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.

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

The impact of COVID passport mandates on the number of cases of and hospitalizations with COVID-19 in the UK: a difference-in-differences analysis (preprint)

BackgroundMandatory COVID-19 certification was introduced at different times in the four countries of the UK. We aimed to study the effect of this intervention on the incidence of cases and hospital admissions. MethodsThe main outcome was the weekly averaged incidence of COVID-19 confirmed cases and hospital admissions. We performed Negative Binomial Segmented Regression (NBSR) and Autoregressive Integrated Moving Average (ARIMA) analyses for the four countries (England, Northern Ireland, Scotland and Wales), and fitted Difference-in-Differences (DiD) models to compare the latter three to England, where COVID-19 certification was imposed the latest. FindingsNBSR methods suggested COVID-19 certification led to a decrease in the incidence of cases in Northern Ireland, but not in hospitalizations. In Wales, they also caused a decrease in the incidence of cases but not in hospital admissions. In Scotland, we observed a decrease in both cases and admissions. ARIMA models confirmed these results. The DiD model showed that the intervention decreased the incidence of COVID compared to England in all countries except Wales, in October. Then, the incidence rate of cases already had a decreasing tendency, as well as in England, hence a particular impact of Covid Passport was less obvious. In Wales, the model coefficients were 2.2 (95% CI -6.24,10.70) for cases and -0.144 (95% CI -0.248, -0.039) for admissions in October and -7.75 (95% CI -13.1, -2.46) for cases and -0.169 (95% CI-0.308, -0.031) for admissions in November. In Northern Ireland, -10.1 (95% CI -18.4, -1.79) for cases and -0.269 (95% CI -0.385, -0.153) for admissions. In Scotland they were 7.91 (95% CI 4.46,11.4) for cases and -0.097 (95% CI - 0.219,0.024) for admissions. InterpretationThe introduction of mandatory certificates decreased cases in all countries except in England. Differences on concomitant measures, on vaccination uptake or Omicron variant prevalence could explain this discrepancy.

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.

Characterization of long-term patient-reported symptoms of COVID-19: an analysis of social media data (preprint)

As the SARS-CoV-2 virus (COVID-19) continues to affect people across the globe, there is limited understanding of the long term implications for infected patients. While some of these patients have documented follow-ups on clinical records, or participate in longitudinal surveys, these datasets are usually designed by clinicians, and not granular enough to understand the natural history or patient experiences of "long COVID". In order to get a complete picture, there is a need to use patient generated data to track the long-term impact of COVID-19 on recovered patients in real time. There is a growing need to meticulously characterize these patients' experiences, from infection to months post-infection, and with highly granular patient generated data rather than clinician narratives. In this work, we present a longitudinal characterization of post-COVID-19 symptoms using social media data from Twitter. Using a combination of machine learning, natural language processing techniques, and clinician reviews, we mined 296,154 tweets to characterize the post-acute infection course of the disease, creating detailed timelines of symptoms and conditions, and analyzing their symptomatology during a period of over 150 days.

Unraveling COVID-19: a large-scale characterization of 4.5 million COVID-19 cases using CHARYBDIS (preprint)

Background: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response [1,2]. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) [3] Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD.Methods: We conducted a descriptive cohort study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11th June 2020 and are iteratively updated via GitHub [4]. Findings: We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19, and 113,627 hospitalized with COVID-19 requiring intensive services. All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts, and are available in an interactive website: https://data.ohdsi.org/Covid19CharacterizationCharybdis/. Interpretation: CHARYBDIS findings provide benchmarks that contribute to our understanding of COVID-19 progression, management and evolution over time. This can enable timely assessment of real-world outcomes of preventative and therapeutic options as they are introduced in clinical practice.

Timing of elective tracheotomy and duration of mechanical ventilation amongst patients admitted to intensive care with severe COVID-19: a multicentre prospective cohort study (preprint)

