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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.

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.

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.

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.

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.

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.

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.

Friday, July 30, 2010

Nudging forward a new paradigm for food allergies

Characterization of food allergies has produced abundant data on their clinical presentation, but the biological construct driving the pathology is a ghost in the machine. In this month’s issue, Vassallo and Camargo make an intrepid, but logical, gesture at a syncretic hypothesis of food allergy evolution.

The authors start with the epidemiologic observation that societal decreases in exposure to sunshine have led to a rise in vitamin D deficiency (VDD) and that these two changes are coeval with the increase in food allergies. They offer a hypothesis linking evidence of VDD to atopic progression, i.e., eczema, respiratory compromise, and food allergy. Specifically, they propose that VDD results in increased infection susceptibility and altered microbiota in the gut, which in turn, cause higher levels of mucosal barrier damage, permitting excessive exposure to food allergens through the “leaky gut.”

Vassallo and Camargo mention known associations between VDD, childhood obesity, and food allergy. Physiologic support for their hypothesis comes from recent evidence that vitamin D is critical to induction of tolerance, as well as antimicrobial peptide (AMP) production in the epithelium, and suppression of inflammatory responses.

It is the AMP factor that the authors use to tie VDD to the effector mechanism. In addition to increased susceptibility to infection, VDD causes dysregulation of AMPs in the intestine, supporting an abnormal intestinal flora. They also point to recent data that suggest VDD has a primary role in mucosal barrier compromise.

Wrapping up, Vassallo and Camargo note several incongruities, including that VDD prevalence is higher than food allergy prevalence and genetic atopic predispositions may act independently to increase food allergy risk, from which they suggest that multiple “hits” are required to result in food allergy. They urge future, cross-disciplinary research designed to examine their hypothesis that correction of VDD during pregnancy and early childhood will lead to improved tolerance, mucosal immunity, and balanced intestinal flora.

We asked the authors whether their hypothesis could be applied to adults as well as children:
JACI: You make the distinction between failure to develop tolerance as seen in childhood and loss of tolerance associated with adult onset of food allergy. Is there reason to believe that vitamin D supplementation might mitigate loss of tolerance as well?

Carlos Camargo: We have chosen to focus on children because that’s when most food allergy begins -- and where we have found supportive epidemiologic data (eg, our recent publication on season of birth and food allergy -- citation below). In brief, we found increased risk of food allergy among children born in fall/winter, as compared to spring/summer. We found no association between season of birth and food allergy in older patients. (Vassallo MF, Banerji A, Rudders SA, Clark S, Mullins RJ, Camargo CA Jr. Season of birth and food allergy in children. Ann Allergy Asthma Immunol 2010; 104: 307-313.)

While it’s theoretically possible that vitamin D supplementation might mitigate loss of tolerance in adults, we will continue to focus our research efforts on childhood food allergy.

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.

Thursday, July 1, 2010

Guest post: A primer on human IgE antibody serology

Dear Readers:

In response to the concerns about an increase in the remote practice of allergy, which may possibly be influenced by direct allergy laboratory marketing campaigns, the AAAAI and ACAAI, in conjunction with Don Aaronson from the JCAAI formed a joint taskforce in 2006 on allergy diagnostic testing called the Specific IgE Test Task Force (SETTaF) . SETTaF’s purpose has been to develop educational materials that focus on the appropriate diagnostic evaluation of the allergic/suspected patient. In late 2008 SETTaF published a monograph directed at health care professionals, who care for allergic patients entitled the “Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force.”(1) The task force is currently engaged in the development of a PowerPoint presentation and several monographs on diagnostic allergy testing that are directed at primary care professionals.

The key message throughout these educational materials is that the allergy evaluation must be initiated by and culminated with the patient's clinical history. It must be directed by a health care professional with sufficient understanding of diagnostic allergy testing to use the information obtained from his/her evaluation of the patient to determine: 1. What diagnostic allergy tests to order. 2. How to interpret the diagnostic allergy test results. 3. How to use the information obtained from the allergy evaluation to develop an appropriate therapeutic treatment plan.

This issue of the Journal of Allergy and Clinical Immunology presents a monograph developed by SETTaF on serological measurement of allergen-specific IgE testing specifically for the North American allergist. Per the protocol of a joint AAAAI/ACAAI task force, the SETTaF’s monographs are reviewed by the Board of Directors/Regents of both organizations. During this review, a question and answer dialogue evolved and the organizations' Boards suggested including the ‘Q&A’ with the document.

The members of SETTaF hope you find the monograph educational. The following questions and answers represent the views of the individuals and not SETTaF or the Board of Directors/Regents of the AAAAI/ACAAI.

Linda Cox, MD
SETTaF chair

Allergy Diagnostic Testing Primer: Questions and Answers

Below are some questions that were raised by ACAAI reviewers that will highlight some of the questions readers may have and an attempt by the authors to provide answers, where they are available.

Issue 1: Use of serum specific-IgE in clinical decision-making

Dana Wallace , MD (ACAAI president-elect): This report on the evolution of serum specific- IgE (s-IgE) testing is a timely and much needed document for the clinical allergist. While technically well written, it brings up perhaps more questions and confusion than it answers or clarifies. While the authors and many other academicians may find it clear and easy to understand, I am not sure that this will be the case for most clinicians. Particularly difficult will be the translation of this information into clinical decision-making support tools. It would be very helpful if an additional section could be added: “When and how to use specific IgE in vitro tests to improve patient care”. I would suggest that in this section, the authors try to answer the following questions (among others):

Linda Cox, MD ( SETTaF chair): I think one has to consider s-IgE similar to skin testing in terms of when and how it would be used in patient care and the decision on which type of test(s) would vary with the patient and other circumstances.

Brock Williams, PhD (Primer author and SETTaF member): The hard question to answer is when and how to use s-IgE testing to improve patient care. To me, this deals mostly with how to interpret the results and this is very patient dependent. Again the problem stems from the fact that allergic symptoms are variable both within and between individuals. This and the large number of variables (age, gender, exposure, infection, etc.) clearly need to be taken into account for the interpretation of s-IgE tests. We do know that s-IgE is closely linked to symptoms but levels and the allergens it is directed against differ among different individuals. Thus, in today’s world, s-IgE results will best be utilized by considering them as a risk factor rather than an absolute diagnostic fact.

