Efficacy of baked milk oral immunotherapy in baked milk-reactive allergic patients

Oral immunotherapy (OIT) has shown overall benefit in desensitizing many patients with persistent IgE-mediated food allergy. Still, the treatment is not without adverse reactions. In a large OIT milk treatment program conducted in Israel, approximately 15% of patients were unable to follow it to completion because of IgE-mediated reactions. Some patients with allergy to unheated milk or egg tolerate such foods when they are heated, as heating likely induces conformational changes to a number of the epitopes responsible for IgE binding.

Goldberg et al present a study of 14 children who failed unheated- or unbaked-milk OIT who received OIT with baked milk testing the hypothesis that this might result in desensitization to to unheated milk as well (J Allergy Clin Immunol 2015; 136(6): 1601-1606). Only three of the children tolerated the primary outcome dose of 1.3 g of baked milk protein, and eight out of the other 11 experienced IgE-mediated reactions, including two patients with anaphylactic episodes requiring intramuscular epinephrine. The three children who reached the 1.3 g baked milk dose were able to tolerate up to 900 mg of unheated milk at the end of the study, and all patients remaining in the program through 12 months demonstrated an increase in tolerance to unheated milk The authors also provide evidence that a basophil activation test, comparing patient reactivity to heated or unheated milk, could prospectively distinguish between patients succeeding or failing to complete the program.

The study contributes to our understanding of the benefits and risks of OIT, which continue to be under close scrutiny. The results indicate caution is required, and more work must be done before baked milk OIT is used freely in milk-reactive patients. 

Randomized controlled trial of primary prevention of atopy using house dust mite oral immunotherapy in early childhood

The epidemic proportion of atopic diseases in the last 30 years has resulted in major health and economic effects. Atopy is believed to be due to a genetic propensity to produce IgE antibodies in response to an allergen; such propensity is due to an imbalance between various lymphocyte subsets,TH1, TH2 and T regulatory (Treg) cells in particular. In the absence of early intervention, children born with atopic diathesis are likely to develop allergic disease. Zolkipli et al. report the results of a house dust mite allergy prevention study conducted in infants (J Allergy Clin Immunol 2015; 136(6): 1541-1547). 

Overcoming maturation deficiencies in the developing immune system and countering T_H2 bias requires a very early strong and adequate immune stimulation. In the first 18 months of life, the gut is the primary site of Treg cells stimulation in response to antigens, suggesting oral exposure is likely the most effective in inducing tolerance. The authors hypothesized that exposure to a ubiquitous allergen, such as house dust mite (HDM), would result in both HDM-allergen-specific and a more generalized desensitization effect preventing the atopic march. One hundred eleven infants less than one year of age who had two or more first-degree relatives with allergic disease received an oral administration of HDM extract twice daily for 12 months.

The authors found that HDM-allergen extract induced a significant reduction in sensitization to any common allergen as compared to placebo. There was, interestingly, no significant difference in the cumulative proportion of infants who developed HDM-specific sensitization between the active and placebo groups, nor did HDM-allergen extract impact the number who developed eczema, wheeze, or food allergy. The intervention was well-tolerated, with no differences between the two groups in relevant adverse events.

This early proof-of-concept study points to a feasible, safe, and effective preventive measure. High-dose HDM-allergen extract appears to exert a prophylactic effect on the development of atopy, as defined by skin prick test response to any common allergen. Preventive reduction in allergen sensitization in early childhood may translate into a reduction of asthma, eczema, rhinoconjunctivitis, and food allergy as children at risk for these diseases grow up.

Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis

Chronic rhinosinusitis affects approximately 10% of the adult population in industrialized countries. Its effects range from pain in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) to nasal obstruction and comorbid asthma in those suffering from chronic rhinosinusitis with nasal polyps (CRSwNP). Current therapy approaches, such as pharmacotherapy and endoscopic surgery, focus on these two phenotypes. They have not, however, proved effective regarding long-term control of symptoms or risk of recurrence for many patients with severe polyp disease. Bachert et al. discuss the current shift in treatment focus from phenotype to endotype and the related innovative therapies on the horizon (J Allergy Clin Immunol 2015; 136(6): 1431-1440).

A clinical phenotype groups patients with similar clinically observable characteristics. Various pathomechanisms underlie a given phenotype. Understanding and characterizing disease via a shared and unique pathomechanism creates an endotype, opening novel targets for therapeutic intervention. Patients with severe CRSwNP, associated with disease recurrence and comorbid asthma, show T_H2-biased inflammation and IgE formation. This has led to proof of concept studies using interventions such as Omalizumab, Reslizumab, Mepolizumab, and Dupilumab to target the associated T_H2 cytokines. None of these has been registered yet for the indication of nasal polyposis, and it is unclear if one has advantages over the others.

For patients with severe CRSwNP, topical glucocorticosteroids are usually not effective. The permanent application of oral corticosteroids would lead to health deterioration, and repeated surgeries are not a feasible option. While biologics pose problems that remain to be solved, including the necessity of regular systemic application with the risk of side effects and the high financial cost, they offer a direction that is nonetheless promising. Approaches including silencing techniques, or the blocking of transcription factor GATA-3, and the local application of apathogenic bacteria to produce therapeutically effective proteins are currently under investigation as well.

Preseasonal treatment with either Omalizumab prevents fall asthma exacerbations

In spite of optimal guidelines-based asthma treatment many children and adolescents with asthma continue to experience exacerbations. Asthma exacerbations have serious consequences, from increased morbidity to disease progression. While exacerbations can occur at any time to any patient, children with advanced disease, greater degrees of atopy, or who have experienced a recent exacerbation appear most susceptible to further exacerbation, and the time of year in which it is most likely to occur is in the autumn.

Previous Inner-City Asthma Consortium (ICAC) studies demonstrated higher daily doses of inhaled corticosteroids (ICSs) or the addition of omalizumab to year-round treatment reduced exacerbation frequency. Continuous treatment with either, however, risks side effects and incurs financial cost. Teach et al. have examined a seasonal, preventive approach, finding the addition of omalizumab four to six weeks prior to the start of school to ongoing guidelines-based management significantly reduces autumn exacerbation occurrence (J Allergy Clin Immunol 2015; 136(6): 1476-1485).

The authors compared the effects of preseasonal treatment with either omalizumab, an ICS boost or placebo in inner-city asthmatic children aged 6 to 17 years who had experienced one or more exacerbations in the 19 months prior. Patients completed a four- to nine-month run-in phase following study enrollment, during which they received guidelines-based care intended to achieve asthma control. Four to six weeks before the start of the school year and the autumn season, they initiated omalizumab, ICS boost, or placebo which continued through the first  90 days of each child’s school year.

The rate of exacerbations in autumn among the children who had received either omalizumab was significantly lower than among the children who had received a placebo. Among the children who had experienced an exacerbation during the run-in phase, omalizumab proved significantly more effective in preventing an exacerbation than ICS boost or placebo with a greater than 80% protection rate. Adverse events across all groups were rare and similar.

      Such a seasonal approach in treatment adjustment represents a first-time report of a novel strategy, indeed suggesting a paradigm shift, in confronting the “September epidemic” of asthma. Those who have experienced a recent exacerbation respond better to Omalizumab. 

Nocturnal eczema: Review of sleep and circadian rhythms in children with atopic dermatitis and future research directions

Atopic dermatitis (AD) is characterized by intense nocturnal pruritis, which can severely impact sleep continuity and quality. Sixty percent of children with AD experience sleep disturbance due to their condition, with 83% reporting disturbance during exacerbations. Sleep deprivation has been shown to alter immune function. In the case of school-aged children, it can impair linear growth, and in fact short stature has been described in children with AD only when associated with insufficient sleep. Fishbein et al review our current understanding of the role of sleep and circadian rhythms in nocturnal AD, current treatments, and future research directions (J Allergy Clin Immunol 2015; 136: 1170-1177).

Despite the widespread prevalence of sleep dysfunction in children with AD, the mechanisms that lead to it are not well understood. Nighttime factors such as cortisol nadir, increased skin temperature, and poor barrier function may contribute to noctural AD exacerbations, as may circadian variation in the expression of inflammatory cytokines such as IL-2, IL-6, and the pruritus-specific T_H2 cytokine IL-31. In addition, children with AD can have comorbidities including increased susceptibility to infection; heightened sensitivity to sensory stimulation; and restless leg syndrome, defined as an urge at night and prior to sleep to move the legs.

