Post-acute sequelae of COVID-19 infection.

To determine if people infected with SARS-CoV-2 were at higher risk of developing selected medical conditions post-recovery, data were extracted from the database of a large health maintenance organization (HMO) in Israel between March 2020 and May 2021. For each condition, a condition-naïve group prior to COVID-19 (PCR-positive) infection were compared to a condition-naïve, non-COVID-19 infected group, matched by gender, age, socioeconomic status, minority group status and number of months visited primary care physician (PCP) in previous year. Diagnosis and recuperation dates for each COVID-19 infected participant were applied to their matched comparison participant (1:1 ratio). Incidence of each condition was measured between date of recuperation and end of study period for each group and Cox regression models developed to determine hazard ratios by group status, controlling for demographic and health variables. Crude and adjusted incidence rates were higher for the COVID-19 infected group than those not infected with COVID-19 for treatment for depression/anxiety, sleep disturbance, diagnosis of deep venous thrombosis, lung disease and fibromyalgia. Differences in incidence were no longer observed between the two groups for treatment of sleep disturbance, and diagnosis of lung disease when those hospitalized during the acute-phase of illness (any reason) were excluded. No difference was found by COVID-19 infection status for post-acute incidence of diabetes, cerebrovascular accident, myocardial infarction, acute kidney disease, hypertension and ischemic heart disease. Patients post-COVID-19 infection should be evaluated for depression, anxiety, sleep disturbance, DVT, lung disease and fibromyalgia.

Effectiveness of the mRNA BNT162b2 vaccine six months after vaccination: findings from a large Israeli HMO (preprint)

Israel is currently experiencing a new wave of CoVid-19 infection, six months after implementing a national vaccination campaign. We carried out three discrete analyses using data from a large Israeli HMO to determine whether IgG levels of those fully vaccinated drop over time, the relationship between IgG titer and subsequent PCR-confirmed infection, and compare PCR-confirmed infection rates by period of vaccination. We found that mean IgG antibody levels steadily decreased over the six-month period in the total tested population, and in all age groups. An inverse relationship was found between IgG titer and subsequent CoVid-19 infection (PCR-positive). Those participants vaccinated in the first two months of the campaign were more likely to become infected than those subsequently vaccinated. The 60+ vaccinated had lower initial IgG levels, and were at greater risk of infection. The findings support the decision to add a booster vaccine for those aged 60 and over. Article Summary LineThe BNT162b2 vaccine was found to be less effective in protecting against Covid-19 infection after six months, and vaccination with a third dose is indicated.

Pfizer-BioNTech Vaccine Effectiveness Against SARS-CoV-2 Infection: Findings From a Large Observational Study in Israel (preprint)

Background: Development of an effective vaccine against Covid-19 is crucial to reducing infection. mRNA BNT162b2, developed and manufactured by Pfizer-BioNTech, was one of the first FDA-approved vaccinations reporting high efficacy (95%) and minimal side effects. Evaluating effectiveness of mRNA BNT162b2 in a general population has been made possible after the implementation of a nation-wide vaccination program in Israel.Methods: This retrospective cohort study was carried out in Maccabi HealthCare services, Israel among 1·6 million members aged 16 and over. The population was divided into those who were at least seven days post- second vaccination and those who had not been vaccinated. Number of days till the end of the study or Covid-19 infection, Covid-19-related hospitalization and mortality was calculated for each participant between 18.1.2021 to 25.4.2021. Participants who had reached day eight after second vaccination during the study period could contribute days to both groups. Vaccine efficacy (VE) was calculated using a conditional Poisson model, controlling for age group, gender, hypertension, diabetes and obesity, fitted within clusters defined by geographical statistical area and calendar week. Findings: mRNA BNT162b2 was found effective for the total population group for infection, hospitalization and mortality, with adjusted VE of 93·0% (CI:92·6-93·4%), 93·4% (CI:91·9-94·7%) and 91·1% (CI:86·5-94·1%) respectively. VE for infection was lower for participants aged 75 and over, and for those with hypertension, diabetes and obesity. Interpretation:This study strengthens the evidence that the Pfizer-BioNTech vaccination is effective in preventing infection, hospitalization and mortality.Funding: Maccabi HealthCare Services.Declaration of Interest: No conflict of interests to report. Authors #1,2,4 & 5 are employed by Maccabi HealthCare Services.Ethical Approval: The study was approved by Maccabi HealthCare Services IRB and Maccabi Helsinki committee (#0178-20-MHS).

