Introducing an environmental assessment and intervention program in inner-city schools

Few studies have comprehensively examined the role the school environment plays in asthma and how effectively changing the environment may reduce morbidity, when adjusting for exposures in the home. In their review, Huffaker and Phipatanakul summarize the importance and common challenges of school-based environmental assessment and intervention studies linked to health effects (J Allergy Clin Immunol 2014; 134: 1232-1237). They discuss the challenges and potential benefits of comprehensive environmental assessment and health outcomes in inner-city schools.

The school environment has been shown to be a significant reservoir for allergens and pollutants. Indoor allergens known to be important in urban home environments may also be important in schools, including cockroach, cat, dog, mouse, dust-mite, and molds. Studies have identified children with asthma in inner-cities have markedly higher levels of mouse allergen in their schools compared to levels in their individual bedrooms. Given the paucity of comprehensive data on school-based environmental interventions and health outcomes, successful home-based strategies currently serve as the model for school-based interventions. For example, practical interventions to reduce environmental exposures at home such as the use of air filtration systems and integrated pest management can be utilized in schools. 

Despite the challenges associated with implementing environmental interventions in schools, evidence supports the importance of school and classroom exposures and health outcomes. School-based interventions have the potential to reduce exposures for many symptomatic children, in contrast to the individual families impacted by home-based interventions. If effective, results from school-based interventional studies could inform public policy change, funding and initiatives. If it can be demonstrated that reduction of classroom-specific exposures leads to improved asthma outcomes, then findings can be translated into efficient and cost-effective strategies to benefit communities of children through improvement of the school environment, where children in America spend the majority of their day.

Establishing School-Centered Asthma Programs

Approximately 36,000 children miss school each day due to asthma which ultimately affects a child’s ability to learn. In fact, according to a U.S National Interview Survey, children with asthma missed three times more school and had a 1.7 times greater risk of having a learning disability compared to well children. Moreover, students attending schools with the highest proportions of low income students are more likely to miss school because of asthma. In their review article, Cicutto et al discuss how asthma and associated causal pathways can have interactive and synergistic effects that result in a complex situation that must be addressed collectively through a coordinated and partnered approach (J Allergy Clin Immunol 2014; 134: 1223-1230). School-centered interventions are thus directed at improving asthma control and reducing asthma-related absenteeism.

Asthma management at schools is important for pediatric pulmonologists and allergists, primary care providers and the whole interdisciplinary team working alongside them to provide quality asthma care. Several studies and systematic reviews demonstrate that students with asthma when supported through school-centered asthma care programs can have improvements in asthma knowledge, confidence in and actual practice of asthma management skills, regular use of preventive asthma medications, reduced school absenteeism, better school performance, and the use of urgent and emergent asthma care. Collectively, available research demonstrates that programs that either provide asthma care directly at-school and/or ensure adequate links between school, family and asthma care provider have achieved a reduction in asthma morbidity. The authors indicate that the synergy created by collaborative and coordinated efforts of schools and asthma care providers assists students and their families to achieve asthma control and reduce associated morbidity.

Future research is needed to determine the cost effectiveness of school-centered asthma programs and how to sustain program implementation once research funding no longer exists. Nonetheless, community asthma care providers are essential to successful asthma management across home and school settings.

Question for the authors:

You emphasize that clinicians must be advocates for appropriate services within inner city schools. What approaches can you suggest clinicians utilize to educate local school administrators?

Schools, especially inner city schools, are very limited in resources that they can devote to health care. Therefore, clinicians can provide a valuable service by partnering with schools in varying ways. The first step would be for the clinician to set up a dialogue with the school nurse that is responsible for a high proportion of the children in their practice.

A multitude of things can be done once this step is taken. First, an understanding of the challenges the nurse faces in delivering medications in school would be a start to the conversation. Many school action plans are not provided to the school nurse and many are not written for the school nurse. Also, availability of and access to rescue medications at school can be a challenge. A dialogue between the school nurse and clinician can help resolve these problems at the core level. Next, steps could be taken to assist the school nurse with education of school staff around medication administration and recognizing symptoms of asthma. The rest will depend on the clinician’s time and interest in improving asthma care in the school setting and developing a sense of community engagement.

Once you do get involved, it is a very rewarding experience. The school nurses really appreciate it, and the clinician will understand the challenges in managing care in the real world setting.

Environmental impacts on immune responses in atopy and asthma

Despite the improvement of air quality in the U.S. since the enhancement of the Clean Air Act in 1990, exposures to outdoor and indoor air pollution remain a significant risk factor for both the development of asthma and the triggering of asthma symptoms.   Clinical studies have shown that significant asthma exacerbations were attributable to air pollution exposure, as a result of living in densely populated cities with elevated ambient fine particulate matter (PM_2.5) and ozone (O₃). In their review, Miller and Peden highlight new data on the effects of pollutant exposure on the innate and adaptive immune responses, genetic and epigenetic modifiers of response to pollutants, and potential interventions to mitigate these effects (J Allergy Clin Immunol 2014; 134(5): 1001-1008).

