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 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.

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.

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.

Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study.

Vitamin D deficiency is a worldwide pandemic. The aim of this study was to evaluate associations of plasma 25(OH)D levels with the likelihood of coronavirus disease 2019 (COVID-19) infection and hospitalization. The study population included the 14 000 members of Leumit Health Services, who were tested for COVID-19 infection from February 1st to April 30th , 2020, and who had at least one previous blood test for the plasma 25(OH)D level. 'Suboptimal' or 'low' plasma 25(OH)D level was defined as plasma 25-hydroxyvitamin D, or 25(OH)D, concentration below the level of 30 ng/mL. Of 7807 individuals, 782 (10.02%) were COVID-19-positive, and 7025 (89.98%) COVID-19-negative. The mean plasma vitamin D level was significantly lower among those who tested positive than negative for COVID-19 [19.00 ng/mL (95% confidence interval (CI) 18.41-19.59) vs. 20.55 (95% CI: 20.32-20.78)]. Univariate analysis demonstrated an association between the low plasma 25(OH)D level and increased likelihood of COVID-19 infection [crude odds ratio (OR) of 1.58 (95% CI: 1.24-2.01, P < 0.001)], and of hospitalization due to the SARS-CoV-2 virus [crude OR of 2.09 (95% CI: 1.01-4.30, P < 0.05)]. In multivariate analyses that controlled for demographic variables, and psychiatric and somatic disorders, the adjusted OR of COVID-19 infection [1.45 (95% CI: 1.08-1.95, P < 0.001)] and of hospitalization due to the SARS-CoV-2 virus [1.95 (95% CI: 0.98-4.845, P = 0.061)] were preserved. In the multivariate analyses, age over 50 years, male gender and low-medium socioeconomic status were also positively associated with the risk of COVID-19 infection; age over 50 years was positively associated with the likelihood of hospitalization due to COVID-19. We concluded that low plasma 25(OH)D levels appear to be an independent risk factor for COVID-19 infection and hospitalization.

COVID-19 Susceptibility in Bronchial Asthma.

BACKGROUND: Bronchial asthma has not been adequately assessed in coronavirus disease 2019 (COVID-19). Respiratory allergy is associated with significant reductions in the expression of angiotensin-converting enzyme 2 receptor, which is the entry receptor for COVID-19. OBJECTIVE: To observe COVID-19 susceptibility in patients with bronchial asthma, analyze the prevalence of asthma in a large cohort of consecutive outpatient subjects who were tested with the RT-PCR assay for COVID-19. METHODS: This was a retrospective population-based cross-sectional study using data from a large nationwide health maintenance organization in Israel. All health maintenance organization enrollees who had been tested for COVID-19 from February to June 2020 were included. Differences in demographic and clinical characteristics between the subjects with negative and positive COVID-19 RT-PCR test results and between COVID-19 RT-PCR-positive subjects with and without asthma were analyzed. RESULTS: A total of 37,469 subjects were tested for COVID-19 RT-PCR, and results for 2,266 (6.05%) of them were positive. A significantly higher proportion of smokers was observed in the COVID-19-negative group than in the COVID-19-positive group (4734 [13.45%] vs 103 [4.55%]; P < .001). Asthma was found in 153 (6.75 %) subjects of the COVID-19-positive group and in 3388 (9.62%) subjects of the COVID-19-negative group (P < .001). No significant impact of antileukotrienes, inhaled corticosteroids, and long-acting beta-blockers use was revealed on COVID-19 positivity proportions. Multiple logistic regression analysis adjusted for sex, age, smoking, and comorbidity revealed a negative association of asthma with the likelihood of being positive for COVID-19 (odds ratio, 0.71; 95% CI, 0.58-0.87; P = .001). CONCLUSIONS: We observed lower COVID-19 susceptibility in patients with preexisting asthma.

Haemoglobin A1c is a predictor of COVID-19 severity in patients with diabetes.

AIM: Poor outcomes of coronavirus disease 2019 (COVID-19) have been linked to diabetes, but its relation to pre-infection glycaemic control is still unclear. MATERIALS AND METHODS: To address this question, we report here the association between pre-infection Haemoglobin A1c (HbA1c) levels and COVID-19 severity as assessed by need for hospitalization in a cohort of 2068 patients with diabetes tested for COVID-19 in Leumit Health Services (LHSs), Israel, between 1 February and 30 April 2020. Using the LHS-integrated electronic medical records system, we were able to collect a large amount of clinical information including age, sex, socio-economic status, weight, height, body mass index, HbA1c, prior diagnosis of ischaemic heart disease, depression/anxiety, schizophrenia, dementia, hypertension, cerebrovascular accident, congestive heart failure, smoking, and chronic lung disease. RESULTS: Of the patients included in the cohort, 183 (8.85%) were diagnosed with COVID-19 and 46 were admitted to hospital. More hospitalized patients were female, came from higher socio-economic background and had a higher baseline HbA1c. A prior diagnosis of cerebrovascular accident and chronic lung disease conferred an increased risk of hospitalization but not obesity or smoking status. In a multivariate analysis, controlling for multiple prior clinical conditions, the only parameter associated with a significantly increased risk for hospitalization was HbA1c ≥ 9%. CONCLUSION: Using pre-infection glycaemic control data, we identify HbA1c as a clear predictor of COVID-19 severity. Pre-infection risk stratification is crucial to successfully manage this disease, efficiently allocate resources, and minimize the economic and social burden associated with an undiscriminating approach.

ADHD as a Risk Factor for Infection With Covid-19.

Background: ADHD limits the ability to comply with Covid-19 prevention recommendations. We hypothesized that ADHD constitutes a risk factor for Covid-19 infection and that pharmacotherapy may lower that risk. Methods: Study population included all subjects (N = 14,022) registered with Leumit Health Services between February 1st and April 30, 2020, who underwent at least one Covid-19 test. Data were collected from the electronic health records. Purchasing consecutively at least three ADHD-medication-prescriptions during past year was considered drug-treatment. Results: A total of 1,416 (10.1%) subjects (aged 2 months-103 years) were Covid-19-positive.They were significantly younger, and had higher rates of ADHD (adjOR 1.58 (95% CI 1.27-1.96, p < .001) than Covid-19-negative subjects. The risk for Covid-19-Positive was higher in untreated-ADHD subjects compared to non-ADHD subjects [crudeOR 1.61 (95% CI 1.36-1.89, p < .001)], while no higher risk was detected in treated ones [crudeOR 1.07 (95% CI 0.78-1.48, p = .65)]. Conclusion: Untreated ADHD seems to constitute a risk factor for Covid-19 infection while drug-treatment ameliorates this effect.