Longitudinal symptom dynamics of COVID-19 infection in primary care (preprint)

Objective : Data regarding the clinical characteristics of COVID-19 infection is rapidly accumulating. However, most studies thus far are based on hospitalized patients and lack longitudinal follow up. As the majority of COVID-19 cases are not hospitalized, prospective studies of symptoms in the population presenting to primary care are needed. Here, we assess the longitudinal dynamic of clinical symptoms in non-hospitalized individuals prior to and throughout the diagnosis of SARS-CoV-2 infection. Design Data on symptoms were extracted from electronic health records (EHR) consisting of both results of PCR tests and symptoms recorded by primary care physicians, and linked longitudinal self reported symptoms. Setting The second largest Health Maintenance Organization in Israel , Maccabi Health Services Participants From 1/3/2020 to 07/06/2020, information on symptoms from either surveys or primary care visits was available for 206,377 individuals, including 2,471 who tested positive for COVID-19. Main Outcomes Longitudinal prevalence of clinical symptoms in COVID-19 infection diagnosed by PCR testing for SARS-CoV-2 from nasopharyngeal swabs. Results: In adults, the most prevalent symptoms recorded in EHR were cough (11.6%), fever (10.3%), and myalgia (7.7%) and the most prevalent self-reported symptoms were cough (21%), fatigue (19%) and rhinorrhea and/or nasal congestion (17%). In children, the most prevalent symptoms recorded in the EHR were fever (7%), cough (5.5%) and abdominal pain (2.4%) . Emotional disturbances were documented in 15.9% of the positive adults and 4.2% of the children. Loss of taste and smell, either self-reported or documented by a physician, 3 weeks prior to testing, were the most discriminative symptoms in adults (OR =11.18 and OR=5.47 respectively). Additional symptoms included self reported headache (OR = 2.03) and fatigue (OR = 1.73) and a documentation of syncope, rhinorrhea (OR = 2.09 for both ) and fever (OR= 1.62 ) by a physician. Mean time to recovery was 23.5 +- 9.9 days. Children had a significantly shorter disease duration (21.7 +- 8.8 days, p-value=0.01). Several symptoms, including fatigue, myalgia, runny nose and shortness of breath were reported weeks after recovery. Conclusions As the COVID-19 pandemic progresses rapidly worldwide, obtaining accurate information on symptoms and their progression is of essence. Our study shed light on the full clinical spectrum of symptoms experienced by infected individuals in primary care, and may alert physicians for the possibility of COVID-19 infection.

Who should we test for COVID-19?A triage model built from national symptom surveys (preprint)

The gold standard for COVID-19 diagnosis is detection of viral RNA in a reverse transcription PCR test. Due to global limitations in testing capacity, effective prioritization of individuals for testing is essential. Here, we devised a model that estimates the probability of an individual to test positive for COVID-19 based on answers to 9 simple questions regarding age, gender, presence of prior medical conditions, general feeling, and the symptoms fever, cough, shortness of breath, sore throat and loss of taste or smell, all of which have been associated with COVID-19 infection. Our model was devised from a subsample of a national symptom survey that was answered over 2 million times in Israel over the past 2 months and a targeted survey distributed to all residents of several cities in Israel. Overall, 43,752 adults were included, from which 498 self-reported as being COVID-19 positive. We successfully validated the model on held-out individuals from Israel where it achieved a positive predictive value (PPV) of 46.3% at a 10% sensitivity and demonstrated its applicability outside of Israel by further validating it on an independently collected symptom survey dataset from the U.K., U.S. and Sweden, where it achieved a PPV of 34.7% at 10% sensitivity. Moreover, evaluating the models performance on this latter independent dataset on entries collected one week prior to the PCR test and up to the day of the test we found the highest performance on the day of the test. As our tool can be used online and without the need of exposure to suspected patients, it may have worldwide utility in combating COVID-19 by better directing the limited testing resources through prioritization of individuals for testing, thereby increasing the rate at which positive individuals can be identified and isolated.

The effect of a national lockdown in response to COVID-19 pandemic on the prevalence of clinical symptoms in the population (preprint)

The vast and rapid spread of COVID-19 calls for immediate action from policy-makers, and indeed, many countries have implemented lockdown measures to varying degrees. Here, we utilized nationwide surveys that assess COVID-19 associated symptoms to analyse the effect of the lockdown policy in Israel on the prevalence of clinical symptoms in the population. Daily symptom surveys were distributed online and included questions regarding fever, respiratory symptoms, gastrointestinal symptoms, anosmia and ageusia. A total of 2,071,349 survey responses were analysed. We defined a single measure of symptoms, Symptoms Average (SA), as the mean number of symptoms reported by responders. Data were collected between March 15th to June 3rd, 2020. Notably, on the population level, following severe lockdown measures between March 15th and April 20th, SA sharply declined by 83.8% (p < 0.05), as did every single symptom, including the most common symptoms reported by our responders, cough and rhinorrhea and\or nasal congestion, which decreased by 74.1% (p < 0.05) and 69.6% (p < 0.05), respectively. Similarly, on the individual level, analysis of repeated responses from the same individuals (N = 208,637) over time also showed a decrease in symptoms during this time period. Moreover, the reduction in symptoms was observed in all cities in Israel, and in several stratifications of demographic characteristics. Different symptoms exhibit different reduction dynamics, suggesting differences in the nature of the symptoms or in the underlying medical conditions. Between May 13th and June 3rd, following several subsequent lockdown relief measures, we observed an increase in individual symptoms and in SA, which increased by 31.42%. Overall, these results demonstrate a profound decrease in a variety of clinical symptoms following the implementation of a lockdown in Israel, and an increase in the prevalence of symptoms following the loosening of lockdown restrictions. As our survey symptoms are not specific to COVID-19 infection, this effect likely represents an overall nationwide reduction in the prevalence of infectious diseases, including COVID-19. This quantification may be of major interest for COVID-19 pandemic, as many countries consider implementation of lockdown strategies.