Several studies have determined that the effects of air pollution are heightened during the prenatal period.  This suggests that there is greater vulnerability of the growing lungs and the developing immune system, thus predisposing towards more airway inflammation later in life.  Similarly, studies suggest that factors such as chronic low-grade inflammation associated with obesity and stress may predispose towards asthma. Furthermore, the authors describe evidence that the mechanism behind these effects alter the innate and adaptive immunity, inducing a heightened immune response. Another emerging area of investigation is the effects of the environment on oxidative stress genes such as glutathione S-transferase (GST) genes as well as genes associated with Toll-like receptors of the innate immune system. Newer mechanistic lines of investigation focus on epigenetic regulation, and identifying asthma genes whose imprinting may be disrupted by environmental exposures.

Pollutant induced asthma exacerbations are less frequent in patients that use inhaled corticosteroids, suggestive that interventions that target acute inflammatory responses are beneficial, however future studies are required to test the efficacy of interventions in this population. Actively minimizing both indoor and outdoor pollutants and government air care regulations could decrease pollutant impacts on allergic lung disease.

Question for the authors:

How has the improved air quality over recent decades relate to the incidence of pollution related asthma exacerbations? 

In studies of both the Atlanta and Beijing Olympic Games, interventions that decreased automotive and point-source combustion were associated with decreased asthma morbidity. Future studies are needed to investigate more thoroughly whether improvements in air quality contribute to fewer asthma exacerbations.   This remains a difficult challenge to show as even the best designed epidemiological studies are unable to prove causality.

Stress and asthma: novel insights on genetic, epigenetic and immunologic mechanisms

In the U.S., ethnic minorities and the economically disadvantaged are disproportionately exposed to chronic psychological stressors such as poverty, discrimination and violence. Recent findings support a causal link between exposure to these stressors at the individual or community level and asthma morbidity. Moreover, current evidence suggests that the relation between stress and asthma is complex and partially mediated or modified by environmental exposures, adherence with treatment, co-morbidities and coping mechanisms.

In a review article, Rosenberg et al discuss recent findings suggesting potential biologic mechanisms for stress-related asthma, including changes in the methylation and expression of genes that regulate behavioral, autonomic, neuroendocrine, and immunologic responses to stress (J Allergy Clin Immunol 2014; 134(5): 1009-1015). For example, there may be susceptibility genes that predispose chronically stressed youth to both post-traumatic stress disorder and asthma. Moreover, recent studies show that low socioeconomic status in early life may program sustained resistance to glucocorticoid signaling, which could undermine the efficacy of steroid therapy in subjects who develop asthma.

The authors emphasize that the development of novel indicators or biomarkers of chronic stress is imperative, given that current stress measures cannot be used in young children or are difficult to implement in large studies. In addition, adequate phenotypic assessment of asthma, accounting for mediators and modifiers of the effects of stress on asthma, and studying the role of stress on treatment responses in vivo are key elements of future longitudinal studies of stress and asthma. Ultimately, further mechanistic insights on stress-related asthma should improve the prevention and treatment of asthma, particularly in vulnerable populations. 

Effect of environmental peanut exposure in children with filaggrin loss-of-function mutations

In the October 2014 issue of Journal of Allergy and Clinical Immunology, Brough et al show that early environmental peanut exposure from house dust increases the risk of peanut allergy in children with impaired skin barrier. Children were assessed for peanut allergy and had genetic studies to determine whether they could produce normal filaggrin levels. Dust samples were collected and analyzed for peanut concentration to determine in which groups of children environmental peanut exposure influenced the development of peanut allergy. In normal children environmental peanut exposure did not influence the development of peanut allergy. In contrast, in filaggrin deficient children the risk of peanut allergy increased as peanut concentration in the house dust increased. To read the full article, please click here: http://bit.ly/1qkfHeY

Standardizing the assessment of clinical signs of atopic eczema

Atopic eczema (AE, syn. atopic dermatitis) is a major medical condition that causes substantial burden to patients, their families, and society. Various different interventions exist, many of which have been assessed in randomized controlled trials (RCTs). However, there is a lack of core outcome sets for atopic eczema (AE) which is a major obstacle for advancing evidence-based treatment.  There are several different instruments identified to assess clinical signs of AE and the global Harmonizing Outcome Measures for Eczema (HOME) initiative has already defined clinical signs, symptoms, quality of life, and long-term control of flares as core outcome domains for AE-trials. To resolve the current lack of standardization of the assessment of clinical signs of AE, the HOME initiative followed a structured process of systematic reviews and international consensus sessions to identify one core outcome measurement instrument to assess clinical signs in all future AE-trials (J Allergy Clin Immunol 2014; 134(4): 800-807).

The authors determined that from 16 different instruments identified to assess clinical signs of AE, only the Eczema Area and Severity Index (EASI) and the objective Scoring Atopic Dermatitis Index (objective SCORAD) were identified as sufficiently tested for inclusion in the core outcome set. The EASI has adequate validity, responsiveness, internal consistency, and intra-observer reliability. The objective SCORAD has adequate validity, responsiveness, and inter-observer reliability, but unclear intra-observer reliability to measure clinical signs of AE. In an international consensus study, patients, physicians, nurses, methodologists, and pharmaceutical industry representatives agreed that EASI is the preferred core instrument to measure clinical signs in all future AE-trials. The EASI was chosen as the core outcome measure for clinical trials because (1) it only includes the 4 essential signs, (2) assesses the severity of AE signs at multiple body sites, rather than at a single representative site for each sign, and (3) gives the extent of AE lesions sufficient weighting.

