Early childhood allergy linked with development of attention deficit hyperactivity disorder and autism spectrum disorder.

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.

Characteristics of patients with spontaneous resolution of sesame allergy.

BACKGROUND: The prevalence of sesame allergy is increasing; strict avoidance is the mainstay of therapy. Lately, sesame oral immunotherapy was presented as an alternative treatment, with a high rate of success. Therefore, data on the natural history and the clinical characteristics of patients with persistent sesame allergy are important for the management of patients with sesame allergy. OBJECTIVE: To describe the natural history of patients with sesame allergy and the clinical characteristics of patients with spontaneous resolution of sesame allergy compared with patients with persistent sesame allergy. METHODS: In our retrospective study, electronic health records of patients with sesame allergy diagnosis were reviewed for demographic and clinical data. Statistical analysis of clinical characteristics of patients with spontaneous resolution compared with persistent sesame allergy was performed. RESULTS: A total of 190 patients with sesame allergy were followed for 3.86 ±4.43 years. Of these patients, 61 (32.1%) had spontaneous resolution of sesame allergy. Patients with mild, early (before the age of 10 months) first sesame allergic reaction, with smaller than 7-mm skin prick test and without concomitant tree nut allergy had better resolution rate (56.1%). CONCLUSION: Sesame allergy spontaneously resolved in approximately one-third of our patients and in more than half of the patients with mild first reaction (grade 1) at a young age (<10 months), with small skin prick test (<7 mm) and no concomitant tree nut allergy. Larger prospective studies with longer follow-up period are needed to better characterize the sesame allergic patients with persistent allergy who may need oral immunotherapy.

Indoleamine-2,3-dioxygenase in murine and human systemic lupus erythematosus: Down-regulation by the tolerogeneic peptide hCDR1.

וֹndoleamine-2,3-dioxygenase (IDO) plays a role in immune regulation. Increased IDO activity was reported in systemic lupus erythematosus (SLE). We investigated the effects of the tolerogenic peptide hCDR1, shown to ameliorate lupus manifestations, on IDO gene expression. mRNA was prepared from splenocytes of hCDR1- treated SLE-afflicted (NZBxNZW)F1 mice, from blood samples of lupus patients, collected before and after their in vivo treatment with hCDR1 and from peripheral blood mononuclear cells (PBMC) of patients incubated with hCDR1. IDO gene expression was determined by real-time RT-PCR. hCDR1 significantly down-regulated IDO expression in SLE-affected mice and in lupus patients (treated in vivo and in vitro). No effects were observed in healthy donors or following treatment with a control peptide. Diminished IDO gene expression was associated with hCDR1 beneficial effects. Our results suggest that the hCDR1-induced FOXP3 expressing regulatory T cells in lupus are not driven by IDO but rather by other hCDR1 regulated pathways.

The tolerogenic peptide hCDR1 immunomodulates cytokine and regulatory molecule gene expression in blood mononuclear cells of primary Sjogren's syndrome patients.

Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands. We investigated whether the tolerogenic peptide, hCDR1, that ameliorates lupus manifestations would have beneficial effects on pSS as well. The in vitro effects of hCDR1 on gene expression of pro-inflammatory cytokines and regulatory molecules were tested in peripheral blood mononuclear cells (PBMC) of 16 pSS patients. hCDR1, but not a control peptide, significantly reduced gene expression of IL-1ß, TNF-α, MX-1 and BlyS and up-regulated immunosuppressive (TGF-ß, FOXP3) molecules in PBMC of pSS patients. hCDR1 did not affect gene expression in patients with rheumatoid arthritis and anti-phospholipid syndrome. Further, hCDR1 up-regulated the expression of Indoleamine 2,3-dioxygenase (IDO) via elevation of TGF-ß. IDO inhibition led to a significant decrease in the expression of FOXP3 which is crucial for the induction of T regulatory cells. Thus, hCDR1 is potential candidate for the specific treatment of pSS patients.

