Clusters of post-acute COVID-19 symptoms: a latent class analysis across 9 databases and 7 countries (preprint)

Prior evidence has suggested the multisystem symptomatic manifestations of post-acute COVID-19 condition (PCC). Here we conducted a network cluster analysis of 24 WHO proposed symptoms to identify potential latent subclasses of PCC. Individuals with a positive test of or diagnosed with SARS-CoV-2 after 09/2020 and with at least one symptom within ≥ 90 to 365 days following infection were included. Sub-analyses were conducted among people with ≥ 3 different symptoms. Summary characteristics were provided for each cluster. All analyses were conducted separately in 9 databases from 7 countries, including data from primary care, hospitals, national health claims and national health registries, allowing to validate clusters across the different healthcare settings. 787,078 persons with PCC were included. Single-symptom clusters were common across all databases, particularly for joint pain, anxiety, depression and allergy. Complex clusters included anxiety-depression and abdominal-gastrointestinal symptoms. Substantial heterogeneity within and between PCC clusters was seen across healthcare settings. Current definitions of PCC should be critically reviewed to reflect this variety in clinical presentation.

Healthy lifestyle for the prevention of post-COVID-19 multisystem sequelae, hospitalization, and death: a prospective cohort study (preprint)

Abstract Background Post-COVID complications are emerging as a global public health crisis. Effective prevention strategies are needed to inform patients, clinicians and policy makers, and to reduce their cumulative burden. We aimed to investigate whether a habitual healthy lifestyle predated pandemic is associated with lower risks of multisystem sequelae and other adverse outcomes of COVID-19, and whether the potential protective effects are independent of pre-existing comorbidities. Methods The prospective population-based cohort study enrolled participants with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction test result between March 1, 2020, and March 1, 2022. Participants with no history of the related outcome one year before infection were included and followed up for 210 days. Exposures included ten modifiable healthy lifestyle factors including past or never smoking, moderate alcohol intake ([≤]4 times week), body mass index <30 kg/m2, at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, less sedentary time (<4 hours per day), healthy sleep duration (7-9 hours per day), adequate intake of fruit and vegetables ([≥]400 g/day), adequate oily fish intake ([≥]1 portion/week), moderate intake of red meat ([≤]4 portions week) and processed meat ([≤]4 portions week). Outcomes included multisystem COVID-19 sequelae (consisting of 75 diseases/symptoms in 10 organ systems), death, and hospital admission following SARS-CoV-2 infection, confirmed by hospital inpatient and death records. Risk was reported in relative scale (hazard ratio [HR]) and absolute scale (absolute risk reduction [ARR]) during both the acute (the first 30 days) and post-acute (30-210 days) phases of infection using Cox models. Findings A total of 68,896 participants (mean [SD] age, 66.6 [8.4]; 32,098 women [46.6%]) with COVID-19 were included. A favorable lifestyle (6-10 healthy lifestyle factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae of COVID-19 (HR, 0.64; 95% CI, 0.58-0.69; ARR, 7.08%; 95% CI, 5.98-8.09), compared with unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions were observed across all 10 prespecified organ systems including cardiovascular, coagulation, metabolic and endocrine, gastrointestinal, kidney, mental health, musculoskeletal, neurologic, and respiratory disorders, and general symptoms of fatigue and malaise. This beneficial effect was largely attributable to direct effects of healthy lifestyle, with mediation proportion ranging from 44% to 93% across organ systems. A favorable lifestyle was also associated with lower risk of post-COVID death (HR, 0.59; 95% CI, 0.52-0.66; ARR, 1.99%; 95% CI, 1.61-2.32) and hospitalization (HR, 0.78; 95% CI, 0.73-0.84; ARR, 6.14%; 95% CI, 4.48-7.68). These associations were observed after accounting for potential misclassification of lifestyle factors, and during acute and post-acute infection, in those tested positive in the hospital and community setting, and independent of vaccination status or SARS-CoV-2 variant. Interpretation Adherence to a healthy lifestyle predated pandemic was associated with substantially lower risk of complications across organ systems, death, and hospitalization following COVID-19, regardless of phases of infection, vaccination status, test setting, and SARS-CoV-2 variants, and independent of comorbidities. These findings illustrate the benefits of adhering to a healthy lifestyle to reduce the long-term adverse health consequences following SARS-CoV-2 infection.