Treatment of pediatric AD should focus on disease control with sleep disturbance as an important measure. Topical steroids can improve sleep disturbance, as can wet wrap therapy. Antihistamines are often first line therapy but there is limited data to support this practice and future research is necessary. Actigraphy has been demonstrated to provide an accurate assessment of sleep in children, and standardized scoring parameters do not currently exist. Children with AD need a standardized, patient-centered outcome tool that could assess their sleep impairment, correlated with objective sleep measures. Given that approximately 10% of genes are under circadian control, future exploration of circadian biomarkers would open possibilities for a novel treatment paradigm as well.

Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10–mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity

The CBM complex consists of three components: a capase recruitment domain (CARD) protein, B-cell lymphoma 10 (BCL10), and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). For the first component, the complex uses one of three CARD family adaptors: CARD9, CARD10, or CARD11. These three proteins activate nuclear factor κB (NF- κB) in both innate and adaptive human immunity, and NF- κB plays a critical role in immune regulation, cell memory, cell survival/apoptosis, and cell-cycle progression. Much remains to be learned about the CBM complex, and inherited defects have been recently reported. Pérez de Diego et al discuss (J Allergy Clin Immunol 2015; 136: 1139-1149).

The authors summarize the reports on four patients with MALT1 deficiency, one patient with BCL10 deficiency, and two patients with autosomal recessive (AR) CARD11 deficiency. Most of these patients carried homozygous mutations with low levels of protein expression, and the broad range of clinical presentations included serious conditions of the skin and of the respiratory and gastrointestinal tracts, infection, and growth retardation. Thirty-eight patients were reported with AR CARD9 deficiency following its initial description in 2009, making it the most common genetic disorder of the CBM complex. All of these 38 patients were highly susceptible to various fungal diseases. Finally, mutations in MALT1, BCL10, and CARD11 have been found in patients with MALT lymphoma and other lymphoproliferative disorders.

It is clear that defects of CARD 11, BCL10, and MALT 1 generate severe forms of combined immunodeficiency. Three of the patients mentioned above have died, and two others have undergone bone marrow transplantation, which appears to be the best treatment currently available. In contrast, patients with CARD9 deficiency have abnormalities in innate immunity leading to increased susceptibility to invasive disease. Adjuvant GM-CSF treatment has shown benefit for one patient with C albicans meningoencephalititis; and terbinafine and posaconazole have been used to treat patients with extensive dermatophytosis. The CBM complex makes substantial contributions to human immunity. Further studies should improve our understanding of the specific role of each of its components.

The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization

Atopic dermatitis (AD) is the most common inflammatory skin disease, with a large and currently unmet need for effective therapeutics. AD and psoriasis, another common skin disease, are recognized as polar inflammatory skin diseases. Psoriasis is emerging as an IL-23/T_H17-skewed disease, whereas AD is considered to be T_H2-centered. These distinctions are relevant to emerging therapies for each. To date, the characterization of AD in different patient populations has made the assumption that disease mechanisms are similar across them. Noda et al present evidence that this is not so (J Allergy Clin Immunol 2015; 136: 1254-1264).

The prevalence of AD among adults in Asia is 7% to 10%, which is considerably higher than in other populations. In addition, prominent T_H17 activation has been observed in blood and acute AD lesions of Asian AD patients. The high prevalence and increased IL-17⁺ T-cell expansion suggest that an Asian AD phenotype may have different immune and barrier characteristics than the European American (EA) one. The authors have thus directly compared AD in European American (EA) and Asian (Japanese and Korean) populations. Their report classifies an Asian AD phenotype that is mixed between the EA AD and psoriasis phenotypes, with features atypical to AD such as parakeratosis and a unique cytokine profile with co-activation of the T_H2 and T_H17 axes. Even in the presence of increased IgE levels, Asian AD shows significantly higher induction of T_H17 and T_H22-related cytokines. Interestingly, psoriasis has a very low prevalence in Asian populations.

Further studies are needed to clarify the extent to which these differences are genetic, environmental, and/or microbiome related; for example, a similar study of Asian AD patients and Asian American AD patients. Additionally, FLG mutation status was unknown for all of the patients the current study includes. Regardless, the differences in the phenotype of Asian AD presented here call for similar description of other racial groups, and they provide a rationale for testing of IL-17/IL-23-targeted therapeutic strategies that have been successfully used in the treatment of psoriasis, in addition to those that are T_H2-specific.

Practice parameter for the diagnosis and management of primary immunodeficiency

Primary Immunodeficiency Diseases (PIDD) are inherited disorders of immune function that result in an increased rate and severity of infection, immune dysregulation, autoimmune disease, abnormal inflammatory responses, and malignancy. More than 300 disorders have been identified to date; they occur in as many as 1:2000 live births. Approximately half of those diagnosed with a PIDD have an antibody deficiency.

The principal clinical manifestation of immunodeficiency is an increased susceptibility to infection. In its evaluation, it is critical to the extent possible to document the foci of infections, the organisms, and the response to treatment. This distinguishes specific infectious agents and may help determine other conditions such as non-infectious inflammation. It is important to note that allergy to environmental allergens, food, or both can be an important element of and diagnostic clue for many PIDDs.

Under the aegis of the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI) Bonilla et al present an updated practice parameter (J Allergy Clin Immunol 2015; 136: 1186-1205) designed to serve as a practical guide for the clinical recognition and diagnosis of immunodeficiency, along with the general principles that guide management of such disorders.

The practice parameter organizes current knowledge and best practices. Its preparation included a review of the medical literature followed by ratings of published clinical studies or reports according to category of evidence. The ratings were then used to establish the strength of a given clinical recommendation. The practice parameter does not focus on detailed pathophysiology of various disorders. It consists of 239 summary statements, each containing a specific recommendation for clinical diagnosis or management. An executive summary and several tables and diagnostic algorithms accompany the text.

While developed with the consultant allergist/immunologist in mind, the practice parameter may serve as a useful reference for physicians in all specialties and at all levels of training. It may also be useful to administrators in the managed care or insurance fields. The authors hope to foster wider recognition of primary immunodeficiency, increase uniformity and efficiency in evaluation, and enhance application of specific diagnoses.

Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials

Allergic diseases are increasingly common, and it is estimated that up to 20% of the US population experiences atopic dermatitis, food allergy, asthma, allergic rhinitis, or conjunctivitis. The decrease in infectious diseases in developed countries has been associated with the risk for allergies, leading to the hygiene hypothesis for the rise of allergic disease. In order to inform World Allergy Organization guidelines, Cuello et al have examined the available data on the use of probiotics for the prevention of allergy (J Allergy Clin Immunol 2015; 136(4):952-961).

The composition of the gastrointestinal microbiota promotes potentially antiallergenic processes: T_H1-type immunity; generation of transforming growth factor (TGF), which has an essential role in suppressing T_H2-induced allergic inflammation and induction of oral tolerance; and IgA production, an essential component of mucosal immune defense. Alterations in these microbiota, the early and most massive source of microbial exposure, may underlie the allergy epidemic. As such, the use of probiotic supplementation could promote an adequate microbiota balance, which could in turn prevent the development of allergies.

The authors systematically reviewed randomized trials assessing the effects of any probiotic administered to pregnant or breastfeeding mothers and/or infants. Infants ingest the supplements as an oral preparation or within formula, and mothers take them while they are pregnant or breastfeeding. The 29 studies that fulfilled the specified inclusion criteria showed probiotic supplementation decreases the risk of eczema, including atopic eczema in infants. There was no evidence that probiotics prevent the development of other allergies.

The authors state the limitations of their findings stem from the limitations of the available body of evidence on this topic. Their confidence that one would observe effects on eczema in real life is low, due to the paucity of direct evidence, high likelihood of bias in primary studies, and great variability in the probiotics that were included. They call for future trials focused on the most common probiotics that measure and report effects in the prevention of all allergic diseases, as well as potential adverse effects, reducing the overall risk of bias.

Atopic dermatitis in children shows an imbalance in cytokine production by their skin homing cells

While pediatric atopic dermatitis (AD) is a common disorder among children, our current understanding of its mechanisms derives largely from studies of adults with long-standing disease. Defining the similarities and differences between activated polarized T-cells in adults and in children with early-onset AD is critical for understanding initial events in disease causation. Further, a better understanding of newly diagnosed disease could help clarify the sequence of events that leads to AD development. Czarnowicki et al compare differences between T-cell memory subset activation within the skin homing and non-skin homing systemic compartments, as well as frequencies of polarized T cell subsets in blood of pediatric and adult patients with AD (J Allergy Clin Immunol 2015; 136(4):941-951). Specifically, they study children with AD, children of the same age without AD, and adults with AD of similar severity.

