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.

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency and COVID-19.

In this cohort study conducted in a national healthcare organization in Israel, we found that individuals with Glucose-6-phosphate dehydrogenase (G6PD) deficiency have an increased risk of COVID-19 infection and severity, with higher rates of hospitalization and diagnosed long COVID.

The Association between Previous Antibiotic Consumption and SARS-CoV-2 Infection: A Population-Based Case-Control Study.

Background: The susceptibility to SARS-CoV-2 infection is complex and not yet fully elucidated, being related to many variables; these include human microbiome and immune status, which are both affected for a long period by antibiotic use. We therefore aimed to examine the association of previous antibiotic consumption and SARS-CoV-2 infection in a large-scale population-based study with control of known confounders. Methods: A matched case-control study was performed utilizing the electronic medical records of a large Health Maintenance Organization. Cases were subjects with confirmed SARS-CoV-2 infection (n = 31,260), matched individually (1:4 ratio) to controls without a positive SARS-CoV-2 test (n = 125,039). The possible association between previous antibiotic use and SARS-CoV-2 infection was determined by comparing antibiotic consumption in the previous 6 and 12 months between the cases and controls. For each antibiotic consumed we calculated the odds ratio (OR) for documented SARS-CoV-2 infection, 95% confidence interval (CI), and p-value using univariate and multivariate analyses. Results: The association between previous antibiotic consumption and SARS-CoV-2 infection was complex and bi-directional. In the multivariate analysis, phenoxymethylpenicillin was associated with increased rate of SARS-CoV-2 infection (OR 1.110, 95% CI: 1.036-1.191) while decreased rates were associated with previous consumption of trimethoprim-sulfonamides (OR 0.783, 95% CI: 0.632-0.971) and azithromycin (OR 0.882, 95% CI: 0.829-0.938). Fluroquinolones were associated with decreased rates (OR 0.923, 95% CI: 0.861-0.989) only in the univariate analysis. Previous consumption of other antibiotics had no significant association with SARS-CoV-2 infection. Conclusions: Previous consumption of certain antibiotic agents has an independent significant association with increased or decreased rates of SARS-CoV-2 infection. Plausible mechanisms, that should be further elucidated, are mainly antibiotic effects on the human microbiome and immune modulation.

The Association between Somatotropin Therapy and the Risk of SARS-CoV-2 Infection in Children with Short Stature: A Population-Based Cross-Sectional Study.

COVID-19 is a worldwide pandemic caused by SARS-CoV-2, to which adults are usually more susceptible than children. Growth hormone (GH) levels differ between children and adults and decrease with age. There is bidirectional crosstalk between the GH/insulin-like growth factor-1 (IGF-1) pathway and the immune system that plays a significant role in SARS-CoV-2 infection. We evaluated the association between somatotropin treatment (GH replacement therapy) and the risk for SARS-CoV-2 positivity (a marker for COVID-19 infection) in children with growth hormone issues (GHI): growth hormone deficiency (GHD) and idiopathic short stature (ISS). A population-based cross-sectional study in Leumit Health Services (LHS) was performed using the electronic health record (EHR) database. The rates of SARS-CoV-2 positivity were evaluated among children with GHI, treated or untreated with somatotropin. Higher rates of SARS-CoV-2 positivity were found in GHI children, influenced by the same confounders reported in the pediatric population. A lower prevalence of SARS-CoV-2 PCR positivity was found among the somatotropin-treated children. A multivariate analysis documented that somatotropin treatment was associated with a reduced risk of SARS-CoV-2 positivity (Odds Ratio (OR) = 0.47, Confidence Interval (CI) 0.24-0.94, p = 0.032). Thus, somatotropin might be a protective factor against SARS-CoV-2 infections, possibly related to its immunomodulatory activity.

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.

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.

Clinical and Socio-Demographic Variables Associated with the Diagnosis of Long COVID Syndrome in Youth: A Population-Based Study.