The HOME initiative recommends that all investigators, pharmaceutical industry, and regulatory authorities observe this consensus and include the EASI in all future atopic eczema trials to enable improved evidence-based decision making and scientific communication in the future. This does not preclude the use of other scales in trials (such as SCORAD) in addition to the core outcome measure. Better training materials for use of EASI are in preparation and will be freely available via the HOME website (www.homeforeczema.org). Furthermore, the process of standardization and selection of measurement instruments for the assessment of the other core outcome domains of AE, i.e. symptoms such as pruritus and sleeping problems, quality of life and long-term control of flares, is currently underway.

Complexities of atopic dermatitis

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and often precedes the development of food allergy and asthma.  The defective skin barrier in AD is thought to allow the absorption of allergens through the skin.  This promotes systemic allergen sensitization, contributing to the development of food allergy and asthma, as well as skin infections such as Staphylococcus aureus and herpes simplex virus (HSV).  This month’s JACI focuses on the importance of both genetic and acquired causes of epithelial skin barrier dysfunction in driving the natural history of AD. In their review, Donald Leung and Emma Guttman-Yassky summarize current insights into AD that may lead to new treatment approaches, including several articles published in this month’s journal (J Allergy Clin Immunol 2014; 134(4): 769-779).

The causes of AD are complex and driven by a combination of genetic, environmental and immunologic factors which likely account for heterogeneity of AD onset, severity and natural history of the disease. While there is currently no cure for AD, recent studies suggest prevention of AD can be achieved by early interventions that protect the skin barrier such as emollients and topical anti-inflammatory treatments. Importantly, the control of lesional AD may improve long term outcomes not only in AD, but in allergic diseases of the gastrointestinal and respiratory tracts as well, due to the reduction of associated allergen sensitization.

Although current treatment options for AD are limited, the authors explain that in addition to Th2 antagonists (i.e. the anti IL-4R drug dupilumab), determining the key role of TSLP-receptor signaling and IL-22 that involve clinical trials with agents that target TSLP, Th22, and TH17/IL-23 will be of interest. Furthermore, the selection of therapeutics for patients with differing degrees of disease severity and /or phenotypes should be guided by defining the extent of activation in the skin and blood. For example, anti IL-23/IL-17 might provide beneficial responses particularly in intrinsic AD patients. The individual contributions of the TH22, Th17, and Th2 immune pathways to the disease phenotype will be clarified through clinical trials coupled with mechanistic studies that are currently in progress. This comprehensive review highlights the importance of translational medicine, from animal models to clinical trials, and how this approach is advancing AD research.

Questions for the authors:

Recently, both basic science and clinical research have provided novel insights into the prevention, identification, and treatment options for AD. Do you anticipate these findings to improve outcomes for not only AD but other allergic diseases as well?

Yes, because the principle underlying causation of allergic diseases likely have in common a defective epithelial barrier and abberant immune response.  This is modulated by different resident cells in each organ.

AD is most often a first step in a series of atopic diseases in the Atopic March that often leads to rhinitis, food allergy, and asthma. Could removing the first step in the Atopic March reduce the global burden of atopic disease? 

Possibly.  The studies in the current issue of JACI support the concept that skin barrier dysfunction enhances sensitization via environmental allergen exposure. A natural progression of this concept would be to correct the skin barrier defect to determine whether elimination of AD could prevent food allergy, asthma and allergic rhinitis.

Allergens and the airway epithelium response: Gateway to allergic sensitization

Allergic sensitization to inhaled antigens is increasingly common; however, the mechanisms remain poorly understood. Lung epithelial cells, once thought to be merely a passive barrier impeding allergen penetrance, have recently been shown to recognize allergens via expression of pattern recognition receptors (PRRs) and mount an innate immune response driven by the activation of the cytokine NF-кB. In their review, Lambrecht and Hammad discuss recent findings that describe epithelial cells as crucial in allergy inhalation outcomes (J Allergy Clin Immunol 2014; 134(3): 499-507).

Traditionally, allergic asthma has been characterized as a disease of the adaptive immune system, whereby lymphocytes overreact to harmless antigens and mount a type 2 immune response, subsequently causing the activation of effector cells like mast cells, basophils and eosinophils. Recently, research has been changing this view to accommodate the concept that cells of the innate immune system contribute significantly to disease pathogenesis, by recognizing allergens and providing an early warning system of cytokine production and danger signals.  The authors discuss the innate immune functions of barrier epithelial cells (AECs) of the airways as they respond to inhaled allergens in mouse models. Specifically, that AECs sense the presence of allergens and relay this information to airway dendritic cells (DCs), which are the most proficient antigen presenting cells of the lung that translate information received by epithelial cells which ultimately signals the T and B lymphocytes of the adaptive immune system.  In response to allergen recognition, AECs also orchestrate the early recruitment and activation of type 2 innate lymphocytes (ILC2s), using the same activation signals that also activate DCs. In turn, this activation leads to the production of type 2 cytokines and thus the adaptive immune response.