The authors find that T_H2 activation, known to induce allergy, within skin-homing T-cells may drive AD in children, with concomitant reduced counter-regulation by T_H1 T-cells involved in infection control. The T_H22 “spreading” of AD common in adults with the condition is not evident in young children, and immune development, disease chronicity, or recurrent skin infections may influence it in the older population. While adults with AD demonstrate higher IL-22⁺ values (known to reduce skin barrier proteins) in skin homing T cells than adult control subjects or children with AD, there are no such differences between healthy children and children with AD. Acute lesions with redness and dryness tend to characterize AD in infants and young children, whereas adults with longstanding disease have marked thickening of lesions. Their data support a role for IL-22 in disease chronicity but not in disease initiation.

Studies have shown that many children outgrow their AD by 10 years of age. Czarnowicki et al suggest age-related disease resolution may reflect increased differentiation of T_H1 T-cells to counter-regulate increased T_H2 cell numbers which suppress T_H2 production. While adults may benefit from IL-22-targeted therapies, approaches to treat AD in children may best be directed to correction of T_H2/T_H1 imbalance.

New and future strategies to improve asthma control in children

Despite advances in care, asthma presents a significant burden on the pediatric population. The age of asthma diagnosis decreased from 4.7 years in 1993 to 2.6 year in 2000. Among children given a diagnosis before the age of 3 years, 35.6% to 45.2% continue to require care for the disease at age 6, and most of them already have lung function abnormalities. Early-onset asthma has long-lasting effects that continue into adolescence and adulthood, and severe childhood asthma is a risk factor for continued active disease as an adult. To date, no therapy has been able to prevent the development of pediatric asthma, and efforts continue to focus on achieving asthma control. Anderson and Szefler review the current and future approaches (J Allergy Clin Immunol 2015; 136(4): 848-859).

Adherence to controller therapies is essential to achieving disease control. Pediatric adherence specifically to inhaled corticosteroids (ICSs) has been reported to fall in the range of 20% to 33.9%, with only 4.7 to 5.5 prescription refills over 1 year. Most non-adherence among asthmatic patients is unintentional, resulting from forgetfulness or lack of parental supervision or health literacy. Electronic monitoring devices (EMDs) are an important development in addressing this problem. They record date, time, and location of inhaler use and provide real-time uploads to an Internet or smartphone application, in addition to providing reminders. Pediatric and adolescent studies using EMDs with reminders demonstrated a 40% to 54% increase in controller medications compared to those without them.

There are also many patients whose asthma remains uncontrolled, despite their closely following treatment regimens consisting of the most optimal current therapies. The need for new therapeutics is great, but there are complications in developing them for children. Traditionally, evidence for dosing, efficacy, and safety from adult studies influences pediatric drug development, but there are differences in pediatric respiratory function, immunology, and disease pathogenesis. Asthma medications are among the most prescribed off-label drugs in children. While second generation ICSs and LABAs appear to have altered the course of severe asthma over the past 20 years, ICS are associated with slowed growth and a reduction in adult height in children.

New inhaled therapies, such as single combination budesonide-formoterol inhaler maintenance and reliever therapy (SMART) and tiotropium provide promise for the future, as do a number of biologic drugs. As these therapies will be expensive, there is a need to identify biomarkers to indicate which patients they are most likely to benefit. The authors conclude the coming years will bring better options to control pediatric asthma, with the essential collaboration of patients, clinicians, and researchers. 

Cockroach sensitization mitigates allergic rhinoconjunctivitis symptom severity in patients allergic to house dust mites and pollen

Allergic rhinoconjunctivitis (AR) is the most common of IgE-mediated diseases, with some surveys indicating it affects as much as 40% of the surveyed population. The familiarity of its symptoms such as itching nose, eyes, or throat; watering eyes; compromised ability to smell; and sneezing underscores its ubiquity. Patients with the same sensitivities to various allergens have wide variation in the severity of their AR symptoms. This may be due to varying allergen-concentration in each patient environment. Alternatively, the sum total of the number and kinds of aeroallergens to which one is sensitive may determine symptom severity.

There is increasing evidence that supports the hygiene hypothesis as a basis for the development of allergy. This is to say that exposure early in life to certain allergens and bacteria helps to reduce AR symptoms and atopy in later life. He et al have thus investigated whether cockroach sensitization (C+) or its lack (C-), used as an indicator of childhood microbial exposure, affects AR symptom severity (J Allergy Clin Immunol 2015; 136(3):658-666).

The authors challenged two study groups and measured their total AR symptom scores (TSS). Group 1 was allergic to house dust mite (HDM). Sixty-seven percent of this group was also allergic to pollen and 43% were C+. Their TSS was recorded following challenge in both allergen challenge chamber (ACC) and natural settings. Group 2 was allergic to various pollens, and these participants recorded their TSS following ACC exposure that took place both during the natural pollination season and out of season.

The data showed participants in Group 1 who are sensitized to both HDM and pollen experience more severe AR symptoms than those who are only sensitized to HDM. However, C+ status associates with reduced symptoms, especially in those who are also allergic to pollen. Participants in Group 2 who are sensitized to pollen and are also C+ experience reduced AR symptoms, both during pollination season and out of season. These observations support the hygiene hypothesis and suggest that accounting for the overall aeroallergen sensitization status of participants in clinical trials could help mitigate confounding variables.

International Consensus on Allergy Immunotherapy

Allergen immunotherapy (AIT), or the administration of an allergen with the intent of decreasing a patient’s sensitivity to it, remains underused. Numerous clinical trials show it is effective in the treatment of those with allergic rhinitis (AR), but it is estimated to be used in treatment of fewer than 10% of these patients worldwide. AIT can stop the progression of AR to asthma and it can be used to treat controlled allergic asthma. Safer and more effective AIT strategies are being developed, but ongoing barriers to its use include questions on cost-effectiveness, the need for an improved safety profile, a lack of standardization of AIT products between companies, and the lack of high quality studies regarding optimal dosing and disease-modifying potential.

The subject calls for a consensus on the best AIT practice, because AIT is the only treatment that can potentially alter the progression of allergic disease and induce allergen-specific immune tolerance. To this end, the International Collaboration in Asthma, Allergy, and Immunology (iCAALL) has issued an International Consensus (ICON) on AIT. Jutel et al review the pertinent literature and summarize the key statements (J Allergy Clin Immunol 2015; 136(3): 556-568).

Historically AIT has been given via subcutaneous injection (SCIT) or allergy shots, and in the past 25 years there has been an increase in the use of sublingual immunotherapy (SLIT). Epicutaneous and intra-lymphatic administration are under current investigation. The duration of AIT is generally three to five years. There are a number of clinical scenarios in which AIT proves an effective therapy. Prospective studies have demonstrated SLIT with house dust mite extract resulted in remission of AR symptoms for seven to eight years after therapy ended. It can be used to treat mild and moderate asthma that is controlled via pharmacotherapy, and there is an expected benefit of the reduced need for steroids as a result. AIT may also be used for patients with respiratory allergic diseases associated with atopic dermatitis. Its use for food allergy is an important area of research, and it is not at this time recommended for clinical practice.

While AIT was introduced over a century ago, work must be done to address the reasons it remains under-used. There is a lack of non-specialist provider awareness and limited access to specialist care. There are concerns about reimbursement policies, safety, and effectiveness. The authors call for better definition of homologous allergen groups, large multi-center studies evaluating the optimal age of treatment initiation in young children, and biomarkers to select study responders and allow for objective evaluation of efficacy.

Treatment of overlapping asthma and COPD –can guidelines contribute in an evidence-free zone?

Asthma and chronic obstructive pulmonary disease (COPD) are often clearly distinguishable diseases. There are, however, many people who demonstrate features of both. This is often termed the asthma-COPD overlap syndrome (ACOS); it is clinically important since these patients have worse health outcomes than those with either disease alone do, and some existing guidelines for treatment of either disease conflict. ACOS patients have also been specifically excluded from major clinical trials related to either condition. There is thus at this time little evidence on how to treat them, many of whom present in primary care settings. Reddel highlights the urgent need for research in this area and summarizes the interim recommendations provided in a collaborative report by Global Initiative for Asthma (GINA) and Global Initiative for chronic Obstructive Lung Disease (GOLD) (J Allergy Clin Immunol 2015; 136(3): 546-552).