Robert Hamilton, PhD: The ultimate decision of when to use a confirmatory IgE antibody test (skin test or serology) comes down to the physician deciding that there is sufficient clinical evidence to warrant a possible diagnosis of allergic disease. This concept is integral to the diagnostic algorithm built into the diagnostic practice parameters. As such, to try to list all the patient and physician decisions to determine when a diagnostic IgE antibody confirmatory test (skin test or serology) should be run is (in my opinion) out of the intended scope of this article. This article summarizes what we know and what we do not know about the assays used to detect allergen-specific IgE antibody. I agree with Brock that prudent use of a positive specific IgE antibody result is as a risk factor for allergic disease and not as a definitive indicator of the presence of allergic disease.

Issue 2: Which is the ‘best’ specific IgE assay?

Dana Wallace, MD: Which of the three methods of specific-IgE measurement described within the Primer is most beneficial for making clinical decisions or should they all be viewed as equal?

Linda Cox, MD: There is agreement that the results are not assay inter-changeable. One thought is the different assays may be measuring different antibodies.

Brock Williams, PhD: Comparability of different methods – most studies indicate that the Phadia ImmunoCAP is far above the other two tests in overall performance (accuracy, precision, and quantitative ability). The problem is that for certain allergens and levels of s-IgE the assays are somewhat in agreement. For others, they are very different. I find the explanation that these assays are sometimes measuring different populations of antibodies to be rather absurd. To begin with I have seen no proof of this concept and our studies with chimeric antibodies (where the total IgE = specific IgE) indicate that for those allergens investigated the Siemens assay (formerly DPC-Alastat/Immulite) has major problems with its calibration and the Hycor assay (Agilent) has problems with under-representation of allergen on some of their solid phases. The major user of the Hycor assay is Labcorp and we know in the past some have suggested that they have modified this test in house to make it more profitable. The ImmunoCAP results (done in triplicate with blinded samples) was ‘spot on’ in these cases.

Robert Hamilton, PhD: I respectfully disagree with Brock on this issue. The most impartial examination of the inter-assay agreement issue indicates that all three methods display excellent precision, reproducibility and linearity. They do differ in the levels of IgE antibody that they detect and we currently do not know the reason for this. It is possibly a calibration issue, however, if there was a systematic bias caused by a calibration issue, we would see a consistent bias which we do not. My belief is that it has more to do with allergen heterogeneity between the methods. Thus to call the suggestion that the assays are measuring different populations of IgE antibody specificities "absurd" is too ‘heavy handed’. Brock, your data with the chimeric antibody are interesting and informative but not conclusive on a calibration issue.

We need to construct a better and more relevant experiment with human sera to try to dissect the answer to this question. Possibly this can be done with milk and peanut where we can identify the component specificities of IgE antibody using the ISAC and the components that are available on the ImmunoCAP. Then sera with defined distributions of IgE antibody can be analyzed by all 3 methods. So the binding of a serum containing 95% IgE anti-casein can be compared to a serum that contains 95% IgE anti-alpha-lactalbumin as a limited illustration of this concept. If we characterize many sera with a sufficient number of these component specificity distributions, we can examine this issue for a restricted number of allergen specificities.

In reality, we will probably not be able to definitively answer this question (at least to my satisfaction). So we are left with the conclusion that is stated in the primer article (which I believe is true) that these 3 assays measure different populations of IgE antibody. The causes are almost irrelevant as the 3 manufacturers are not in a position to change their assay formats. I discussed this issue personally with representative of each company during the last AAAAI meeting. At this point, we cannot say for sure which IgE antibody assay result is more "clinically relevant".

Issue 3: Is one assay too sensitive?

Dana Wallace, MD: Should one consider the Immulite too sensitive as it gives a higher reading of specific-IgE than the Hycor or ImmunoCap? Is there any general guide on comparing the results as the graph seems to show a trend?

Linda Cox, MD: One study did suggest Immulite overestimated s-IgE when the results of total IgE were compared with the hybridoma s-IgE results, which were all s-IgE. Brock and Bob are likely to have different answers

Brock Williams, PhD: The idea that if an assay gives a higher result it is better is fallacious. Again, the chimeric antibody results clearly demonstrate this. Accuracy is more important. Again, the calibration curve (total IgE tied to WHO standard) is very different for the Immulite system. This causes the amount of s-IgE measured to be overestimated particular at the high end with a number of different allergens. A requirement for quantification is that different dilutions (corrected for dilution) give you the same answer. In other words, they are linear and we have only seen this with the ImmunoCAP system.

The idea of sensitivity is also an area of great misunderstanding. This is because analytical sensitivity is a very different concept than clinical sensitivity and the two have often been confused. Analytical sensitivity deals with the low end of the assay, before you run into the background and is determined experimentally with statistical analysis in the laboratory. Clinical sensitivity deals with determining what level of s-IgE is capable of causing clinical symptoms upon exposure and in the near future, what particular allergenic substance it is directed against. Since the determination of clinical sensitivity depends upon the comparison to standards (patient history, puncture skin test, allergen organ challenges, etc.), which themselves have not been standardized and many of the cutoffs are arbitrary. In addition, the studies are dependent on the patient population studied so we really have very poor information in this area. Nevertheless, we mistakenly continue to use this concept to describe how well in a clinical sense these assays work. The same arguments can be used with regard to clinical specificity and, in my opinion, this has been very misleading in this field for quite some time.

Robert Hamilton, PhD: I agree with Brock that higher results produced by any one of the 3 assays are not more clinically relevant. The predictive power of the quantitative level of IgE antibody is discussed in the Primer article, with a caution that these published values need to be used judiciously. . On this issue I agree with what Brock has said about analytical versus clinical sensitivity. Analytically, all three assays can technically detect IgE antibody levels down to 0.1 kUa/L. Historically, the 0.35 kUa/L positive cutpoint was set based on the fact that levels above 0.35 had some clinical significance. We do not know and may never know the clinical significance of levels between 0.1 and 0.35 kUa/L. Interpretation also differs by allergen specificity as some clinicians judge low level Hymenoptera or peanut specific IgE levels differently than a ragweed specific IgE of the same level, because of their clinical relevance in relation to systemic reactions. Thus, a specific IgE level between 0.1 and 0.35 kUa/L needs to be cautiously and judiciously interpreted within the context of the patient’s clinical history.

Issue 4: Can the clinician compare a patient’s s-IgE if they were performed utilizing different assays?

Dana Wallace, MD: If one needs to compare levels of s-IgE and different methods have been used, should the clinician insist that they be repeated so that at least the methods match?

Recognizing that the ImmunoCap has the most published literature in food allergy and predictive levels for a negative food challenge, the clinician has often looked to this as preferred method. Is this still correct?