Although it is now clear how AECs are activated to ultimately recruit and activate DCs leading to Th2 immunity in mouse models in response to allergen, it is unclear if this scheme is reproduced in humans, or if it is true for all allergens. The authors explain that we are only beginning to understand how genetics and environment influence the epithelia-DC crosstalk that leads to allergy and further research will expand how the AEC/DC/ILC2 interaction bridges innate and adaptive immunity at the origin of the allergic sensitization process.

Epithelial barrier function: at the frontline of asthma immunology and allergic airway inflammation

Airway epithelial cells are an important part of the innate immune system in the lung. Not only do they establish mucociliary clearance, epithelial cells produce anti-microbial peptides, chemokines, and cytokines that recruit and activate other cell types and promote pathogen clearance. Recent studies emphasize the importance of epithelial derived cytokines in the promotion of Th2 immune responses, at least in part by conditioning local dendritic cells (DCs). Epithelial cells also from a barrier to the outside world comprised of airway surface liquids, mucus, and apical junctional complexes (AJC) that form between neighboring cells. In their recent review, Georas and Rezaee discuss why defective epithelial barrier function may be linked to Th2 polarization in asthma, and propose a rheostat model of barrier dysfunction that implicates the size of inhaled allergen particles as an important factor influencing adaptive immunity (J Allergy Clin Immunol 2014; 134(3): 509-520). 

Increasing evidence indicates that defective epithelial barrier function is a feature of airway inflammation in asthma. A challenge in this area is that barrier function and junctional integrity are difficult to study in the intact lung, but innovative approaches are providing new knowledge in this area. The authors review the structure and function of epithelial apical junctional complexes, emphasizing how regulation of the epithelial barrier impacts innate and adaptive immunity. They propose that epithelial barrier dysfunction is not “all or none”, but rather a graded phenomenon with consequences for allergen uptake and processing that may impact subsequent adaptive immune responses. For example, inducible barrier dysfunction caused by environmental exposures can vary in severity and will affect the penetration of fate of inhaled particles, depending on their size and other physical characteristics. While inhaled allergens alone may be capable of promoting transient barrier disruption, sustained dysfunction is more likely to follow inhalation of toxic air pollutants and respiratory viral infections. In fact, inducible barrier dysfunction is a strategy used by viruses to promote their replication, but likely represents a risk factor for allergen sensitization. 

This review goes into great detail about the complexity of the epithelial barrier function and how it relates to the involvement of allergic diseases of the airway. The understanding of the basic structure and function of apical junctional complexes is necessary to determine the mechanisms involved in allergic disease, as is the understanding of epithelial permeability which is a hallmark of mucosal inflammation. Future studies of the mechanisms and consequences of airway epithelial barrier dysfunction in asthma should enhance our understanding of asthma heterogeneity as well as the pathogenesis of allergic diseases. 

Questions for the authors: The importance of the epithelial barrier function is relatively new to the study of allergic diseases. What do you think are likely implications of these findings in regards to prevention of allergic diseases? For example, does research suggest that barrier dysfunction could be prevented, thus preventing the cascade of events that causes allergy?

This is a very important question in an area where we need more research.  For example, we do not know the relationship between airway epithelial barrier dysfunction and whether this precedes sensitization to aeroallergens.  Emerging data indicate that alterations in lung development either in utero or early in life are a risk factor for asthma, and may even precede allergic inflammation.  It will be interesting to determine whether altered epithelial barrier integrity is a feature of these alterations in lung development, which will require non-invasive assays that are safe in infants.  Although certain therapeutic agents have been shown to have barrier protective / restorative effects on epithelial monolayers in vitro, we have limited understanding of how most commonly used therapies affect airway epithelial integrity and tight junction expression / function in vivo.  This is another area that is ripe for future research.

Risks for infection in patients with asthma (or other atopic conditions): is asthma more than a chronic airway disease?

There is evidence that the presence of asthma can influence patients’ susceptibility to infections, yet research in this aspect of asthma has been limited. Additionally, there is a debate in the field with current literature tending to suggest an increased risk of infection among atopic patients as due to opportunistic infections secondary to airway inflammation, especially in severe atopic diseases. Other evidence suggests that such risk and its underlying immune dysfunction may be a phenotypic or clinical feature of atopic conditions. In his review, Young J. Juhn argues that improved understanding of the effects of atopic conditions on the risk of microbial infections will bring important new perspectives to clinical practice, research, and public health concerning atopic conditions [J Allergy Clin Immunol 2014; 134(2): 247-57].

The review focuses on the effect of atopic conditions on the risk of infections, termed reverse causality. For example, asthma is associated with a broad range of common and serious viral and bacterial respiratory tract infections controlled by different types of immunity (e.g. Th1 or Th2). However, given the association of atopic dermatitis and allergic rhinitis with risks of such infections, the results may imply that immunologic dysfunctions might have a role, while the structural alterations of airways observed in asthma may also need to be taken into account. Furthermore, research suggests that the effects of asthma on risk of infection may not be limited to the airways but go beyond the airways, for example, patients with asthma have an increased risk of contracting various types of herpes viruses.

