JACI Journal Club

TSLP, asthma heterogeneity, and human nuocytes

2012-01-03T09:55:00.000-08:00

It seems that the variable presentation of asthma is even more variable than imagined. Just listing some of the known pathological variables in asthma, there is eosinophilic, atopic, IL-13 dominant, IL-5 dominant, treatment-refractory, and now, TSLP-associated asthma, the majority of which characterize the disease in its more severe forms. Shikotra and colleagues report findings in this month’s issue (J Allergy Clin Immunol 2012;129:104-111.e9) of upregulation of the innate Th2 cytokine TSLP in asthmatic epithelium, but also predominant expression of IL-13 protein in non-epithelial CD45+ cells found in the airway mucosa and the lamina propria.

Shikotra et al. demonstrate increased TSLP production in the airway mucosa with mild, moderate and severe asthma. TSLP expression was also found in the lamina propria of subjects with severe asthma. The authors note that increased TSLP production was inversely correlated to FEV1/FVC ratio. Increased TSLP production is associated with increased IL-13 and IL-4 production, but only in a subset of asthma subjects. Shikotra et al. comment that their results suggest that there are Th2-high- and -low- asthma phenotypes.

Interestingly, the authors find that the dominant sources of TSLP are from airway epithelial cells and both mast cells and lineage-negative CD45+ cells within the airway epithelium and the lamina propria. These findings support a previous hypothesis of a TSLP-mast cell pathway in the development of asthma. Additionally, the authors suggest that the CD45+ non-epithelial cells within the airway epithelium and lamina propria, may represent the human equivalent of nuocytes, innate Th2 immune cells characterized by high IL-13 production. Since nuocyte-associated IL-13 would be expected to increase TSLP production in both mast cells and epithelial cells, Shikotra et al. further suggest that this observation implies both TSLP-mast cell and TSLP-nuocyte pathways.

In the final summary, Shikotra et al. note that TSLP is a possible therapeutic target, but caution that like other anti-cytokine drugs, anti-TSLP will most likely be effective in asthma subjects with high TSLP and Th2 cytokine profiles.

Update on biomass smoke and traffic pollution and respiratory health

2011-12-28T07:39:00.000-08:00

Laumbach and Kipen (J Allergy Clin Immunol 2012;129: 3-11) present a report this month on the contributions of burning biomass fuels (BMF) and traffic-related air pollution (TRAP) to respiratory disease. The authors begin by noting that both TRAP and BMF burning have become critical factors for increased incidence of respiratory infections, COPD, and asthma in developed and less developed countries (DC & LDC, respectively), with both being very preventable causes.

In their introduction, they point out that global pollution monitoring has been under way for half a century, but the effects of microenvironment pollutants, such as BMF and TRAP, are less studied because of the difficulty of evaluating their impact at the level of the individual. New statistical approaches have begun to close this gap to demonstrate strong correlations between TRAP and allergic respiratory diseases as well as between BMF and COPD.

Laumbach and Kipen delve into exposure patterns for BMF burning and TRAP, commenting that the greatest burdens are on women and children in LDCs and adults and children in inner city, low socioeconomic communities in DCs. BMFs are significantly linked to lower respiratory infection in children and COPD in women in LDCs due to greater exposure to cooking and heating in poorly or unventilated households. TRAP exposure is rising in both DCs and LDCs, with LDC experiencing growth in heavy industries reliant on diesel transport.

The authors review the literature on associations of BMF with COPD, tuberculosis, and asthma, TRAP with COPD, childhood asthma and adult asthma, and indoor air pollution and respiratory infection. They briefly discuss mechanistic evidence as well as intervention studies, such as the Beijing Olympics Intervention Study and the Mexico Patsari stove study.

Laumbach and Kipen conclude by commenting on the highly political nature of reducing BMF and TRAP, pointing out that public policy and individual action will be necessary to alleviate the disparate health burden on citizens of LDCs. They urge clinicians to counsel their patients on immediate impact ways to lessen their exposure, such as improving ventilation and avoiding high traffic roadways while exercising outside.

Chinese herbal formula shows promise for protection from peanut-allergy anaphylaxis

2011-12-01T13:47:00.000-08:00

Traditional Chinese medicine (TCM) has been practiced in humans for thousands of years, and is growing in popularity in the US. Herbal remedies, in particular, are attractive for their low cost and favorable side effect profiles. Recently, animal research on an herbal preparation, derived from a TCM formula called Wu Mei Wan, demonstrated 100% protection from peanut allergy anaphylaxis that persisted for 6 months. In the mouse-model peanut allergy study, mast cell and basophil activation and numbers were significantly decreased as well.

In this issue, Patil et al. (J Allergy Clin Immunol 2011;128:1259-1265.e2) report promising results from an extended safety study in peanut allergic subjects of Food Allergy Herbal Formula 2 (FAHF 2), an FDA-approved botanical drug, in which they also evaluated the immunomodulatory effects of FAHF 2 on basophils. After 6 months of treatment with FAHF 2, significant reductions in basophil activation markers and circulating basophil titers were demonstrated in peripheral blood allergen stimulation tests. Patil et al. also report a concomitant decrease in eosinophils, though no change in specific IgE from baseline values. They speculate that the effect on basophils is independent of IgE-mediated basophil activation and related to FAHF 2.

They report that FAHF 2 is safe based on the absence of change from baseline of laboratory values, pulmonary function testing, and electrocardiographic results. Among 14 subjects that completed the trial, the authors report one adverse event: exacerbation of eosinophilic esophagitis. The subject stopped FAHF 2 and was able to return to the study after gastroenterologic consultation.

In conclusion, FAHF 2 therapy results in reductions in basophil activation, hyperreleasibility, and circulating titers. Patil et al. note that a double-blind, placebo-controlled efficacy study is in planning stages.

We asked senior authors Xiu-Min Li and Hugh Sampson, from Mount Sinai School of Medicine, New York, to tell us about the implications of this study and future research directions:

Li and Sampson: FAHF-2 appeared safe and well-tolerated in this long-term clinical trial of food allergic patients. Although patients were not challenged in this phase I trial, basophil activation was inhibited following therapy as anticipated, suggesting that this formulation may provide a safe immunotherapeutic option for food allergic patients. A phase II trial of FAHF-2 is now underway and if it demonstrates protection against food allergic reactions, the goal is to conduct further studies to obtain FDA approval for FAHF-2 as a prescription botanical drug.

The search for reliable predictors for developing asthma

2011-12-01T13:44:00.000-08:00

In the context of the increasing prevalence and public health burden of asthma, reliable predictors of asthma development are being sought in order to prevent or mitigate the impact of the disease. Recent research findings of the asthma risk predictive value of infant-onset eczema combined with presence of filaggrin (FLG) null mutation and food sensitization are very promising. This month’s issue presents a report by Filipiak-Pittroff and colleagues (J Allergy Clin Immunol 2011;128:1235-1241.e5), on behalf of 2 large European birth cohort studies of nutritional and environmental factors in the development of allergic diseases, in which they sought to validate the eczema+FLG+food allergy predictors and to determine if the combination was useful in predicting persistent eczema.

Filipiak-Pittroff et al. assembled a dataset of almost 300 children with infant-onset eczema and known FLG and food allergy status and retrospectively examined the relation of these conditions with the presence of asthma and persistent eczema at age 10. The authors report that all three factors are risk factors for asthma, and their combination is highly specific, but not sensitive, for predicting asthma. This finding implies that a prediction cannot be made with sufficient confidence based on these criteria only, since there might be many false negatives, i.e. many children at risk for asthma development would not be identified correctly.

Thus, their findings did not corroborate previous research suggesting a nearly 100% predictive value for asthma development for the combined presence of early eczema, food allergy, and FLG null mutation, and shows that for a precise prediction of asthma more than these three variables are needed.