HLA Alleles, COVID-19 Vaccine Antibody Response and Real-World Breakthrough Outcomes (preprint)

The rapid development, approval, and global distribution of COVID-19 vaccines represent an unprecedented intervention in public health history, with over 13 billion doses administered worldwide in two years. However, our understanding of the HLA genetic underpinnings of COVID-19 vaccine-induced antibody responses and their clinical implications for breakthrough outcomes remain limited. To bridge this knowledge gap, we designed and performed a series of genetic and epidemiological analyses among 368,098 vaccinated individuals, and a subset of 194,371 participants who had antibody serology tests. Firstly, we corroborated earlier findings that SNPs associated with antibody response were predominantly located in Major Histocompatibility Complex region, and that the expansive HLA-DQB1*06 allele family was linked to better antibody responses. However, our findings contest the claim that DQB1*06 alleles alone significantly impact breakthrough risks. Additionally, our results suggest that the specific DQB1*06:04 subtype could be the true causal allele, as opposed to the previously reported DQB1*06:02. Secondly, we identified and validated six new functional HLA alleles that independently contribute to vaccine-induced antibody responses. Moreover, we unravelled additive effects of variations across multiple HLA genes that, concurrently, change the risk of clinically relevant breakthrough COVID-19 outcomes. Finally, we detangled the overall vaccine effectiveness and showed that antibody positivity accounts for approximately 20% protection against breakthrough infection and 50% against severe outcomes. These novel findings provide robust population evidence demonstrating how variations within HLA genes strongly, collectively, and causally influence vaccine-induced antibody responses, and the risk of COVID-19 breakthrough infection and related outcomes, with implications for subsequent functional research and personalised vaccination.

COVID-19 Infection and Dementia: Analyses of time-varying risk, subtypes, and subpopulations from the UK Biobank (preprint)

Background Although COVID-19 patients were suggested to experience worse cognitive outcomes, there is a paucity of evidence on time-varying risk of dementia, especially the subtypes, as well as among critical subpopulations.Methods Out of over 50000 individuals from general population in the UK Biobank, SARS-COV-2 infected patients between March 1, 2020, and July 31, 2021 and maximally 5:1 propensity score matched contemporary non-infected individuals were selected, with baseline dementia excluded. Matching was done on demographic characteristics, lifestyle, and comorbidities. Dementia was captured according to primary care, inpatient records, and death registry, with the follow-up ending at the earliest of outcome occurrence, death, or August 31, 2021. Associations were evaluated using time-varying hazard ratios (HRs) and odds ratios (ORs).Results With a mean age of 64.5 years for 18032 COVID-19 patients and 83,008 controls, participants were followed for a median of 247 (IQR: 204–305) days and 255 dementia cases occurred, including 90 Alzheimer’s disease (AD) cases and 42 vascular dementia (VaD) cases. Compared with matched controls, dementia risk declined drastically after COVID-19 infection and sustained for all-cause dementia, VaD, and other dementia. During the acute phase (first 30 days), COVID-19 infection was associated with increased risks of dementia, with HRs (95% CIs) being 12.77 (6.77, 24.08) for all-cause dementia, 9.21 (2.77, 30.59) for AD, 5.53 (1.69, 18.11) for VaD, and 25.35 (8.74, 73.56) for other dementia. Among those not hospitalized within 30 days of enrollment, elevated dementia risk remained for all-cause dementia, VaD, and other dementia, with ORs being 1.82, 4.55, and 1.64, respectively. Among most of the subpopulations classified by demographic characteristics, APOE genotype, and comorbidities (except for those with chronic obstructive pulmonary diseases at enrollment), COVID-19 infection was associated with an elevated all-cause dementia risk and no modification effect was detected.Conclusions Declined yet sustained elevated dementia risk since COVID-19 infection was found and vascular risk factors may need extra attention during the long-term follow-up. Increased dementia risk from COVID-19 infection also applied for the non-hospitalized during the acute phase and most subpopulations. The potential dementia risk associated with Omicron and newer variants warrants further evaluation.