 As effects of atopic conditions on the risks of various infectious diseases emerge, it will be increasingly necessary to address a broader range of patient care issues in the current guidelines. Also, the roles of allergists, immunologists, and pulmonologists may be broader in the future. This review provides insight into the foreseeable needs and challenges of the effects of atopic conditions.

Gene hunting in the genomic era: approaches to diagnostic dilemmas in primary immunodeficiencies

Over the past four decades, over 180 molecular defects causing primary immunodeficiencies (PIDs) have been discovered through advances in immunology and genetics. Recent studies have identified ways to solve difficult cases such as diseases with autosomal dominant inheritance, incomplete penetrance, or mutations in non-coding regions. In their review, Platt et al focus on selected causes to illustrate a spectrum of approaches for identifying causative mutations [J Allergy Clin Immunol 2014; 134(2): 262-68].  They broadly classified these approaches into 3 different strategies: 1) educated guesses based on known signaling pathways essential for immune cell development and function, 2) similarity of clinical phenotypes to mouse models, and 3) unbiased genetic approaches. They also address methods of overcoming challenges in identifying molecular causes of PIDS.

Since the majority of PIDs are monogenic, whole exome/genome sequencing has expedited the discovery of pathogenic mutations, particularly when combined with classical methods of identifying genetic defects. Recently, an unbiased approach to sequencing called next generation sequencing (NGS) has revolutionized genetics by making it possible to sequence entire human genomes within days. Although this technology offers comprehensive sequencing data, it is challenging to distinguish pathogenic variants within the 3.2 billion bases present in the human genome. NGS and other methods have greatly expedited the discovery of pathogenic mutations; however, there are still limitations.

Advances in immunology and genetics have facilitated the discovery of novel defects underlying PIDs. However, the authors explain that there is still much progress to be made despite what is already known. Epigenetic modifications regulating gene expression, such as DNA methylation, histone modifications, and non-coding RNAs, modulate the immune system and defects in these mechanisms may contribute to PIDs. Furthermore, the use of NGS can be used to investigate the transcriptome to detect disease-causing splice variants leading to exon skipping, alternative splicing, and alternative start and polyadenylation sites. These advances can benefit patients in that the identification of the defects underlying PID enables genetic counseling and pre-implantation diagnosis. The authors conclude that pinpointing these genetic defects is the foundation for the development of gene therapy as a cure.

Progress in HIV-1 Vaccine Development

Advances in HIV vaccine development have been hampered by roadblocks associated with failure to prevent infection. In recent years, a number of basic and translational science advances have shown promise in the development for an effective vaccine. In their review, Haynes and colleagues summarize these advances along with the roadblocks that still remain, as well as the most promising approaches to successful vaccine design (J Allergy Clin Immunol 2014, 134(1): 3-10). 

This year, the field of HIV-vaccine research had a major disappointment in the announcement of the lack of a vaccine efficacy seen in a DNA prime, recombinant adenovirus type 5 (rAd5) boost HIV-1 vaccine trial developed by the NIH Vaccine Research Center. The vaccine was designed to test the hypothesis that high levels of CD8+ cytotoxic T cells (CTLs) could either protect against transmission or lead to control of plasma HIV-1 viral load. The second failed trial, the Merck recombinant adenovirus type 5 trail, not only lacked vaccine efficacy, but also appeared to enhance infection in those vaccines seropositive for Ad5. Although these 2 trials were of great disappointment, they provided valuable information on the types of immune responses that are unlikely to be protective.

New advances have demonstrated a variety of promising results such as the discovery of new envelope (Env) targets of potentially protective antibodies. A recent study shows promise with the finding that CD8+ T cells are associated with control and eradication of early retrovirus infections in rhesus macaques. Another recent study shows that the development of immunogens to overcome HIV-1 T cell epitope diversity while another study identifies correlates of transmission risk in an HIV-1 efficacy trail. And finally, a recent advancement has mapped the co-evolution of HIV-1 founder Env mutants in infected individuals who develop broad neutralizing antibodies (bnAbs), thereby defining bnAb developmental pathways.

Despite these advances, the field is still years away from deployment of an effective vaccine. Moving forward in HIV-1 vaccine research requires the conversion of subdominant immune responses into dominant ones, which has yet to be accomplished by an infectious disease vaccine. HIV-1 vaccine research is breaking promising new ground in vaccinology, and success in its development will herald success for other difficult vaccines such as influenza and hepatitis C. 

Prenatal exposure to diesel exhaust induces asthma susceptibility through NK cell priming

Asthma often begins early in life and is attributed to more than just genetic factors, because the prevalence continues to rise. Epidemiological studies have indicated roles for prenatal and early childhood exposures, including exposure to diesel exhaust, however, little is known about the mechanisms involved. To elucidate this, Manners et al developed a mouse model of asthma susceptibility through prenatal exposure to diesel exhaust (J Allergy Clin Immunol 2014; 134(1): 63-72).

In this model, pregnant mice were repeatedly exposed to diesel exhaust particles (DEPs). Offspring were immunized and challenged with ovalbumin (OVA) or exposed to PBS (control) then examined for features of asthma. Compared to controls, offspring that were exposed to DEP were hypersensitive to OVA, indicated by airway hyperresponsiveness, elevated serum levels of OVA-specific IgE, and elevated levels of pulmonary and systemic T-helper type 2 (Th2) and Th17 cytokines. The authors determined that natural killer (NK) cells were the primary source of cytokine production and airway inflammation was diminished by antibody-mediated depletion of NK cells. Furthermore, asthma susceptibility was associated with increased transcription of genes known to be specifically regulated by the aryl hydrocarbon receptor (AhR) and oxidative stress.