Filipiak-Pittroff et al. conclude that their results underscore the complex presentation of atopic diseases and reinforce the need to identify reliable methods for prediction.

Do the NAEPP Guidelines need updating?

2011-10-31T09:58:00.000-07:00

Stanley Szefler, MD, Deputy Editor of the JACI, provides much food-for-thought in an editorial in this month’s issue focusing on the asthma guidelines (J Allergy Clin Immunol 2011;128:937-938). Dr. Szefler asks whether our current understanding of asthma compels a review of the NAEPP EPR-3 guidelines, which were last updated in 2007. He points out accumulated evidence has changed our thinking on add-on therapy, the role of vitamin D, and the public health implications of severe asthma. Additionally, Dr. Szefler highlights recent contributions focused on biomarkers in asthma management and skin prick testing in young children as predictive of wheezing in later childhood, as well as the conundrum of asthma heterogeneity that confounds our efforts to alleviate disease burden.

What do you think? We want to hear from you. Post your comments, experience, and insights below.

A psychological construct that influences clinical findings in asthma

2011-10-31T09:56:00.000-07:00

It’s well known that psychosocial mechanisms and socioeconomic factors modify disease presentation. In this month’s issue, Chen et al. (J Allergy Clin Immunol 2011;128:970-976) report interesting findings on just such effects in low socioeconomic status (SES) children with asthma. Noting that SES and related stressors contribute to poor health outcomes, they ask why some people do not succumb to illness in these settings, then look for answers among children with asthma from a range of socioeconomic levels.

Chen et al. postulated that low-SES asthmatic children with “shift and persist” adaptive strategies would have a psychological advantage that would be clinically demonstrable, compared to low-SES asthmatic children who did not use those strategies. Shift and persist strategies are adaptive psychological responses to stressors wherein the person tries to interpret stressors in less negative ways (shift) and remains optimistic about the future in spite of the stressors (persist).

The authors found that low-SES asthmatic children employing shift and persist strategies had less asthma-associated inflammation and less impairment at baseline as well as at the 6-month follow-up. In fact, these children exhibited low levels of inflammation and impairment that were similar to high-SES asthmatic children. Of particular interest, Chen et al. note that shift and persist strategies were not effective in high-SES asthmatic children.

They conclude by commenting on application of these observations as a starting point to address health disparities associated with disadvantaged individuals. Chen et al. also suggest that additional research on these effects should cover other chronic illnesses.

We asked lead author Edith Chen, PhD, from the University of British Columbia, to tell us about the potential implications of this study.

Dr. Chen: The hope is that by identifying strategies that are used naturally by some, resilient low SES children and which are beneficial to asthma, these strategies could then be taught to other low SES children in an effort to reduce stressful experiences and their adverse effects on asthma in this population.

Asthma protection may be in the whey.

2011-09-30T10:00:00.000-07:00

The GABRIELA (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community) study group provides this month’s contribution to the mounting evidence supporting the hygiene hypothesis with important findings on early consumption of farm milk and asthma and allergies.

Loss et al (J Allergy Clin Immunol 2011;128:766-773) report on results from an extensive study in rural Germany, Austria and Switzerland that collected questionnaire data from parents of over 8,000 children, with over 7000 consenting to provide serum samples for specific IgE levels. Additionally, 800 cow’s milk samples from the children’s homes were analyzed for viable bacteria, whey protein levels, and total fat content.

The GABRIELA protocol divided milk consumption into two categories: “shop” milk and “farm” milk. Farm milk consumption was further divided into “only boiled farm milk drinkers” and “any unboiled farm milk drinkers.” Children drinking exclusively farm milk had significantly lower risk for asthma, current asthma, atopy and hay fever as compared to children exclusively drinking shop milk. This relationship held for consumption of any unboiled farm milk. Consumption of farm milk was also inversely correlated to food allergen sensitization.

Loss et al. describe microbiological analysis of shop milk and heated farm milk, which detected microorganisms in only a few samples. Raw farm milk, in contrast, contained significant amounts of micrococci, staphylococci, and lactobacilli as well as other bacteria. Only 3 milk samples contained human pathogens, Listeria innocua and Listeria ivanovii. Consumption of the analyzed raw farm milk was inversely correlated with asthma and current asthma, but not with atopy as compared to heated shop milk. Total fat and viable bacterial load did not associate with any health outcomes; however, increased levels of whey proteins were inversely associated with asthma, but not atopy. Specific significant associations were found for α-lactalbumin, β-lactoglobulin and bovine serum albumin and protection from asthma.

Loss et al. comment that higher bacterial load in raw farm milk might be expected to cause the protective effects, but instead, no association was observed between viable bacteria counts and any of the health outcomes. Surprisingly, the authors found that some whey proteins were inversely associated with asthma. They state that this finding is perplexing given that two of the three proteins inversely associated with asthma, α-lactalbumin and β-lactoglobulin, are the major allergens in milk. Loss et al. note that the inverse relationship of bovine serum albumin, α-lactalbumin and β-lactoglobulin to asthma does not apply to atopy and speculate that other milk components may be responsible for epidemiologic data that demonstrate inverse association between farm milk consumption and atopy.

UPDATE 10 October 2011:

We asked senior author Charlotte Braun-Fahrländer to comment on the implications of this report:

Dr. Braun-Fahrländer: The study is the first to point to the role of whey proteins in the prevention of asthma and thus offers new options to eventually develop a safe and protective milk. Yet, our results also raise many questions for future research ranging from confirming the findings to understanding the mechanism underlying the effects to possible preventive implications. It is intriguing that major milk allergens might be involved in reducing the risk of asthma and future research needs to unravel the mechanisms involved. Nevertheless, it has previously been shown that high dose exposure to cat allergen was associated with less sensitization (Platts-Mills et al. 2011) and recent results from a mouse model of oral tolerance suggested that the context of allergen presentation might be relevant as complexing the allergen with immunoglobulins that were transferred to the newborn by breastfeeding induced oral tolerance in the offsprings (Verhasselt et al. 2008).

References:

Platts-Mills TAE, Woodfolk JA. Allergens and their role in the allergic immune response. Immunological Reviews 2011;242(1): 51-68.

Verhasselt V, et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat Med 2008;14(2): 170-175.

Refining the phenotypes and diagnosis of chronic sinusitis

2011-09-30T09:58:00.000-07:00

Payne, Borish, and Steinke (J Allergy Clin Immunol 2011;128:710-720) characterize chronic sinusitis (CS), its presentation, diagnosis and treatment in the “Mechanisms of allergic diseases” section in this issue. Pointing out that CS has been considered a single clinical presentation in the past, the authors make clear that it is a complicated disease entity requiring clinical distinction for effective treatment. Definitionally, they state that the cardinal features of CS are nasal irritation, anterior and posterior rhinorrhea, and nasal blockage with pressure or pain in a sinus pattern that lasts more than 12 weeks. Payne et al. emphasize that, fundamentally, CS is an inflammatory disease of the sinus that occurs with and without nasal polyps (NP). Importantly, eosinophilia distinguishes two subsets of CS and they note that NP is predictive of eosinophilic CS, but not diagnostic.

Chronic infectious sinusitis. Payne et al. point out that all forms of CS are associated with barrier and immune disruption that compromise the sterility of the sinus. Chronic infection is not causally related to CS, but instead, CS is associated with abnormal microbial colonization as a result of loss of sterility. Clinically, patients with chronic infectious sinusitis (CIS) have neutrophilia and profound bacterial load within their sinuses. Additionally, the presence of biofilms (bacterial and DNA matrices embedded with bacteria) is critical to the pathology of CIS, providing a source for superinfection and constant inflammatory factors. The authors note that biofilms are probably involved in most forms of CS.

