The Association Between Repeated Measured Febrile Episodes During Early Childhood and Attention Deficit Hyperactivity Disorder: A Large-Scale Population-Based Study.

OBJECTIVE: We examined the association between the number, magnitude, and frequency of febrile episodes during the 0 to 4 years of life and subsequent diagnosis of ADHD. METHODS: This population-based case-control study in an Israeli HMO, Leumit Health Services (LHS), uses a database for all LHS members aged 5 to 18 years between 1/1/2002 and 1/30/2022. The number and magnitude of measured fever episodes during the 0 to 4 years were recorded in individuals with ADHD (N = 18,558) and individually matched non-ADHD controls in a 1:2 ratio (N = 37,116). RESULTS: A significant, independent association was found between the number and magnitude of febrile episodes during the 0 to 4 years and the probability of a later diagnosis of ADHD. Children who never had a measured temperature >37.5°C had a significantly lower rate of ADHD (OR = 0.834, 95% CI [0.802, 0.866], p < .0001). CONCLUSIONS: Febrile episodes during 0 to 4 years are associated with a significantly increased rate of a later diagnosis of ADHD in a doseresponse relationship.

A case-control study for comorbidity and laboratory factors associated with food-induced anaphylaxis.

Background: Food-induced anaphylaxis (FIA) is a serious and potentially life-threatening allergic reaction triggered by food allergens. Objective: This case-control study aimed to investigate comorbidities and laboratory factors associated with FIA in the pediatric population of Israel. Methods: Retrospective data from the electronic health records of Leumit Health Care Services were used to identify 711 pediatric patients with FIA and 2560 subjects with food allergy and without anaphylaxis matched for age, gender, and ethnicity. Comorbidities were identified based on medical billing diagnosis codes, and laboratory characteristics were compared between the two groups. Results: The mean ± standard deviation age of patients with FIA was 4.1 ± 4.1 years, and 37.3% were girls. Laboratory analysis revealed increased eosinophil counts (p < 0.001), elevated immunoglobulin E (IgE) (p < 0.001), and IgA levels (p = 0.001) in the FIA group compared with the controls. With regard to comorbidities, the FIA group had higher prevalence rates of allergic diseases, including allergic rhinitis (odds ratio [OR] 1.72; p < 0.001), allergic conjunctivitis (OR 1.84; p = 0.001), asthma (OR 1.36; p < 0.001), angioedema (OR 6.37; p < 0.001), atopic dermatitis (OR 1.77; p < 0.001), and contact dermatitis (OR 1.42; p = 0.001). There was a trend toward significance for chronic spontaneous urticaria (p = 0.051). There was a significant negative association between helminthiases, particularly enterobiasis, and FIA (OR 0.76 [95% confidence interval, 0.59-0.98]; p = 0.029). Conclusion: This study provides valuable epidemiologic evidence on the associations among FIA, comorbidities, and laboratory factors in the pediatric population.

The Association between Glucose 6-Phosphate Dehydrogenase Deficiency and Attention Deficit/Hyperactivity Disorder.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, impacting 4.9% of the population and more prevalent in Mediterranean communities, is a common enzymopathy with potential relevance to Attention Deficit/Hyperactivity Disorder (ADHD). This study investigated this association. METHODS: The clinical characteristics of 7473 G6PD-deficient patients and 29,892 matched case-controls (selected at a 1:4 ratio) from a cohort of 1,031,354 within the Leumit Health Services database were analyzed using Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. RESULTS: In total, 68.7% were male. The mean duration of follow-up was 14.3 ± 6.2 years at a mean age of 29.2 ± 22.3 years. G6PD deficiency was associated with an increased risk of being diagnosed with ADHD (Odds Ratio (OR) = 1.16 [95% CI, 1.08-1.25], p < 0.001), seeking care from adult neurologists (OR = 1.30 [95% CI, 1.22-1.38], p < 0.001), and consulting adult psychiatrists (OR = 1.12 [95% CI, 1.01-1.24], p = 0.048). The use of stimulant medications among G6PD-deficient individuals was 17% higher for the methylphenidate class of drugs (OR = 1.17 [95% CI, 1.08, 1.27], p < 0.001), and there was a 16% elevated risk for amphetamine use (OR = 1.16 [95% CI, 1.03, 1.37], p = 0.047). CONCLUSIONS: G6PD deficiency signals an increased risk of ADHD diagnosis, more severe presentations of ADHD and a greater need for psychiatric medications to treat ADHD.

Interleukin-33, endothelin-1, and inflammatory parameters in chronic spontaneous urticaria.