Patients with ACOS present widely varying clinical histories, from adult cigarette smokers with childhood-onset asthma to lifelong non-smokers with fixed airflow limitation to emphysema patients who also have allergic disease. ACOS cannot be thought of as a single disease or phenotype, yet primary care settings rarely permit in-depth diagnostic consultations, and forming clinical guidelines is challenging in the absence of relevant data from similar patient populations.

Some countries have recognized the overlap in recently published national asthma guidelines and COPD guidelines, but often only with the concept of two separate, coexisting diseases. The joint GINA/GOLD interim ACOS recommendations, first published in 2014, recognize that asthma and COPD form part of a spectrum of overlapping phenotypes of airways disease. They suggest targeting treatment on the basis of predictors of risk, which is useful given the lack of evidence for treatment efficacy or effectiveness for the ACOS-affected population, and they outline five pragmatic steps to diagnose and initially treat ACOS.

Interest in and recognition of the importance of overlapping asthma and COPD is rapidly escalating. It is urgently necessary to study broad populations with chronic respiratory disease in order to develop a precise definition for ACOS, characterize its phenotypes, and identify opportunities for targeted treatment.

Therapeutic approaches to asthma-COPD overlap syndromes

While asthma and chronic obstructive pulmonary disease (COPD) are distinct clinical entities, they are often treated with the same medications. There are many patients who present with features of both diseases, a condition called asthma-COPD overlap syndrome (ACOS). ACOS is currently poorly defined or understood, and it encompasses several phenotypes that require specific therapeutic approaches. For example, there are patients with COPD who have eosinophilic inflammation that may respond to inhaled corticosteroids (ICS), or severely asthmatic patients who smoke cigarettes and have COPD inflammation. Barnes summarizes three ACOS phenotypes and addresses the therapies currently available and those in development (J Allergy Clin Immunol 2015; 136(3): 531-545).

 The range of phenotypes is a challenge in treating ACOS patients, and the selection of appropriate therapy requires biomarkers that are predictive of a patient’s response to them. These include blood biomarkers such as eosinophil counts and fractional exhaled nitric oxide (F_ENO). In specialized centers, a patient’s sputum cell count can be useful to determine the cause of inflammation. Whether a patient has asthma, COPD, or both, a predominance of eosinophilic inflammation can be treated with bronchodilators, ICS, or more specific anti-eosinophilic therapies, many of which are in development. Macrolides offer a current therapy, with CXCR2 antagonists and antibodies to block interleukins and TNF under current study, for those with increased neutrophilic inflammation. Patients with largely fixed airway obstruction with little inflammation, the paucigranulocytic phenotype, may benefit from long-acting inhaled bronchodilators including LABA and LAMA, and triple inhalers containing an ICS, LABA, and LAMA are in clinical development.

Corticosteroid resistance is common in ACOS patients, and the molecular mechanisms that contribute to it may differ among ACOS phenotypes. Promising work with patients with severe asthma, smoking asthma, and COPD suggests, however, therapies that can restore responsiveness. These include existing, well-tolerated drugs such as theophylline, nortriptyline, and macrolides, or novel therapies such as inhaled PI3Kσ or p38 MAPK inhibitors.

There is little information about the long-term stability of inflammatory phenotypes of airway disease and some evidence the patterns of inflammation described above can vary within the same patient from time to time. Much remains to be learned. At the same time, the recognition that patients with ACOS present a range of phenotypes and require the development of specific treatments is an important one.

Measuring the corticosteroid responsiveness endophenotype in asthmatic patients

Inhaled corticosteroids (ICSs) constitute the most commonly prescribed therapies for asthma. They are effective, but there are up to 24% of asthma patients who do not achieve significant improvement with them. ICSs produce treatment responses in six clinical phenotypes: lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids, and frequency of emergency department visits or need for hospitalization. For the past 15 years and in an escalating prevalence of asthma, researchers have considered these phenotypes to be guided by separate mechanisms.

Clemmer et al propose a move away from the focus on single phenotypes to a more holistic approach. They suggest that there is a corticosteroid responsiveness endophenotype that modulates the asthma disease process, is latent in ICS-untreated patients, and is active in ICS-treated patients. Under this hypothesis, the corticosteroid responsiveness endophenotype influences the asthma disease process to produce the treatment effect observed in all the clinical phenotypes (J Allergy Clin Immunol 2015; 136(2): 274-281).

As such, the authors present a composite phenotype responsiveness model that combines the six clinical phenotypes and measures the endophenotype. They used principal component analysis (PCA) to determine the model in a study population of both ICS-treated and non-ICS-treated patients with mild to moderately severe asthma. The model was then tested in four replication populations. Using treatment effect area under the receiver operating characteristic curve (AUC), they demonstrate that a composite phenotype measures corticosteroid responsiveness with greater accuracy and stability across populations than the individual clinical phenotypes do.

The potential applications of the composite phenotype are many. It should enable asthma pharmacogenetic studies with more power for a given sample size or that require a smaller sample to achieve a given power. Given that it collapses multiple longitudinal clinical observations into a corticosteroid response metric and that it is easily implemented in a single computer program, it could allow a clinical practitioner to more accurately estimate ICS response. Finally, the model could be used to characterize the many asthma patients who do not respond to ICS treatment with better accuracy.

Report from the National Institute of Allergy and Infectious Disease Workshop on Drug Allergy

Allergic reaction to drugs is a serious and often underserved public health concern. In 2013, the National Institute of Allergy and Infectious Diseases (NIAID) Division of Allergy, Immunology and Transplantation convened a workshop on the issue. Representatives from several NIH institutes and from the FDA joined experts in drug allergy for a day-long discussion. Wheatley et al present a summary of the topics and recommendations (J Allergy Clin Immunol 2015; 136(2): 262-271).

The authors define “drug allergy” as any adverse drug reaction (ADR) that has a proven immunologic mechanism, including but not limited to IgE-mediated disease. There are currently no systematic epidemiologic studies of drug allergy. Most of the epidemiologic data on adverse drug reactions (ADRs) at this point relies on clinical diagnosis. With few specific diagnostic tests, physician-based assessment remains the gold standard for phenotyping the reactions.

ADRs are categorized as type A or type B. Type A reactions result from known pharmacologic/toxic effects of the drug often related to dosage. Mechanisms other than pharmacologic toxicity mediate type B reactions, which constitute approximately 20% of ADRs. The majority of type B reactions have an immunological basis. In particular, IgE-mediated reactions, whether immediate or delayed, often occur with a single encounter with the allergen. The mechanisms underlying both immediate-onset and delayed-onset reactions remain elusive. In no small part, this is due to a lack of appropriate reagents and reliable tests to detect drug-specific IgE antibodies and an absence of model systems.

While drug desensitization has a risk of inducing an allergic reaction, it is the only currently available approach that appears to provide clinical benefit. There is a need for valid, rapid, and inexpensive screening tests. While immunologically mediated ADRs are common, there will be few patients with the same reaction to the same drug in the same clinical context in any one institution. The authors call for multi-center clinical networks and communication between investigators, funding and regulatory agencies, and the pharmaceutical industry as the field grows.

Consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants

While means of measurement and estimates differ, in the past ten to fifteen years the prevalence of peanut allergy may have as much as tripled in countries such as the United States. This translates to nearly 100,000 new cases a year in the United States and United Kingdom. Fleischer et al. highlight emerging evidence that supports early, rather than delayed, peanut introduction in the period of complementary food introduction in infants, including many of those considered to be at high risk for peanut allergy. (J Allergy Clin Immunol 2015; 136(2): 258-261)

In the Learning Early About Peanut Allergy (LEAP) trial, 640 infants between the ages of four and eleven months, who were considered to be at high-risk because of egg allergy and/or severe eczema, were randomized to consume peanut at least 6 grams of peanut protein three times a week or to completely avoid peanut for the first five years of life. Five hundred and forty-two of these infants had a negative skin prick test (SPT) response to peanut at study entry, and ninety-eight of them had a minimally positive SPT response to peanut (1-4 mm; children with a SPT response to peanut of ≥5 mm were presumed peanut-allergic and excluded from the trial.)

In an intention-to-treat analysis, 17.2% of the children in the peanut-avoidance group had food-challenged-proven peanut allergy by the age of five years; 3.2% of the children in the consumption group did by the same age. This corresponds to a 14% absolute risk reduction, a number needed to treat (NNT) of 7.1, and a relative risk reduction of 80%. Overall, the risk of early peanut introduction in this group was low: 7 of the 319 children randomized to the consumption group reacted to peanut at the baseline food challenge, suggesting that peanut food challenges and introduction, even in children with other risk factors or with minimally positive peanut SPT responses, are safe and feasible.

