inhaled corticosteroids and oral medications, close evaluation of drug side-effects, and management of comorbid lung disease.
Do you have any questions for Dr. Reed, 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.
Tuesday, August 31, 2010
State of the science: Allergy and asthma genetics
In our August News Beyond Our Pages section, we covered the consensus of the NHLBI Lung Division workshop on future directions of genomic research. This month, Deborah Meyers, PhD, co-director of the Center for Human Genomics and Personalized Medicine at Wake Forest University, presents a concise overview of what we know about the genetics of asthma and allergy.
Focusing on results from genome-wide association studies (GWAS), she discusses 5 pivotal research areas: phenotypic diversity, genetic susceptibility influence on disease expression, racial genotyping, the role of normal lung function variation in asthma, and influences of other inflammatory diseases on asthma and allergy.
Dr. Meyers comments that phenotypic heterogeneity seen in asthma will require genetic characterization to realize new approaches to prevention and management. She points out that this same phenotypic heterogeneity may explain why GWAS often identify different sets of genes across different asthma populations. She discusses the need to characterize racial genetic variation, especially in light of recent research that demonstrated that an alternate allele was critical for asthma susceptibility in African Americans in contrast to the relevant allele identified in the white population. Further, she discusses the need to correlate normal lung function variation and epigenetic influence on asthma/allergy disease susceptibility and severity.
Dr. Meyers notes that DNA susceptibility testing is already available. She states, however, that susceptibility testing will probably not pan out to be useful as a diagnostic tool. Dr. Meyers concludes with the comment that systems biology will provide necessary rigor to synthesize the great volume of data into cogent, useful disease profiles.
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.
Focusing on results from genome-wide association studies (GWAS), she discusses 5 pivotal research areas: phenotypic diversity, genetic susceptibility influence on disease expression, racial genotyping, the role of normal lung function variation in asthma, and influences of other inflammatory diseases on asthma and allergy.
Dr. Meyers comments that phenotypic heterogeneity seen in asthma will require genetic characterization to realize new approaches to prevention and management. She points out that this same phenotypic heterogeneity may explain why GWAS often identify different sets of genes across different asthma populations. She discusses the need to characterize racial genetic variation, especially in light of recent research that demonstrated that an alternate allele was critical for asthma susceptibility in African Americans in contrast to the relevant allele identified in the white population. Further, she discusses the need to correlate normal lung function variation and epigenetic influence on asthma/allergy disease susceptibility and severity.
Dr. Meyers notes that DNA susceptibility testing is already available. She states, however, that susceptibility testing will probably not pan out to be useful as a diagnostic tool. Dr. Meyers concludes with the comment that systems biology will provide necessary rigor to synthesize the great volume of data into cogent, useful disease profiles.
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.
Spectroscopy mirrors AD genotypes
Mutations in the filaggrin gene family are known to be associated with atopic dermatitis (AD). Filaggrin (FLG) is a critical component of the epidermal differentiation complex and its degradation products accumulate in the stratum corneum (SC) layer with hygroscopic amino acids to produce natural moisturizing factor (NMF), which is lost via transepidermal water depletion in AD patients. In this issue, O’Regan and co-authors propose that the filaggrin-associated AD genotype could be detected by Raman spectroscopy of the NMF content of the SC and that the NMF content could serve to separate FLG-associated AD from non-FLG-associated AD. Further, they examine the correlation of FLG-associated AD to transepidermal water loss (TEWL) and palmar hyperlinearity.
O’Regan and colleagues generate depth profiles of NMF content from AD study subjects and compare the profiles to Raman spectra for normal SC. Reference spectra profiles include tyrosine, which is known to be elevated in FLG-associated AD. They find that NMF content spectra can distinguish not only FLG-associated AD from non-FLG-associated AD, but also minor allele heterozygosity. Additionally, tyrosine content is significantly associated with the homozygous FLG genotype, suggesting a possible clinical biomarker. O’Regan et al. also report significant relationship between the clinical finding of palmar hyperlinearity, NMF content and filaggrin genotype.
Finally, the authors find that TEWL in moderate to severe AD is independent of filaggrin genotype, suggesting that TEWL results from other AD immunopathology.
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.
O’Regan and colleagues generate depth profiles of NMF content from AD study subjects and compare the profiles to Raman spectra for normal SC. Reference spectra profiles include tyrosine, which is known to be elevated in FLG-associated AD. They find that NMF content spectra can distinguish not only FLG-associated AD from non-FLG-associated AD, but also minor allele heterozygosity. Additionally, tyrosine content is significantly associated with the homozygous FLG genotype, suggesting a possible clinical biomarker. O’Regan et al. also report significant relationship between the clinical finding of palmar hyperlinearity, NMF content and filaggrin genotype.
Finally, the authors find that TEWL in moderate to severe AD is independent of filaggrin genotype, suggesting that TEWL results from other AD immunopathology.
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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