Background: Endothelin-1 (ET-1) and interleukin-33 (IL-33) can modulate the activation of mast cells and basophils in the pathophysiology of allergic diseases, interplaying with other mediators of "low-grade inflammation." Objective: To compare ET-1, IL-33, the neutrophil-lymphocyte ratio (NLR), eosinophil-lymphocyte ratio (ELR), platelet-lymphocyte ratio (PLR), eosinophil-basophil ratio (EBR), systemic immune inflammation index (SII), and system inflammation response index (SIRI) in patients with chronic spontaneous urticaria (CSU) and are antihistamine sensitive (AHS), antihistamine resistant (AHR), omalizumab sensitive (OmS), and omalizumab resistant (OmR). Methods: A prospective observational study enrolled 68 consecutive patients with CSU diagnosed and managed according to the dermatology section of the European Academy of Allergology and Clinical Immunology (EAACI), the European Union funded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization guidelines. Patients with a urticaria control test score of >12 are considered treatment sensitive, and ≤ 12 are considered resistant. The control group consisted of 20 sex-matched subjects without urticarial diseases. Total immunoglobulin E (IgE), antinuclear antibodies (ANA), thyroid stimulating hormone, antithyroid peroxidase, mean platelet volume (MPV), NLR, ELR, PLR, EBR, SII, SIRI, ET-1, and IL-33 were measured at the study entry and compared between the study groups. Results: Thirty AHS group, 38 AHR group, and 20 control group patients were included. The AHS, AHR, and control groups did not differ in demographic parameters, but the CSU groups were characterized by higher indicators of inflammation. In comparison with the AHS group, the AHR group was characterized by higher levels of IL-33 (p = 0.007), ET-1 (p = 0.032), C-reactive protein (p = 0.016), MPV (p = 0.002), and higher rates of positive ANA (p = 0.019). Of the 38 patients from the AHR group, 30 (79%) were included in the OmS group and 8 (21%) were included in the OmR group. The OmR group was characterized by higher levels of C-reactive protein (p = 0.022), EBR (p < 0.001), higher rates of ANA (p = 0.004), and lower levels of ET-1 (p = 0.025) than the OmS group. Conclusion: Our study did not confirm NRL, PRL, SII, and SIRI, PLR as the biomarkers of treatment response to antihistamines and/or omalizumab in CSU. Higher blood levels of IL-33 and ET-1 characterize AHR CSU.

Glucose-6-phosphate dehydrogenase deficiency and long-term risk of immune-related disorders.

Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic disorder that is particularly prevalent in Africa, Asia, and the Middle East. This study aimed to assess the long-term health risks associated with G6PD deficiency. Methods: A retrospective cohort study was conducted using data from a national healthcare provider in Israel (Leumit Health Services). A total of 7,473 G6PD-deficient individuals were matched with 29,892 control subjects in a 1:4 ratio, based on age, gender, socioeconomic status, and ethnic groups. The exposure of interest was recorded G6PD diagnosis or positive G6PD diagnostic test. The main outcomes and measures included rates of infectious diseases, allergic conditions, and autoimmune disorders between 2002 and 2022. Results: Significantly increased rates were observed for autoimmune disorders, infectious diseases, and allergic conditions in G6PD-deficient individuals compared to the control group. Specifically, notable increases were observed for rheumatoid arthritis (odds ratio [OR] 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR 18.70, p<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, p=0.001), and Hashimoto's thyroiditis (OR 1.26, p=0.001). These findings were supported by elevated rates of positive autoimmune serology and higher utilization of medications commonly used to treat autoimmune conditions in the G6PD-deficient group. Discussion: In conclusion, individuals with G6PD deficiency are at a higher risk of developing autoimmune disorders, infectious diseases, and allergic conditions. This large-scale observational study provides valuable insights into the comprehensive association between G6PD deficiency and infectious and immune-related diseases. The findings emphasize the importance of considering G6PD deficiency as a potential risk factor in clinical practice and further research is warranted to better understand the underlying mechanisms of these associations.

Prevalence of neurological diseases among patients with selective IgA deficiency.

Background: There are no published epidemiologic studies with regard to the prevalence of neurologic diseases among subjects with selective immunoglobulin A (IgA) deficiency (sIgAD). Objective: To investigate the prevalence of neurologic diseases among the Israeli population with sIgAD. Methods: A population-based case-control study among members of a large nationwide health maintenance organization in Israel providing services to > 700,000 members. The sIgAD group included individuals ≥4 years of age with a serum IgA level of <0.07 g/L and with a diagnosis of sIgAD. The control group was randomly sampled from the entire study population with a case-control ratio of five controls for each case (1:5), with exact matching for age, gender, ethnic group, and socioeconomic status category. Results: A total of 796 subjects ages 20.58 ± 15.46 years; 391 female subjects (49.1%) were identified as having sIgAD. The control group was constituted of 3980 matched subjects. The sIgAD group was characterized by a higher prevalence of autism spectrum disorder and tic disorders. Migraine was less prevalent in the sIgAD group (19 [2.39%]) than in the control group (168 [4.22%]), odds ratio (OR) 0.55 (95% confidence interval {CI}, 0.34-0.90); p = 0.016]. More cases of subjects with epilepsy were observed in the sIgAD group (14 [1.76%]) than in the control group (31 [0.80%]), OR 2.28 (95% CI, 1.12 - 4.44; p = 0.015). Conclusion: Our observation raises the question of the role of IgA in noninfectious diseases of the central nervous system. Further basic studies are needed to explain our observation.

