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.