COVID-19 Infection and Dementia: A Prospective Analysis of Time-Varying Risk, Subtypes, and Subpopulations from the UK Biobank (preprint)

Background: Although COVID-19 patients were suggested to experience worse cognitive outcomes, there is a paucity of evidence on time-varying risk of dementia, especially the subtypes, as well as among critical subpopulations. Methods: Out of over 50000 individuals from general population in the UK Biobank, SARS-COV-2 infected patients between March 1, 2020, and July 31, 2021 and maximally 5:1 propensity score matched contemporary non-infected individuals were selected, with baseline dementia excluded. Matching was done on demographic characteristics, lifestyle, and comorbidities. Dementia was captured according to primary care, inpatient records, and death registry, with the follow-up ending at the earliest of outcome occurrence, death, or August 31, 2021. Associations were evaluated using time-varying hazard ratios (HRs) and odds ratios (ORs). Results: With a mean age of 64.5 years for 18032 COVID-19 patients and 83,008 controls, participants were followed for a median of 247 (IQR: 204–305) days and 255 dementia cases occurred, including 90 Alzheimer’s disease (AD) cases and 42 vascular dementia (VaD) cases. Compared with matched controls, dementia risk declined drastically after COVID-19 infection and sustained for all-cause dementia, VaD, and other dementia. During the acute phase (first 30 days), COVID-19 infection was associated with increased risks of dementia, with HRs (95% CIs) being 12.77 (6.77, 24.08) for all-cause dementia, 9.21 (2.77, 30.59) for AD, 5.53 (1.69, 18.11) for VaD, and 25.35 (8.74, 73.56) for other dementia. Among those not hospitalized within 30 days of enrollment, elevated dementia risk remained for all-cause dementia, VaD, and other dementia, with ORs being 1.82, 4.55, and 1.64, respectively. Among most of the subpopulations classified by demographic characteristics, APOE genotype, and comorbidities (except for those with chronic obstructive pulmonary diseases at enrollment), COVID-19 infection was associated with an elevated all-cause dementia risk and no modification effect was detected. Conclusion: Declined yet sustained elevated dementia risk since COVID-19 infection was found and vascular risk factors may need extra attention during the long-term follow-up. Increased dementia risk from COVID-19 infection also applied for the non-hospitalized during the acute phase and most subpopulations. The potential dementia risk associated with Omicron and newer variants warrants further evaluation.

Observational methods for COVID-19 vaccine effectiveness research: a trial emulation and empirical evaluation (preprint)

Despite much research on the topic, little work has been done comparing the use of methods to control for confounding in the estimation of COVID-19 vaccine effectiveness in routinely collected medical record data. We conducted a trial emulation study to replicate the ChAdOx1 (Oxford/AstraZeneca) and BNT162b2 (BioNTech/Pfizer) COVID-19 phase 3 efficacy studies. We conducted a cohort study including individuals aged 75+ from UK CPRD AURUM (N = 916,128) in early 2021. Three different methods were assessed: Overlap weighting, inverse probability treatment weighting, and propensity score matching. All three methods successfully replicated the findings from both phase 3 trials, and overlap weighting performed best in terms of confounding, systematic error, and precision. Despite lack of trial data beyond 3 weeks, we found that even 1 dose of BNT162b2 was effective against SARS-CoV-2 infection for up to 12 weeks before a second dose was administered. These results support the UK Joint Committee on Vaccination and Immunisation modelling and related UK vaccination strategies implemented in early 2021.

Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19 (preprint)

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19 (preprint)

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

Long-term mental health outcomes after SARS-CoV-2 infection: prospective cohort study (preprint)

Background Despite previous evidence from retrospective cohorts suggest that survivors of COVID-19 may be at increased risk of psychiatric sequelae, questions remain on the incidence and absolute risk of psychiatric outcomes, and on the potential protective effect of vaccination. Addressing these knowledge gaps will help public health and clinical service planning during the ongoing pandemic. Methods Based on UK Biobank prospective data, we constructed a SARS-CoV-2 infection cohort including participants with a positive PCR test for SARS-CoV-2 between March 1, 2020 and September 30, 2021; a contemporary control cohort with no evidence of SARS-CoV-2, and a historical control cohort predating the COVID-19 pandemic. Additional control cohorts were constructed for benchmarking, including participants diagnosed with other respiratory tract infection, or with a negative SARS-CoV-2 test. We used propensity score weighting using predefined (clinically informed) and data-driven covariates to minimize confounding. We then estimated incidence rates and risk of first psychiatric disorders diagnosed by ICD-10 codes and psychotropic prescriptions after SARS-CoV-2 infection using cause-specific Cox models. Results In this prospective cohort including 406,579 adults (224,681 women, 181,898 men; mean [SD] age 66.1 [8.4] years), 26,181 had a SARS-CoV-2 infection. Compared with contemporary controls (n=380,398), COVID-19 survivors had increased risks of subsequent psychiatric diagnoses (HR: 2.02, 95% CI 1.85-2.21; difference in incidence rate: 24.85, 95 CI 20.69-29.39 per 1000 person-years) and psychotropic prescriptions (HR: 1.61, 95% CI 1.48-1.75; difference in incidence rate: 21.77, 95% CI 16.59-27.54 per 1000 person-years). Regarding individual mental health related outcomes, the SARS-CoV-2 infection cohort showed an increased risk of psychotic disorders (2.26, 1.28-3.98), mood disorders (2.19, 1.92-2.50), anxiety disorders (2.08, 1.82-2.38), substance use disorders (1.59, 1.34-1.90), sleep disorders (1.95, 1.60-2.39); and prescriptions for antipsychotics (3.78, 2.74-5.21), antidepressants (1.55, 1.29-1.87), benzodiazepines (1.82, 1.58-2.11), and opioids (1.40, 1.26-1.55). Overall, the risk of any mental health outcome was increased with a HR of 1.58, 95% CI 1.47-1.70; and difference in incidence rate of 32.04, 25.76-38.81 per 1000 person-years. These results were consistent when comparing to a historical control cohort. Additionally, mental health risks were increased even further in participants who tested positive in hospital settings. Finally, participants who were fully vaccinated had a lower risk of mental health outcomes compared to those infected when unvaccinated or partially vaccinated. All observed risks of mental health outcomes were attenuated or even lower after SARS-CoV-2 infection compared with those with other respiratory infections, or with participants in the test-negative control cohort. Conclusions In this prospective cohort study, people who survived COVID-19 were at increased risk of psychiatric outcomes and related psychotropic medications. These risks were higher in those with more severe disease, treated in hospital settings, and were significantly reduced in fully vaccinated people. Of note, compared to participants with other respiratory infections or with only negative testing results, those infected with SARS-CoV-2 had an even lower risk of mental health outcomes, warranting further research into causation. The early identification and treatment of psychiatric disorders among survivors of COVID-19 should be a priority in the long-term management of COVID-19. Particular attention might be needed for those with severe (hospitalized) disease and those who were not fully vaccinated at the time of infection.

Genetic risk and incident venous thromboembolism in middle-aged and older adults following Covid-19 vaccination (preprint)