Noneosinophilic sinusitis (NES). NES is an idiopathic form of CS resulting from chronic or recurrent obstruction of the sinus ostia by any number of causes such as anatomic variation and allergic rhinitis. Clinically, NES is associated with significant mononuclear cell infiltrate with few neutrophils, and remodeling with dense collagen and matrix deposition. Also, B cell and plasma cell infiltrations are seen in conjunction with B-cell activating cytokines. Increased numbers of connective tissue-associated mast cells are common, which contrasts with eosinophilic forms of CS. Payne et al note that NES+NP is associated with increased expression of hypoxia-inducible factor (HIF) 1α which supports the idea that chronic obstruction of the ostia causes hypoxic damage to the sinus. The authors report that limited genetic work has been published, though an early study from their research group identified plasminogen activator inhibitor 1 (PAI-1) gene as a possible candidate. They note that surgical treatment for both CIS and NES is effective when conservative therapies have failed.

Chronic hyperplastic eosinophilic sinusitis (CHES). As the name implies, CHES is characterized by dominant eosinophilia of the sinuses and NP, if present. Immunohistochemistry has demonstrated increases in cytokines, chemokines, and inflammatory mediators that reinforce the eosinophilia. Payne et al describe it as a self-perpetuating syndrome and note that surgery is insufficient for mitigation or resolution. CHES patients are allergen sensitized and experience exacerbation of sinus inflammation and eosinophilia after aeroallergen exposure. Abnormal colonization of the sinus may contribute to the pathology as well. The authors note that CHES patients often have asthma and that CHES shares pathological features with asthma, suggesting that CHES and asthma are manifestations of the same dysfunctional immune process. Initial treatment for CHES involves nasal saline irrigation with and without surfactants, and add-on therapies, such as oral and topical steroids, that are effective in asthma patients are often effective in CHES patients as well.

Payne, Borish, and Steinke extensively discuss clinically distinct features of two other forms of CS, allergic fungal sinusitis and aspirin-exacerbated respiratory disease, and current knowledge of their phenotypes, genetics and effective management. The authors emphasize in their conclusion the primary requirement to determine the presence or absence of eosinophilia, regardless of NP presence, to predict treatment outcomes. They suggest that tissue biopsy from the sinus or NP may be the most appropriate step to confirm diagnostic classification.

Compelling support for the hygiene hypothesis in asthmagenesis

2011-09-01T07:37:00.000-07:00

The hygiene hypothesis is certainly in the category of “grand old theories” stacked nicely on a shelf with other grand old theories, waiting for its eureka moment. There has been a decent effort in the scientific community to validate it over the last 10-15 years, but definitive evidence is wanting. A small group of investigators have continued the pursuit of supportive evidence for this very intuitive, but minimally substantiated, theory and have been rewarded with an exceptional finding, published in this month’s issue (J Allergy Clin Immunol 2011;128:618-625.e7).

Brand et al. report the results of a mouse study designed to determine if maternal microbial exposure during pregnancy works epigenetically to confer asthma protection to their offspring. Using an accepted mouse model of airway hyper-reactivity and inflammation, the authors demonstrate that intranasal delivery of Acinetobacter lwoffi to pregnant mice significantly shifted the TH1/TH2 profile in the offspring. In vitro stimulation of mononuclear cells from the offspring of A. lwoffi-exposed mothers showed a marked decrease in production of TH2 cytokines, IL-4, IL-5, and IL-13 in conjunction with increased IFN-γ production and responsiveness. This resulted in protection from the asthma phenotype in the F1.

Further, Brand et al. demonstrate, using antibody blockade that histone modifications to the IFNG promoter and, to a lesser extent, the IL4 and IL5 promoters, directly modifies the TH1/TH2 balance towards TH1. They note that CpG methylation of these sites is not affected.

The authors present the first-ever findings that asthma protection is mediated epigenetically by maternal exposure to environmental microbes, and, in particular, that the effect of A. lwoffi exposure is mediated by histone acetylation of the IFNG promoter. Noting that other genetic and environmental factors must be considered, Brand et al. suggest that maternal epigenetic interventions may be preventative in offspring with asthma risk.

We asked senior author Harald Renz, MD, to comment on the implications of the study:
Dr. Renz: “With this study the books are far from being closed. [Quite] the contrary, our results raise many questions for future research ranging from the whole mechanistic machinery of epigenetic regulation to possible therapeutic implications in the future. We are convinced that many other research teams will joining this exciting journey of transgenerational asthma and allergy development.”

State of the art: Asthma treatment effects on airway remodeling

2011-09-01T07:32:00.000-07:00

In this month’s issue, Durrani, Viswanathan, and Busse take a look at what we know – and what we don’t know – about the effects of asthma therapy on airway mesenchymal-epithelial remodeling in asthma (J Allergy Clin Immunol 2011;128:439-448). After summarizing the current information about remodeling mechanisms, Durrani et al. discuss the effects of specific asthma drugs.

Airway remodeling is known to occur in some asthma patients, but the authors point out that it is not linked to any clinical indicators. While remodeling is considered to contribute to the pathology of asthma, the causal relationship has not been confirmed. Typically, remodeling has been considered a response to chronic inflammation and dysregulation of repair mechanisms in the lung, so it has been suggested that treatments aimed at reducing inflammation would impact remodeling. Durrani et al. note that this concept has not held out, in light of evidence that suggests remodeling occurs in parallel with inflammation, as well as clinical data that traditional therapies, such as ICSs, are not effective for all asthma patients. Of interest, they comment that there is new evidence that remodeling is a direct response to increased inflammation during asthma exacerbation, supporting the idea that remodeling and inflammation are concomitant. The authors then focus their review on what is known about effects of asthma therapies on aspects of remodeling, such as airway smooth muscle (ASM) hyperplasia, subepithelial fibrosis, and goblet cell hypertrophy.

Inhaled corticosteroids. Durrani et al. discuss several studies that have reported positive effects of ICSs on elements of airway remodeling, such as decreasing reticular membrane thickening, goblet cell hypertrophy, and vascular remodeling. They note that the same is not true of ASM hyperplasia and epithelial injury and detachment where both positive and negative effects have been observed.

Combination treatments. The authors discuss in vitro studies that have shown that ICS+LABA combination products are more effective than monotherapy with either on matrix deposition in human fibroblasts. Another study reported decreased airway wall thickness and epithelial growth factors in asthma subjects on combination product. The authors are cautiously optimistic about these findings, but note a paucity of research specifically evaluating the effects of ICSs+LABAs and LABAs alone on airway remodeling mechanisms.

Monoclonal antibody therapy. Reviewing studies on omalizumab, mepolizumab, and golimumab, Durrani et al. comment on the lack of direct evidence suggesting that mAb therapy mitigates airway remodeling, even though there are reports of mAb decreasing inflammatory cytokines, eosinophilia, and exacerbations, all of which have been associated with remodeling.

The authors briefly cover other therapies, such as leukotriene antagonists and tyrosine kinase inhibitors, before concluding that pivotal pathways in remodeling need to be identified prior to outcomes research on the clinical impact of remodeling to exacerbation and impairment in asthma.

We asked senior author William W. Busse, MD, from the University of Wisconsin, what he felt the most promising areas are for future research on airway remodeling:

Dr. Busse: As pointed out in our review, there are a number of complicating features which make it difficult to determine the best treatment for processes involved in remodeling. First, as noted, the mechanisms underlying remodeling have not been fully identified making the selection of a target intervention difficult. Second, it is likely for those patients in whom remodeling becomes a part of their disease processes, it begins early in life and is linked to other events in asthma, i.e., injury and repair. Given this information, it is likely that treatment most likely to prevent remodeling will need to begin early in life and in the development of asthma. Since two early life events that are key to asthma development include allergic sensitization and respiratory infections, these two areas are likely to be the best targets. Of these two events, allergic sensitization is emerging to be perhaps the most important and amendable to treatment and, perhaps, prevention.