Upper Extremity Deep Vein Thrombosis: Symptoms, Diagnosis, and Treatment.

BACKGROUND: Upper extremity deep vein thrombosis (UEDVT) is defined as thrombosis of the deep venous system (subclavian, axillary, brachial, ulnar, and radial veins), which drains the upper extremities. It can be caused by thoracic outlet anatomic obstruction, such as Paget-Schroetter syndrome, (primary) or by central intravenous catheters (secondary). UEDVT may be asymptomatic or present with acute severe pain and arm swelling. Clinical suspicion should be confirmed by diagnostic imaging procedures such as duplex ultrasound, computed tomography scan, or magnetic resonance imaging. UEDVT is managed by anticoagulant treatment. In addition to that, early thrombolysis aimed at preventing post-deep vein thrombosis syndrome and thoracic outlet decompression surgery should be given to patients with primary UEDVT. Anticoagulation without thrombolysis is the treatment of choice for patients with catheter-related thrombosis. Mandatory functioning catheters can remain in place with anticoagulant treatment. All other catheters should be immediately removed. The management of patients with UEDVT requires an experience multidisciplinary team comprised of internists, radiologists, hematologists, and vascular surgeons. Understanding the risk factors for the development of UEDVT, the diagnostic procedures, and the treatment modalities will improve the outcome of those patients.

Anti-BLyS Treatment of 36 Israeli Systemic Lupus Erythematosus Patients.

BACKGROUND: Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment. OBJECTIVES: To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers. METHODS: We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response. RESULTS: The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%). CONCLUSIONS: Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

Increased soluble CD72 in systemic lupus erythematosus is in association with disease activity and lupus nephritis.

INTRODUCTION: B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in autoimmune diseases. The significance of soluble CD72 (sCD72) has not been elucidated. METHODS: Soluble CD72 was analyzed in the serum of 159 SLE patients, 40 rheumatoid arthritis (RA) patients, and 100 healthy individuals. Correlations between sCD72 and SLE disease activity (SLEDAI) were assessed. RESULTS: Soluble CD72 was found increased in SLE patients, when compared to both RA patients and healthy individuals (20.2 ± 1.2 ng/ml; 10.6 ± 4.6 ng/ml and 7.2 ± 3.3 ng/ml; p < 0.001). Soluble CD72 level was significantly higher in SLE patients with renal involvement than in patients without (31.8 ± 2.3 ng/ml vs 13.9 ± 0.9 ng/ml; p < 0.001) and also with the presence of auto-antibodies. CONCLUSION: Soluble CD72 is significantly increased in SLE patients mainly in those with renal involvement. Increased sCD72 may become a potential biomarker for renal involvement in SLE.

Granulomatous Lobular Mastitis.

BACKGROUND: 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. OBJECTIVES: To assess a series of GLM patients, including their clinical presentation, diagnosis, treatment and outcome. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Novel approaches to the development of targeted therapeutic agents for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic multisystem disease in which various cell types and immunological pathways are dysregulated. Current therapies for SLE are based mainly on the use of non-specific immunosuppressive drugs that cause serious side effects. There is, therefore, an unmet need for novel therapeutic means with improved efficacy and lower toxicity. Based on recent better understanding of the pathogenesis of SLE, targeted biological therapies are under different stages of development. The latter include B-cell targeted treatments, agents directed against the B lymphocyte stimulator (BLyS), inhibitors of T cell activation as well as cytokine blocking means. Out of the latter, Belimumab was the first drug approved by the FDA for the treatment of SLE patients. In addition to the non-antigen specific agents that may affect the normal immune system as well, SLE-specific therapeutic means are under development. These are synthetic peptides (e.g. pConsensus, nucleosomal peptides, P140 and hCDR1) that are sequences of conserved regions of molecules involved in the pathogenesis of lupus. The peptides are tolerogenic T-cell epitopes that immunomodulate only cell types and pathways that play a role in the pathogenesis of SLE without interfering with normal immune functions. Two of the peptides (P140 and hCDR1) were tested in clinical trials and were reported to be safe and well tolerated. Thus, synthetic peptides are attractive potential means for the specific treatment of lupus patients. In this review we discuss the various biological treatments that have been developed for lupus with a special focus on the tolerogenic peptides.