Background: The COVID-19 pandemic has strained intensive care unit (ICU) resources. Tracheotomy is the most common surgery performed on ICU patients and can affect the duration of ICU care. We studied the association between when tracheotomy occurs and ICU stay length, mortality, and intraoperative and postoperative complications. Methods: Multicentre prospective cohort including all COVID-19 patients admitted to ICUs in 36 hospitals in Spain who received invasive mechanical ventilation and tracheotomy between 11 March and 20 July 2020. We used a target emulation trial framework to study the causal effects of early (7 to 10 days post-intubation) versus late (>10 days) tracheotomy on time from tracheotomy to weaning, postoperative mortality, and tracheotomy complications. Cause-specific Cox models were used for the first two outcomes and Poisson regression for the third, all adjusted for potential confounders. Findings: We included 696 patients, of whom 142 (20.4%) received early tracheotomy. Using late tracheotomy as the reference group, multivariable cause-specific analysis showed that early tracheotomy was associated with faster post-tracheotomy weaning (hazard ratio (HR) [95% confidence interval (CI)]: 1.28 [1.01 to 1.61]) without differences in mortality (HR [95% CI]: 0.94 [0.65 to 1.36]) or intraoperative or postoperative complications (adjusted rate ratio [95% CI]: 0.56 [0.23 to 1.38] and 1.31 [0.89 to 1.93], respectively). Interpretation: Early tracheotomy reduced post-tracheotomy weaning time, resulting in fewer mechanical ventilation days and shorter ICU stays, without changing complication or mortality rates. These results support early tracheotomy for COVID-19 patients when clinically indicated.

Characteristics and outcomes of 118,155 COVID-19 individuals with a history of cancer in the United States and Spain (preprint)

PurposeWe aimed to describe the demographics, cancer subtypes, comorbidities and outcomes of patients with a history of cancer with COVID-19 from March to June 2020. Secondly, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza. MethodsWe conducted a cohort study using eight routinely-collected healthcare databases from Spain and the US, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: i) diagnosed with COVID-19, ii) hospitalized with COVID-19, and iii) hospitalized with influenza in 2017-2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes. ResultsWe included 118,155 patients with a cancer history in the COVID-19 diagnosed and 41,939 in the COVID-19 hospitalized cohorts. The most frequent cancer subtypes were prostate and breast cancer (range: 5-19% and 1-14% in the diagnosed cohort, respectively). Hematological malignancies were also frequent, with non-Hodgkins lymphoma being among the 5 most common cancer subtypes in the diagnosed cohort. Overall, patients were more frequently aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 8% to 14% and from 18% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n=242,960) had a similar distribution of cancer subtypes, sex, age and comorbidities but lower occurrence of adverse events. ConclusionPatients with a history of cancer and COVID-19 have advanced age, multiple comorbidities, and a high occurence of COVID-19-related events. Additionaly, hematological malignancies were frequent in these patients.This observational study provides epidemiologic characteristics that can inform clinical care and future etiological studies.

Use of dialysis, tracheostomy, and extracorporeal membrane oxygenation among 240,392 patients hospitalized with COVID-19 in the United States (preprint)

Objective To estimate the proportion of patients hospitalized with COVID-19 who undergo dialysis, tracheostomy, and extracorporeal membrane oxygenation (ECMO). Design A network cohort study. Setting Six databases from the United States containing routinely-collected patient data: HealthVerity, Premier, IQVIA Open Claims, Optum EHR, Optum SES, and VA-OMOP. Patients Patients hospitalized with a clinical diagnosis or a positive test result for COVID-19. Interventions Dialysis, tracheostomy, and ECMO. Measurements and Main Results 240,392 patients hospitalized with COVID-19 were included (22,887 from HealthVerity, 139,971 from IQVIA Open Claims, 29,061 from Optum EHR, 4,336 from OPTUM SES, 36,019 from Premier, and 8,118 from VA-OMOP). Across the six databases, 9,703 (4.04% [95% CI: 3.96% to 4.11%]) patients received dialysis, 1,681 (0.70% [0.67% to 0.73%]) had a tracheostomy, and 398 (0.17% [95% CI: 0.15% to 0.18%]) patients underwent ECMO over the 30 days following hospitalization. Use of ECMO was generally concentrated among patients who were younger, male, and with fewer comorbidities except for obesity. Tracheostomy was used for a similar proportion of patients regardless of age, sex, or comorbidity. While dialysis was used for a similar proportion among younger and older patients, it was more frequent among male patients and among those with chronic kidney disease. Conclusion Use of dialysis among those hospitalized with COVID-19 is high at around 4%. Although less than one percent of patients undergo tracheostomy and ECMO, the absolute numbers of patients who have undergone these interventions is substantial and can be expected to continue grow given the continuing spread of the COVID-19.