These results coincide with previous data that suggests NK cells initiate allergic inflammation. AhR is expressed in NK cells which may provide a link between maternal exposure to diesel exhaust and asthma in offspring. Taken together, this data provides mechanistic insight into the process of prenatally-induced asthma susceptibility. 

The effects of calcitriol treatment in glucocorticoid resistant asthma

The current and most effective treatment for asthma therapy is the use of glucocorticoids by improving the clinical features and airway inflammation associated with asthma. However, a cohort of well-defined asthma patients exists in whom high-dose glucocorticoid treatment is not only clinically ineffective, but potentially detrimental.  Several mechanisms have been proposed to contribute to glucocorticoid resistance, including vitamin D insufficiency. Nanzer et al recently published data that glucocorticoid resistant patients fail to synthesize the anti-inflammatory cytokine interleukin-10 (IL-10) in response to glucocorticoid in vitro compared to glucocorticoid sensitive patients (J Allergy Clin Immunol 2014; 133(6): 1755-1757). When resistant patients ingested a form of vitamin D called calcitriol (1,25-dihydroxyvitamin D3) in combination with glucocorticoid, levels of IL-10 were restored in vivo and ex-vivo. Taken together, these data along with epidemiological evidence linking vitamin D insufficiency/deficiency with poor clinical response to asthma treatment provided the rationale for the authors to perform a proof-of-concept clinical trial.

A small group of glucocorticoid resistant severe asthmatics were chosen and placed on a 2-week course of oral prednisolone and then randomly assigned placebo or 0.25ug calcitriol twice daily for 4 weeks. During the last 2 weeks patients repeated a course of oral prednisolone. The authors hypothesized that the concomitant calcitriol therapy would improve clinical glucocorticoid responsiveness in these patients. They did not expect the short course of calcitriol to restore Vitamin D sufficiency, but to address the short-term effects of calcitriol itself.

A within group comparison showing the change in lung function during the initial screening in response to 2-weeks oral prednisolone versus the response to an identical course of prednisolone plus either placebo or calcitriol, revealed a modest but significant improvement in absolute and predicted FEV₁ within the calcitriol but not the placebo arm. Furthermore, a trend for a positive correlation between baseline serum Vitamin D concentrations and change in predicted lung function following prednisolone was observed in placebo patients. This data suggests that treatment with a short course of calcitriol may improve the clinical glucocorticoid responsiveness in asthma, including patients classified as clinically glucocorticoid resistant. While larger studies with clinically well-defined cohorts are warranted, these results are very encouraging for the treatment of glucocorticoid resistant asthma. 

Mechanisms underlying the neuronal based symptoms of allergy

People with allergies often present with symptoms that are the result of alterations in the nervous system in the organ in which the reaction occurs. Common neuronal symptoms include itchy eyes, sneezing, nasal congestion, rhinorrhea, cough, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. Mediators released during an allergic reaction interact with sensory nerves, altering the transmission of signals in the sympathetic and parasympathetic autonomic nerves. Undem and Taylor-Clark describe how the nervous system itself is altered in allergic disease either due to events occurring during critical periods of neuronal development or to persistent nerve stimulation (J Allergy Clin Immunol 2014; 133(6): 1521-1534).

Those that suffer from allergic rhinitis for example, more often react strongly by sneezing when stimulants are applied to the nasal mucosa compared to healthy controls. Considering sneezing is a parasympathetic reflex, it is not surprising that these allergic individuals are often more likely to have nasal allergic symptoms when exposed to smoke, irritants, and cold air.  Similarly, in response to food allergy, immunological activation of mast cells in the gut is associated with alterations in neurotransmission. The authors detail the basic mechanisms of allergen-induced neuromodulation, highlighting the molecular interactions and phenotypic changes that occur. 

The authors emphasize that not only those with allergy produce neuroactive mediators at sites of allergic inflammation, but that the nervous system itself is altered in allergic diseases. Whether this is due to events occurring during critical periods of neuronal development or to persistent nerve activation, the nervous system is rendered hyperactive. As the understanding of basic mechanisms continue to evolve, new therapeutic strategies that target the nervous system will continue to emerge that work synergistically with anti-inflammatory treatments that allow for new, more powerful therapeutic options for allergy sufferers.

Potential food allergens in medications

Excipients are all of the substances found in pharmaceuticals that are added to the active ingredient to provide a benefit in manufacturing, stability, bioavailability, or patient acceptability.  Some excipients are foods or substances derived from foods.  Food allergic patients may rarely have reactions to these products. In his review, John M. Kelso, MD details which food-derived substances are used as pharmaceutical excipients and in which medications. Furthermore, the safety of administration of these medications in food allergic patients is also discussed (J Allergy Clin Immunol 2014; 133(6): 1509-1518). 

