TSLP, asthma heterogeneity, and human nuocytes

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

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

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

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?

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

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.

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.