BACKGROUND Covid-19 vaccination has been associated with an increased risk of venous thromboembolism (VTE). However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination. METHODS Using data from the UK Biobank, which contains in-depth genotyping data and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants identified from a previous large genome-wide association study. We prospectively assessed associations between PRS and incident VTE after first and the second-dose vaccination separately. We conducted sensitivity analyses stratified by vaccine type (adenovirus- and mRNA-based) and using two historical unvaccinated cohorts. We estimated hazard ratios (HR) for PRS-VTE associations using Cox models. RESULTS Of 359,310 individuals receiving one dose of a Covid-19 vaccine, 160,327 (44.6%) were males, and the mean age at the vaccination date was 69.05 (standard deviation [SD] 8.04) years. After 28- and 90-days follow-up, 88 and 299 individuals developed VTE respectively, equivalent to an incidence rate of 0.88 (95% confidence interval [CI] 0.70 to 1.08) and 0.92 (95% CI 0.82 to 1.04) per 100,000 person-days. The PRS was significantly associated with a higher risk of VTE (HR per 1 SD increase in PRS, 1.41 (95% CI 1.15 to 1.73) in 28 days and 1.36 (95% CI 1.22 to 1.52) in 90 days). Similar associations were found after stratification by vaccine type, in the two-dose cohort and across the historical unvaccinated cohorts. CONCLUSIONS The genetic determinants of post-Covid-19-vaccination VTE are similar to those seen in historical data. This suggests that, at the population level, post-vaccine VTE has similar aetiology to conventional VTE. Additionally, the observed PRS-VTE associations were equivalent for adenovirus- and mRNA-based vaccines.

Venous Thromboembolism in Ambulatory Covid-19 patients: Clinical and Genetic Determinants (preprint)

Background Substantial evidence suggests that severe Covid-19 leads to an increased risk of Venous Thromboembolism (VTE). We aimed to quantify the risk of VTE associated with ambulatory Covid-19, study the potential protective role of vaccination, and establish key clinical and genetic determinants of post-Covid VTE. Methods We analyzed a cohort of ambulatory Covid-19 patients from UK Biobank, and compared their 30-day VTE risk with propensity-score-matched non-infected participants. We fitted multivariable models to study the associations between age, sex, ethnicity, socio-economic status, obesity, vaccination status and inherited thrombophilia with post-Covid VTE. Results Overall, VTE risk was nearly 20-fold higher in Covid-19 vs matched non-infected participants (hazard ratio [HR] 19.49, 95% confidence interval [CI] 11.50 to 33.05). However, the risk was substantially attenuated amongst the vaccinated (HR: 2.79, 95% CI 0.82 to 9.54). Older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 2.00 (1.61 to 2.47) per 10 years, 1.66 (1.28 to 2.15), and 1.85 (1.29 to 2.64), respectively. Further, inherited thrombophilia led to an HR 2.05, 95% CI 1.15 to 3.66. Conclusions Ambulatory Covid-19 was associated with a striking 20-fold increase in incident VTE, but no elevated risk after breakthrough infection in the fully vaccinated. Older age, male sex, and obesity were clinical determinants of Covid-19-related VTE. Additionally, inherited thrombophilia doubled risk further, comparable to the effect of 10-year ageing. These findings reinforce the need for vaccination, and call for targeted strategies to prevent VTE during outpatient care of Covid-19

Comparative effectiveness of the BNT162b2 vs ChAdOx1 vaccine against Covid-19 (preprint)

Although pivotal trials with varying populations and study methods suggest higher efficacy for mRNA than adenoviral Covid-19 vaccines, no direct evidence is available. Here, we conducted a head-to-head comparison of BNT162b2 versus ChAdOx1 against Covid-19. We analysed 235,181 UK Biobank participants aged 50 years or older and vaccinated with one or two doses of BNT162b2 or ChAdOx1. People were followed from the vaccination date until 18/10/2021. Inverse probability weighting was used to minimise confounding and the Cox models to derive hazard ratio. We found that, compared with two doses of ChAdOx1, vaccination with BNT162b2 was associated with 30% lower risks of both SARS-CoV-2 infection and related hospitalisation during the period dominated by the delta variant. Also, this comparative effectiveness was consistent across several subgroups and persisted for at least six months, suggesting no differential waning between the two vaccines. Our findings can inform evidence-based Covid-19 vaccination campaigns and booster strategies.