Type I interferon signature in systemic lupus erythematosus.

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.

BLyS levels in sera of patients with systemic lupus erythematosus: clinical and serological correlation.

BACKGROUND: 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. OBJECTIVES: To study sera BLyS level and its clinical significance in Israeli lupus patients overtime. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[AIDS - an old disease with new challenges].

Due to highly effective anti-retroviral therapy the mortality rate from AIDS has been significantly reduced and HIV infection has became a chronic rather than a terminal disease. In Israel there are more than 5,631 people known to be HIV positive. The increased life expectancy of HIV-infected persons leads to an increase in HIV prevalence among older adults. Both HIV infection and anti-retroviral therapy exacerbate diseases that occur in older people, including cardiovascular, neurologicaL and renal diseases, as well as diabetes and osteoporosis. Caring for HIV-infected patients with other chronic diseases is challenging and requires a muLtidisciplinary approach. .

[Situations in which the primary care physician should suspect the presence of HIV-1 infection].

We are living in an era in which AIDS is no longer a terminal disease. It has become a chronic treatable disease. HIV-1 patients are mostly treated in specialized clinics by specialists in cLinical immunology or infectious diseases. In Israel, there are seven authorized centers for the diagnosis and treatment of HIV/AIDS. The primary caregiver for patients (family physician or internist) has to know the risk factors, risk groups and cLinical situations which are highly related to HIV-1 infection. These situations obligate a high clinical suspicion for early detection and diagnosis of HIV-1 infection. Early diagnosis has high clinical, prognostic and even epidemiological value. In this review, we highlight the main clinical situations in which the primary care physician should conduct an HIV-1 test as part of the clinical and Laboratory workup performed on the patient.

[The immunological mechanisms contributing to the clinical efficacy of allergen specific immunotherapy (SIT) in allergic diseases].

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.

[SOCS--suppressor of cytokine signaling proteins and their role in the pathogenesis of allergic and autoimmune disorders].

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.

[Demographic and clinical characterizations of newly diagnosed patients with HIV/AIDS above fifty years of age].

BACKGROUND: Major changes happened in the last decade in the HIV/AIDS pandemic. The disease is no longer limited to young age. Due to the effectiveness of HAART (Highly Active Anti-Retroviral Therapy) as well as new diagnosis in older age groups, many patients in AIDS centers are above 50 years of age. AIM: To determine the prevalence, demographics and clinical characteristics of newly diagnosed HIV/AIDS patients older than 50 years compared to younger newly diagnosed patients. METHODS: Retrospective single center analysis of the demographics and clinical characterizations of 62 newly diagnosed HIV/AIDS patients over 50 years of age. RESULTS: The average age at diagnosis of the whole cohort was 39+/-16 years. There was a gradual increase in the age at diagnosis over the years, as well as the percent of patients above the age of 50 diagnosed with the disease. In comparison to younger patients, in the older group there were more males compared to females and less patients who acquired the HIV/AIDS in unprotected homosexual sex. Furthermore, CD4 cells counts were lower and viral load leveLs were higher at diagnosis in the older group. Despite good adherence, patients above the age of 50 don't achieve adequate immunological response and many are left with significant immunodeficiency (CD4<200). CONCLUSION: The prevaLence of patients above the age of 50 Living with HIV/AIDS in Israel is rising. Programs aimed at prevention, education and screening for this unique group are mandatory. An AIDS center should adopt new programs and routines to cope with the increasing number of patients over the age of 50 Living with HIV/AIDS.

[HIV post exposure prophylaxis therapy - the experience of two major AIDS centers].

