Long-term Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in COVID-19 Survivors: A Retrospective Cohort Study.

BACKGROUND: Growing evidence suggests that some coronavirus disease 2019 (COVID-19) survivors experience a wide range of long-term postacute sequelae. We examined the postacute risk and burden of new-incident cardiovascular, cerebrovascular, and other thrombotic complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a highly vaccinated multiethnic Southeast Asian population, during Delta predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals who had a positive SARS-CoV-2 test between 1 September and 30 November 2021 when Delta predominated community transmission. Concurrently, we constructed a test-negative control group by enrolling individuals between 13 April 2020 and 31 December 2022 with no evidence of SARS-CoV-2 infection. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular, cerebrovascular, and other thrombotic complications using doubly robust competing-risks survival analysis. Risks were reported using 2 measures: hazard ratio (HR) and excess burden (EB) with 95% confidence intervals. RESULTS: We included 106 012 infected cases and 1 684 085 test-negative controls. Compared with the control group, individuals with COVID-19 exhibited increased risk (HR, 1.157 [1.069-1.252]) and excess burden (EB, 0.70 [.53-.88]) of new-incident cardiovascular and cerebrovascular complications. Risks decreased in a graded fashion for fully vaccinated (HR, 1.11 [1.02-1.22]) and boosted (HR, 1.10 [.92-1.32]) individuals. Conversely, risks and burdens of subsequent cardiovascular/cerebrovascular complications increased for hospitalized and severe COVID-19 cases (compared to nonhospitalized cases). CONCLUSIONS: Increased risks and excess burdens of new-incident cardiovascular/cerebrovascular complications were reported among infected individuals; risks can be attenuated with vaccination and boosting.

Differences in virus and immune dynamics for SARS-CoV-2 Delta and Omicron infections by age and vaccination histories.

Vaccination against COVID-19 was integral to controlling the pandemic that persisted with the continuous emergence of SARS-CoV-2 variants. Using a mathematical model describing SARS-CoV-2 within-host infection dynamics, we estimate differences in virus and immunity due to factors of infecting variant, age, and vaccination history (vaccination brand, number of doses and time since vaccination). We fit our model in a Bayesian framework to upper respiratory tract viral load measurements obtained from cases of Delta and Omicron infections in Singapore, of whom the majority only had one nasopharyngeal swab measurement. With this dataset, we are able to recreate similar trends in URT virus dynamics observed in past within-host modelling studies fitted to longitudinal patient data.We found that Omicron had higher R0,within values than Delta, indicating greater initial cell-to-cell spread of infection within the host. Moreover, heterogeneities in infection dynamics across patient subgroups could be recreated by fitting immunity-related parameters as vaccination history-specific, with or without age modification. Our model results are consistent with the notion of immunosenescence in SARS-CoV-2 infection in elderly individuals, and the issue of waning immunity with increased time since last vaccination. Lastly, vaccination was not found to subdue virus dynamics in Omicron infections as well as it had for Delta infections.This study provides insight into the influence of vaccine-elicited immunity on SARS-CoV-2 within-host dynamics, and the interplay between age and vaccination history. Furthermore, it demonstrates the need to disentangle host factors and changes in pathogen to discern factors influencing virus dynamics. Finally, this work demonstrates a way forward in the study of within-host virus dynamics, by use of viral load datasets including a large number of patients without repeated measurements.

Long-term neuropsychiatric sequelae of Delta versus Omicron SARS-CoV-2 infection.

OBJECTIVES: Studies have reported increased rates of long-term neuropsychiatric sequelae after SARS-CoV-2 infection using electronic health-record (EHR) data; however, the majority were conducted before Omicron and booster rollout. We estimated the long-term risks and excess burdens of pre-specified new-incident neuropsychiatric diagnoses after Delta versus Omicron BA.1/2 infection in a highly-vaccinated and boosted cohort of adult Singaporeans. METHODS: The national SARS-CoV-2 testing registry was used to construct cohorts of Singaporean adults infected during periods of Delta and Omicron BA.1/2 predominance and a contemporaneous test-negative control group. New-incident neuropsychiatric diagnoses recorded in the national health care claims database were identified up to 300 days postinfection. Risks and excess burden were estimated using a doubly robust competing-risks survival analysis. RESULTS: 104 179 and 375 903 infected cases were assigned to Delta and Omicron cohorts and compared against test-negative controls (Delta: N = 666 575 and Omicron: N = 619 379). Elevated risk of cognition or memory disorders was consistently reported across Omicron (Adjusted hazards ratio [aHR], 1.24; 95% CI, 1.12-1.38) and Delta cohorts (aHR, 1.63; 95% CI, 1.39-1.92). Delta-variant infection was associated with an increased risk of anosmia or dysgeusia (aHR, 4.53; 95% CI, 2.78-7.41) and psychosis (aHR, 1.65; 95% CI, 1.22-2.22). By contrast, Omicron-variant infection was associated with a risk of abnormal involuntary movements (aHR, 1.93; 95% CI, 1.32-2.83). Risks of neuropsychiatric sequelae predominantly accrued in hospitalized individuals. DISCUSSIONS: A modestly increased risk of cognition and memory disorders at 300 days after SARS-CoV-2 infection was observed among adult Singaporeans infected during the Delta/Omicron BA.1/2 transmission. There was no overall increased risk of neuropsychiatric sequelae observed across other domains. Variant-specific differences were also observed in individual neuropsychiatric sequelae, including an elevated risk of anosmia or dysgeusia after Delta-variant infection.

