Risk of SARS-CoV-2 infection and hospitalization in individuals with natural, vaccine-induced and hybrid immunity: a retrospective population-based cohort study from Estonia.

A large proportion of the world's population has some form of immunity against SARS-CoV-2, through either infection ('natural'), vaccination or both ('hybrid'). This retrospective cohort study used data on SARS-CoV-2, vaccination, and hospitalization from national health system from February 2020 to June 2022 and Cox regression modelling to compare those with natural immunity to those with no (Cohort1, n = 94,982), hybrid (Cohort2, n = 47,342), and vaccine (Cohort3, n = 254,920) immunity. In Cohort 1, those with natural immunity were at lower risk for infection during the Delta (aHR 0.17, 95%CI 0.15-0.18) and higher risk (aHR 1.24, 95%CI 1.18-1.32) during the Omicron period than those with no immunity. Natural immunity conferred substantial protection against COVID-19-hospitalization. Cohort 2-in comparison to natural immunity hybrid immunity offered strong protection during the Delta (aHR 0.61, 95%CI 0.46-0.80) but not the Omicron (aHR 1.05, 95%CI 0.93-1.1) period. COVID-19-hospitalization was extremely rare among individuals with hybrid immunity. In Cohort 3, individuals with vaccine-induced immunity were at higher risk than those with natural immunity for infection (Delta aHR 4.90, 95%CI 4.48-5.36; Omicron 1.13, 95%CI 1.06-1.21) and hospitalization (Delta aHR 7.19, 95%CI 4.02-12.84). These results show that risk of infection and severe COVID-19 are driven by personal immunity history and the variant of SARS-CoV-2 causing infection.

The use of prescription drugs and health care services during the 6-month post-COVID-19 period.

COVID-19 and other acute respiratory viruses can have a long-term impact on health. We aimed to assess the common features and differences in the post-acute phase of COVID-19 compared with other non-chronic respiratory infections (RESP) using population-based electronic health data. We applied the self-controlled case series method where prescription drugs and health care utilisation were used as indicators of health outcomes during the six-month-long post-acute period. The incidence rate ratios of COVID-19 and RESP groups were compared. The analysis included 146 314 individuals. Out of 5452 drugs analysed, 14 had increased administration after COVID-19 with drugs for cardiovascular diseases (trimetazidine, metoprolol, rosuvastatin) and psychotropic drugs (alprazolam, zolpidem, melatonin) being most prevalent. The health impact of COVID-19 was more apparent among females and individuals with non-severe COVID-19. The increased risk of exacerbating pre-existing conditions was observed for the COVID-19 group. COVID-19 vaccination did not have effect on drug prescriptions but lowered the health care utilisation during post-acute period. Compared with RESP, COVID-19 increased the use of outpatient services during the post-infection period. The long-term negative impact of COVID-19 on life quality must be acknowledged, and supportive health care and public health services provided.

Fear of COVID-19 among patients with prior SARS-CoV-2 infection: A cross-sectional study in Estonian family practices.

BACKGROUND: Fear of coronavirus disease (COVID-19) has been associated with significant health effects. OBJECTIVES: To assess COVID-19 fear and investigate factors associated with higher fear among COVID-19 survivors over 6 months after infection. METHODS: Cross-sectional study using multistage sampling (family practices within the highest 5th percentile of numbers of SARS-CoV-2 infected patients and random sample of patients within these practices) performed from March 15 to 17 July 2021. Adult patients with a laboratory-confirmed history of COVID-19 were recruited for a self-administered 79-item questionnaire including demographics, self-rated health, physical activity, COVID-19 characteristics, severity and the fear of COVID-19 Scale (FCV-19S). Comorbidity data were extracted from Estonian Health Insurance Fund. Logistic regression models were used to evaluate factors associated with COVID-19 fear. RESULTS: Of 341 participants included, 60% were women, 24.2% were hospitalised due to COVID-19 and 22.2% had long COVID, 143 (42%) participants reported high levels of fear (cut-off FCV-19S >17.8). Higher fear was associated with being female (aOR 2.12, 95% CI 1.14-3.95), age ≥61 years (aOR 3.23, 95% CI 1.28-8.16), two-member-households (aOR 3.70, 95% CI 1.40-9.77) physical inactivity 6 months prior to COVID-19 (aOR 3.53, 95% CI 1.26-9.95), and symptom severity during acute COVID-19. Long COVID was not associated with higher COVID-19 fear (aOR 1.82 95% CI 0.91-3.63). CONCLUSION: Almost half of participants reported COVID-19 fear more than 6 months after infection. Greater fear was associated with sociodemographic factors, physical activity prior to COVID-19 and COVID-19 symptom severity. There is a need to target this population to develop appropriate interventions.