Six children in the consumption group developed peanut allergy during the study, which indicates allergy can still develop despite primary intervention. In addition, this study focused only on infants considered to be at high-risk and did not extend to the general infant population. Still, the study is the first prospective, randomized trial for early peanut intervention, which its results suggest may reduce the risk of peanut allergy in this patient population by as much as 80%.

Existing guidelines from 2013, which recommended not delaying the introduction of any highly allergenic food beyond 4-6 months of age, did not actively recommend peanut introduction between four and six months of age in high-risk infants. Based on the data presented above, the authors suggest the following interim guidelines to aid in clinical decision-making for early peanut introduction. First, providers should recommend the introduction of peanut into the diets of high-risk infants between four and eleven months of age, as an association has been identified between delaying the introduction and the development of peanut allergy. Second, the evaluation by an allergist or appropriately-trained physician can assess the appropriateness of peanut introduction for a given high-risk infant that has severe eczema or egg allergy, and whether possible allergy testing and observed peanut ingestion would be recommended first. Finally, the outcomes of the LEAP regimen do not address the effects of alternative doses of peanut protein, the minimum length of treatment necessary to induce tolerance, or potential risks of premature discontinuation or sporadic feeding of peanut. More specific guidelines are expected later this year from an Expert Panel sponsored by the NIAID.

Respiratory allergy caused by house dust mites: What do we really know?

The house dust mite (HDM) is present in human habitats around the globe, and it is a significant factor in allergic rhinitis and allergic asthma. Sensitization to mite allergens in early life compromises lung function and leads to wheezing in children, and it associates with poorer outcomes in a patient’s respiratory health in the long term. Calderón et al review the epidemiology of HDM allergy and the effect of HDM allergens on the human immune system (J Allergy Clin Immunol 2015; 136(1): 38-48).

Both assessing prevalence of HDM sensitivity and controlling a patient’s exposure to the allergen pose challenges. Prevalence data for HDM sensitization vary according to targeted population: from estimating 65 million to 130 million people in the global general population may be affected to as many as 50% of those with asthma. In addition, results vary within geographic locations, meaning studies have found significant differences in prevalence within a given country or region. In terms of a patient’s exposure, house dust mites are ubiquitous. Humidity levels have been shown to affect HDM propagation, and a recent practice parameter recommends the use of a hygrometer in the home. Studies indicate that HDM allergen levels should be maintained at less than 2 μg/g to decrease the likelihood of sensitization, yet measures to decrease HDM exposure have shown little benefit on symptoms in sensitized patients. Finally, the quantitative relationship between exposure to HDM and symptoms in asthmatic patients is complicated, as many of these patients are sensitized to more than one allergen.

Allergenic effects in HDM allergy are thought to be orchestrated via two main routes: through the CD4⁺ T_H2 cells that induce and drive the IgE-dependent allergic response and through the innate immune system. It is this combined effect of adaptive and innate immune reactions that makes the allergen so powerful. Current guidelines for allergic rhinitis and allergic asthma classify disease based on severity of symptoms. That HDM is often the underlying cause is an important step in managing clinical control, as well as potentially preventing disease progression.

Anti–IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

Psoriasis is a chronic immune-mediated inflammatory skin disease with a global incidence of approximately 2%. The extent of the affected body surface area and degree of erythema, induration, and scaling in four areas define its severity, and approximately 25% of patients have moderate-to-severe disease. Genome-wide association studies have linked variants in the gene for the IL-23 receptor and the p19 subunit of IL-23 to psoriasis susceptibility. IL-23 induces differentiation of T_H17 cells and T_H22 cells. The former are a primary cellular source of proinflammatory cytokines, including IL-17, and the latter are a primary source of IL-22. Both interleukins can mediate the development of the epidermal hyperplasia and tissue inflammation that occurs in psoriasis.

Krueger et al present the first-in-human proof-of-concept study to evaluate the clinical and biological effects of BI 655066 in patients with moderate-to-severe psoriasis. BI 655066 is a novel, fully human IgG₁ mAb selective for IL-23A. It binds to IL-23A with high affinity and blocks the biologic activity of IL-23 (J Allergy Clin Immunol 2015; 136(1):116-124).

Thirty-nine patients received single-dose BI 655066 intravenously, subcutaneously, or placebo. The patients who received the antibody showed clinical improvement after two weeks that, in a subset of those treated, was maintained for up to 66 weeks after treatment. After 12 weeks, 87% of treated patients experienced a decrease in the Psoriasis Area and Severity Index of at least 75% (PASI75). The three groups reported adverse events with similar frequency.  The authors measured strong inhibition of IL-17 and disease-related genes related to the IL-23/Th17 axis, in addition to a significant correlation between treatment-associated molecular changes and improvement in PASI scores. The results support a new model for treating psoriasis and raise the possibility of attaining long-term remission from a single drug intervention. 

Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33

Little is known about the mechanisms regulating the persistence of chronic asthma. Because many allergens are perennially present, it has been difficult to ascertain whether persistence depends on this proximity. Studies of patients with occupational asthma have shown they experience symptoms for years after occupational exposure has ended. Christianson et al developed a mouse model in which asthma persisted for six months after allergen exposure ceased. They then used a combination of immunologic, genetic, microarray, and pharmacologic approaches to identify the factors contributing to symptom persistence (J Allergy Clin Immunol 2015; 136(1):59-68).

The authors found increased ILC2 levels characterize chronic asthma. In addition, IL-33-driven ILC2s prove to be an essential factor. The blockade of epithelial IL-33 led to a complete resolution of airway hyperactivity and a significant reduction of airway inflammation. They found IL-13, a product of ILC2s, can induce production of IL-33. It also generates a forward-feed mechanism on IL-33R expression, creating a positive feedback loop. Elimination of any component of the circuit resulted in disease resolution. They found finally that elimination of T-cells resolved airway inflammation but not airway hyperactivity or remodeling.

While previous studies have shown increased IL-33 in bronchoalveolar lavage (BAL) fluid, here the authors demonstrate an increase in ILC2 numbers. The results have implications for the treatment of chronic illnesses in general, suggesting that they depend on feedback and feed-forward circuits, interconnected systems that fail if a component is removed, and that it is these circuits that transition a disease from an acute condition to a chronic one.

The mechanism or mechanisms driving atopic asthma initiation: The infant respiratory microbiome moves to center stage

It is acknowledged that key events that determine risk for the development of allergic disease frequently occur years before manifestation of symptoms. Recent culture-based studies, in combination with population-wide bacterial metagenomic data, suggest that parallel bacterial interactions may contribute to disease development. Holt reviews these and related issues of immune competence in infancy (J Allergy Clin Immunol 2015; 136(1): 15-22).

A number of factors specific to  infancy can contribute to disease development. Prospective tracking of postnatal IgE titres in serum samples collected over the first five years of life strongly suggests IgE antibody production against aeroallergens rarely begins before the age of six months. Airway mucosal dendritic cells (AMDC) transmit aeroallergen-specific signals from the airway mucosal surface to the central immune system and program the balance between the Th2 and T regulatory cell components of the immunological memory that results. The immaturity of this network in infants is likely a risk factor for early respiratory infection, itself a risk factor for early atopic asthma.

The focus on respiratory pathogens that contribute to the immunopathogenesis of atopic asthma has in the past been almost exclusively on viral pathogens: respiratory syncitial virus (RSV) and human rhinovirus (HrV). Emerging studies include consideration of the role of bacterial pathogens. Data suggests qualitative and quantitative differences in the lower airway bacterial populations of asthmatic children, including the mix of the strains present and the overall bacterial burden. The findings call for an accurate understanding of the full spectrum of strains that constitute the respiratory tract microbiome, particularly  nasopharyngeal microbial populations which function as a resevoir from which seeding into the lower airways occurs, in terms of population level and dynamics, across the average age range for asthma onset. The Perth CAS cohort study of 234 infants has provided the first foundation for this work. Questions, such as whether the replacement of commensal bacteria species in the nasopharyngeal microbiome of infants with known pathogens precede or result from local viral infection, remain to be answered.

