Zev Sthoeger

BACKGROUND: Corticosteroids, which are anti-inflammatory and immunosuppressive agents used for the treatment of various diseases including allergic disorders, can induce immediate and delayed hypersensitivity reactions. Although these reactions are not common, due to the wide usage of corticosteroid medications, corticosteroid hypersensitivity reactions are clinically important. OBJECTIVE: In this review, we summarise the prevalence, pathogenetic mechanism, clinical manifestations, risk factors, diagnostic and therapeutic approach for corticosteroid-induced hypersensitivity reactions. METHODS: An integrative review of the literature was conducted using PubMed searches (mainly large cohort-based studies) regarding the different aspects of corticosteroid hypersensitivity. RESULTS: Hypersensitivity reactions to corticosteroids can be immediate or delayed and can follow all modes of corticosteroid administration. Prick and intradermal skin tests are useful diagnostic tools for immediate hypersensitivity reactions, patch tests are useful for delayed hypersensitivity reactions. According to the diagnostic tests an alternative (safe) corticosteroid agent should be administered. CONCLUSION: Physicians of all medical disciplines should be aware that corticosteroids can cause (“paradoxically”) immediate or delayed allergic hypersensitivity reactions. The diagnosis of such allergic reactions is challenging since it is often difficult to distinguish between hypersensitivity reactions and deterioration of the basic inflammatory disease (e.g., worsening of asthma or dermatitis). Thus, a high index of suspicion is needed in order to identify the culprit corticosteroid.

Background: Previous studies reported controversial results regarding the association between allergic disorders and attention deficit hyperactivity disorder (ADHD)/autism spectrum disorder (ASD). The aim of this article was to investigate whether allergic disorders are associated with ADHD/ASD in a large cohort of pediatric patients.Methods: A retrospective study using the pediatric (0–18 year) database (ICD‐9‐CM codes) of Clalit Health Services during the years (2000–2018). Diagnosis of all disorders was made by specialist physicians.Results: A total of 117 022 consecutive non‐selective allergic children diagnosed with one or more allergic disorder (asthma, rhinitis, conjunctivitis, skin, food, or drug allergy) and 116 968 non‐allergic children were enrolled to our study. The mean follow‐up period was 11 ± 6 years. The presence of allergic disorders in early childhood (mean age of allergic diagnosis 4.5 ± 4.3 years) in boys as well as in girls significantly increased the risk to develop ADHD (O.R 2.45, CI 2.39–2.51; p < .0001), ASD (O.R 1.17, CI 1.08–1.27; p < .0001), or both ADHD + ASD (O.R 1.5, CI 1.35–1.79; p < .0001). Children with more than one allergic comorbidity revealed a much higher risk. In a multivariable analysis (adjusted for age at study entry, number of yearly visits, and gender), the risk of allergic children to develop ADHD and ADHD + ASD, but not ASD alone, remained significantly higher.Conclusion: Allergic disorder in early childhood significantly increased the risk to develop ADHD, and to a less extend ASD, in later life.

Venous thromboembolism (VTE) is a preventable cause of morbidity and mortality in acutely ill patients hospitalized in medical departments. Thromboprophylaxis with anticoagulants was shown to be safe and effective in medical patients with high risk to develop VTE. Despite guidelines recommendations, the rate of thromboprophylaxis in those patients is low. The objective of the study was to evaluate the rate of VTE risk assessment in routine medical department practice, the rate of eligible patients for thromboprophylaxis, the rate of patients who received thromboprophylaxis, and their outcome. Medical records of consecutive patients (3000 at 2013, 1000 at 2018) hospitalized in medical department were reviewed, retrospectively, for demographic, clinical characteristics, thromboprophylaxis treatment with enoxaparin and outcome (up to 90 days following discharge). Padua score was used for VTE risk assessment. VTE diagnosis was based on clinical suspicion. The mean patient's age (52.6% females) was 67.95 ± 21.56 years. 21% were eligible for thromboprophylaxis. Routine VTE risk assessment rate increased significantly following its incorporation into quality parameters, but the rate of treated patients was low (22% at 2013; 46% at 2018). The patients who received thromophylaxis were sicker compared to eligible patients without thromboprophylaxis. The rate of symptomatic VTE was low (0.24%; 0.12% and 0.55% for low and high VTE risk, respectively). Thromboprophylaxis did not have significant effect on the low number of VTE events. No major bleeding was observed. Major efforts are still needed to increase the rate of thromboprophylaxis in all eligible medical patients according to the guidelines recommendations.