Using large population metrics to improve asthma outcomes

2011-08-01T09:07:00.000-07:00

In this month’s issue, Schatz and Zeiger (J Allergy Clin Immunol 2011;128: 273-277) bring us validation results comparing administrative and clinical tools for assessing asthma outcomes from a Kaiser Permanente patient population. They describe their assessment experience in two primary areas: population management and quality of care.

The authors look at three elements of population management, beginning with the definition of persistent asthma. They use the modified, 2-year (current year and previous year) Health Effectiveness and Data Information Set (HEDIS) and compare it to a 2007 patient survey based on the EPR3 clinical definition. Schatz and Zeiger find that the majority of patients with HEDIS-defined persistent asthma in 2006 reported clinically defined persistent asthma in 2007, demonstrating that 2-year HEDIS definition correlates well with the EPR3 definition. Next they assessed impairment based on comparison of the administrative data on SABA use in the past 12 months and telephone-implemented Asthma Control Test (ACT), again finding useful convergent and predictive correlation between the two. Lastly, they assessed administratively defined risk with clinical risk, correlating healthcare utilization in the past 12 months and pharmacy data, then evaluated the predictive power of several different asthma control questionnaires. Of note, Schatz and Zeiger find that any one asthma questionnaire was a sensitive as the others for predicting exacerbation and suggest that using only one questionnaire is sufficient to detect risk.

Finally, the authors address quality of care metrics and evaluate an administrative data outcome called the medication ratio measure, which is defined from pharmacy data as ratio of controller medications to total asthma medications (controllers + relievers) dispensed in a 12-month period. Their results show that patients with a ratio of 0.5 or higher were significantly less likely to require emergent hospital care and were more likely to report higher quality of life than patients with a ratio of less than 0.5.

In conclusion, Schatz and Zeiger comment that administrative outcome data and survey data appropriately reflect asthma severity, impairment, risk and quality of care in a large patient population. They note that generalizability of their findings may require additional research in order to capture disparities among specific populations. Further, they suggest that individual or group practitioners would benefit from the application of any single outcome measure validated in their large population study.

Dr. Schatz will be talking about this article as part of our next podcast, “Reducing Asthma Burden.” Look for it on http://www.jacionline.org/content/podcast starting August 15.

Validated strategies for decreasing the frequency of asthma exacerbations

2011-08-01T08:55:00.000-07:00

Asthma exacerbations are extremely high risk for asthma patients and impose a great cost burden on healthcare providers. Perhaps equally important is the evidence that full symptomatic recovery from exacerbation can result, nevertheless, in persistent decreased lung function after recovery. To this issue, Paul O’Byrne inventories current therapies directed specifically at preventing or mitigating asthma exacerbations in this month’s issue (J Allergy Clin Immunol 2011;128: 257-263).

O’Byrne notes that exacerbations are thought to be precipitous, emergent events. In fact, they have a gradual development over approximately a week as symptoms increase and lung function decreases until the point of urgent intervention. Additionally they are frequently associated with upper respiratory infections (URI) caused typically by human rhinovirus (HRV) or allergen exposure in atopic patients. The author notes that URI or allergen exposure alone is not sufficient to elicit exacerbation and other conditions are required, therefore, prevention is targeted at risk mitigation.

The author discusses inhaled corticosteroids (ICS) as the primary intervention aimed at reducing airway inflammation, and subsequently, risk of infection or reactivity. ICS have a positive effect on airway eosinophilia, a primary cause of inflammation, but O’Byrne notes that slightly less than half of asthma patients have airway neutrophilia that doesn’t respond to ICS therapy. Symptom rescue is managed through use of short- and long-acting bronchodilators, used separately or in steroid + long-acting bronchodilator combination products. O’Byrne comments on recent research supporting the use of the combination product budesonide + formoterol for maintenance as well as exacerbation, noting that budesonide + formoterol was as effective as oral steroids for common outcomes, such as nighttime awakenings and albuterol rescue use.

O’Byrne discusses the beneficial effects of anti-leukotriene therapy, especially in pediatric asthma patients. Anti-IgE antibody therapy is helpful in allergic asthma and inner city children with asthma, though anti-IL-5 antibody therapy for reducing airway eosinophilia in refractory asthma has not yet proven unequivocally beneficial. Finally, the author discusses bronchial thermoplasty for refractory asthma, which has approval in only a few countries.

Editor's note: Readers interested in learning more about asthma exacerbations may want to consult the August 2009 supplement, Supplemental Recommendations for the Management and Follow-up of Asthma Exacerbations, written by representatives of the American Academy of Allergy, Asthma & Immunology, the American Academy of Emergency Medicine, and the American Thoracic Society. The supplement is available for free download at: http://www.jacionline.org/issues?issue_key=S0091-6749(09)X0009-6.

Eosinophilic esophagitis: Updated consensus recommendations

2011-07-01T10:07:00.000-07:00

A task force made up of 33 experts from multiple disciplines present updated recommendations for the diagnosis and management of eosinophilic esophagitis (EoE) in this month’s issue (J Allergy Clin Immunol 2011;128:3-20). Liacouras and colleagues performed an exhaustive literature review to inform new clinical recommendations (CR) for 5 categories: diagnostics, genetics, allergy evaluation, therapies, and complications. They also offer recommendations for future critical research areas. Importantly, they provide a concept definition to assist clinicians with framing the clinical presentation of EoE. Liacouras et al. state this concept definition: “Eosinophilic esophagitis represents a chronic, immune/ antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation.”

Overview of diagnostic recommendations: The task force makes recommendations in the diagnostic areas of history and physical exam, endoscopy, histology, pH monitoring, and laboratory findings. Among these are a thorough H & P, with emphasis on eating and swallowing symptoms, proximal and distal endoscopic biopsies, and gastric pH and pH impedance testing. Additionally, Liacouras et al. recommend that any and all histological findings be reported until EoE-specific findings are identified. The authors note that very few laboratory tests have been demonstrated to be informative, with the exception of peripheral esosinophil count and skin prick testing.

Overview of genetic studies and recommendation: Noting that the previous consensus report, published in 2007 (Gastroenterology 2007;133:1342–1363), presented a single genotype study, Liacouras et al. provides a substantial review of recent genetic research. Two important genetic findings are the description of an EoE transcriptome with increased expression of eotaxin-3 and IL-13, and the report of a single susceptibility locus, 5q22, for EoE that contains genes encoding thymic stromal lymphopoetin (TSLP), a critical cytokine in TH2 cell commitment. An X-linked variant of TSLP and a common deletion mutation in the filaggrin gene family have also been identified.

Overview of allergic evaluation: Atopic conditions including food allergy, asthma and eczema are known to associate with EoE and the task force emphasizes allergist/immunologist consultation for management of comorbid allergic symptoms. Skin prick testing is necessary to identify reactive allergens and eliminate or mitigate them. Liacouras et al. recommend assessment of allergen-specific IgE to document sensitivity prior to initiating desensitization/tolerance protocols.

Overview of therapeutic options: Liacouras et al. review and recommend a multifocal treatment strategy that includes proton-pump inhibitors (PPI), dietary restrictions, and topical corticosteroids. Oral steroids are recommended only for severe symptom presentations. They also state that alternative therapies, such as cromolyn sodium, LTR antagonists and immunosuppressive drugs, are not recommended based on lack of efficacy data.

Overview of complications: Liacouras et al. point out the common complications, namely, emergent food impaction, esophageal stricture, and non-interventional (“spontaneous”) esophageal perforation. They go on to discuss esophageal dilation for mitigation, but advise that it is best applied as an “add-on” intervention to the recommended clinical management.

Liacouras et al. provide recommendations for the focus of future studies for each of the 5 areas they cover and conclude that the most pressing need is for research to distinguish EoE from gastric esophageal reflux disease (GERD), with several other priorities, such as translational analysis to describe EoE phenotypes, and idenfication of EoE biomarkers and unique histological findings.