This study examines the demographic, clinical and socioeconomic factors associated with diagnosis of long COVID syndrome (LCS). Data of 20,601 COVID-19-positive children aged 5 to 18 years were collected between 2020 and 2021 in an Israeli database. Logistic regression analysis was used to evaluate the adjusted odds ratio for the characteristics of the COVID-19 infection and pre-COVID-19 morbidities. Children with LCS were significantly more likely to have been severely symptomatic, required hospitalization, and experienced recurrent acute infection within 180 days. In addition, children with LCS were significantly more likely to have had ADHD, chronic urticaria, and allergic rhinitis. Diagnosis of LCS is significantly associated with pre-COVID-19 ADHD diagnosis, suggesting clinicians treating ADHD children who become infected with COVID-19 remain vigilant for the possibility of LCS. Although the risk of severe COVID-19 infection and LCS in children is low, further research on possible morbidity related to LCS in children is needed.

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.

The Association of Previous Vaccination with Live-Attenuated Varicella Zoster Vaccine and COVID-19 Positivity: An Israeli Population-Based Study.

The Bacillus Calmette-Guérin (BCG) vaccine affords indirect protection against COVID-19, which is presumably due to priming of the innate immune system. It was hypothesized that the live attenuated Varicella Zoster (LAVZ) vaccine, recommended for the elderly population, would also protect against COVID-19 infection. A retrospective population-based cross-sectional study was conducted using the Leumit Health Services (LHS) database. LAVZ-vaccinated patients were matched with controls based on a propensity score model using 1:9 nearest-neighbor matching. Matching was based on age, gender, and the presence of some chronic disorders, which were selected according to their association with COVID-19 infection. Multivariate logistic regression analyses, adjusted for sex, age, smoking status, comorbidities, and chronic medications associated with COVID-19 risk, were used to estimate the association between LAVZ vaccination and COVID-19 RT-PCR results. Subjects (625) vaccinated with LAVZ and RT-PCR-tested for COVID-19 were identified. After 1:9 matching of subjects who received the LAVZ vaccine, 6250 subjects were included in the study. Multivariate logistic regression analysis demonstrated a significant and independent negative association between having received the LAVZ vaccine and the likelihood of COVID-19 infection (adjusted OR = 0.47 (95% CI 0.33-0.69, p < 0.001)). This association was further strengthened after separate analysis based on the time of LAVZ vaccination before COVID-19 RT-PCR testing. Individuals aged ≥50 years vaccinated with LAVZ had a decreased likelihood of being tested positive for COVID-19.

Chronic spontaneous urticaria after BNT162b2 mRNA (Pfizer-BioNTech) vaccination against SARS-CoV-2.

Background: The factors that trigger and exacerbate chronic spontaneous urticaria (CSU) are well known, but it is not unclear whether messenger RNA (mRNA) vaccination against severe acute respiratory syndrome coronavirus 2 can trigger new cases of CSU or a relapse of CSU after long-term remission. Objective: To study the clinical cases of patients with new-onset CSU and CSU in remission who relapsed within 3 months after BNT162b2 mRNA vaccination. Methods: All patients with a CSU diagnosis within 12 weeks of BNT162b2 mRNA vaccination were retrospectively identified and included in the new-onset CSU and the relapsed CSU groups. The first control group (CSU control group) retrospectively consisted of patients diagnosed with CSU in complete clinical remission for ≥ 6 months, with no CSU relapse after vaccination. The second control group (healthy control group) consisted of subjects who were fully vaccinated and without CSU, matched 1:2 for age and sex with patients with CSU. Results: Twenty-seven patients were included in the relapsed CSU group, 32 patients in the new-onset CSU group, 179 patients in the CSU control group, and 476 subjects in the healthy control group. The relapsed CSU and new-onset CSU groups had more allergic comorbidities overall (19 [70.4%] and 13 [40.6%], respectively) than the CSU control group and the healthy control group (50 [27.9%] and 110 [23.1%], respectively; p < 0.001). Multiple logistic regression analysis showed that a positive autologous serum skin test result, overall allergic comorbidities, and basopenia were positively associated with the probability of CSU relapse within 3 months after BNT162b2 mRNA vaccination (odds ratio [OR] 5.54 [95% confidence interval {CI}, 2.36-13.02], p < 0.001); OR 6.13 [95% CI, 2.52-14.89], p = 0.001; and OR 2.81 [95% CI, 1.17-6.72, p = 0.020, respectively). Conclusion: It is possible that BNT162b2 mRNA vaccination serves as a provoking and/or relapsing factor of CSU in individuals with allergic diseases and/or predisposed autoimmunity.