Glucose-6-Phosphate Dehydrogenase Deficiency and Coronavirus Disease 2019.

In this cohort study conducted in a national healthcare organization in Israel, we found that individuals with glucose-6-phosphate dehydrogenase deficiency had an increased risk of coronavirus disease 2019 (COVID-19) infection and severity, with higher rates of hospitalization and diagnosed long COVID.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population. METHODS: In this retrospective cohort study, health records from G6PD deficient individuals were compared to matched controls in a national healthcare provider in Israel (Leumit Health Services). Rates of infectious diseases, allergic conditions and autoimmune disorders were compared between groups. RESULTS: The cohort included 7,473 G6PD deficient subjects (68.7% men) matched with 29,892 control subjects (4:1 ratio) of the same age, gender, socioeconomic status and ethnic group, followed during 14.3±6.2 years.Significantly increased rates for autoimmune disorders, infectious diseases and allergic conditions were observed throughout this period. Notable increases were observed for rheumatoid arthritis (OR 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR=18.70, P<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, P=0.001), and Hashimoto's thyroiditis (OR 1.26, P=0.001). These findings were corroborated with elevated rates of positive autoimmune serology and higher rates of treatment with medications commonly used to treat autoimmune conditions in the G6PD deficient group. CONCLUSION: G6PD deficient individuals suffer from higher rates of autoimmune disorders, infectious diseases, and allergic conditions.

A comparative study of chronic spontaneous urticaria and chronic mast cell mediated angioedema.

Background: Mast cell-mediated angioedema (MC-AE) is considered a form of chronic spontaneous urticaria (CSU). Objective: To investigate the clinical and laboratory features that distinguish MC-AE from antihistamine-responsive CSU (CSU), and antihistamine-resistant CSU (R-CSU) with and without concomitant AE. Methods: A retrospective observational study using the electronic patient record data base of patients with MC-AE, CSU, R-CSU, and sex- and age-matched control group (control), with a case-control ratio of 1:2. Results: A total of 986 subjects in the CSU group, 148 in the R-CSU group, 64 in the MC-AE group, and 1198 in the control group were compared. The R-CSU group without AE was characterized by lower total IgE levels (118.5 ± 84.7 IU/mL) and higher High sensitivity-C reactive protein (hs-CRP) levels (138.9 ± 94.2 IU/mL, p = 0.027; and 7.4 ± 6.9 mg/L versus 5.1 ± 6.8 mg/L, p = 0.001) than the CSU without AE group. The R-CSU group with AE was characterized by lower total IgE levels (112.1 ± 81.3 IU/mL) than the CSU group with AE (141.7 ± 89.5 IU/mL; p < 0.001), higher hs-CRP levels (7.1 ± 6.1 mg/L versus 4.7 ± 5.9 mg/L; p < 0.001). There were fewer female subjects in the MC-AE group (31 [48.4%]) than in the CSU with AE and in the R-CSU with AE 223 (67.8%) and 18 (66.7%), respectively; p = 0.012). MC-AE group was characterized by less eyelid/perioral/facial involvement and more limb involvement than in the CSU with AE and R-CSU with AE groups (p < 0.001). Conclusion: Low IgE in MC-AE and higher IgE in CSU may signify two distinct types of immune dysregulation. Due to clinical and laboratory differences between MC-AE and CSU, we suggest questioning the assumption that MC-AE is a form of CSU.

A higher frequency of physical activity is associated with reduced rates of SARS-CoV-2 infection.

BACKGROUND: Physical activity (PA) is associated with health benefits. Previous studies have shown that regular PA decreases the incidence of viral respiratory tract infections, but data on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are unavailable. OBJECTIVES: The objective of this study is to examine the association between PA frequency and SARS-CoV-2 infection. METHODS: A population-based cross-sectional study was conducted on data from 1 February 2020 to 31 December 2020, using the registry of Leumit Health Services (LHS), a national health maintenance organisation in Israel. All LHS patients aged 18 to 80 years who underwent at least one RT-PCR test for SARS-CoV-2 during the study period were included. We examined the association between PA frequency (hours per week) and being tested positive for SARS-CoV-2. RESULTS: Of 113,075 subjects tested for SARS-CoV-2 by RT-PCR (mean age 41.6 years, 54.4% female), 17,465 (15%) were positive. In the SARS-CoV-2-negative group, significantly more subjects were engaged with PA than in the SARS-CoV-2-positive group [crude odds ratio (OR) for any PA 0.75 (95% confidence interval (CI) 0.72-0.77)]. After adjusting for possible confounders, PA frequency had a significant negative association with the likelihood of being SARS-CoV-2 positive (adjusted OR 0.67, 95% CI 0.64-0.68). Moreover, as the frequency of PA increased, the ORs of being SARS-CoV-2-positive decreased (occasional PA: OR 0.71, 95% CI 0.67-0.74; PA 1-3 times/week: OR 0.62, 95% CI 0.58-0.65 and PA > 3 times/week: OR 0.54, 95% CI 0.49 - 0.59). CONCLUSION: Our large population-based study in patients undergoing SARS-CoV-2 RT-PCR testing showed that a higher frequency of PA is associated with a lower rate of positive test results.