Granulomatous lobular mastitis (GLM) is a rare disorder that can clinically mimic breast carcinoma. The recommendation for diagnosis and treatment of GLM has not yet been established. To assess a series of GLM patients, including their clinical presentation, diagnosis, treatment and outcome. We retrospectively analyzed the clinical data and treatment of 17 female patients with biopsy-proven GLM. Breast tissue was obtained by a core needle biopsy (15 patients) or open biopsy (2 patients). Images were reviewed by an experienced radiologist. The mean age of the patients at diagnosis was 44.6 ± 12.6 years. Five patients (29%) presented with bilateral disease, and seven (41%) presented with a mass, suggesting the initial diagnosis of breast carcinoma. Treatment comprised observation alone (23%), antibiotics (58.8%) and/or corticosteroids (with or without methotrexate) (35%). At the end of the study 70.6% of the patients demonstrated complete remission. None of the patients developed any systemic (granulomatous) disease or breast carcinoma during the follow-up period (4.7 ± 3.8 years). Core needle biopsy is mandatory for the diagnosis of GLM and the exclusion of breast carcinoma. The recommended treatment modalities are observation alone or corticosteroids; surgery should be avoided. GLM is a benign disease with a high rate of resolution and complete remission.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by disturbance of the innate and adaptive immune systems with the production of autoantibodies by stimulated B lymphocytes. The BLyS protein (B lymphocyte stimulator) is secreted mainly by monocytes and activated T cells and is responsible for the proliferation, maturation and survival of B cells. To study sera BLyS level and its clinical significance in Israeli lupus patients overtime. The study population included 41 lupus patients (8 males, 33 females; mean age 35.56 +/- 15.35 years) and 50 healthy controls. The patients were followed for 5.02 +/- 1.95 years. We tested 221 lupus sera (mean 5.4 samples/patient) and 50 normal sera for BLyS levels by a capture ELISA. Disease activity was determined by the SLEDAI score. Sera BLyS levels were significantly higher in SLE patients than in controls (3.37 +/- 3.73 vs. 0.32 +/- 0.96 ng/ml, P < 0.05). BLyS levels were high in at least one sera sample in 80.5% of the patients but were normal in all sera in the control group. There was no correlation between sera BLyS and anti-ds-DNA autoantibody levels. BLyS levels fluctuated over time in sera of lupus patients with no significant correlation to disease activity. Most of our lupus patients had high sera BLyS levels, suggesting a role for BLyS in the pathogenesis and course of SLE. Our results support the current novel approach of targeting BLyS (neutralization by antibodies or soluble receptors) in the treatment of active lupus patients.

Type I interferons (IFN) are primarily regarded as an inhibitor of viral replication. However, type I IFN, mainly IFNalpha, plays a major role in activation of both the innate and adaptive immune systems. Systemic lupus erythematosus (SLE) is a chronic, multi-systemic, inflammatory autoimmune disease with undefined etiology. SLE is characterized by dysregulation of both the innate and the adaptive immune systems. An increased expression of type I IFN-regulated genes, termed IFN signature, has been reported in patients with SLE. We review here the role of IFNalpha in the pathogenesis and course of SLE and the possible role of IFNalpha inhibition as a novel treatment for lupus patients.

The prevalence of allergic diseases has increased dramatically in the western world. In the last 2 decades, the frequency of asthma and allergic rhinitis has doubled. Allergen specific immunotherapy [SIT] has been used successfully for more than 100 years for the treatment of allergic disorders. Allergen SIT provides not only symptomatic relief, but it is potentially curative. The immunologic mechanisms of allergen SIT include all parts of the immune system. Regulatory T cells (TR1, Treg), have a major pivotal role in the success of immunotherapy. Along with the regulatory T cells, elevated suppressor cytokines (IL-10), suppression of TH2 cells, increasing titer of specific IgG4 and gradual decline in the number and function of basophils and mast cells also contribute to the success of the treatment (SIT). The above immune mechanisms are connected and related to each other acting at different times with the treatment with SIT. In this review we focused on the current knowledge and understanding of the different immune mechanisms which are involved in the success of SIT.

Cytokines play a major role in the innate and the adaptive immune responses. Since cytokines are very powerful messengers, several regulatory systems (in all levels: production, secretion, effect on target) control their action in order to prevent overstimulation of cytokines. Recently, a negative feedback of cytokine activity in the target cell, namely suppressor of cytokine signaling (SOCS) was defined. This regulatory system consist of 8 proteins (CIS.SOCS 1-7) n which each one of them specifically regulates one or more cytokines. Malfunction of the SOCS proteins may lead to unregulated activity of cytokines which may lead to the development of allergic and autoimmune disorders.