Linda Cox, MD: Yes. When the laboratory findings are inconsistent with the clinical history, it is recommended to repeat the analysis at the same or a different laboratory. If the results are different, how does the clinician interpret this data? Also recommend repeating with a different method-skin test if sIgE or vice versa. Clinical history is generally the deciding factor. This was a key message in the first SETTaF paper.

I believe the predictive value established in the earlier studies were somewhat specific to a particular population and cannot be universally applied across other age groups/disease.

Robert Hamilton, PhD: We know from the College of American Pathologists Proficiency Survey data that all 3 assay methods from 90% of the laboratories agree well in producing dichotomous measures of IgE antibody (presence/positive vs absence/negative). Therefore, if you are using IgE antibody measurements as a “risk factor” to consider with all the other variables in making the diagnosis, then the Immulite can detect the presence of IgE anti-peanut in a serum as well as an ImmunoCAP. So, if you are asking about the presence of IgE antibody as a risk factor, then “No”, re-analysis by a second assay method is not necessary.

However, there are the occasional spurious results generated by the occasional laboratory or spurious skin test results generated by the occasional clinic. These do occur. So, if the IgE antibody result (skin test or serology) is inconsistent with the clinical history, then it should be repeated, possibly with a different method. We learned this from Dr. Shapiro’s legal case involving Hymenoptera venom sensitivity.

If you are attempting to use the quantitative level to make a prediction about the presence of a clinically evident food allergy or wheeze in an asthmatic child, then published data will dictate what assay needs to be used. In this case the published quantitative predictive data to date are all from the ImmunoCAP. One cannot use the Immulite or Hycor data to make a decision based on published criteria generated with the ImmunoCAP. This will change if new published data are generated with the other two IgE antibody methods.

Issue 5: How important are patient characteristics (age, disease state, etc.) in interpreting s-IgE results?

Dana Wallace, MD: However, the article seems to imply that without knowing the age of the patient, the disease state, the allergen exposure mode and extent, and ratio of Specific IgE/Total IgE that was used in the published research studies and in the individual patient, these published guidelines may be inaccurate and perhaps useless. If this is the correct interpretation, it should be more clearly stated.

Just how important are the lack of affinity and clonality measurements in the overall clinical usefulness of interpreting the results of specific-IgE measurements?

Should we be dividing patient into groups below and above the 4% specific- IgE/Total IgE ratios? Would this help to predict severity of allergic reaction and/or response to treatment?

Linda Cox, MD: I not sure how important sIgE/total IgE. Again Bob and Brock can comment further. I think the importance of affinity and clonality is still be elucidated. This is an area that needs further research but an area of particular interest for Bob.

Brock Williams, PhD: I agree with Linda, that affinity and clonality are parameters that still need to be evaluated. I believe that the realization that certain allergens are much more relevant to symptom production (component resolved diagnosis) is likely to rectify this.

Robert Hamilton, PhD: Four variables contribute to the effectiveness of the IgE antibody response in inducing effector cell function: IgE antibody concentration, affinity, epitope clonality and specific to total IgE ratio or IgE specific activity. This has been clearly shown by the Christensen et al article in the JACI.2 All of these variables are important and constantly changing as the humoral immune response matures with continuing allergen exposure. And one of these alone cannot be shown at present to be an exclusive risk factor for interpreting IgE antibody results in the diagnostic decision process. I agree with Brock that future modifications to our serological assays (e.g., use of components, microarrays) may help us understand this better at the time of interpreting the diagnostic data. The patient demographics will always be critical to the interpretation of the IgE antibody serology as the clinical history is the final arbiter of the definitive diagnosis.

Issue 6: Is the significance of the s-IgE level different when the total IgE is low vs. high?

Dana Wallace, MD: Is it fair to say that when the total IgE level is very high, a high specific-IgE has limited meaning while a high specific-IgE with a low total IgE level is very significant?

Linda Cox, MD: Probably.

Brock Williams, PhD: Specific activity (s-IgE/T-IgE). While this concept makes some intuitive sense, it hasn’t yielded any concrete benefits. This is likely to be important when low levels of t-IgE are seen but really falls apart when multiple allergens and higher levels of s-IgE are seen. While this could be important in immunotherapy, presently it is an area for investigation and not ready for prime time in my opinion. This is particularly true when you investigate monosensitized patients, which is a rare situation for U.S. allergists. Again, I believe we have to further evaluate this concept in lieu of s-IgE to the allergens that actually are relevant (component resolved diagnosis).

Robert Hamilton, PhD: I agree with you all. The IgE specific activity has its most relevance when the total IgE is low and the % specific to total IgE is high. Use of the 4% IgE specific activity as a general criterion can be useful for evaluating patients on Xolair as Johannson et al have shown. However, we need more data to confirm its utility in applying it across the board in the general interpretation of IgE antibody data.

Issue 7: Can the clinician use the s-IgE/t-IgE ratio to predict response to allergen immunotherapy?

Dana Wallace, MD: Is there enough data for the clinician to calculate the specific IgE to total IgE ratio and predict the response to specific immunotherapy? If so what is the magic ratio? If not is there ongoing research that will answer this question? One paper looked at this and 16% was ≥16% was the magic number.3

Robert Hamilton, PhD: No. we need more data to show the utility of this measure in assessing immunotherapy efficacy. It should however be computed to evaluate its utility in future immunotherapy studies.
Brock Williams, Ph.D: I agree with Bob that it is premature to use s-IgE results to guide immunotherapy. This area certainly needs more study and again will probably be better understood when patients and their responses are understood in terms of the specific allergen components that are responsible for symptoms.

Issue 8: Can s-IgE be measured in a patient on Xolair® (omalizumab)?

Dana Wallace, MD: Should the clinician be using ImmunoCAP s-IgE when assessing the patient onXolair? What would be the utility of doing so?Is one looking for a defined endpoint?

Linda Cox, MD: I believe one can get reliable results with ImmunoCAP on s-IgE testing in patients on Xolair, which might be useful in determining if you are adequately dosing (i.e., under) but again Bob is the better person to answer this question

Brock Williams, PhD: Bob has shown quite clearly that the ImmunoCAP can be used with confidence in patients on Xolair.

Robert Hamilton, PhD: The article Brock is referring to clearly shows that IgE (total and allergen specific) can be accurately measured in patients on Xolair with the ImmunoCAP and not with the other two assay methods.4 The important questions are (1) what utility does the measurement of total IgE and specific IgE provide for a patient on Xolair? and (2) where do “free IgE” measurements (IgE not bound with Xolair) fit into the evaluation of the Xolair patient? Examine the Primer article as it addresses these questions.

Issue 9: Will ImmuoCAP rapid®, a non-quantitative allergy test designed for the office setting useful tool for primary care professionals?