The allergy epidemics: 1870-2010

Allergic reactions were virtually unknown prior to 1870, and this is still the case in pre-hygiene villages in parts of the world today. While it has been previously implied that the increase in allergic disease was unimodal, Platts-Mills traces how history indicates this is not the case. Hay fever was first reported in the UK and the United States in 1870, the first clear reports of an increase in pediatric asthma appeared in the 1970s, and the current epidemic of food allergy became apparent in the 1990s. In a fascinating review, Platts-Mills traces the emergence and development of respiratory and food allergies and asthma (J Allergy Clin Immunol 2015; 136(1): 3-13).

Sequential changes in agriculture and trade, hygiene, diet, lifestyle, and environment in the past 150 years have likely contributed to an increase in allergic disease. In England and the US in the latter half of the nineteen century and start of the twentieth century, cultivation of land and the introduction of non-native plant species occurred at the same time that urban centers established clean public water systems. Thyphoid and cholera became rare, and hay fever rose. By the mid-1950s to mid-1960s, the first reports of increasing incidences of asthma appeared, with house dust mites cited as the dominant allergen. Homes during this time were increasingly airtight and carpeted, and with the advent of television children were spending more time inside them. By the 1990s in the US, parents were strongly advised both to avoid giving peanuts to small children and to frequently wash and sanitize children’s hands. Early exposure to peanuts can be protective against the allergy, and it is conceivable that skin permeability to foreign proteins has changed.

Finally, with the influx of technology, we as a culture from childhood forward are increasingly indoors. This has shown consequences including the rise in obesity and decline in physical fitness. The consequences most relevant to the topic at hand are the steady increase in exposure to indoor allergens, the decline in outdoor exposure, and exercise. Changes in environment and lifestyle will likely continue to result in unforeseen allergic developments.

Development and validation of a novel risk score for asthma exacerbations: The risk score for exacerbations

Asthma management involves achieving and maintaining current asthma control and preventing exacerbations. Reports have shown, however, that there can be a disassociation between these two goals, meaning control may be achieved but risk of exacerbations may remain, or the opposite. The identification of patients at risk of future severe exacerbations, whose asthma might be less treatment-responsive, or both could focus treatment selection. To this end, Bateman et al have developed a simple risk score for exacerbations (RSE) for clinical use (J Allergy Clin Immunol 2015; 135(6): 1457-64).

The authors analyzed a large data set of patients enrolled in studies comparing the efficacy of budesonide-formoterol (BUD/FORM) maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β₂-agonist (ICS/LABA) therapy. They included patients whose symptoms were not controlled on Global Initiative for Asthma (GINA) treatment steps 3 and 4 and who had experienced 1 or more exacerbations in the previous year. Using multivariate analysis, they found 4 dominant (all P <.001) predictors for both the risk of uncontrolled asthma and severe exacerbations: GINA step, reliever use, postbronchodilator FEV₁, and 5-item Asthma Control Questionnaire score. Smoking status and asthma symptom scores were additional predictors for uncontrolled asthma, and body mass index was a fifth predictor for severe exacerbation.

Bateman et al show risk of uncontrolled asthma at 3 months of treatment and a severe exacerbation within 12 months can be estimated from simple clinical assessments. The prediction of treatment outcome could be particularly useful for patients similar to those in the current analysis, all of whom were receiving moderate-to-high ICS doses and 52% of whom were receiving LABAs and who had experienced at least 1 recent exacerbation, as it could identify patients who might benefit from intensified or alternative therapeutic measures.

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

Platelet-activating factor (PAF) is a potent phospholipid-derived mediator thought to play a pivotal role in the etiology of numerous immune and inflammatory conditions. Our knowledge of its effects has broadened to include those as a vasodilator and broncho-constrictor, a contributor to host defenses, and a mediatory of the inflammatory response, and PAF has been well-demonstrated in experimental models to function as a central mediator of anaphylaxis. Gill et al review what we know (J Allergy Clin Immunol 2015; 135(6): 1424-32).

PAF is produced and secreted by several types of cells including mast cells, monocytes, tissue macrophages, eosinophils, endothelial cells, neutrophils, and platelets. It is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in effects including increased vascular permeability, circulatory collapse, and decreased cardiac output. Studies have shown patients with acute allergic reactions had elevated PAF serum levels, and patients with severe anaphylaxis had higher levels still. The latter group had respiratory or cardiovascular compromise, where both organ systems were targets of PAF bioactivity.

PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF-acetylhydrolase (PAF-AH), whose activity correlates inversely with PAF levels and predisposition to severe anaphylaxis. Several studies have confirmed more rapid rates of inactivation of PAF result in milder allergic manifestations. There is much interest around the development of therapies that selectively block the actions of PAF as both long-term prophylaxis and emergency treatment. In animal models, treatment with platelet-activating factor receptor (PAF-R) antagonists significantly reduced the severity of peanut-induced anaphylaxis and accelerated recovery from anaphylactic reactions. We are, however, still in the early stages of understanding PAF signaling, and further investigation of its role in pathology and therapeutic modulation is anticipated.

The role of platelets in allergic airway inflammation

Platelets are anucleated blood elements involved in hemostasis and thrombosis. It is now understood that they can also act as inflammatory cells and contribute to host defense against infection, performing many functions normally associated with leukocytes. Studies have shown that platelet depletion compromises ability to resist microorganism infection. Given that many inflammatory diseases are the result of inappropriate activation of defense pathways, it is likely inappropriate platelet activation contributes to the pathogenesis of these diseases. Idzko et al present the currently available data investigating the role of platelets in allergic airway inflammation and asthma (J Allergy Clin Immunol 2015; 135(6): 1416-23).

Of particular relevance to allergic inflammation, it has been shown that platelets express IgE receptors on their surfaces. They play an essential role in killing certain parasites, and platelet activation has been shown to accompany allergen exposure of sensitized patients. Platelet activation has also been observed in patients with asthma, measured as an increase in the levels of a number of platelet-derived mediators in peripheral blood or in bronchoalveolar lavage fluid (BAL). It is evident that platelets can release a number of spasmogens that can constrict human airway smooth muscle, including 5-HT, which has been demonstrated to induce bronchoconstriction in asthmatic patients. And platelet depletion has been reported to reduce allergen-induced bronchial hyperresponsiveness in sensitized rabbits, associated with a reduction in eosinophil infiltration in the lungs.

The increasing number of observations suggesting a dichotomy of platelet activation between the signaling involved in thrombosis and hemostasis and the activation during inflammatory responses has considerable implication. For example, using adenosine diphosphate (ADP), the authors have recently demonstrated that P2Y₁ receptors are required for platelet activation by inflammatory stimuli, whereas PY₁₂ receptors required for platelet aggregation have no such effect. The dichotomy of function opens the real possibility of developing anti-inflammatory and anti-allergic therapies that target the novel pathways of platelet activation. It also raises the possibility of finding novel biomarkers for assessing disease, given the clear role of platelets in leukocyte recruitment.

Platelets in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease (AERD) is an acquired syndrome that is irreversible and debilitating. A chronic inflammatory disease characterized by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after the ingestion of aspirin, it presents with an onset in young adulthood. Estimations indicate there are approximately 1.2 million adults in the United States living with AERD. Its pathogenesis likely involves disturbances in the mechanisms that regulate tissue recruitment of immune effector cells and activity of the 5-LO/LTC₄S pathway. There is substantial evidence that platelets contribute to these mechanisms. Laidlaw et al review the evidence regarding asthma in general and AERD in particular (J Allergy Clin Immunol 2015; 135(6): 1407-14).

Platelets lack a nucleus and have no DNA. They are derived from cytoplasmic fragments of megakaryocytes and have a life span in the circulation of approximately 8-10 days before being removed by the spleen. In addition to their role in hemostasis, activated platelets can activate other immune cells, and upon adhesion to granulocytes, they can facilitate granulocyte recruitment into body tissues. They also secrete mediators including chemokines and lipids, which are released upon platelet activation. All of these contribute to symptomatic asthma exacerbations. Specific to AERD, patients with the condition have high numbers of platelet-adherent granulocytes in their nasal polyp tissue, which contributes to the overproduction of cysteinyl leukotrienes.

Whether or not the circulating platelets implicated in AERD possess an intrinsic defect is still unknown. In vitro stimulation studies have shown platelets from AERD patients released nearly twice as much ATP when activated with platelet-activating factor than those from healthy controls did. The platelets also released significantly increased levels of TXB₂, which was not seen in the controls. Differences in biochemistry seem possible, suggesting trials examining targeted anti-platelet therapeutics may be appropriate. Studies have also suggested therapies aimed at reducing numbers of platelet-leukocyte aggregates, T-prostanoid receptor blockade, and P2Y₁₂ receptor antagonism all may be of use, and relevant clinical trials are in their early stages.