Large-Scale Study of Antibody Titer Decay following BNT162b2 mRNA Vaccine or SARS-CoV-2 Infection.

Immune protection following either vaccination or infection with SARS-CoV-2 is thought to decrease over time. We designed a retrospective study, conducted at Leumit Health Services in Israel, to determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated individuals. Antibody titers were measured between 31 January 2021, and 31 July 2021 in two mutually exclusive groups: (i) vaccinated individuals who received two doses of BNT162b2 vaccine and had no history of previous infection with COVID-19 and (ii) SARS-CoV-2 convalescents who had not received the vaccine. A total of 2653 individuals fully vaccinated by two doses of vaccine during the study period and 4361 convalescent patients were included. Higher SARS-CoV-2 IgG antibody titers were observed in vaccinated individuals (median 1581 AU/mL IQR [533.8-5644.6]) after the second vaccination than in convalescent individuals (median 355.3 AU/mL IQR [141.2-998.7]; p < 0.001). In vaccinated subjects, antibody titers decreased by up to 38% each subsequent month while in convalescents they decreased by less than 5% per month. Six months after BNT162b2 vaccination 16.1% subjects had antibody levels below the seropositivity threshold of <50 AU/mL, while only 10.8% of convalescent patients were below <50 AU/mL threshold after 9 months from SARS-CoV-2 infection. This study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group.

Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection: test negative design study.

OBJECTIVES: To determine whether time elapsed since the second injection of the Pfizer-BioNTech BNT162b2 mRNA vaccine was significantly associated with the risk of covid-19 infection after vaccination in people who received two vaccine injections. DESIGN: Test negative design study. SETTING: Electronic health records of a large state mandated healthcare organisation, Israel. PARTICIPANTS: Adults aged ≥18 years who had received a reverse transcription polymerase chain reaction (RT-PCR) test between 15 May 2021 and 17 September 2021, at least three weeks after their second vaccine injection, had not received a third vaccine injection, and had no history of covid-19 infection. MAIN OUTCOME MEASURES: Positive result for the RT-PCR test. Individuals who tested positive for SARS-CoV-2 and controls were matched for week of testing, age category, and demographic group (ultra-orthodox Jews, individuals of Arab ancestry, and the general population). Conditional logistic regression was adjusted for age, sex, socioeconomic status, and comorbid conditions. RESULTS: 83 057 adults received an RT-PCR test for SARS-CoV-2 during the study period and 9.6% had a positive result. Time elapsed since the vaccine injection was significantly longer in individuals who tested positive (P<0.001). Adjusted odds ratio for infection at time intervals >90 days since vaccination were significantly increased compared with the reference of <90 days: 2.37 (95% confidence interval 1.67 to 3.36) for 90-119 days, 2.66 (1.94 to 3.66) for 120-149 days, 2.82 (2.07 to 3.84) for 150-179 days, and 2.82 (2.07 to 3.85) for ≥180 days (P<0.001 for each 30 day interval). CONCLUSIONS: In this large population of adults tested for SARS-CoV-2 by RT-PCR after two doses of mRNA BNT162b2 vaccine, a gradual increase in the risk of infection was seen for individuals who received their second vaccine dose after at least 90 days.

Specific Susceptibility to COVID-19 in Adults with Down Syndrome.

The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer's disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.