Dana Wallace, MD: Will the ImmunoCAP rapid be a good tool for primary care physicians? Should we embrace it?

Linda Cox, MD: The rapid screen office allergy test, which is similar to a pregnancy test is intended for the primary care office. It will likely bring more attention to allergy and to the allergist. Thus, indirectly, I think it is good for the specialty, but there needs to be some education about appropriate use and referral.

Robert Hamilton, PhD: The ImmunoCAP rapid is FDA cleared and we will see how it fits into the overall diagnostic process in the USA. It is too early to tell if it will be useful or abused. The Primer article simply introduces the ImmunoCAP rapid . Allergists need to know that the ImmuoCAP rapid®, data may be introduced by the patient at an allergist’s office visit.
Brock Williams, Ph.D. The ImmunoCap rapid is much like a laboratory test for cholesterol in that it can be interpreted as a measure of risk. The caveats mentioned above in interpreting the results in lieu of the patient’s history most certainly will have to be evaluated on a case by case basis.

1. Cox L, Williams B, Sicherer S, et al. Pearls and pitfalls of allergy diagnostic testing: report from the American College of Allergy, Asthma and Immunology/American Academy of Allergy, Asthma and Immunology Specific IgE Test Task Force. Ann Allergy Asthma Immunol 2008;101:580-92.
2. Christensen LH, Holm J, Lund G, Riise E, Lund K. Several distinct properties of the IgE repertoire determine effector cell degranulation in response to allergen challenge. J Allergy Clin Immunol 2008;122:298-304.
3. Di Lorenzo G, Mansueto P, Pacor ML, et al. Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. J Allergy Clin Immunol 2009;123:1103-10, 10 e1-4.
4. Hamilton RG. Accuracy of US Food and Drug Administration-cleared IgE antibody assays in the presence of anti-IgE (omalizumab). J Allergy Clin Immunol 2006;117:759-66.

A new genotype associated with abnormal NFκB function in immunodeficiency without ectodermal dyplasia

A scaffolding protein, NEMO, associated with a complex required in the NFκB translocation pathway has been previously associated with ectodermal dysplasia-associated immune deficiency (EDID) syndrome. The syndrome is X-linked, and presents clinically as a history of recurrent infections, hypogammaglobulinemia, and poor memory B cell function. Affected individuals have abnormalities of ectoderm-derived tissues, such as hair, skin, nails, and teeth. NEMO, in complex with inhibitor of NFκB kinase (IKK) proteins, is necessary for NFκB translocation and gene activation.

This month, Mooster et al. describe a male patient and brother with immunodeficiency, but without ectodermal dysplasia, that was traced to a novel gene mutation in the 5’ untranslated region in the NFκB essential modifier gene (NEMO) gene. They report that TLR-activated production of TNFα and IFNα in peripheral blood is significantly decreased in the index patient, consistent with impaired innate immune response.

The authors find that a G→T mutation in the +1 position of the intron 1B causes destruction of the exon 1B to exon 2 splice in the NEMO gene. Two abnormally sized NEMO mRNAs with intact coding regions are produced, causing inefficient translation that results in inadequate levels of functional NEMO proteins. NEMO mRNA is 4-fold lower and NEMO protein expression is 8-fold lower in the index patient as compared to normal controls. The brother of the index patient is also affected by the same mutation. Their report is the first description of an immunodeficiency that results from decreased levels of functional NEMO protein, rather than functionally impaired protein.

The authors comment that the absence of ectodermal involvement suggests that either normal ectodermal development has a less stringent requirement for NEMO than does immune function, or other NEMO isoforms are able to compensate for the reduction in the 1B isoform.

We asked the authors about the implications of their report:
JACI: In your conclusion, you suggest that clinical work-up of patients presenting with immunodeficiency consistent with EDID, but without ectodermal involvement, should be evaluated for NEMO mRNA and proteins levels, followed by coding analysis. What implications does the characterization of these patients have for their treatment?

Jana Mooster and Douglas McDonald: In patients with immunodeficiency consistent with EDID, but without ectodermal dysplasia or even with a normal NEMO coding sequence, one should consider evaluating NEMO protein levels and NFκB function. Patients with NEMO deficiency but without ectodermal dysplasia can appear clinically similar to patients with common variable immune deficiency. NEMO deficiency, however, is known to cause susceptibility to atypical mycobacterial infections. Thus, identification of a NEMO mutation identifies patients that require monitoring for potential atypical mycobacterial infections.

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Tuesday, June 1, 2010

Tracking peanut and tree nut allergy in the US

Peanut and tree nut allergies garner attention because reactions to these common foods are characteristically severe, are responsible for the majority of fatalities caused by food allergy, are persistent, and appear to be increasing in prevalence. Although there is great interest in tracking the prevalence of these allergies, determining the exact number of those affected over time has remained elusive.

To estimate the general population prevalence of food allergies, researchers have sometimes had to content themselves with assessments based on self-report of “convincing” reactions, because the diagnostic standard of oral challenge is impractical, risky, and expensive. Using this approach, Sicherer et al (J Allergy Clin Immunol 2010;125:1322-6) report findings of the most recent cross-sectional telephone survey to collect self-reported information on peanut, tree nut, and, additionally, sesame allergy. They employed the same survey used in 1997 and 2002 to assess prevalence in 2008, then compared the results from all three surveys.

Significant increases in peanut/tree nut and tree nut allergy in children were reported from 2002 to 2008, though increase in peanut allergy was not significant in that period. Self-reported peanut allergy in children increased significantly from 0.4% in 1997 to 1.4% in 2008. Tree nut allergy also showed significant increased from 0.2% to 1.1% across the same period. Sesame allergy was reported from only 13 survey participants at a rate of 0.1%; however, 2008 was the first year that information on sesame allergy was collected. The authors report that no significant increase in peanut and/or tree nut allergy was reported in adults.

They suggest that possible explanations for the increased rate of self-reported peanut allergy might be increased availability of peanuts in many food products, especially in highly allergenic roasted form, as well as oral exposure that is either immunologically too early or late, and/or environmental exposure. Also, Sicherer et al. point out that the prevalence in US children is similar to the prevalence reported by recent studies in Canada, the UK, and Australia.

We asked lead author Scott Sicherer, MD, from Mount Sinai School of Medicine, to comment on the study. “To my knowledge, this is the first attempt to track these allergies on a population basis in the US using the same methods thrice over a decade,” says Sicherer. “A recent review of the food allergy literature in JAMA [Journal of the American Medical Association] pointed out that due to various methodological issues, we do not have solid data on prevalence, with estimates that food allergy affects more than 1-2% but less than 10% of the population and there are limited data on time trends. Although our study has limitations inherent to self reported allergy and participation rates of telephone surveys, it provides an interesting perspective supporting a likely increase of childhood peanut/tree nut allergies and underscores that millions are affected by these allergies.”