BACKGROUND: During recent years, the use of antiretroviral therapy expanded beyond the treatment of HIV-infected patients. Since the outset of the HIV epidemic, antiretroviral drugs were also used for post-exposure prevention of HIV infection in health workers and implemented after possible exposure during sex. In this study, we summarize the cases from the AIDS center in the Kaplan Medical Center and the Sheba Medical Center after possible exposure to HIV (occupational or sexual). AIM: The study aims to validate the different types of potential exposures to HIV encountered, the treatment and outcomes. METHODS: All the data regarding attendance at the AIDS Center in the Kaplan Medical Center during the years 2008-2010 for any possible HIV exposure (occupational or sexual) and for sexual exposure in the Sheba Medical Center AIDS Clinic during the years 2003-2008 was collected retrospectively. RESULTS: During the years of the study, 448 patients attended the Kaplan Medical Center for consultation after a potential exposure to HIV; 314 of the cases were because of occupational exposure, however, only in 11 (3.5%) of the cases, post exposure prophylaxis (PEP) treatment was advised. In the other 134 patients who attended for non-occupational potential exposure to HIV (18 cases of needle stick or sharp object injury and 116 of sexual exposure), for 46 (40%) of these cases, PEP was recommended. No evidence of HIV infection was found for any of the 448 patients who attended the clinic for possible exposure to HIV, regardless of the consultation that they received. In the Sheba Medical Center, during the years 2003-2008, 175 patients attended for consuLtation after potential sexual exposure to HIV. The medical staff of the clinic decided, after risk assessment, to recommend PEP to 140 (80%) of the cases. Similarly, in this case, no evidence of HIV infection was found (regardless of whether PEP was given or not). DISCUSSION: In potential occupational exposure to HIV it is possible, in most cases, to assess the risk for infection sufficiently so that only a few cases will need PEP. In potential sexual exposure to HIV, there are many cases where data regarding the potential source of infection is partial or missing, making the risk assessment more difficult. This may be the reason for the high percentage of patients in this situation who received PEP. From the data in this study, our cohort support PEP as being effective and safe.

Immediate and delayed hypersensitivity reactions to corticosteroids - prevalence, diagnosis and treatment.

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.

Modification of allergen subcutaneous immunotherapy safety precautions and systemic allergic reaction rate reduction.

Background: Despite their life-threatening potential, medical team mistakes during subcutaneous immunotherapy are rarely discussed. Real data are missing, and a survey study estimated that dosing errors are responsible for 25% of systemic reactions during immunotherapy. To minimize errors, we modified our safety precautions and compared the rates of systemic allergic reactions before and after the change. Methods: Our retrospective comparative cohort study compared systemic allergic reaction rates during 2012-2015 and 2016-2019, after a second check of the injected allergen/s by another nurse/physician was added to the treatment protocol. Results: The rate of systemic allergic reaction per injection was reduced from 0.93 to 0.71%; p = 0.023. Conclusion: A second check prior to injection is beneficial and can reduce the allergic reaction rate during immunotherapy.

Many people suffer from allergies to dust or pollen, and they might suffer from a running nose when they come into contact with the allergens. This reaction is called hayfever or allergic rhinitis. Immunotherapy is a treatment which can help to treat patients with allergic rhinitis. During treatment, the patients receive injections of small amounts of dust or pollen, and with time become less allergic. The injections themselves might cause allergic reactions such as rash, hives, swelling or trouble breathing. Sometimes these allergic reactions are related to mistakes made by the medical team. In our study we changed safety instruction to add a second check of the materials and amounts before the injections were given to the patient. This was checked by two different nurses. We compared the number of allergic reactions to the shots before and after the change. We found that the number of allergic reactions was 9.3 for 1000 injections before and 7.1 for 1000 injections after the change. We think that a second check of the materials and amounts before giving the injections is helpful and can prevent some of the allergic reactions.