A retrospective cohort study of incidence and risk factors for severe SARS-CoV-2 breakthrough infection among fully vaccinated people.

SARS-CoV-2 vaccination is currently the mainstay in combating the COVID-19 pandemic. However, there are still people among vaccinated individuals suffering from severe forms of the disease. We conducted a retrospective cohort study based on data from nationwide e-health databases. The study included 184,132 individuals who were SARS-CoV-2 infection-naive and had received at least a primary series of COVID-19 vaccination. The incidence of BTI (breakthrough infection) was 8.03 (95% CI [confidence interval] 7.95⎼8.13/10,000 person-days), and for severe COVID-19 it was 0.093 (95% CI 0.084⎼ 0.104/10,000 person-days). The protective effect of vaccination against severe COVID-19 remained constant for up to six months, and the booster dose offered an additional pronounced benefit (hospitalization aHR 0.32, 95% CI 0.19⎼0.54). The risk of severe COVID-19 was higher among those ≥ 50 years of age (aHR [adjusted hazard ratio] 2.06, 95% CI 1.25⎼3.42) and increased constantly with every decade of life. Male sex (aHR 1.32, 95% CI 1.16⎼1.45), CCI (The Charlson Comorbidity Index) score ≥ 1 (aHR 2.09, 95% CI 1.54⎼2.83), and a range of comorbidities were associated with an increased risk of COVID-19 hospitalization. There are identifiable subgroups of COVID-19-vaccinated individuals at high risk of hospitalization due to SARS-CoV-2 infection. This information is crucial to driving vaccination programs and planning treatment strategies.

Post-acute sequelae of COVID-19 among hospitalized patients in Estonia: Nationwide matched cohort study.

BACKGROUND: Post-acute COVID-19 sequelae refers to a variety of health complications involving different organ systems that have been described among individuals after acute phase of illness. Data from unselected population groups with long-time follow up is needed to comprehensively describe the full spectrum of post-acute COVID-19 complications. METHODS: In this retrospective nationwide cohort study, we used data obtained from electronic health record database. Our primary cohort were adults hospitalized with confirmed COVID-19 and matched (age, sex, Charlson Comorbidity Index) unaffected controls from general population. Individuals included from February 2020 until March 2021 were followed up for 12 months. We estimated risks of all-cause mortality, readmission and incidence of 16 clinical sequelae after acute COVID-19 phase. Using a frailty Cox model, we compared incidences of outcomes in two cohorts. RESULTS: The cohort comprised 3949 patients older than 18 years who were alive 30 days after COVID-19 hospital admission and 15511 controls. Among cases 40.3% developed at least one incident clinical sequelae after the acute phase of SARS-CoV-2 infection, which was two times higher than in general population group. We report substantially higher risk of all-cause mortality (adjusted hazard ratio (aHR) = 2.57 (95%CI 2.23-2.96) and hospital readmission aHR = 1.73 (95%CI 1.58-1.90) among hospitalized COVID-19 patients. We found that the risks for new clinical sequalae were significantly higher in COVID-19 patients than their controls, especially for dementia aHR = 4.50 (95% CI 2.35-8.64), chronic lower respiratory disease aHR = 4.39 (95% CI 3.09-6.22), liver disease aHR 4.20 (95% CI 2.01-8.77) and other (than ischemic) forms of heart diseases aHR = 3.39 (95%CI 2.58-4.44). CONCLUSION: Our results provide evidence that the post-acute COVID-19 morbidity within the first year after COVID-19 hospitalization is substantial. Risks of all-cause mortality, hospitalisation and majority of clinical sequelae were significantly higher in hospitalized COVID-19 patients than in general population controls and warrant targeted prevention efforts.

Clinical characteristics and risk factors for COVID-19 infection and disease severity: A nationwide observational study in Estonia.