Comparative effectiveness and safety of homologous two-dose ChAdOx1 versus heterologous vaccination with ChAdOx1 and BNT162b2: a cohort analysis (preprint)

Small trials have suggested that heterologous vaccination with first-dose ChAdOx1 and second-dose BNT162b2 may generate a better immune response than homologous vaccination with two doses of ChAdOx1. We used linked data from Catalonia (Spain), where those aged <60 who received a first dose of ChAdOx1 could choose between ChAdOx1 and BNT162b2 for their second dose. Comparable cohorts were obtained after exact-matching 14,325/17,849 (80.3%) people receiving heterologous vaccination to 14,325/149,386 (9.6%) receiving homologous vaccination by age, sex, region, and date of second dose. Of these, 238 (1.7%) in the heterologous and 389 (2.7%) in the homologous groups developed COVID-19 between 1st June 2021 and 11th October 2021. The resulting hazard ratio (95% confidence interval) was 0.61 [ 0.52-0.71 ], favouring heterologous vaccination, with a Number Needed to Treat of 94.9 [ 71.8 - 139.8 ]. The two groups had similar testing rates and safety outcomes. Sensitivity and negative control outcome analyses confirmed these findings. In conclusion, we demonstrate that a heterologous vaccination schedule with ChAdOx1 followed by BNT162b2 was more efficacious than and similarly safe to homologous vaccination with two doses of ChAdOx1. Most of the infections in our study occurred when Delta was the predominant SARS-CoV-2 variant in Spain. These data agree with previous phase 2 randomised trials.

Alpha-1 blockers and susceptibility to COVID-19 in benign prostate hyperplasia patients : an international cohort study (preprint)

Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.

Risk of depression, suicidal ideation, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multi-national network cohort study (preprint)

ABSTRACT Objectives Concern has been raised in the rheumatological community regarding recent regulatory warnings that hydroxychloroquine used in the COVID-19 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation, or psychosis associated with hydroxychloroquine as used for rheumatoid arthritis (RA). Methods New user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and US). RA patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine (active comparator) and followed up in the short (30-day) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation, and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HR), with estimates pooled where I 2 <40%. Results 918,144 and 290,383 users of hydroxychloroquine and sulfasalazine, respectively, were included. No consistent risk of psychiatric events was observed with short-term hydroxychloroquine (compared to sulfasalazine) use, with meta-analytic HRs of 0.96 [0.79-1.16] for depression, 0.94 [0.49-1.77] for suicide/suicidal ideation, and 1.03 [0.66-1.60] for psychosis. No consistent long-term risk was seen, with meta-analytic HRs 0.94 [0.71-1.26] for depression, 0.77 [0.56-1.07] for suicide/suicidal ideation, and 0.99 [0.72-1.35] for psychosis. Conclusions Hydroxychloroquine as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation, or psychosis compared to sulfasalazine. No effects were seen in the short or long term. Use at higher dose or for different indications needs further investigation. TRIAL REGISTRATION Registered with EU PAS; Reference number EUPAS34497 ( http://www.encepp.eu/encepp/viewResource.htm?id=34498 ). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine . WHAT IS ALREADY KNOWN ON THIS TOPIC Recent regulatory warnings have raised concerns of potential psychiatric side effects of hydroxychloroquine at the doses used to treat COVID-19, generating concern in the rheumatological community Serious psychiatric adverse events such as suicide, acute psychosis, and depressive episodes have been identified by the US Food and Drug Administration (FDA) adverse events reporting system and at case report level WHAT THIS STUDY ADDS This is the largest study on the neuro-psychiatric safety of hydroxychloroquine to date, including >900,000 users treated for their RA in country-level or private health care systems in Germany, the UK, and the US We find no association between the use of hydroxychloroquine and the risk of depression, suicide/suicidal ideation, or severe psychosis compared to sulfasalazine HOW MIGHT THIS IMPACT ON CLINICAL PRACTICE Our data shows no association between hydroxychloroquine treatment for RA and risk of depression, suicide or psychosis compared to sulfasalazine. These findings do not support stopping or switching hydroxychloroquine treatment as used for RA due to recent concerns based on COVID-19 treated patients.