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Monday, October 5, 2015

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: TH1-type immunity; generation of transforming growth factor (TGF), which has an essential role in suppressing TH2-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 TH2 activation, known to induce allergy, within skin-homing T-cells may drive AD in children, with concomitant reduced counter-regulation by TH1 T-cells involved in infection control. The TH22 “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 TH1 T-cells to counter-regulate increased TH2 cell numbers which suppress TH2 production. While adults may benefit from IL-22-targeted therapies, approaches to treat AD in children may best be directed to correction of TH2/TH1 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.