Characteristics, outcomes, and mortality amongst 133,589 patients with prevalent autoimmune diseases diagnosed with, and 48,418 hospitalised for COVID-19: a multinational distributed network cohort analysis (preprint)

Objective: Patients with autoimmune diseases were advised to shield to avoid COVID-19, but information on their prognosis is lacking. We characterised 30-day outcomes and mortality after hospitalisation with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza. Design: Multinational network cohort study Setting: Electronic health records data from Columbia University Irving Medical Center (CUIMC) (NYC, United States [US]), Optum [US], Department of Veterans Affairs (VA) (US), Information System for Research in Primary Care-Hospitalisation Linked Data (SIDIAP-H) (Spain), and claims data from IQVIA Open Claims (US) and Health Insurance and Review Assessment (HIRA) (South Korea). Participants: All patients with prevalent autoimmune diseases, diagnosed and/or hospitalised between January and June 2020 with COVID-19, and similar patients hospitalised with influenza in 2017-2018 were included. Main outcome measures: 30-day complications during hospitalisation and death Results: We studied 133,589 patients diagnosed and 48,418 hospitalised with COVID-19 with prevalent autoimmune diseases. The majority of participants were female (60.5% to 65.9%) and aged [≥]50 years. The most prevalent autoimmune conditions were psoriasis (3.5 to 32.5%), rheumatoid arthritis (3.9 to 18.9%), and vasculitis (3.3 to 17.6%). Amongst hospitalised patients, Type 1 diabetes was the most common autoimmune condition (4.8% to 7.5%) in US databases, rheumatoid arthritis in HIRA (18.9%), and psoriasis in SIDIAP-H (26.4%). Compared to 70,660 hospitalised with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2% to 4.3% versus 6.3% to 24.6%). Conclusions: Patients with autoimmune diseases had high rates of respiratory complications and 30-day mortality following a hospitalization with COVID-19. Compared to influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality. Future studies should investigate predictors of poor outcomes in COVID-19 patients with autoimmune diseases.

Baseline characteristics, management, and outcomes of 55,270 children and adolescents diagnosed with COVID-19 and 1,952,693 with influenza in France, Germany, Spain, South Korea and the United States: an international network cohort study (preprint)

Objectives To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children/adolescents diagnosed or hospitalized with COVID-19. Secondly, to describe health outcomes amongst children/adolescents diagnosed with previous seasonal influenza. Design International network cohort. Setting Real-world data from European primary care records (France/Germany/Spain), South Korean claims and US claims and hospital databases. Participants Diagnosed and/or hospitalized children/adolescents with COVID-19 at age <18 between January and June 2020; diagnosed with influenza in 2017-2018. Main outcome measures Baseline demographics and comorbidities, symptoms, 30-day in-hospital treatments and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome (ARDS), multi-system inflammatory syndrome (MIS-C), and death. Results A total of 55,270 children/adolescents diagnosed and 3,693 hospitalized with COVID-19 and 1,952,693 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were all more common among those hospitalized vs diagnosed with COVID-19. The most common COVID-19 symptom was fever. Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital treatments for COVID-19 included repurposed medications (<10%), and adjunctive therapies: systemic corticosteroids (6.8% to 37.6%), famotidine (9.0% to 28.1%), and antithrombotics such as aspirin (2.0% to 21.4%), heparin (2.2% to 18.1%), and enoxaparin (2.8% to 14.8%). Hospitalization was observed in 0.3% to 1.3% of the COVID-19 diagnosed cohort, with undetectable (N<5 per database) 30-day fatality. Thirty-day outcomes including pneumonia, ARDS, and MIS-C were more frequent in COVID-19 than influenza. Conclusions Despite negligible fatality, complications including pneumonia, ARDS and MIS-C were more frequent in children/adolescents with COVID-19 than with influenza. Dyspnea, anosmia and gastrointestinal symptoms could help differential diagnosis. A wide range of medications were used for the inpatient management of pediatric COVID-19.

Baseline phenotype and 30-day outcomes of people tested for COVID-19: an international network cohort including >3.32 million people tested with real-time PCR and >219,000 tested positive for SARS-CoV-2 in South Korea, Spain and the United States (preprint)

Early identification of symptoms and comorbidities most predictive of COVID-19 is critical to identify infection, guide policies to effectively contain the pandemic, and improve health systems' response. Here, we characterised socio-demographics and comorbidity in 3,316,107 persons tested and 219,072 persons tested positive for SARS-CoV-2 since January 2020, and their key health outcomes in the month following the first positive test. Routine care data from primary care electronic health records (EHR) from Spain, hospital EHR from the United States (US), and claims data from South Korea and the US were used. The majority of study participants were women aged 18-65 years old. Positive/tested ratio varied greatly geographically (2.2:100 to 31.2:100) and over time (from 50:100 in February-April to 6.8:100 in May-June). Fever, cough and dyspnoea were the most common symptoms at presentation. Between 4%-38% required admission and 1-10.5% died within a month from their first positive test. Observed disparity in testing practices led to variable baseline characteristics and outcomes, both nationally (US) and internationally. Our findings highlight the importance of large scale characterization of COVID-19 international cohorts to inform planning and resource allocation including testing as countries face a second wave.

