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Wednesday, September 16, 2015

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.

Monday, September 14, 2015

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.

Tuesday, September 8, 2015

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 (FENO). 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.

Tuesday, August 11, 2015

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.