Readers interested in this topic might also want to see the article by Ben-Shoshan et al., also in the June issue (J Allergy Clin Immunol 2010;125: 1327-1335), which looks at prevalence of peanut, tree nut, fish, shellfish, and sesame allergies in Canada.

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Exactly how can specific IgE levels help in the diagnosis of food allergy?

An important question for researchers and clinicians who work with food allergies is whether food-specific IgE and skin prick test results can be used reliably as ersatz measures of allergen sensitization (see also our News Beyond Our Pages blog from May 14). The reason is that the clinical standard for food allergy diagnoses is double-blind, placebo-controlled food challenge, which is expensive, costly, and requires dedicated personnel and facilities because of the risk of anaphylaxis.

In a Letter to the Editor in JACI (J Allergy Clin Immunol 2010;125:1391-2), van Nieuwaal et al. report results from a study conducted in 103 children with suspected peanut allergy. Peanut-specific IgE levels were correlated to results of diagnostic food challenge to evaluate the predictive power of specific IgE and food challenges were performed regardless of a possible history of anaphylaxis. The population was very atopic as well, with greater than 80% having atopic dermatitis. The authors report that peanut-specific IgE was correlated to positive food challenge results in approximately 55% of the children. Specificity of IgE values of 10.4 [92%], 24.8 [98%] and 25.5 kU/L [100%] were significant for predicting outcome of food challenge. The authors note that the specific IgE levels were not sensitive, though, and that values lower than these do not indicate that there would be no reaction to oral food challenge.

The authors conclude that using these IgE levels as cutoffs would obviate diagnostic oral food challenges in at least some of the children. Oral food challenge would still be needed to determine the sensitivity and severity of the peanut allergy.

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Monday, May 3, 2010

Food allergy: An immunological picture of atopy development

What, exactly, does the phenotypic evolution of food allergy look like? Which factors, such as environment or genotype, exert the most influence? Is food allergen avoidance the key or is it irrelevant? The NIH/NIAID-supported Consortium of Food Allergy Research (CoFAR) has established an infant cohort with likely milk and/or egg allergy with the intent to describe and characterize the natural history of food allergies in children in hopes of being able to answer these questions.

In this month's issue of the JACI, Sicherer et al. present early results from the 1st of several studies being conducted by CoFAR. [Access this article for free at:] Their question: Among infants presenting with a clinical reaction to milk and/or egg, and a positive prick skin test (PST) to either, or children with moderate to severe atopic dermatitis and a positive skin test to milk or egg, what factors will be associated with developing a peanut allergy and resolution or persistence of milk/egg allergy? The authors note that known clinical allergy to peanuts was an exclusion; nevertheless, almost 70% of the infants had evidence of sensitization to peanut, with 27% having greatly elevated peanut-IgE (> 5 kUA/L). They compare sensitivity of PST and serum IgE and report significant association of wheal size and IgE concentrations across milk, egg, and peanut. They do note that there was unexpected discordance between peanut PST and peanut-specific serum IgE, where some infants have one positive and the other negative. In these cases, the serum IgE is more sensitive than the PST in detecting sensitization, which is in contradiction to the conventional wisdom that PST in infants is more sensitive.

In vitro analyses demonstrate that CD25 and IL4 expression are up-regulated in milk and peanut sensitized infants; this is not the case for egg sensitivity, where there was only a slight increase in CD25 expression and no related increase in IL4. The authors further address Th2 bias by looking at GATA3/Tbet ratios. Surprisingly, they found no increased GATA3/Tbet ratios, though GATA3 was detectable. Since Sicherer et al. speculate that Th2 activation is the background to food allergy, what is providing the increased IL4? The authors suggest that basophils may have been the source of IL4 in the sensitized infants.

Wrapping up, Sicherer et al. address the astonishingly high prevalence of peanut sensitization in their cohort and suggest that this indicates a need for caution in introducing peanut to infants with the enrollment characteristics and that clinical testing for food allergy may be warranted.

We asked first author Scott Sicherer, MD, for his take on the study's findings:

JACI: In your opinion, what is the most likely point of exposure leading to peanut sensitization in the infants?

Dr. Sicherer: We will be evaluating potential determinants that could include maternal ingestion, household exposure and other factors, but these are under analysis.

JACI: The findings associated with CD25 and IL4 gene expression under egg stimulation were not remarkable and you attributed this to possible effects of using whole egg extracts. What mechanism might account for the diminished IL4 expression associated with whole extracts?

Dr. Sicherer: We were surprised that egg behaved differently in the in vitro studies and are currently considering the possibility that if we had used a stimulant that was enriched with a major egg allergen, for example ovomucoid, we may have seen a response that was more similar to the milk (caseins) or peanut response.

JACI: Is it conceivable that basophils might be the source of IL4?

Dr. Sicherer: Our preparations were enriched for CD25. Basophils constitutively express CD25, are enriched with mononuclear cells during density gradient isolation and produce high levels of IL-4 in sensitized subjects. Recently, basophils have been implicated in allergy model systems for playing an important role in priming and enhancing memory Th2 responses. Murine basophils have been shown to express IL-4 in the absence of detectable GATA-3 or c-maf, expression, suggesting that IL-4 may be regulated distinctly in these cells. Thus, new paradigms are emerging that basophils play a key role in directing Th2 responses and our data may provide additional support for this observation. Preliminary studies utilizing flow cytometry revealed that basophils (CD3- CD123+ CD203+ HLA-DR dim and IL4+) are present in the CD25 preparation.

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.

Vitamin D and corticosteroid use in children

Evidence is accumulating rapidly for the association between vitamin D insufficiency, lung function, and corticosteroid use and sensitivity. Pivotal studies have been published examining a number of parameters, including effect of latitude, skin pigmentation, and body mass index.

In this month's JACI, Searing et al. provide the first report on prevalence of vitamin D insufficiency or deficiency in children with asthma living in latitudes higher than 20° N. [This article can be accessed for free at] Several significant correlations are reported: age, BMI, and positive skin tests are inversely correlated to vitamin D levels, while FEV1% and FEV1/FVC ratio are significantly correlated to vitamin D level.