We asked lead author Chris Liacouras, from the Children’s Hospital of Philadelphia, to tell us more about our current understanding of EoE and where the research will go from here:

JACI: How has our understanding of EoE changed since the 2007 consensus recommendations were published?

Liacouras: We have been been extremely fortunate that the number of physicians and scientists interested in EoE has grown tremendously since the original Consensus Report in 2007 as noted by the number of additional authors included in the 2011 Updated Guidelines. The most important component of the Updated recommendations continues to be the understanding of the definition which attempts to explain that EoE is an antigen/immune medicated disease process different from acid induced or PPI-responsive esophageal eosinophilia. Additionally, the other most significant advances since 2007 have been made in genetics and with the identification of specific esophageal biochemical tissue markers.

JACI: In your opinion, what is the next priority area in EoE research after the need to distinguish it clinically and pathologically from GERD?

Liacouras: Currently, EoE has become one of the interesting and confusing disorders for both gastroenterologists and allergists. Apart from the need for physicians to identify and accurately diagnose patients with EoE, there are many areas of ongoing research that need to be explored. Clinically, it is essential that we continue to pursue the natural history, non-invasive testing, best treatment options and which patients are likely to develop complications. In addition, scientifically, we need to identify the etiology, pathophysiology, and development of esophageal fibrosis in patients with EoE. We also need to continue to explore the genetics of the disease.

Eating baked cow’s milk products may facilitate resolution of cow’s milk allergy

2011-07-01T10:06:00.000-07:00

Kim et al. (J Allergy Clin Immunol 2011;128:125-131.e2) investigate the clinical implications of the empirical observation that 75% of milk-allergic children tolerate extensively heated milk in foods such as baked goods. These children have been observed to have milk-specific IgE directed at conformational epitopes rather than sequential epitopes. Heating (such as baking) disrupts the tertiary structure and consequently, reduces the allergenicity of milk proteins to which these children are sensitive. In contrast, children who are reactive to heated milk products have milk-specific IgE to heat-stable, sequential epitopes.

Kim et al. report on their findings from a clinical study of baked milk tolerant and baked milk reactive subjects, wherein baked milk tolerant subjects were advised to include baked milk food products in their diet on a daily basis, while baked milk reactive subjects were advised to practice complete strict avoidance. A comparison group, not initially challenged to baked milk products, was also observed over the study period.

Overall, Kim et al. report that initially baked milk tolerant subjects were 28 times more likely to become unheated milk tolerant than those initially baked milk reactive subjects, as compared to those subjects who observed strict avoidance. Baked milk tolerant subjects that received active treatment (that is, were able to include baked milk products into their diets) were significantly more likely to develop tolerance to unheated milk compared to the comparison group.

The authors demonstrate two important outcomes of their study: 1) baked milk tolerance is a marker of mild, transient cow’s milk allergy; baked milk reactivity implies a more persistent, severe form of cow’s milk allergy and, 2) the majority of children with baked milk tolerance that routinely eat baked milk food products will develop unheated milk tolerance at an accelerated rate compared to children prescribed a strict avoidance diet.

Kim et al. suggest that ingestion of baked milk products by tolerant patients is a safer, more convenient and cost-effective method of immunotherapy. They also comment that their results might be extrapolated to children with egg allergy in light of reports on heat-related changes in allergenicity of egg proteins.

We asked first author Jennifer Kim, from Mt. Sinai School of Medicine, to tell us about the implications of this work for future research. According to Dr. Kim, “These findings have provided the impetus for a more rigorously designed study that has been developed by our group to determine whether more rapid introduction of increasingly allergenic forms of baked-milk products in baked-milk non-reactive participants shortens the time until they tolerate higher doses of less heated milk and ultimately unheated milk.”

Tell us what you think. Please feel free to post your comments below.

Psoriasis and atopic dermatitis: The same, only different

2011-06-02T14:38:00.000-07:00

In the May issue of JACI, Guttman-Yassky et al. (J Allergy Clin Immunol 2011;127:1110-1118), in part 1 of a 2-part review, covered the clinical and pathological similarities and differences between psoriasis and atopic dermatitis (AD) with AD as the point of reference. They finish up in this month’s issue (J Allergy Clin Immunol 2011;127:1420-1432) with a broad discussion comparing the immune phenotypes and therapies for AD and psoriasis.

In part 1, Guttman-Yassky et al. pointed out that psoriasis and AD both present with defects in skin barrier function, skin lesions infiltrated by increased numbers of T cells and dendritic cells and upregulation of epidermal proliferation genes. They note that the chronic phase of AD is more similar to psoriasis than the acute phase. There are distinct differences though. AD patients are susceptible to bacterial and viral skin infections, which is not true for psoriasis patients. Also, AD skin is characterized by decreases in keratinocyte differentiation, cornification, moisture and lipid content. Though lipid depletion is also observed for psoriasis, it is characterized by increased differentiation and cornification. Cytokine milieu in AD is dominated by TH2 cells, while psoriasis is associated with TH1 and TH17 cytokines. Additionally, AD is associated with structural protein anomalies (e.g., filaggrin dysfunction) that are not observed in psoriasis.

The authors discuss in part 2 how the disorders were thought to be mediated by polarized T helper cell responses with TH2 dominance seen in AD; however, this simple dichotomy did not account for all observations, such as hyperkeratinization, seen in chronic AD. They point out that the discovery that TH17 and T22 cells affected epidermal activation eventually led to a new working model wherein psoriasis is mediated by TH1 and TH17 immunity, and AD is mediated by TH2 and T22 cell effects. Production of anti-microbial peptides (AMP) is known to be compromised in AD compared to psoriasis. This was originally attributed to the TH2 environment, but the authors comment that IL-17 deficiency as well as excessive TH2 cytokines can explain the decreased AMP production found in AD. Guttman-Yassky et al note that the impaired AMP production would explain increased susceptibility to skin infections in AD. In contrast, psoriasis is characterized by increased AMP production. The authors also discuss basic differences between AD and psoriasis with regard to differences in dendritic cell populations, AD-associated eosinophilia, barrier defects and inflammation, and mast cell production of interferon gamma (IFN-γ) in psoriasis.

Guttman-Yassky et al. finish up part II with a discussion of the prognosis and intervention for psoriasis and AD. Unlike AD, they note that active psoriasis can be completely resolved and treatment time is short. The authors comment that, in spite of their differences, both AD and psoriasis share epidermal hyperplasia, aberrant immunity, and skin barrier anomalies. This would suggest that immune-based strategies to correct barrier defects that have been developed for psoriasis might be effective for AD. Guttman-Yassky et al. detail current AD treatments and make a case for psoriasis therapies as intervention for AD.

Tell us what you think. Please feel free to post your own comments and/or predictions below.

Chronic mucocutaneous candidiasis associated with impaired TH17 cell differentiation

2011-06-02T14:37:00.000-07:00

In this month’s issue, Hanna and Etzoni (J Allergy Clin Immunol 2011;127:1433-1437) shed light on the primary players in the pathogenesis of chronic mucosal candidiasis (CMC). They review current knowledge of CMC as it is most commonly observed; namely, as secondary to other clinical conditions, particularly those that cause immunocompromise, such as HIV, diabetes mellitus, and T-cell deficiency disorders. Hanna and Etzoni then discuss CMC as a primary symptom in immunodeficiency disease, such as in hyper-IgE syndrome (HIES) and autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), or, more rarely, with no other related clinical presentation.

The authors review the primary innate immune defense against Candida albicans, noting that activation of the Dectin-1 and -2 receptors mediate host response through spleen tyrosine kinase (Syk) and caspase recruitment domain member 9 (CARD9) to initiate T cell differentiation to produce multiple cytokines, particularly those associated with TH17 differentiation, IL-17 and IL-22. T regulatory cells are also mobilized and critical for containing the TH17 inflammatory response to C. albicans.