Clinical characteristics, symptoms, management and health outcomes in 8,598 pregnant women diagnosed with COVID-19 compared to 27,510 with seasonal influenza in France, Spain and the US: a network cohort analysis (preprint)

OBJECTIVES: To describe comorbidities, symptoms at presentation, medication use, and 30-day outcomes after a diagnosis of COVID-19 in pregnant women, in comparison to pregnant women with influenza. DESIGN: Multinational network cohort SETTING: A total of 6 databases consisting of electronic medical records and claims data from France, Spain, and the United States. PARTICIPANTS: Pregnant women with [≥] 1 year in contributing databases, diagnosed and/or tested positive, or hospitalized with COVID-19. The influenza cohort was derived from the 2017-2018 influenza season. OUTCOMES: Baseline patient characteristics, comorbidities and presenting symptoms; 30-day inpatient drug utilization, maternal complications and pregnancy-related outcomes following diagnosis/hospitalization. RESULTS: 8,598 women diagnosed (2,031 hospitalized) with COVID-19 were included. Hospitalized women had, compared to those diagnosed, a higher prevalence of pre-existing comorbidities including renal impairment (2.2% diagnosed vs 5.1% hospitalized) and anemia (15.5% diagnosed vs 21.3% hospitalized). The ten most common inpatient treatments were systemic corticosteroids (29.6%), enoxaparin (24.0%), immunoglobulins (21.4%), famotidine (20.9%), azithromycin (18.1%), heparin (15.8%), ceftriaxone (7.9%), aspirin (7.0%), hydroxychloroquine (5.4%) and amoxicillin (3.5%). Compared to 27,510 women with influenza, dyspnea and anosmia were more prevalent in those with COVID-19. Women with COVID-19 had higher frequency of cesarean-section (4.4% vs 3.1%), preterm delivery (0.9% vs 0.5%), and poorer maternal outcomes: pneumonia (12.0% vs 2.7%), ARDS (4.0% vs 0.3%) and sepsis (2.1% vs 0.7%). COVID-19 fatality was negligible (N<5 in each database respectively). CONCLUSIONS: Comorbidities that were more prevalent with COVID-19 hospitalization (compared to COVID-19 diagnosed) in pregnancy included renal impairment and anemia. Multiple medications were used to treat pregnant women hospitalized with COVID-19, some with little evidence of benefit. Anosmia and dyspnea were indicative symptoms of COVID-19 in pregnancy compared to influenza, and may aid differential diagnosis. Despite low fatality, pregnancy and maternal outcomes were worse in COVID-19 than influenza.

Heterogeneity and temporal variation in the management of COVID-19: a multinational drug utilization study including 71,921 hospitalized patients from China, South Korea, Spain, and the United States of America (preprint)

Objectives: A plethora of medicines have been repurposed or used as adjunctive therapies for COVID-19. We characterized the utilization of medicines as prescribed in routine practice amongst patients hospitalized for COVID-19 in South Korea, China, Spain, and the USA. Design: International network cohort Setting: Hospital electronic health records from Columbia University Irving Medical Centre (NYC, USA), Stanford (CA, USA), Tufts (MA, USA), Premier (USA), Optum EHR (USA), department of veterans affairs (USA), NFHCRD (Honghu, China) and HM Hospitals (Spain); and nationwide claims from HIRA (South Korea) Participants: patients hospitalized for COVID-19 from January to June 2020 Main outcome measures: Prescription/dispensation of any medicine on or 30 days after hospital admission date Analyses: Number and percentage of users overall and over time Results: 71,921 people were included: 304 from China, 2,089 from Spain, 7,599 from South Korea, and 61,929 from the USA. A total of 3,455 medicines were identified. Common repurposed medicines included hydroxychloroquine (<2% in NFHCRD to 85.4% in HM), azithromycin (4.9% in NFHCRD to 56.5% in HM), lopinavir/ritonavir (<3% in all US but 34.9% in HIRA and 56.5% in HM), and umifenovir (0% in all except 78.3% in NFHCRD). Adjunctive medicines were used with great variability, with the ten most used treatments being (in descending order): bemiparin, enoxaparin, heparin, ceftriaxone, aspirin, vitamin D, famotidine, vitamin C, dexamethasone, and metformin. Hydroxychloroquine and azithromycin increased rapidly in use in March-April but declined steeply in May-June. Conclusions: Multiple medicines were used in the first months of COVID-19 pandemic, with substantial geographic and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed medicines. Antithrombotics, antibiotics, H2 receptor antagonists and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of COVID-19.