The authors demonstrate significant association between inhaled corticosteroids, oral steroid use, and total steroid dose with low levels of vitamin D. They suggest that insufficient vitamin D might increase asthma severity, requiring greater treatment intervention or possibly that down-regulation of glucocorticoid pathways due to insufficient vitamin D dictates the need for increased steroid doses.

In vitro analyses of vitamin D activity in PBMCs demonstrated that vitamin D augments induction of MKP-1 and IL10 by steroids. Additionally, effects were observed that support vitamin D supplementation to increase steroid sensitivity, thereby permitting lower doses to obtain an optimal response.

We asked Dr. Daniel Searing, first author on the paper, about the implications of this research:

JACI: Is there baseline evidence of decreased vitamin D levels secondary to corticosteroid exposure in pediatric asthma patients?

Dr. Searing: Our study demonstrated correlations between vitamin D levels and steroid exposure in pediatric asthmatic patients from northern latitudes. To our knowledge, this is the first study looking at vitamin D levels in this patient population. Our study was not designed to examine causation of the low vitamin D levels. We are conducting a study currently looking to examine vitamin D levels in patients with asthma while also controlling for other known confounders (age, BMI, etc) to examine how strong the correlation of corticosteroid use and vitamin D levels is.

JACI: Is it possible that vitamin D insufficiency/deficiency is iatrogenic in children with asthma?

Dr. Searing: It is possible that low vitamin D levels are iatrogenic. However, the vitamin D levels in our patients with asthma seem to mirror levels in the general pediatric population. Whether escalating amounts of corticosteroid therapy in worsening asthma directly lower vitamin D levels versus other potential causes, such as vitamin D having effects on glucocorticoid pathways that leads to higher doses to achieve treatment effect is unknown at the present time. Future studies will help clarify this issue.

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, April 2, 2010

Administration of influenza vaccines to egg-allergic patients

In this month’s issue, John Kelso, MD, wrangles with the very important clinical issue of vaccinating patients with egg allergy against influenza. Starting with a review of the Vaccine Adverse Event Reporting System (VAERS) from 1990 to 2005, he finds only 4 reports of deaths that occurred after vaccination and were attributed to anaphylaxis. Approximately 747 million vaccinations were given during the time period. On the down side, about 540,000 deaths from seasonal influenza were reported for the same 15 years. Kelso poses the conundrum: most of those deaths could have been prevented by vaccination, and, in particular, many of them may have been egg-allergic patients.

Two recent JACI publications are addressed in the editorial. The first, a Clinical Pearls article by Rank and Li, recommends vaccination protocols for asthma patients. Specifically, the vaccination protocol for asthma patients with confirmed or suspected egg allergy was conservative and included skin prick testing and intradermal testing of both ovalbumin and influenza vaccine, followed by 2-dose or graded multiple dose vaccine administration. Rank and Li imply the possibility of no vaccination, though this is considered the least desirable approach.

The second article, by Waibel and Gomez, challenges this highly conservative approach, noting previous research establishing that a 2-dose protocol is safe in egg-allergic patients when the vaccine contains ≤ 1.2μg/ml of egg. Manufacturers of vaccines approved by FDA in 2009-2010 state a maximum ovalbumin content of ≤ 1μg/dose, with only one exception reporting greater than that. Since there is more than one vaccine dose, the authors tested lots of H1N1 and/or seasonal flu vaccines from 6 manufacturers to determine the μg/ml ovalbumin content. In all cases, the actual ovalbumin content was lower than the manufacturers stated content, leading Waibel and Gomez to suggest a single dose administration of vaccines with ≤ 1.2μg/ml ovalbumin to egg-allergic patients.

In the editorial, Kelso argues that pre-testing of egg-allergic patients was a good idea when the maximum ovalbumin content was not provided by manufacturers, but in light of safety research and voluntary reporting by manufacturers, these recommendations may be too conservative.

Kelso points out that egg allergic patients react to egg ingestion, but typically not flu vaccination. He suggests there is sufficient clinical and epidemiological evidence to support single dose vaccinations for egg allergic patients, unless the ovalbumin content is not known or if the egg allergy is severe.

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Monday, March 8, 2010

Stress and asthma

In this issue of JACI, Haczku and Panettieri review the evidence for the involvement of stress in asthma and find that it suggests that psychosocial stressors are important in asthma morbidity.

Chronic psychosocial stress has been correlated with asthma severity and exacerbations, as well as overall immunocompromise that leads to or worsens disease. The authors developed a mouse model of social stress in order to mimic socially disruptive stressors experienced by humans. They showed that mice exposed to allergen and persistent social stress had increased airway reactivity and lowered Th2 cell sensitivity to glucocorticoids. In their mouse model, Haczku and Panettieri noted that the social stress did not result in immunosuppression, but instead, activated innate and Th2 immune responses that resulted in sustained increases in circulating corticosterone. They suggest that this may lead to corticosteroid insensitivity and perpetuate airway inflammation.

Altered function, reduced expression and impaired translocation of the glucocorticoid receptor (GR) are among the possible mechanisms for steroid insensitivity proposed by Haczku and Panettieri. They suggest that GR may be down-regulated by agonistic ligands, or NF-κB transrepression of gene transcription. Their own studies reported increased expression of NF-κB concomitant with decreased GR nuclear translocation, DNA binding and GR expression.

Bias toward inflammatory cytokine stimulation by innate immune cells is another mechanism the authors discuss. Mice exposed to stress alone produced macrophage and dendritic cell secretion of IL-13 associated IgG1 and TARC as well as TNF-α and IL-6.

Finally, the authors talk about the role of structural cell responses to glucocorticoids, citing recent findings of reduced surfactant protein D (SP-D) in patients with chronic lung disease. Corticosteroids greatly increase the amounts of SP-D, which is known to have immunosuppressive effects, and they suggest that corticosteroid insensitivity of epithelial cells in chronic lung pathology is responsible for the impairment of this protective mechanism.

Haczku and Panettieri propose new approaches to circumvent corticosteroid non-response. They have shown that corticosteroid insensitive airway smooth muscle and whole lung tissue are still responsive to I κB and MAP kinase inhibitors, reducing cytokine secretion. This may be a possible pathway for therapeutic intervention in asthma patients who are steroid-insensitive.

We asked Dr. Haczku some questions about the implications of this review:

JACI: Since the evidence is pointing to a multiple-scale physiologic response, would this problem lend itself to a systems analysis approach to coordinate effective therapy?
Dr. Haczku: Susceptibility to the detrimental effects of chronic stress exposure on the neuro-endocrine, immune and hematopoietic systems as well as on various target organs maybe genetically regulated, organ- and cell type specific. A systems analysis approach therefore to disease assessment and effective therapy would be very beneficial.
JACI: Do you think kinase inhibitors would be primary or add-on therapy for patients with corticosteroid-resistant lung disease?
Dr. Haczku: Kinase inhibitors once developed would form a useful second line (add-on) therapy for patients with corticosteroid resistant chronic inflammatory diseases.