Long-term cardiovascular, cerebrovascular, and thrombotic complications after SARS-CoV-2-Omicron infection: a retrospective cohort study.

OBJECTIVES: Evidence suggests that some COVID-19 survivors experience a wide range of post-COVID-19 sequelae; however, the majority of studies were conducted before the emergence of the milder Omicron variant. We examined the post-acute risk of new-incident cardiovascular complications after SARS-CoV-2 infection in a multi-ethnic Asian population, during Omicron predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals with confirmed SARS-CoV-2 infection during Omicron BA.1/2 transmission and a contemporaneous test-negative group. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular complications using doubly robust competing-risks survival analysis. Risks were reported using two measures: hazard ratio and excess burden. RESULTS: We included 375 903 test-positive, infected individuals (mean age 48 years) and 619 379 test-negative controls (mean age 47 years). The majority (97.5%, 366 593/375 903) of infected individuals had mild infection not requiring hospitalization. There was no overall increased risk of new-incident cardiovascular complications, (adjusted hazards ratio, aHR = 1.01 [0.97-1.07]) amongst COVID-19 survivors when compared against test-negatives. A modestly increased risk and excess burden of dysrhythmias amongst COVID-19 survivors (aHR = 1.09 [1.01-1.19]) was observed. Risk and burdens of new-incident cardiovascular complications predominantly accrued in hospitalized (aHR = 2.81 [2.26-3.50]) and severe COVID-19 cases (aHR = 5.52 [3.76-8.10]). DISCUSSION: No significantly increased overall risk of any cardiovascular complication was observed in the 300 days following COVID-19 infection during the Omicron-dominant period when compared against test-negatives, with the exception of a small increased occurrence of dysrhythmias.

Real-world effectiveness of nirmatrelvir/ritonavir against COVID-19 hospitalizations and severe COVID-19 in community-dwelling elderly Singaporeans during Omicron BA.2, BA.4/5, and XBB transmission.

OBJECTIVES: Real-world data on continued effectiveness of nirmatrelvir/ritonavir against hospitalization and severe COVID-19 in the context of widespread booster mRNA vaccine uptake and more immune-evasive Omicron sub-variants are lacking. We conducted a retrospective cohort study in adult Singaporeans aged ≥60 years presenting to primary care with SARS-CoV-2 infection, during waves of Omicron BA.2/4/5/XBB transmission. METHODS: Binary logistic regression was used to estimate the effect of treatment (receiving nirmatrelvir/ritonavir) on outcomes (hospitalization, severe COVID-19). Additional sensitivity analyses, including inverse-probability-of-treatment-weighting-adjusted analysis and adjustment using overlap weights, were performed to account for observed differences in baseline characteristics among treated/untreated cohorts. RESULTS: We included 3959 nirmatrelvir/ritonavir recipients and 139 379 untreated controls. Almost 95% received ≥3 doses of mRNA vaccines; 5.4% had preceding infection. Overall 26.5% of infections occurred during the Omicron XBB period and 1.7% were hospitalized. On multivariable logistic regression, receipt of nirmatrelvir/ritonavir was independently associated with lower odds of hospitalization (adjusted odds ratio [aOR] = 0.65, 95% CI = 0.50-0.85). Consistent estimates were obtained after inverse-probability-of-treatment-weighting adjustment (aOR for hospitalization = 0.60, 95% CI = 0.48-0.75) and adjustment using overlap weights (aOR for hospitalization = 0.64, 95% CI = 0.51-0.79). Although receipt of nirmatrelvir/ritonavir was associated with lower odds of severe COVID-19, it was not statistically significant. DISCUSSION: Outpatient usage of nirmatrelvir/ritonavir was independently associated with reduced odds of hospitalization amongst boosted older community-dwelling Singaporeans during successive waves of Omicron transmission, including Omicron XBB; however, it did not significantly reduce the already low risk of severe COVID-19 in a highly vaccinated population.