Hanna and Etzoni move on to discuss CMC as the primary clinical feature of HIES and point to research that has shown that a heterozygous mutation in the transcription factor, STAT3, is the cause of this syndrome. Impaired STAT3 signaling negatively impacts RORγt function, which is required for TH17 cell development. The authors point out that this is supported by clinical findings of very low circulating markers for TH17 cell lineage in patients with HIES.

They also review severe CMC as a major feature of the autoimmune disease, APECED. Unlike the transcription dysregulation in HIES, CMC in APECED results from high titers of neutralizing autoantibodies against IL-17 and IL-22. Finally, Hanna and Etzoni describe less common presentations of non-syndromic CMC, some of which are idiopathic, while others have autosomal inheritance associations. In the latter, the authors discuss a genetic analysis of familial CMC in 5 generations of an Iranian family, which revealed a loss-of-function mutation in CARD9.

The authors conclude noting that in most non-syndromic CMC cases the genetic defects are still unknown, though abnormal TH17 function or production was observed.

Tell us what you think. Please feel free to post your own comments and/or predictions below.

Dietary fat intake linked directly to airway inflammation

2011-05-06T12:25:00.000-07:00

What you eat determines how you breathe whether or not you have asthma. Wood et al. (J Allergy Clin Immunol 2011;127:1133-1140) present first-ever findings on the local inflammatory effects of high fat food, in this month’s issue.

The authors examine the effect of single high-fat or low-fat meals on non-obese subjects with asthma. Then, healthy, non-obese subjects and obese subjects with asthma were administered a single high-fat meal. All groups that consumed a high fat meal showed increased neutrophilic airway inflammation as measured by sputum induction and IL-6 levels, decreased % predicted FEV1 post-bronchodilator, and increased TLR4 expression and TNF-α levels. Wood et al. report that increased total plasma fatty acid levels were correlated significantly to increases in TNF-α and neutrophil percentage in sputum. Additionally, increased fatty acid levels were inversely correlated to change in % FEV1, %FVC, and FEV1/FVC.

They also examined the effect of meals containing trans-fatty acids as compared to meals with no trans-fatty acids. Subjects consuming trans-fatty acids demonstrated increased sputum neutrophilia compared to those that consumed no trans-fatty acids, which is consistent with other research reporting the pro-inflammatory properties of trans-fat.

Wood et al. state in conclusion that consumption of a high fat meal causes local airway inflammation and asthma worsening through activation of the innate immune response. They recommend that future research on this subject should focus on the effects of chronic consumption of high fat food in patients with asthma.

Have a comment? Tell us what you think. Please feel free to post your own comments and/or predictions below.

A look at commensal gut bacteria, probiotics and atopy and obesity

2011-05-06T12:24:00.000-07:00

In a clinical review in this month’s issue, Ly et al. (J Allergy Clin Immunol 2011;127:1087-1094) pull together what is known currently about gut microbiota influence on immunity, the association of abnormal microflora with eczema, asthma and obesity, the usefulness of probiotics for normalizing commensal gut bacteria, and newer information about vitamin D interactions with intestinal flora.

The authors begin commenting on how infants achieve gut colonization peri- and post-natally and note that vaginal delivery results in different gut flora in the infant than cesarean delivery. In particular, infants delivered by cesarean establish gut flora dominated by Klebsiella and Clostridum species, and enterobacteria other than E. coli, with later and less colonization by Bacteroides sp. and Bifidobacterium sp. Ly et al. point out that hospitalized neonates have gut flora similar to infants delivered by cesarean, suggesting that standard of care antibiotic use could be related to the decreased colonization by healthy bacteria.

They continue with a review of current knowledge of differential gut microbial populations between atopic and non-atopic infants, noting that atopic infants have lower fractions of lactobacilli, bifidobacteria, and Bacteroides sp. than their non-atopic counterparts. Ly et al. comment that current studies on neonatal gut commensalism and atopy are inconclusive, then discuss the design variability and limitations that result in contradictory findings.

The authors move to the evidence supporting a relationship between disturbance of the gut microflora and diet-related obesity, linking it to inflammation and impaired energy metabolism. They further note that gut flora composition shifts toward healthier bacteria dominance in obese subjects on dietary restriction for weight loss.

Ly et al. wrap up with a discussion of the equivocal findings from studies employing probiotics as prevention or mitigation of atopic diseases and a short note on the requirement of vitamin D for healthy gut microbial effects on inflammation. They conclude stating that evidence suggests early diversity of microbiota is pivotal to healthy gut-immune dynamics and that future research must comprise data on maternal flora-neonate flora interactions, vitamin D’s role and dietary confounders.

Have a comment? Tell us what you think. Please feel free to post your own comments and/or predictions below.

Severity of human rhinovirus infection in infants linked to maternal atopy

2011-04-05T09:54:00.000-07:00

Human rhinoviruses (HRV) are known to be associated with asthma exacerbations in both children and adults. Additionally, bronchiolitis, which is usually associated with respiratory syncytial virus (RSV), is being associated with HRV as well. Typically, HRV is a viral infection associated with older children and has not been closely examined in infants with low risk for atopy.

Miller and colleagues in this month’s issue (J Allergy Clin Immunol 2011;127:883-891) examine the HRV burden in upper respiratory infections (URI) and bronchiolitis among children that had participated in the Tennessee Children’s Respiratory Initiative. They collected atopy risk information, clinical severity from hospital admission records, and performed type testing on the three HRV strains, A, B, and C.

Miller et al find that both URI and bronchiolitis in healthy infants are commonly caused by HRV. Maternal atopy and asthma were associated significantly with risk of more severe bronchiolitis, with maternal atopy conferring more than double the severity risk. Of the three strains of HRV, the newly described group, HRVC was very common and occurred more often in black infants thnt HRVA and HRVB. Infants infected with HRVB had higher severity scores and were more likely to require oxygen supplementation and have longer hospital stays.

The authors conclude that an infant’s susceptibility to severe HRV illness is significantly correlated to asthma and atopy susceptibility in the mother.

Tell us what you think. Please feel free to post your own comments below.

Developing countries feeling the effects of increased traffic-related pollution

2011-04-05T09:42:00.000-07:00

Studies of proximity to major roadways and asthma symptoms in urban environments are demonstrating that there is a significant relationship between the two. There are some reports that traffic pollution also affects FEV1. For the most part, these studies have measured pollution effects from multiple traffic networks, such as mass transit, in developed countries. Few studies in developing countries, with a focus on the impact of individual roadways, have been attempted.

Peru has the highest reported prevalence of childhood asthma symptoms in Latin America, and its capital, Lima, is representative of rapid urban development and expansion. In this month’s issue, Baumann et al. (J Allergy Clin Immunol 2011; 127:875-882) examine the effect of a single, high traffic road in a shanty town outside of Lima, Peru. They evaluate current asthma symptoms, pollution inside and outside the home, and allergen sensitivity as a marker of atopy.

The authors find asthma symptoms and atopy are inversely correlated to proximity to the high traffic road that runs through the shanty town. Airflow limitation was also negatively correlated to roadway proximity, but only in girls. The authors report no increase in airway inflammation or indoor pollution in homes closer to the road. Interestingly, they did find that greater than half the children that participated were atopic, with 23% testing positive to 3 or more allergens. The authors note that theirs is the first epidemiologic report correlating proximity to a roadway and atopy risk.

Tell us what you think. Please feel free to post your own comments below.