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Fungal exposure and inner-city children

In another effort to pin down factors that increase asthma morbidity in inner-city children, Pongracic et al. report results from their study of effects of indoor and outdoor fungal exposure in children with asthma and fungal sensitivity. The authors use a subset of children from the Inner City Asthma Study (ICAS) with positive skin tests to at least one of four fungi: Alternaria, Cladosporium, Penicillium, and Aspergillus (mixed species). Indoor and outdoor fungal sampling was performed every six months for 2 years. Questionnaires were administered by phone every 2 months collecting data about number of symptom days, nighttime awakening due to asthma, number of days the child’s activities were limited by asthma, missed school days, and ED and unscheduled doctor visits.

Compared to other subjects in the ICAS who had negative skin tests to fungi, the fungi-sensitive children had significant increases of number of symptomatic days and unscheduled clinic or ED visits on days when total combined fungal exposure was increased. Increased indoor fungal exposure was associated significantly with unscheduled visits, with Pencillium exposure having the most profound effect.

Pongracic and colleagues also report effects of specific fungal exposure in children that had negative skin tests to one or more of the 4 fungal extracts tested, but with at least one positive skin test to a fungal allergen. Increased outdoor exposure to Alternaria and Penicillium in children not sensitized to either was found to increase the number of symptomatic days, while increased indoor exposure to Penicillium was associated with increased medical visits, which is similar to the finding in children sensitive to Pencillium.

The authors discuss several limitations associated with their research. Sampling technique did not include collection of indoor floor dust samples, and was of short duration during low-activity periods in the home. The fungal sampling design did not include sampling in the homes of unsensitized children. Outdoor sample collection was short duration and episodic, which might not reflect fungal counts over a long period of time. Additionally, the finding of increased impairment among children not sensitized to one or more of the fungi used in the skin testing confounds the outcomes on numerous levels.

Dr. Pongracic shared the following comments with us:

“It is our hope that these findings, which have shed light on the role of outdoor and indoor fungi in asthma morbidity among inner-city children, will lead us and others to several avenues of clinical and translational investigation. Future directions include (1) environmental interventions directed against fungi and their ability to reduce asthma exacerbations and to improve asthma control; (2) mechanistic studies of the health effects of fungi on non-sensitized individuals; (3) development of novel methodologies to assess ongoing fungal allergen exposure; (4) exploration of viral-fungal allergen and pollutant-fungal allergen interactions as they pertain to asthma exacerbations in urban populations; and (5) performing similar studies of other populations, including suburban and rural children, to ascertain whether these relationships exist beyond the inner city.

There are a variety of opportunities to extend these findings to clinical practice. Certainly, assessment of the inner-city child with asthma should include investigation for sensitization to multiple fungal allergens, through skin testing or in vitro testing. Our findings should also prompt health care providers to not only consider cockroach, mouse and dust mite allergens in their assessment of the home environment but also fungal allergens. Given the extensive use of cellphones among inner-city families and the widespread availability of digital camera functionality on these phones, individuals could be instructed to photograph household conditions that promote/reveal mold growth to help identify specific sources of problems and inform potential interventions. Broader education should be instituted regarding understanding risk factors for household mold contamination, how to identify it when it occurs and how to intervene. Public service announcements for notification of periods of high concentrations of outdoor airborne fungi could be an efficient and effective means to inform people of potential increased exposures and to recommend keeping windows closed to reduce indoor entry of fungal allergens.”

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Grading systemic reactions to immunotherapy

The potential for anaphylaxis in subcutaneous specific immunotherapy (SCIT) is obvious. Current practice standards for evaluating, grading, and treating systemic reactions are vague, and in some cases, too rigid to encompass the highly variable symptom presentation. On top of this, the judicious application of epinephrine in anaphylaxis evolution has not been evaluated in a systematic way.

Cox et al., representing the AAAAI/ACAAI Joint Task Force for Grading Systemic Reactions to Immunotherapy, in collaboration with the WAO, present a draft recommendation for SCIT systemic reaction (SR) grading system in this month’s issue. It is based on the Internet Immunotherapy Safety Survey, started in 2008, from which the task force hoped to learn the incidence rate of systemic reactions, especially fatal or near-fatal reactions, and how and when epinephrine was given. The goal: to develop a global, functional SR grading system that could be used to standardize intervention, especially epinephrine use, to minimize the risk of fatal or near-fatal reactions.

The Task Force proposes a grading system based on the organ system involved and severity. Organ systems are defined as: cutaneous, conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular and other. A reaction from a single organ system such as cutaneous, conjunctival, upper respiratory, but not asthma, gastrointestinal or cardiovascular is classified as a Grade 1 Symptoms from more than one organ system or asthma, gastrointestinal, cardiovascular are classified as Grades 2 or 3. Grade 4 includes the conventional clinical indicators of a severe reaction, such as loss of consciousness, hypotension, and respiratory failure, while Grade 5 is death. Clinician judgment assesses the grade. The proposed system also includes time of onset, first symptom, and time when epinephrine was given, if at all.

The authors suggest additionally that this grading system allows flexibility to accommodate the clinical management details. The task force contends that a common grading approach that can be used by clinicians and researchers will make it easier to compare SRs and interventions between different SCITs from surveillance and clinical trial data.

Dr. Cox notes, “The WAO grading system for SR has been endorsed by the following WAO Regional and National Member Societies: AAAAI, Latin American Society of Allergy and Immunology (SLAAI), Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI), and the ACAAI.

The rostrum includes an Excel spreadsheet for documenting SR grade and treatment that can downloaded and used by clinicians and researchers to collect on SR frequency, severity and response to treatment.”

We asked Dr. Cox to comment on how the treatment thresholds mentioned in the paper are more discriminating than those used in the past, given that the authors note that using response to treatment to assess severity is misleading as both mild and severe reactions may or may not resolve after IM epinephrine. Dr. Cox responded as follows:

“The grading table [uses] response to treatment or drop in PEF as an example of… a Grade 2 or 3 reaction to provide the clinicians with some general guidelines. That is why it is prefaced as an e.g. and it is not a specific requirement/criteria for... that particular grade. We also stipulate that 'The grade is determined by the physician’s clinical judgment,' so it is up to the physician to decide whether the asthma reaction is Grade 2 or 3 and they may or may not decide to include response to treatment in determining the Grade…. These were added during the review process at the request of some reviewers who wanted more specific guidelines.”

