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Thursday, November 5, 2015

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 TH2 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/TH17-skewed disease, whereas AD is considered to be TH2-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 TH17 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 TH2 and TH17 axes. Even in the presence of increased IgE levels, Asian AD shows significantly higher induction of TH17 and TH22-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 TH2-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.

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.