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.

Refining the phenotypes and diagnosis of chronic sinusitis

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

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

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

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

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

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.