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Wednesday, February 10, 2010

Genome-wide association studies

What are we to make of genome-wide association studies (GWAS)? In an editorial highlighting 3 articles in this month’s issue (Wu et al.; Li et al.; and Mathias et al.), Donata Vercelli, MD, explores this question. Dr. Vercelli points out the advantage that GWAS offer over linkage and candidate gene studies; namely, that GWAS can look for susceptibility SNPs across a whole genome without a priori assumptions. That’s also the difficulty, because GWAS are now uncovering SNP associations from surprising gene families, and biological validation will be required for these results. Additionally, currently available GWAS technologies may contribute to variability of results because they do not account for rare SNPs and admixed populations. Finally, Dr. Vercelli talks about the bugbear of epigenetic influence, which is difficult to account for in GWAS.

As for the articles themselves:

Mathias et al. look at genome-wide associations in asthmatic and non-asthmatic African American and African Caribbean populations. They identify only 3 SNPs in 3 genes with significant association from combined analysis of the results of GWAS of each population. The role of the genes they single out–ADRA1B, PRNP, and DPP10–in asthma susceptibility is not yet understood. The authors also report that their results did not generalize to 2 white populations. They also stress the difficulties inherent to studying non-Caucasian populations by using genotyping platforms designed to assess variants common in Caucasians.

Li et al. investigate SNP associations in severe and difficult-to-treat, white, asthmatic populations using 14, highly replicated, candidate genes. Li and co-authors show that SNPs in two regions, RAD50-IL13 and HLA-DR/DQ, have consistent association with asthma, with SNPs in the RAD50 region having the strongest association. While the former regions have functional impact on Th2 cytokine expression and antigen-presentation respectively, RAD50 is involved in DNA repair and its effect on asthma susceptibility isn’t known. Li et al. propose that a RAD50 region characterized in mice as affecting Th cytokine expression may have a functional role in humans. The authors suggest that variants in the RAD50locus should be considered new asthma candidates.

Wu et al. report results of a GWA study that focused on previously published asthma candidate genes in the hope that this approach would improve signal detection. Out of 118 asthma candidate genes, 4 with multiple SNPs had significant associations in the pediatric asthma/Mexican population studied: TGFB1, IL1RL1, IL18R1, and DPP10.

Do you have any questions or comments about these studies? We want to hear from you. Please post your questions and comments below.

Omalizumab pre-treatment and immunotherapy

Following up on significant results from a study that demonstrated benefit of pre-treatment with omalizumab prior to initiation of specific allergen immunotherapy (SIT) in subjects with ragweed allergic rhinitis, Massanari et al. report their results from a similarly designed study in subjects with persistent allergic asthma undergoing SIT.

Study subjects with at least moderate persistent allergic asthma that was inadequately controlled by inhaled corticosteroid (ICS) therapy were enrolled to receive 13 weeks pre-treatment with omalizumab or placebo before initiation of 4 weeks cluster regimen SIT followed by 7 weeks of maintenance therapy.

Compared to placebo, the omalizumab group had fewer systemic allergic reactions (SARs) during SIT (placebo: 26.2%; omalizumab: 13.5%), improved asthma symptoms and rescue medication use during pre-treatment, and were more likely to achieve target maintenance dose. Discontinuations due to SARs, were higher in the placebo group (9.6%) than in the omalizumab group (5.0%)

Grade 3 respiratory SARs were most common. Among 30 documented SARs, 24 of the subjects were on placebo and 6 were on omalizumab. Additionally, 87% of the omalizumab group achieved targeted maintenance dose in contrast to 72% of the placebo group.

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.

Tuesday, January 19, 2010

Air cleaners and filters - A rostrum

We focus this week on a Rostrum contribution, "Air filters and air cleaners: Rostrum by the American Academy of Allergy, Asthma & Immunology Indoor Allergen Committee," by Sublett et al. (J Allergy Clin Immunol 2009;125:32-38). The authors tackle the topic of air cleaners and air filtration by providing technical information on efficiency testing, and specifications of available technology as well as summarizing a literature review on the effects of air cleaning on asthma and allergy. Two air cleaning modalities are covered: portable room air cleaners and whole-house systems installed in HVAC units. The published studies reviewed by the authors typically presented findings from a single method air cleaner across short durations up to 6 months. The authors note that most results demonstrated minimal or no benefit. Overall, HEPA-filtered, portable air cleaners, and HVAC filtration systems that used high-efficiency filters and frequent routine maintenance had limited benefits. Sublett and coauthors suggest that air cleaning should be viewed as mitigation of disease progression rather than treatment for asthma and allergies. The authors go on to conclude that short-duration, single-method studies are not enough to demonstrate mitigation and that long-duration studies involving multiple air-cleaning methods are needed.

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 4, 2010

“Long-term clinical efficacy in grass pollen rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet”

The featured article for this first blog is “Long-term clinical efficacy in grass pollen rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet” (Durham et al. J Allergy Clin Immunol 2009;125:131-138.e7), from our January issue. The authors report, for the first time, long-term benefit associated with sublingual immunotherapy for timothy grass pollen studied in a multisite, randomized, placebo-controlled trial. They describe significant decreases in daily allergy symptoms as well as medication use both during the study and for 1 year after subjects’ participation ended. Durham and colleagues also report progressive changes in specific IgG4 and IgE-blocking factor in subjects receiving active treatment, demonstrating disease modification, which has been previously reported for subcutaneous administration. Because oral administration was associated with only mild, local adverse effects, such as oral pruritis, Durham et al. suggest that patient-administration with prescription is supported by the safety profile.

We asked lead author Stephen R. Durham, MD, to tell us a little more about this paper, and what follow-up studies are needed:

“The results of this multicentre trial confirm long-term efficacy of sublingual grass pollen allergen tablet immunotherapy and its disease modifying potential. It will be of great interest to see whether these long-term benefits are sustained for more than one year following discontinuation. Patients had confirmed IgE-mediated disease and a suboptimal response to usual pharmacotherapy. Although local side effects of itching/swelling in the mouth were common, in general they resolved within 1-2 weeks and were not bothersome and no serious side effects were observed. The data raise the question whether the treatment should be introduced earlier in the course of the disease and in a broader range of patients. As for the subcutaneous route, initial prescription of sublingual immunotherapy should be by a Specialist in Allergy, with observation of the first dose, whereas the treatment is thereafter suitable for home self-administration. Similar studies are required for other allergens and possible preventive effects should be explored in high risk children with sensitisation with/without associated early atopic disease.”

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.