Tight junctions compromised in atopic dermatitis

2011-03-04T07:14:00.000-08:00

Skin barrier compromise is a defining characteristic of atopic dermatitis (AD). Research has uncovered several possible explanations for this barrier disruption including lipid and structural defects in the stratum corneum (SC), mutations of the filaggrin gene, and various genetic or acquired abnormalities of proteases and their inhibitors. Scratching irritated skin doesn’t help, either. Part and parcel with this is a persistent, inflammatory Th2-dominant microenvironment. In this month’s issue, De Benedetto et al. (J Allergy Clin Immunol 2011; 127:773-786.e7), for the NIH/NIAID/Atopic Dermatis and Vaccinia Network, report novel evidence that the barrier dysfunction doesn’t stop at the SC.

De Benedetto et al. provide the first evidence that strongly implicates abnormalities of tight junctions (TJs) found in the stratum granulosum in AD patients. They find that claudin-1, a critical component of TJ is significantly reduced in nonlesional epidermis from AD patients. This finding was specific to AD as skin biopsies from psoriasis patients had levels of claudin-1 equal to that of nonatopic, healthy controls. Additionally, nonlesional AD epidermis has increased permeability and decreased trans-epithelial electrical resistance (TEER). Clinically, decreased claudin-1 production was strongly associated with increased total serum IgE and total Eosinophil count in AD patients, as well.

In vitro claudin-1 knockdown caused increased TJ permeability and decreased TEER without affecting other structural components of TJ or the SC, suggesting that claudin-1 is required for a competent epidermal TJ barrier. Further, claudin-1 knockdown caused increased keratinocyte proliferation. De Benedetto et al. speculate that the hyper-proliferation effect of claudin-1 depletion may account for increased epithelial thickness observed even in nonlesional AD skin. Findings that claudin-1 knockdown increased small- and large-pore permeability leads the authors to suggest that AD skin may be more easily breached by allergens, irritants, nanoparticles and microbial products or enable the dendritic processes of antigen presenting cells to sample these products on the skin surface.

In a twist, they find that Th2 cytokines enhance TJ function and increase claudin-1 expression in differentiated keratinocyte monolayers, leading the authors to conclude that impaired claudin-1 expression and TJ dysfunction are not likely the result of Th2 cytokine dominance in AD. In fact they suggest that the TJ defects may be promoting a Th2 immune response that is a response designed to minimize reactions to environmental allergens.

De Benedetto et al. also report on gene association studies in two populations, African Americans (EA) and European Americans (EA). Significant associations were found between CLDN1 gene SNPs and AD or disease severity in both AA and EA.

The authors conclude that barrier compromise in AD involves the secondary skin barrier as well as the stratum corneum and that correlation of serum IgE and total Eosinophil count and claudin-1 expression demonstrates that this deficiency promotes Th2 responses as well.

We asked lead author Anna De Benedetto for more about the implications of this study:

JACI: How do you reconcile the relative importance of claudin defects in comparison with the other defects in barrier function that have now been reported?

Dr. De Benedetto: Our work demonstrating that subjects with atopic dermatitis have a tight junction (TJ) defect complements studies that have reported a number of stratum corneum (SC) defects including altered lipid composition, dysregulated EDC genes, altered protease/antiprotease activity and simply trauma from scratching. We think it is no coincidence that the skin epidermis, which must endure significant environmental exposures, has two formidable barrier structures, namely the SC and TJ. Once the SC is compromised the TJ located just below provide a second line of defense. We believe that immunological responsiveness to environmental insults requires a breach in both structures and that this occurs in subjects with AD. We hope our work will spawn further studies to address the interaction between these two barrier structures and address treatment strategies that would improve either TJ or SC function. If our hypothesis that immunologic responses require a hit to both SC and TJ it may be possible that enhancing the function of one of these barrier structures would be an effective strategy.

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.

The scope and efficacy of intravenous immunoglobulin therapy

2011-02-01T15:11:00.000-08:00

Departing AAAAI president, Mark Ballow, MD, chose the mechanism(s) of action of IVIG (intravenous immunoglobulin) therapy as his contribution to this month’s presidential theme issue (J Allergy Clin Immunol 2011;127:315-323). Dr. Ballow reviews the interesting research that has begun to characterize how IGIV modulates the immune and inflammatory pathways that are associated with a variety of diseases.

Dr. Ballow begins by noting that anaphylaxis risks dictated that early IG therapy for humoral and B-cell immune deficiencies be given by intramuscular route, but by the 1980’s an intravenous preparation was available, making the therapy even more effective in establishing normal serum IgG levels in immunodeficiency patients. Serendipitous observation was made that IVIG therapy also increased platelet counts significantly in patients with co-morbid idiopathic thrombocytopenia purpura (ITP) and led to research on IVIG therapy for other autoimmune/inflammatory diseases. Dr. Ballow points out that approximately 70% of IVIG therapy administered currently is used to treat autoimmune and inflammatory disorders.

The review discusses the multiple mechanisms that have been described for IgG therapy in the context of the diseases in which they have been identified. For example, Fc receptor blockade effects by IVIG were first described in patients with ITP. Other authors reported that idiotypic antibodies in the IVIG neutralizes the autoantibodies that lead to acquired hemophilia, though Fc receptor interactions were found more commonly in other disorders. Research on IVIG efficacy for Kawasaki disease, dermatomyositis, and toxic epidermal necrolysis revealed that IgG therapy had the capacity to interfere in many places along and within the inflammatory cascade at the cellular levels and with inflammatory mediators, such as cytokine inhibition, chemokine production, suppression of adhesion molecule activity, inhibition of complement binding, and modulation of apoptotic processes through anti-Fas antibody components.

Dr. Ballow also describes other research on IVIG immune-modulating mechanisms associated with the Fc inhibitory receptor, FcRIIB, and C-type lectin receptors on effector macrophages that may act to reduce circulating autoantibodies. Finally, the author discusses recent findings that IgG increased suppressive function of Tregs and that therapy in Kawasaki disease and Guillain-Barré syndrome is associated with increased numbers of T regulatory cells.

Dr. Ballow wraps up commenting that “the IgG molecule is the single most important naturally occurring specific immune component capable of modulating the immune system.” Further, that many mechanisms for IVIG efficacy have been identified and that it is likely that they all work in concert depending on IVIG dose and disease context.

We asked Dr. Ballow to tell us about why we chose this focus for his presidential theme issue:

Dr. Ballow: This is the 100th year anniversary for "traditional" immunotherapy celebrated in the Jan. issue of JACI. However, allergist/immunologist have to go beyond traditional immunotherapy (IT) to other forms of "immune therapy" including bone marrow transplantation for patients with primary immune deficiency, IVIG as replacement therapy in patients with hypogammaglobulinemia, and immune response modifiers such as monoclonal antibodies, fusion proteins. The latter therapies have carved an important treatment modality in patients with autoimmune diseases (see review by Betty Diamond). In fact, IVIG has turned out to be one of the most important immune response modifiers in the treatment of inflammatory and autoimmune disease. These topics are emphasized in the upcoming annual Academy meeting, and underscores one of my Presidential themes of expanding the scope of practice for the allergist/immunologist. My motto - "better health through immune based therapies."

The lung microbiome and asthma pathogenesis

2011-01-31T15:29:00.000-08:00

In this issue, Huang et al. (J Allergy Clin Immunol 2011;127: 372-381.e3), reporting on behalf of the NHLBI’s Asthma Clinical Research Network [ACRN], report first-ever research findings associating the composition of airway flora with clinical features of asthma. They postulate that the airway supports a complex community of bacteria that may contribute to clinical features of asthma among asthmatics taking inhaled corticosteroids (ICS). The researchers use a microarra-based method that detects distinct 16S rRNA gene sequences permitting detection and identification of bacterial taxa without previous knowledge of their presence in the relevant sample. Huang et al. report that using this tool, taxa in the phylum Proteobacteria were the most abundant in the cohort of patients studied.