Characteristics and outcomes of 627 044 COVID-19 patients with and without obesity in the United States, Spain, and the United Kingdom (preprint)

Background: COVID-19 may differentially impact people with obesity. We aimed to describe and compare the demographics, comorbidities, and outcomes of obese patients with COVID-19 to those of non-obese patients with COVID-19, or obese patients with seasonal influenza. Methods: We conducted a cohort study based on outpatient/inpatient care, and claims data from January to June 2020 from the US, Spain, and the UK. We used six databases standardized to the OMOP common data model. We defined two cohorts of patients diagnosed and/or hospitalized with COVID-19. We created corresponding cohorts for patients with influenza in 2017-2018. We followed patients from index date to 30 days or death. We report the frequency of socio-demographics, prior comorbidities, and 30-days outcomes (hospitalization, events, and death) by obesity status. Findings: We included 627 044 COVID-19 (US: 502 650, Spain: 122 058, UK: 2336) and 4 549 568 influenza (US: 4 431 801, Spain: 115 224, UK: 2543) patients. The prevalence of obesity was higher among hospitalized COVID-19 (range: 38% to 54%) than diagnosed COVID-19 (30% to 47%), or diagnosed/hospitalized influenza (15% to 48%) patients. Obese hospitalized COVID-19 patients were more often female and younger than non-obese COVID-19 patients or obese influenza patients. Obese COVID-19 patients were more likely to have prior comorbidities, present with cardiovascular and respiratory events during hospitalization, require intensive services, or die compared to non-obese COVID-19 patients. Obese COVID-19 patients were also more likely to require intensive services or die compared to obese influenza patients, despite presenting with fewer comorbidities. Interpretation: We show that obesity is more common among COVID-19 than influenza patients, and that obese patients present with more severe forms of COVID-19 with higher hospitalization, intensive services, and fatality than non-obese patients. These data are instrumental for guiding preventive strategies of COVID-19 infection and complications

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.

The natural history of symptomatic COVID-19 in Catalonia, Spain: a multi-state model including 109,367 outpatient diagnoses, 18,019 hospitalisations, and 5,585 COVID-19 deaths among 5,627,520 people (preprint)

Background The natural history of Coronavirus Disease 2019 (COVID-19) has yet to be fully described, with most previous reports focusing on hospitalised patients. Using linked patient-level data, we set out to describe the associations between age, gender, and comorbidities and the risk of outpatient COVID-19 diagnosis, hospitalisation, and/or related mortality. Methods A population-based cohort study including all individuals registered in Information System for Research in Primary Care (SIDIAP). SIDIAP includes primary care records covering > 80% of the population of Catalonia, Spain, and was linked to region-wide testing, hospital and mortality records. Outpatient diagnoses of COVID-19, hospitalisations with COVID-19, and deaths with COVID-19 were identified between 1st March and 6th May 2020. A multi-state model was used, with cause-specific Cox survival models estimated for each transition. Findings A total of 5,664,652 individuals were included. Of these, 109,367 had an outpatient diagnosis of COVID-19, 18,019 were hospitalised with COVID-19, and 5,585 died after either being diagnosed or hospitalised with COVID-19. Half of those who died were not admitted to hospital prior to their death. Risk of a diagnosis with COVID-19 peaked first in middle-age and then again for oldest ages, risk for hospitalisation after diagnosis peaked around 70 years old, with all other risks highest at oldest ages. Male gender was associated with an increased risk for all outcomes other than outpatient diagnosis. The comorbidities studied (autoimmune condition, chronic kidney disease, chronic obstructive pulmonary disease, dementia, heart disease, hyperlipidemia, hypertension, malignant neoplasm, obesity, and type 2 diabetes) were all associated with worse outcomes. Interpretation There is a continued need to protect those at high risk of poor outcomes, particularly the elderly, from COVID-19 and provide appropriate care for those who develop symptomatic disease. While risks of hospitalisation and death are lower for younger populations, there is a need to limit their role in community transmission. These findings should inform public health strategies, including future vaccination campaigns.