BACKGROUND: COVID-19 pandemic has led to overloading of health systems all over the world. For reliable risk stratification, knowledge on factors predisposing to SARS-CoV-2 infection and to severe COVID-19 disease course is needed for decision-making at the individual, provider, and government levels. Data to identify these factors should be easily obtainable. METHODS AND FINDINGS: Retrospective cohort study of nationwide e-health databases in Estonia. We used longitudinal health records from 66,295 people tested positive for SARS-CoV-2 RNA from 26 February 2020 to 28 February 2021 and 254,958 randomly selected controls from the reference population with no known history of SARS-CoV-2 infection or clinical COVID-19 diagnosis (case to control ratio 1:4) to predict risk factors of infection and severe course of COVID-19. We analysed sociodemographic and health characteristics of study participants. The SARS-CoV-2 infection risk was slightly higher among women, and was higher among those with comorbid conditions or obesity. Dementia (RRR 3.77, 95%CI 3.30⎼4.31), renal disease (RRR 1.88, 95%CI 1.56⎼2.26), and cerebrovascular disease (RRR 1.81, 95%CI 1.64⎼2.00) increased the risk of infection. Of all SARS-CoV-2 infected people, 92% had a non-severe disease course, 4.8% severe disease (requiring hospitalisation), 1.7% critical disease (needing intensive care), and 1.5% died. Male sex, increasing age and comorbid burden contributed significantly to more severe COVID-19, and the strength of association for male sex increased with the increasing severity of COVID-19 outcome. The strongest contributors to critical illness (expressed as RRR with 95% CI) were renal disease (7.71, 4.71⎼12.62), the history of previous myocardial infarction (3.54, 2.49⎼5.02) and obesity (3.56, 2.82⎼4.49). The strongest contributors to a lethal outcome were renal disease (6.48, 3.74⎼11.23), cancer (3.81, 3.06⎼4.75), liver disease (3.51, 1.36⎼9.02) and cerebrovascular disease (3.00, 2.31⎼3.89). CONCLUSIONS: We found divergent effect of age and gender on infection risk and severity of COVID-19. Age and gender did not contribute substantially to infection risk, but did so for the risk of severe disease Co-morbid health conditions, especially those affecting renin-angiotensin system, had an impact on both the risk of infection and severe disease course. Age and male sex had the most significant impact on the risk of severe COVID-19. Taking into account the role of ACE2 receptors in the pathogenesis of SARS-CoV-2 infection, as well as its modulating action on the renin-angiotensin system in cardiovascular and renal diseases, further research is needed to investigate the influence of hormonal status on ACE2 expression in different tissues, which may be the basis for the development of COVID-19 therapies.

Long-term mortality following SARS-CoV-2 infection: A national cohort study from Estonia.

Background: The objective of this study was to describe 12-month mortality following SARS-CoV-2 infection compared with a reference population with no history of SARS-CoV-2. Methods: Nationwide cohort study using electronic health care data on SARS-CoV-2 RNA positive cases (n= 66,287) and reference group subjects (n=254,969) with linkage to SARS-CoV-2 testing and death records. Findings: People infected with SARS-COV-2 had more than three times the risk of dying over the following year compared with those who remained uninfected (aHR 3·1, 95%CI 2·9-3·3). Short-term mortality (up to 5 weeks post-infection) was significantly higher among COVID-19 group (1623·0/10 000) than in the reference group (118/10 000). For COVID-19 cases aged 60 years or older, increased mortality persisted until the end of the first year after infection, and was related to increased risk for cardiovascular (aHR 2·1, 95%CI 1·8-2·3), cancer (aHR 1·5, 95%CI 1·2-1·9), respiratory system diseases (aHR 1·9, 95%CI 1·2-3·0), and other causes of death (aHR 1·8, 95%CI 1·4-2·2). Interpretation: Increased risk of death from SARS-CoV-2 is not limited to the acute illness: SARS-CoV-2 infection carries a substantially increased mortality in the following 12 months. This excess death mainly occurs in older people and is driven by broad array of causes of death. Funding: Research was carried out with the support of Estonian Research Council (grants PRG1197, PRG198), European Regional Development Fund (RITA 1/02-120) and European Social Fund via IT Academy program.