The Association between ADHD and the Severity of COVID-19 Infection.

OBJECTIVE: Patients with ADHD are at increased risk of acquiring COVID-19. The present study assessed the possibility that ADHD also increases the risk of severe COVID-19 infection. METHOD: We assessed 1,870 COVID-19 positive patients, aged 5 to 60 years, registered in the database of Leumit Health Services (LHS, Israel), February to -June 2020, of whom 231 with ADHD. Logistic regression analysis models evaluated the association between ADHD and the dependent variables of being symptomatic/referral to hospitalization, controlling for demographic and medical variables. RESULTS: Age, male sex, and BMI were confirmed to be significant risk factors for increased COVID-19 severity. ADHD was found to be associated with increased severity of COVID-19 symptoms (OR = 1.81, 95% CI [1.29, 2.52], p < .05) and referral to hospitalization (OR =1.93, 95% CI [1.06, 3.51], p = .03). CONCLUSION: ADHD is associated with poorer outcomes in COVID-19 infection.

The use of aspirin for primary prevention of cardiovascular disease is associated with a lower likelihood of COVID-19 infection.

Acetylsalicylic acid (aspirin) is commonly used for primary and secondary prevention of cardiovascular diseases. Aspirin use is associated with better outcomes among COVID-19 positive patients. We hypothesized that the aspirin use for primary cardiovascular disease prevention might have a protective effect on COVID-19 susceptibility and disease duration. We conducted a retrospective population-based cross-sectional study, utilizing data from the Leumit Health Services database. The proportion of patients treated with aspirin was significantly lower among the COVID-19-positive group, as compared to the COVID-19-negative group [73 (11.03%) vs. 1548 (15.77%); P = 0.001]. Aspirin use was associated with lower likelihood of COVID-19 infection, as compared to nonusers (adjusted OR 0.71 (95% CI, 0.52 to 0.99; P = 0.041). Aspirin users were older (68.06 ± 12.79 vs. 56.63 ± 12.28 years of age; P < 0.001), presented a lower BMI (28.77 ± 5.4 vs. 30.37 ± 4.55; P < 0.0189), and showed higher prevalence of hypertension (56, 76.71%), diabetes (47, 64.38%), and COPD (11, 15.07%) than the aspirin nonusers (151, 25.64%, P < 0.001; 130, 22.07%, P < 0.001; and 43, 7.3%, P = 0.023, respectively). Moreover, COVID-19 disease duration (considered as the time between the first positive and second negative COVID-19 RT-PCR test results) among aspirin users was significantly shorter, as compared to aspirin nonusers (19.8 ± 7.8 vs. 21.9 ± 7.9 P = 0.045). Among hospitalized COVID-positive patients, a higher proportion of surviving subjects were treated with aspirin (20, 19.05%), as opposed to 1 dead subject (14.29%), although this difference was not significant (P = 0.449). In conclusion, we observed an inverse association between the likelihood of COVID-19 infection, disease duration and mortality, and aspirin use for primary prevention.

The association of previous influenza vaccination and coronavirus disease-2019.

Studies have shown similarities in the structure of influenza and coronaviruses, in their binding receptors and in patterns of immune responses; and that influenza vaccine can induce cross-immunity. We examined the association of previous influenza vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, resulting in coronavirus disease-2019 (COVID-19), among 715,164 members of a health maintenance organization. In a multivariate regression model, the odds ratios for SARS-CoV-2 infection among individuals vaccinated for influenza in 2018-2019, 2019-2020, and in both seasons, compared to non-vaccinated individuals, were 0.82 (95% CI 0.68-0.99, p = .048), 0.79 (95% CI 0.67-0.98, p = .005), and 0.76 (95% CI 0.61-0.97, p = .004), respectively. Based on our findings, administration of influenza vaccine before the influenza season is highly recommended to reduce the burden of influenza, which is critical in scenarios of outbreaks of both influenza and SARS-CoV-2 infections, and also regarding its association with reduced rate of COVID-19.