The study occurred in parallel with a clinical trial examining the effects of long-term clarithromycin therapy in subjects with sub-optimal asthma control. Bronchial brushings were obtained from 65 asthma subjects and 10 healthy subjects. The authors find that airway colonization is variable in both healthy and asthmatic subjects, but that asthmatic subjects had significantly greater bacterial diversity than controls. Further, subjects in the clarithromycin treatment group with the highest bacterial diversity pre-treatment, had the greatest improvement in airway hyperresponsiveness following treatment.

Huang et al. comment that finding an airway microbiota in asthma patients on ICS therapy may not be surprising, but in fact, is also consistent with the notion that disturbances in epithelial/mucosal-associated microbiomes are known to be associated with disease as is the case with intestinal inflammatory diseases. They suggest that colonization by specific bacteria may contribute to persistence of inflammation, disease presentation, and/or disease heterogeneity; in particular, they cite the example of bacteria in the family Comamonadaceae, which are known to have steroid degrading capacity, as potentially contributory to steroid-resistant asthma pathology. Further, Huang et al. propose that the effectiveness of macrolide therapy on reducing airway reactivity may be a combined effect of their anti-inflammatory and antibacterial properties.

The authors state that discerning whether increased bacterial burden and diversity is a function of having asthma or being on ICS therapy is an important research question in light of the widespread use of ICS in many airway diseases. Concluding, Huang et al. comment that their findings open new research paths on disease mechanisms in asthma.

We asked senior author Dr. Susan Lynch, PhD, from the University of California - San Francisco, to tell us a little more about the study:

JACI: Your findings have far-reaching implications for airway disease and systems biology research. In your opinion, what are the proximate priorities?

Dr. Lynch: Establishment of cross-disciplinary, integrated research efforts to define microbiota structure, function and host interplay in well defined cohorts of patients. Openness to the possibility that this field of research may dramatically change our long-held perceptions of chronic inflammatory disease genesis and progression.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.

Gene-environment protective effects are context-dependent in development of asthma

2011-01-07T11:27:00.000-08:00

Recent genomic studies have begun to demonstrate that adaptive genotypes are only adaptive when expressed in their relevant context. In this month’s issue, Ege et al. and the European consortium, GABRIEL, present surprising findings from a gene-environment (G*E) interaction analysis for childhood asthma and the farming environment (J Allergy Clin Immunol 2011;127:138-144.e4).

Ege et al. report that previously identified common SNPs associated with asthma in urban populations did not interact with farming environment parameters. Previously identified interactions with farming related exposures were not confirmed despite adequate statistical power.

Among rarer SNPs, however, significant interactions were detected with farming related exposures such as
consumption of raw milk, and exposure to cow and/or straw. By this approach the authors identified new genes that differed from those reported as asthma-associated. SNPs in the GRM1 (metabotropic glutamate receptor 1) gene specifically and significantly interacted with farm exposures. The GRM1 is involved in immunological and neuronal synaptic function. The authors note that these results must be interpreted carefully as the SNPs are rare.

Ege et al. conclude that there may exist different phenotypes of asthma that are susceptible to either genetic or environmental effects, but rarely to both at the same time. They propose that genotypes which are protective for one exposed population do not carry an effect in an unexposed population.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.

Advances in immunotherapy for allergies have increased safety and effectiveness

2011-01-06T12:40:00.000-08:00

Casale and Stokes take a look at new technologies and experimental therapies developed to improve on the standard approach of subcutaneous injection of increasing concentrations of allergens (SCIT) in this month’s issue (J Allergy Clin Immunol 2011;127:8-15). They discuss omalizumab add-on therapy to conventional SCIT and report on studies in which omalizumab was administered concurrently and prior to initiation of SCIT. Omalizumab plus SCIT showed significant reduction in allergic rhinitis symptoms, and less use of rescue medication compared to SCIT alone. When omalizumab was given as pre-treatment to SCIT, both allergic rhinitis and allergic asthma subjects had fewer severe reactions and more subjects were able to achieve target maintenance dose than subjects receiving placebo plus SCIT.

The authors continue with recent efforts to mobilize mitigating Th1 responses through Toll-like receptor (TLR) agonists and CpG immunostimulatory responses. Combined allergen and TLR therapy is reported to provide significant improvements in rhinitis symptoms and medication use in both adults and children. They also discuss effectiveness associated with bonding immunostimulatory CpG sequences with ragweed allergen to influence T cell responses toward Th1 dominance and reduced eosinophilia; however, clinical impact was minimal. Engineering the allergen and CpG sequences, as well as CpG sequences alone, into virus-like particles provided significantly greater improvements in symptoms and immunologic markers.

Casale and Stokes cover the use of T-cell derived peptides in the treatment of allergies including cat allergy and bee venom allergy. They describe increased benefit and safety of SCIT therapy with newer preparations of Fel d 1 peptides, and early impressive results with Api m 1 and phospholipase A2.

Different routes of administration are also reviewed by the authors such as intranasal and intrabronchial, focusing on escalating oral and sublingual (SLIT) therapies. They report encouraging results from oral desensitization/tolerance studies for subjects with food allergies, which included decreased inflammation markers, decreased specific IgE, increased specific IgG, and achievement of tolerance in a majority of subjects. Results from SLIT therapy trials have been positive as well. SLIT clinical trials for grass and ragweed allergies have shown efficacy in subjects with seasonal allergic rhinitis, and there are positive results noted for other allergens in seasonal allergic rhinitis and allergic asthma.

In conclusion, the authors comment that adjunct omalizumab therapy clearly improves safety and TLR agonists are more effective for shifting to Th1 response. They are optimistic about the future of immunotherapy, although they feel that with the rapid evolution in new technology and increased knowledge of the immune system, how immunotherapy will be used in the future will be substantially different than what is occurring today.

SARP reports differences in asthma genotypes & phenotypes are race-associated

2010-12-06T07:17:00.000-08:00

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

2010-12-06T07:15:00.000-08:00

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.

New definitions for severe asthma recommended to WHO

2010-11-03T22:19:00.000-07:00

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.

New evidence relates prebiotics to reduced occurrence of AD

2010-10-01T13:32:00.000-07:00

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

2010-10-01T13:30:00.000-07:00

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.

State of the science: Allergy and asthma genetics

2010-08-31T12:12:00.000-07:00

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

2010-08-31T12:09:00.000-07:00

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.

Nudging forward a new paradigm for food allergies

2010-07-30T14:15:00.000-07:00

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.

Guest post: A primer on human IgE antibody serology

2010-07-01T07:00:00.000-07:00

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.

Sincerely,
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.

References:
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

2010-07-01T06:59:00.000-07:00

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.

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.

Tracking peanut and tree nut allergy in the US

2010-06-01T07:25:00.000-07:00

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.

We want to hear from you. Please feel free to post your questions or comments below. All questions and comments will be forwarded to the authors for a response.

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

2010-06-01T07:21:00.000-07:00

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.

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.

Food allergy: An immunological picture of atopy development

2010-05-03T09:58:00.000-07:00

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: http://www.jacionline.org/article/S0091-6749(10)00430-6/fulltext.] 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

2010-05-03T09:56:00.000-07:00

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 http://www.jacionline.org/article/S0091-6749(10)00505-1/fulltext.] 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.

Administration of influenza vaccines to egg-allergic patients

2010-04-02T14:22:00.000-07:00

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.

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.

Stress and asthma

2010-03-08T11:56:00.000-08:00

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.

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.

Fungal exposure and inner-city children

2010-03-08T11:54:00.000-08:00

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.”

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.

Grading systemic reactions to immunotherapy

2010-03-08T11:47:00.000-08:00

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.”

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.

Genome-wide association studies

2010-02-10T07:02:00.000-08:00

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

2010-02-10T06:59:00.000-08:00

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.

Air cleaners and filters - A rostrum

2010-01-19T13:33:00.000-08:00

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.

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

2010-01-04T08:27:00.000-08:00

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.