Clinical and Molecular Characterization of a Rare Case of BNT162b2 mRNA COVID-19 Vaccine-Associated Myositis.

Initial clinical trials and surveillance data have shown that the most commonly administered BNT162b2 COVID-19 mRNA vaccine is effective and safe. However, several cases of mRNA vaccine-induced mild to moderate adverse events were recently reported. Here, we report a rare case of myositis after injection of the first dose of BNT162b2 COVID-19 mRNA vaccine into the left deltoid muscle of a 34-year-old, previously healthy woman who presented progressive proximal muscle weakness, progressive dysphagia, and dyspnea with respiratory failure. One month after vaccination, BNT162b2 vaccine mRNA expression was detected in a tissue biopsy of the right deltoid and quadriceps muscles. We propose this case as a rare example of COVID-19 mRNA vaccine-induced myositis. This study comprehensively characterizes the clinical and molecular features of BNT162b2 mRNA vaccine-associated myositis in which the patient was severely affected.

A Calculator for COVID-19 Severity Prediction Based on Patient Risk Factors and Number of Vaccines Received.

Vaccines have allowed for a significant decrease in COVID-19 risk, and new antiviral medications can prevent disease progression if given early in the course of the disease. The rapid and accurate estimation of the risk of severe disease in new patients is needed to prioritize the treatment of high-risk patients and maximize lives saved. We used electronic health records from 101,039 individuals infected with SARS-CoV-2, since the beginning of the pandemic and until 30 November 2021, in a national healthcare organization in Israel to build logistic models estimating the probability of subsequent hospitalization and death of newly infected patients based on a few major risk factors (age, sex, body mass index, hemoglobin A1C, kidney function, and the presence of hypertension, pulmonary disease, and malignancy) and the number of BNT162b2 mRNA vaccine doses received. The model's performance was assessed by 10-fold cross-validation: the area under the curve was 0.889 for predicting hospitalization and 0.967 for predicting mortality. A total of 50%, 80%, and 90% of death events could be predicted with respective specificities of 98.6%, 95.2%, and 91.2%. These models enable the rapid identification of individuals at high risk for hospitalization and death when infected, and they can be used to prioritize patients to receive scarce medications or booster vaccination. The calculator is available online.

Case of benralizumab-induced exacerbations of chronic spontaneous urticaria.

The role of IL-5 in chronic spontaneous urticarial (CSU) is unclear. It may be that benralizumab is an important bidirectional modifier of CSU; that is, blocking IL-5 may improve CSU in some patients, but it is possible that it may worsen CSU in others.

Clinical and Laboratory Features in the Israeli Population with COVID-19 Infection after Pfizer-BioNTech mRNA Booster Vaccination.

Background: Immune protection following either vaccination or infection with SARS-CoV-2 decreases over time. Objective: We aim to describe clinical and sociodemographic characteristics associated with COVID-19 infection at least 14 days after booster vaccination in the Israeli population. Methods: We conducted a population-based study among adult members of Leumit Health Services (LHS) in Israel. Nasopharyngeal swabs were examined for SARS-CoV-2 by real-time RT-PCR. The hematological and biochemical parameters in the peripheral blood before booster vaccination were evaluated. Results: Between 1 February 2021 and 30 November 2021, 136,683 individuals in LHS were vaccinated with a booster (third dose) of the BNT162b2 vaccine. Of these, 1171 (0.9%) were diagnosed with COVID-19 by testing positive for SARS-CoV-2 RT-PCR at least >14 days after the booster vaccination. The COVID-19-positive group was characterized by higher rates of chronic kidney disease than the matched COVID-19-negative group (43 (3.7%) vs. 3646 (2.7%); p = 0.039). Anemia, lower peripheral blood lymphocytes, monocytes, basophils, C3 Complement, cholesterol, and prothrombin time were also associated with COVID-19 after booster vaccination. Conclusion: People with chronic kidney disease and anemia should be included in possible future annual SARS-CoV-2 vaccination recommendations.