Celiac Disease

Given an increasing awareness of gluten-related disorders, medical professionals are encountering patients diagnosed with celiac disease or thought to have food intolerance to gluten. Green et al provide a review of the pathogenesis, clinical manifestations, diagnosis, and management of celiac disease (J Allergy Clin Immunol 2015; 135(5):1099-1106).

There are currently three major wheat-related food illnesses: celiac disease (CD), non-celiac gluten sensitivity (NCGS), and wheat allergy. CD is an autoimmune disorder involving both an innate and adaptive response in genetically predisposed individuals. Unlike food allergies, the pathogenesis of CD is not mediated by an immediate hypersensitivity reaction via an immunoglobulin (IgE) dependent mechanism. Instead, gluten protein is a pathogenic agent activated by the enzyme tissue transglutaminase (TTG) allowing its presentation to CD4+ T cells in the small intestine. NCGS is a term that refers to a spectrum of clinical phenotypes, without the identification of characteristic histologic or serologic abnormalities. Wheat allergy is distinct from both, in that it is an IgE mediated hypersensitivity response that occurs within minutes to hours of wheat ingestion.

Celiac disease has prevalence of nearly 1% among Western nations. Its distribution extends into such disparate populations as the Middle East, South America, Asia, and North Africa. A proposed reason for this trend is a globalizing world market bringing wheat-based foods into cultures that traditionally relied on gluten-free grains. There is evidence CD is a missed diagnosis in many children where infection and malnutrition are the presumed etiology for diarrheal illness. Its pathogenesis depends on the interaction of three factors. The first is predisposing genes, HLA DQ2 and DQ8, and the second is exposure to gluten. The third, environmental factors, includes many under investigation, including breastfeeding and the intestinal microbiome.

There is increasing evidence that CD includes extra-intestinal manifestations, and the terminology for describing it is changing to allow for these. Common presentations include anemia and osteoporosis. Despite increased awareness of the condition and gluten, the rate of diagnosis in the US remains low, with less than 20% of those with the actual condition having been diagnosed. The IgA TTG assay is the initial test of choice to detect antibodies associated with CD. Treatments in addition to the gluten-free diet, such as intraluminal agents, immunomodulators, and vaccination, are currently under investigation.

Question for the authors: 
Is there data available for the prevalence of wheat allergy in Western nations?

Although some overlap exists in the symptoms attributed to wheat allergy, specific pathophysiological reactions to wheat are currently classified into three categories: 1) IgE hypersensitivity associated wheat allergy 2) autoimmune IgA related celiac disease and 3) non celiac gluten sensitivity (NCGS). The prevalence of IgE related wheat allergy, which is most common in childhood, is estimated around 0.4-1.3%. Our review describes the prevalence of celiac disease near 1% in Western nations; however, the incidence of celiac disease has increased over time, and there is evidence of its underdiagnosis among the general population. NCGS is currently not as well understood as the other two wheat related allergies, and estimates of its prevalence are wide-ranging from 0.5-6%.

Immunopathophysiology of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced proctocolitis are non-IgE-mediated gastrointestinal allergies. Our current understanding of the mechanisms of these allergies linking exposure to the typical symptoms of vomiting, hypotension, and diarrhea falls behind that of other food-induced allergic disorders. Accompanying a comprehensive review of clinical features by Nowak-Wegrzyn that also appears in this issue, Berin assesses the state of our knowledge of the immune mechanisms of FPIES (J Allergy Clin Immunol 2015; 135(5):1108-1113).

FPIES is most commonly triggered by the protein component in cow’s milk, but a host of other foods can be triggers as well. Many of the foods that trigger FPIES reactions are also IgE-mediated food allergens, such as soy, fish, wheat, and egg, but many are not common in that regard. For example, rice is the third most common cause of FPIES in US cohorts, followed by oats. The fact that a range of common foods have the potential to trigger it is in contrast to celiac disease, in which pathology is triggered by a well-defined antigen in a restricted subset of foods.

Studies have demonstrated FPIES leads to changes in the intestinal architecture in response to chronic exposure to a trigger such as milk. Avoiding milk results in normalization, and its reintroduction results in a recurrence of partial villous atrophy. While this is similar to celiac disease, the two conditions differ in pathophysiology. For example, the latter is thought to be a food antigen-triggered autoimmunity. There is a lack of evidence for an autoimmune component in FPIES, but there is an association between it and atopy. There is mast cell degranulation in common between the two, which is an important factor that requires investigation.

The facts that FPIES commonly develops in response to the first food introduced into the diet and adverse reactions can develop in response to many foods that are not typically allergenic suggests there may be a regulatory defect in patients with FPIES. The presence and phenotype of food-specific T cells in the intestinal mucosa of patients with FPIES needs to be demonstrated, as has been done with celiac patients. There is even less data to explain the immune basis of acute FPIES reactions. In one case study, milk administered via enema resulted in diarrhea and weight loss, whereas drinking the milk induced vomiting, pallor, and diarrhea in the same infant. Thus, the chronic and acute manifestations of FPIES can be triggered at different sites. Is processing of the allergen during digestion required to trigger symptoms? Much remains to be investigated about its underlying immune mechanisms.

Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years)

Anaphylaxis is reported to occur with increasing frequency in infants. An illustrated Rostrum on the diagnosis, treatment, and long-term management of anaphylaxis in this age group has been published by Simons and Sampson (J Allergy Clin Immunol 2015;135: 1125-31).

Foods such as milk, egg, and peanut are by far the most common triggers of anaphylaxis in infancy, although medications and other triggers can also be implicated. Infants with anaphylaxis typically present with sudden onset of skin signs such as generalized urticaria, respiratory symptoms such as cough, wheeze, stridor, and dyspnea, and/or gastrointestinal symptoms such as persistent vomiting.

Clinical criteria for diagnosis of anaphylaxis are validated for use in children and adults, but have not yet been validated for use in infants. A high index of suspicion is required to diagnose anaphylaxis in babies, as they cannot describe symptoms such as itching, and signs of infant anaphylaxis such as flushing, dysphonia, incontinence, and behavior changes (irritability, somnolence) also occur in healthy infants.

The differential diagnosis of anaphylaxis in infancy includes unique entities such as congenital abnormalities of the respiratory tract or gastrointestinal tract, and food protein-induced enterocolitis syndrome. Epinephrine injection is the treatment of choice in both clinical and community settings.

Co-morbidities that increase the risk of severe anaphylaxis are not well-defined, but probably include croup, bronchiolitis, or asthma; likewise, amplifying co-factors are not well-defined in this age group.

Long-term management focuses on follow-up with a physician, preferably an allergy/immunology specialist who can train caregivers of infants to recognize and treat anaphylaxis in the community and help them to prevent anaphylaxis episodes.

Epinephrine auto-injectors (EAIs) are under-prescribed and under-used for anaphylaxis in infants. In a study in which a minority of infants with severe anaphylaxis were treated with epinephrine, reasons for not using it included failure to recognize anaphylaxis symptoms and being afraid to inject epinephrine.

Strict avoidance of exposure to culprit allergens (as confirmed by skin prick tests and specific IgE measurements) prevents recurrences but requires sustained vigilance from all the infant’s caregivers. Natural desensitization to foods such as milk or egg eventually occurs in many infants and children, especially those with mild initial reactions and low levels of sensitization.

Simons and Sampson have outlined specific goals for research on anaphylaxis in infancy. These include validation of the clinical criteria for diagnosis, studies of infant co-morbidities and amplifying co-factors that increase the risk of severe anaphylaxis, development of EAIs containing a 0.1 mg epinephrine dose suitable for this age group, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis.

 Question for the authors: In addition to being alert to the possibility of some infants eventually undergoing natural desensitization to milk or egg and helping to facilitate this desensitization, what other possibilities for prevention of anaphylaxis in infants do you see?

Answer: In an important prospective randomized trial in carefully-selected, high-risk infants age 4-11 months (Du Toit G et al, N Engl J Med 2015;372:803-13), early introduction of peanut significantly decreased the frequency of the development of peanut allergy and modulated immune responses to peanut. Although it remains to be proven whether these findings can be translated to other foods such as milk and egg and additional questions need to be addressed, this research suggests that the increase in prevalence of food-induced anaphylaxis in infants might eventually be halted. 