Food allergens are proteins that can generate IgE-mediated responses in food-allergic individuals. Since some food-derived excipients in medications are proteins, there is potential for an allergic response.  However, in most cases there is not enough of the food protein present to cause a reaction even in an allergic individual.  For example, most influenza vaccines are grown in eggs,  however there are only trace amounts of the protein in the vaccines and they are considered safe in egg-allergic recipients.  Other vaccines, however, contain substantial quantities of gelatin and do pose a risk of an allergic reaction in those with gelatin allergy.  Other excipients are derived from foods but do not contain protein, thus fish-allergic patients need not avoid fish oil for example.  In some cases, a food-derived excipient such as lactose may be contaminated with milk protein accidentally.

Although food-derived excipients may contain food proteins, reactions are generally quite rare likely because protein amounts are too low to elicit a reaction. If there is a reaction to a medication, it may be from a specific lot that was accidentally contaminated with food protein. However, if a reaction occurs, allergy to the food component should be investigated as a possible cause.

Effects of antioxidants on asthma

While the prevalence of asthma and allergic diseases continues to rise, the consumption of dietary antioxidants is decreasing around the world.  The western diet is becoming more popular around the world even though it is characterized by a reduction of fresh fruits and vegetables with an increase of processed foods and antioxidant enriched foods. As pulmonary and systemic oxidative stress increase allergic inflammation, dietary or supplemental antioxidants have been proposed to counteract the incidence and morbidity of allergic disease.  Moreno-Macias and Romieu summarize various studies associated with the effects of antioxidants on asthma and allergic diseases (J Allergy Clin Immunol 2014; 133(5): 1237-44).

Meta-analyses of epidemiologic studies of variable quality suggest associations of low dietary intake of antioxidants and increased asthma and allergy. Compared to asthma, few trials have looked at associations between diet and atopic dermatitis, allergic rhinitis, or IgE levels.  Large trials of antioxidant supplementation to prevent cancer suggest an increased mortality with supplementation at least in populations with sufficient dietary intake of antioxidants.  High levels of antioxidants are found in the Mediterranean diet which is associated with a decrease in asthma and allergic disease suggesting high levels of antioxidants in the diet are beneficial. However, antioxidant supplementation may be protective under certain conditions where vulnerable populations have a deficiency in dietary antioxidants and/or are exposed to environmental oxidants. 

The authors explain that while appropriate levels of antioxidants are necessary to eliminate oxidants, the source of the antioxidant intake may be crucial when counteracting oxidative stress. Taken together, these data highlight the importance of antioxidant effects in asthma and allergic diseases and that future studies should focus on the source of antioxidant intake.

Question for the authors:  The source of antioxidants is likely relevant in other inflammatory conditions similar to the cancer study. Being that this sheds more light on the quality of the Western diet, what types of future research do you foresee coming from such important information?

We think that dietary interventions based on food exchange may be useful.  In addition, although following people over time implies big efforts in terms of money and human resources,  it is necessary to understand the disease dynamic taking into account variables that may change over time such as antioxidant intake and life styles. The use of biomarkers instead of surrounding variables would be more informative. Since the source of the antioxidant diet is relevant, this variable should be included as well.  Moreover, since we are in the genomic era, epigenetic,  nutrigenomic and toxicogenomic analyses  will be incorporating relevant information.

Peanut, milk and wheat intake during pregnancy is associated with reduced allergy and asthma in children

The relationship between maternal diet and childhood allergy and asthma is controversial.  Not long ago, the American Academy of Pediatrics advised that maternal dietary restrictions are not necessary with the possible exception of excluding peanuts.  Subsequent systematic reviews concluded that the evidence was inadequate to support any dietary restrictions during pregnancy. In fact, recent research suggests that fetal exposure to common food allergens may be beneficial. Bunyavanich et al examined the associations between maternal intake of common childhood food allergens during pregnancy and childhood asthma and allergies (J Allergy Clin Immunol 2014; 133(5): 1373-1382).

 

The authors studied a healthy pre-birth cohort of 1277 mother-child pairs from the United States and used food frequency questionnaires administered during pregnancy. Children were assessed for food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum specific IgE levels at a mean age of 7.9 years. They discovered that higher maternal peanut intake during the first trimester was associated with 47% reduced odds of peanut allergic reaction. Higher milk intake during the first trimester was associated with reduced asthma and allergic rhinitis, while higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis. The authors discuss that the first trimester is a formative period of fetal immune development and the mother’s diet may influence helper T cell differentiation as well as fetal airway differentiation. 

The results of this study do not support avoidance of specific foods during pregnancy to prevent allergy and asthma in children.  The authors conclude that the inclusion of peanut, milk, and wheat during pregnancy could be beneficial for the prevention of allergic diseases.

Exposure to food allergens through inflamed skin promotes intestinal food allergy via the TSLP-basophil axis

Along with all allergic diseases, the prevalence of food allergies has increased markedly in recent decades in industrialized nations. An estimated 5% of children and up to 4% of adults are living with food allergy and the fear of having a life threatening allergic reaction. Incidentally, atopic dermatitis (AD) is a known risk factor for developing food allergies later in life. However, the mechanisms through which antigen sensitization in the skin can predispose to allergic inflammation in the intestine remain unclear. Considering AD skin lesions are associated with elevated thymic stromal lymphopoietin (TSLP) expression and basophil infiltration, Noti et al determined that TSLP-elicited basophils promote antigen-induced intestinal food allergy (J Allergy Clin Immunol 2014; 133(5): 1390-99).

