Wednesday, December 28, 2011
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.
Thursday, December 1, 2011
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.
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.
Monday, October 31, 2011
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.
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.
Friday, September 30, 2011
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.
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.
Thursday, September 1, 2011
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.”
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.
Monday, August 1, 2011
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.
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.
Friday, July 1, 2011
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.
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.
Thursday, June 2, 2011
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.
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.
Friday, May 6, 2011
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.
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.
Tuesday, April 5, 2011
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.
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.
Friday, March 4, 2011
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.
Tuesday, February 1, 2011
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, FcRIIB, 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."
Monday, January 31, 2011
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.
Friday, January 7, 2011
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.
Thursday, January 6, 2011
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.