Biomarker-based asthma phenotypes of corticosteroid response

Inhaled corticosteroids (ICSs) are the mainstay of treatment of asthma. However, a considerable proportion of asthmatic patients do not respond to ICSs based on lung function, or other clinical outcomes, or both. Therefore, biomarkers relevant to the underlying pathophysiologic process, the response to treatment, or both would be useful in personalizing care of asthmatic patients. This need led Cowan et al to follow up from an original study of a 2 phase trial consisting of a steroid-naïve phase 1 and a 28-day trial of ICSs (phase 2) during which fraction of exhaled nitric oxide (FENO) values, eosinophil counts, and urinary bromotyrosine (BrTyr) levels were measured in asthmatic patients (J Allergy Clin Immunol 2015; 135(4): 877-883).

Over the last decade, FENO values and sputum eosinophil counts have been used as biomarkers of airway inflammation and predictors of steroid responsiveness. FENO values are correlated with airway eosinophilia and associated with airway hyper-responsiveness. Moreover, studies indicate that high FENO values in asthmatic patients indicate an at-risk phenotype for exacerbations and predict clinical response to ICSs or oral corticosteroids. Eosinophils are well recognized as biomarkers of active atopic inflammation and a relationship exists between sputum eosinophil counts and exacerbation of withdrawal of steroids. Upon activation, eosinophils undergo respiratory burst, generating high levels of reactive oxygen species and eosinophil peroxidase that is unique in its ability to convert respiratory burst-generated hydrogen peroxide into hypobromous acid, a reactive brominating oxidant that modifies protein tyrosine residues forming urinary BrTyr.

The authors compared the utility of a panel of biomarkers consisting of FENO, sputum eosinophils, and urine BrTyr that identify the presence of atopic inflammation and oxidative stress for prediction of clinical response to steroids. They show that the effect of ICSs on inflammatory biomarkers was not uniformly concordant, although there were substantial parallel decreases among biomarkers. Each of the biomarkers had utility for predicting steroid responsiveness; the combination of high FENO values and high urinary BrTyr levels had particular power to predict a favorable clinical response to ICS therapy with either improvement in Asthma Control Questionnaire score, FEV₁ or airway reactivity. Cowan concludes that future studies must focus on evaluation of biomarker panels for assessment of exacerbation risk and whether the magnitude of change in biomarker values might predict the magnitude of clinical benefit with treatments.

Question for the authors:

Do you see other applications for this biomarker panel for the clinical benefit of asthma, such as aiding in the determination of asthma subtypes early in diagnosis?

Response from the authors:

Our study highlights the potential for utilizing the combination of urinary Br Tyr and FENO to predict the likelihood of steroid responsiveness in asthmatic individuals, without resorting to sputum induction, preparation and analysis.  These measurements could be made at the first clinic visit so that treatment can be tailored to the individual allowing steroids to be prescribed in a targeted fashion whilst also allowing the earlier consideration of other treatments in non-steroid responsive asthma subtypes.  Further studies should focus on the identification of alternative treatments in these steroid-unresponsive phenotypes.

Overweight children report qualitatively distinct asthma symptoms: Analysis of validated symptom measures

The relationship between overweight/obesity and asthma phenotype in children remains inadequately defined. Several large epidemiologic studies have demonstrated that obesity increases the risk of physician-diagnosed asthma and is associated with greater asthma-related health utilization and asthma that is more problematic and difficult to control. This discrepancy regarding the impact of obesity suggests that more in-depth and novel assessments of lean and obese asthmatic children may be required. Specifically, few studies have addressed how obese patients perceive and report asthma symptoms. This led Lang et al to determine the qualitative differences in symptoms between lean and overweight/obese children with early-onset, atopic asthma (J Allergy Clin Immunol 2015; 135(4): 886-893).

The authors conducted a cross-sectional analytic study of lean and overweight/obese 10-17 year old children with persistent, early-onset asthma. Participants provided a complete history, qualitative and quantitative asthma symptom characterization, and lung function testing. They determined associations between weight status and symptoms using multivariable linear and logistic regression methods. The authors report that overweight/obese and lean children displayed similar baseline spirometry values. However, despite lower fraction of exhaled nitric oxide and reduced methacholine responsiveness, overweight/obese children reported requiring rescue treatments more than 3x that of lean children. Weight status affected the child’s primary symptom reported with loss of asthma control; overweight/obese children more often reported shortness of breath and less often reported cough.   Using three validated questionnaires for assessing asthma symptom control, the authors showed that overweight/obese status was consistently associated with greater symptom reporting.  Subscale analysis suggested that shortness of breath and self-medication with rescue medication consistently drove the worse asthma scoring.  Gastroesophageal reflux (GER) scores were higher in overweight/obese children and appear to mediate overweight/obesity-related asthma symptoms.

Lang concludes that overweight/obese children with early-onset asthma display poorer asthma control and a distinct pattern of symptoms. Moreover, greater shortness of breath and β-agonist use appears to be partially mediated via esophageal reflux symptoms, which may lead to overweight children with asthma falsely attributing exertional dyspnea and esophageal reflux to asthma and excess rescue medication use. Because dyspnea from asthma is a major driver of anxiety, reduced quality of life, health care utilization, and medication use, a greater understanding of the distinct sensory mechanisms of dyspnea is needed. Until systematic weight loss interventions become more feasible, respiratory physicians may serve their patients better by considering and discussing alternative causes of dyspnea in self-management plans.

Question for the authors:

Are there other factors associated with obesity that may be a factor in the severity of asthma symptoms, such as socioeconomic and health related factors?

Several comorbidities associated with obesity are also likely to influence asthma either directly or by complicating its perception and management.  The best examples include snoring/sleep apnea, immune and metabolic derangements and impaired cardiopulmonary reserve.  We adjusted for presence of snoring in our analysis which did not affect our results (as did adjusting for GER scores).  Lower socioeconomic status has been associated in the past with greater prevalence of obesity and worse asthma control, thereby making it a possible confounding factor.  However, several socioeconomic and environmental factors were measured in our study including race, ethnicity, parental education, income, inutero smoking and later environmental smoke exposure.  None of these measures were associated with overweight/obesity status in our study.  We did not measure for levels of activity.  The effect of daily activity on disease activity, response to controller therapy, and perception of asthma symptoms requires more investigation and may provide important insights into the relationship between obesity and asthma.  

The prevalence of severe refractory asthma

Severe asthma is characterized by difficulty to achieve disease control despite high-dose inhaled glucocorticoids plus long acting β₂ –agonists (LABAs) or oral corticosteroids (OCSs). In 2011, the Innovative Medicine Initiative (IMI) published an international consensus statement in which a more accurate definition of severe asthma was proposed. In this statement, a clear distinction was made between “difficult to control asthma” and “severe refractory asthma.” In patients with difficult to control asthma, the lack of asthma control is due to other factors than asthma itself, such as nonadherence to treatment or incorrect inhalation technique. On the other hand, in patients with severe refractory asthma, the disease remains uncontrolled despite addressing and removing all possible factors that might aggravate the underlying disease. Hekking et al sought to estimate the prevalence of severe refractory asthma as defined by the IMI consensus (J Allergy Clin Immunol 2015; 135(4): 896-902).

Adult patients with a prescription for high-intensity treatment were extracted from 65 Dutch pharmacy databases, representing 3% of the population. Questionnaires were sent to patients and about half (2312) were analyzed. The diagnosis of asthma and degree of asthma control were derived from the questionnaires to identify patients with difficult-to-control asthma and inhalation technique was assessed in a random sample of 60 adherent patients. The authors determined that patients with difficult to control asthma, adherence to treatment, and a correct inhalation technique were qualified as having severe refractory asthma. The results indicated that of asthmatic adults, 3.6% qualified for a diagnosis of severe refractory asthma, representing 10.4 patients per 10,000 inhabitants.

The authors speculate about the reasons for the difference between the prevalence of severe refractory asthma mentioned in the literature (5%-10%) and their results (3.6%). Estimations in the literature are based on expert opinion and clinical experience, it is reasonable to believe that not all factors that negatively influence asthma control are receiving full attention in the consulting room. Therefore clinical overestimation of the prevalence of truly severe refractory asthma might easily occur because of misclassification of patients with difficult-to-control asthma as patients with severe refractory asthma. Clinicians should be aware of the distinction between these 2 conditions and check potential aggravating factors, in particular poor adherence with treatment and inadequate inhalation technique. Another important result of this study is because the prevalence of this condition might be lower than previously thought, severe refractory asthma could fulfill the criteria of a rare disease and qualifies for niche drugs. Together, these data will hopefully facilitate the development and reimbursement of novel targeted treatments.