 The authors employed a new model of food allergy by sensitizing mice to food antigens on an AD-like skin lesion that predisposed to allergic inflammation in the intestine upon oral antigen feeding. Oral antigen exposure of skin-sensitized mice resulted in antigen specific IgE responses, type-2 inflammation and the accumulation of mast cells in the intestine. In addition to intestinal food allergy, mice also developed eosinophilic esophagitis (EoE)-like disease, a food allergy related disorder. They determined that antigen-induced food allergy is dependent on TSLP that elicits basophils to promote antigen-specific Th2 cytokine responses. Furthermore, the authors demonstrate that TSLP-elicited basophils are both necessary and sufficient to promote IgE-mediated intestinal food allergy in their model.

Despite the challenges associated with mouse models, Noti and colleagues have provided significant insight into mechanisms that mediate food allergy by using  a novel animal model that mimics some characteristics of human disease.  Targeting the TSLP-basophil axis may offer a novel therapeutic approach to treatment and prevention of food allergy.  

Innate lymphoid cells and asthma

The recent discovery of innate lymphoid cells (ILCs) has changed our understanding of immune regulation and uncovers the importance of innate immunity in the development of asthma. Historically, asthma was thought to be a Th2 mediated disease of the adaptive immune system but it has recently become clear that there are several different phenotypes of asthma some of which are non-allergic. In their review, Yu et al discuss the various roles of ILCs in the immune system specific to different asthma phenotypes and other allergic diseases (J Allergy Clin Immunol 2014; 133(4): 943-950).

ILCs are lymphocytes that produce a variety of cytokines similar to CD4+ T cells, but are antigen non-specific, which allows them to function independently of adaptive immunity.  The authors explain that ILC1s are similar to Th1 cells and have been shown to inhibit eosinophilic airway inflammation by promoting eosinophil apoptosis. Several studies show the likeness of ILC2s to Th2 cells in that they produce Th2 cytokines IL-4, IL-5, and IL-13.  ILC2s are found in the lungs of mice and humans with airway hyper responsiveness (AHR) and in the skin of atopic dermatitis patients. Similar to Th17 cells, ILC3s producing IL-17 have been found in the lung of some asthma patients and in the gut of colitis patients, and have been proposed to be implicated in obesity induced asthma, based on studies in mice. 

The authors conclude that at least two of the three types of ILCs are likely to be involved in human asthma, and in regulating both inflammation and homeostasis. The discovery of ILCs also suggests that innate immunity profoundly shapes allergic disease, in the presence or absence of adaptive immunity. For example, while the markers of ILC2s are not fully understood, the ability of ILC2s to interact with other Th2 associated cell types involved in allergy shows promise for asthma research that may lead to improved therapies.

Question for the authors:

Could you elaborate further on how ILCs managed to elude scientists for so long?  

ILCs eluded scientists in the past because they do not express cell surface markers associated with adaptive lymphocytes (e.g., T cells and B cells).  In our zeal to understand adaptive lymphocytes, we gated out other lymphocytes (including ILCs) during flow cytometric analyses.  In effect, we “threw out the baby with the bath water.”

Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts

Live vaccines and the growing neglect of adherence to routine immunizations can be life-threatening to immunodeficient patients.  This prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on the literature and the collective experience of the committee members. Shearer et al describe the relative risk for a child with severe immunodeficiency from close-contact spread of infectious diseases that are vaccine-preventable or from the shedding of live virus or bacteria from individuals who have received a live vaccine (J Allergy Clin Immunol 2014; 133(4): 961-966).  

The risk of acquiring an infection is well known to immediate family members of an immunodeficient child. However, relatives and non-family members who have not been vaccinated or have been vaccinated with live virus or bacteria pose a serious threat to these patients. Complacency is prevalent in society regarding pertussis, measles, mumps, and rubella vaccines. For example, the threat of pertussis to the pediatric population is alarming, especially for immunodeficient patients. This rise of preventable disease is associated with loss of the herd immunity in the general population along with parents avoiding vaccines out of fear of autism despite overwhelming evidence to the contrary. The immunosuppressed subject is at most risk of contracting these infections in crowded living conditions due to the ease of spread of disease by aerosol or oral-fecal route.  While avoidance of these diseases is ideal, the parent of an immunodeficient child must maintain a balance with the needs of a child to develop socially and educationally.

Vaccination for common infections represents a major advancement in the battle of communicable disease that threatens the welfare of humankind, especially the pediatric population. However, the alarming rise of non-immunized individuals could lead to a return of avoidable global epidemics.  Close contact with individuals recently vaccinated with live vaccines may cause the spread of infection to an immunodeficient child.  Shearer et al stress the importance of herd immunity, avoidance of live vaccines, and balancing the needs of this fragile population.

Questions for the authors:

What are the political implications of these findings?

There is no political agenda for those who have vaccine immunizations, only evidence-based science.

Could federal law mandate that all children and adults receive appropriate vaccinations?

That is most unlikely to happen.