Socioeconomic inequalities in COVID-19 infection and vaccine uptake among children and adolescents in Catalonia, Spain (preprint)

IMPORTANCE The relationship between socioeconomic deprivation and COVID-19 infection and vaccination among children and adolescents remains unclear. OBJECTIVE To investigate the association between deprivation and COVID-19 vaccine uptake and infection among children and adolescents before and after the vaccination rollout in Catalonia, Spain. DESIGN AND SETTING Population-based cohort study using primary care electronic health records from the Information System for Research in Primary Care. Individuals were followed 3 months before the start of the vaccination campaign in Spain and 3 months after the vaccination rollout among adolescents and children. PARTICIPANTS Children (5-11 years) and adolescents (12-15 years) with at least 1 year of prior history observation available and without missing deprivation data. EXPOSURE Deprivation, assessed using an ecological socioeconomic deprivation index (SDI) score for census tract urban areas and categorized into quintiles. MAIN OUTCOMES AND MEASURES COVID-19 infection and COVID-19 vaccination. For each outcome, we calculated cumulative incidence and crude Cox proportional-hazard models by SDI quintiles, and estimated hazard ratios (HRs) of COVID-19 infection and vaccine uptake relative to the least deprived quintile, Q1. RESULTS Before COVID-19 vaccination rollout, 290,625 children and 179,685 adolescents were analyzed. Increased HR of deprivation was associated with a higher risk of COVID-19 infection in both children (Q5: 1.55 [95% CI, 1.47 - 1.63]) and adolescents (Q5: 1.36 [95% CI, 1.29 - 1.43]). After the rollout, this pattern changed among children, with lower risk of infection in more deprived areas (Q5: 0.62 [95% CI, 0.61 - 0.64]). Vaccine uptake was higher among adolescents (72.6%) than children (44.8%), but in both age groups, non-vaccination was more common among those living in more deprived areas (39.3% and 74.6% in Q1 vs. 26.5% and 66.9% in Q5 among children and adolescents, respectively). CONCLUSIONS AND RELEVANCE In this cohort study, children and adolescents living in deprived areas were at higher risk of COVID-19 non-vaccination. Socioeconomic disparities in COVID-19 infection were also evident before vaccine rollout, with a higher infection risk in deprived areas across age groups. Our findings suggest that changes in the association between deprivation and infections among children after the vaccine rollout were likely due to testing disparities.

The role of COVID-19 vaccines in preventing post COVID-19 thromboembolic and cardiovascular complications: a multinational cohort study (preprint)

ImportanceThe overall effects of vaccination on the risk of cardiac, and venous and arterial thromboembolic complications following COVID-19 remain unclear. ObjectiveWe studied the association between COVID-19 vaccination and the risk of acute and subacute COVID-19 cardiac and thromboembolic complications. DesignMultinational staggered cohort study, based on national vaccination campaign rollouts. SettingNetwork study using electronic health records from primary care records from the UK, primary care data linked to hospital data from Spain, and national insurance claims from Estonia. ParticipantsAll adults with a prior medical history of [≥]180 days, with no history of COVID-19 or previous COVID-19 vaccination at the beginning of vaccine rollout were eligible. ExposureVaccination status was used as a time-varying exposure. Vaccinated individuals were classified by vaccine brand according to the first dose received. Main OutcomesPost COVID-19 complications including myocarditis, pericarditis, arrhythmia, heart failure (HF), venous (VTE) and arterial thromboembolism (ATE) up to 1 year after SARS-CoV-2 infection. MeasuresPropensity Score overlap weighting and empirical calibration based on negative control outcomes were used to minimise bias due to observed and unobserved confounding, respectively. Fine-Gray models were fitted to estimate sub-distribution Hazard Ratios (sHR) for each outcome according to vaccination status. Random effect meta-analyses were conducted across staggered cohorts and databases. ResultsOverall, 10.17 million vaccinated and 10.39 million unvaccinated people were included. Vaccination was consistently associated with reduced risks of acute (30-day) and subacute post COVID-19 VTE and HF: e.g., meta-analytic sHR 0.34 (95%CI, 0.27-0.44) and 0.59 (0.50-0.70) respectively for 0-30 days, sHR 0.58 (0.48 - 0.69) and 0.71 (0.59 - 0.85) respectively for 90-180 days post COVID-19. Additionally, reduced risks of ATE, myocarditis/pericarditis and arrhythmia were seen, but mostly in the acute phase (0-30 days post COVID-19). ConclusionsCOVID-19 vaccination reduced the risk of post COVID-19 complications, including cardiac and thromboembolic outcomes. These effects were more pronounced for acute (1-month) post COVID-19 outcomes, consistent with known reductions in disease severity following breakthrough vs unvaccinated SARS-CoV-2 infection. RelevanceThese findings highlight the importance of COVID-19 vaccination to prevent cardiovascular outcomes after COVID-19, beyond respiratory disease. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the impact of COVID-19 vaccination to prevent cardiac complications and thromboembolic events following a SARS-CoV-2 infection? FindingsResults from this multinational cohort study showed that COVID-19 vaccination reduced risk for acute and subacute COVID-19 heart failure, as well as venous and arterial thromboembolic events following SARS-CoV-2 infection. MeaningThese findings highlight yet another benefit of vaccination against COVID-19, and support the recommendations for COVID-19 vaccination even in people at high cardiovascular risk.

The burden of long COVID: a multinational cohort analysis of Spanish and UK data including SARS-CoV-2 infections, reinfections, and matched contemporaneous test negative controls (preprint)

As limited data was available on the effect of persisting COVID-19 symptoms, we characterised long COVID and identified key symptoms associated with persistent disease. Using primary care data from Spain and UK, we estimated incidence rates of long COVID in the population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential for long COVID by comparing their frequency in COVID-19 patients vs matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections. Fortunately, the proportion of COVID-19 cases resulting in long COVID declined over the study period.  Risk for altered smell/taste, dyspnoea, and fatigue were consistently higher in long COVID patient vs controls [RR between 5.97-1.09]. All persistent symptoms were less common after reinfection than first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.

Establishing and characterising large COVID-19 cohorts after mapping the Information System for Research in Primary Care in Catalonia to the OMOP Common Data Model (preprint)

Background Few datasets have been established that capture the full breadth of COVID-19 patient interactions with a health system. Our first objective was to create a COVID-19 dataset that linked primary care data to COVID-19 testing, hospitalisation, and mortality data at a patient level. Our second objective was to provide a descriptive analysis of COVID-19 outcomes among the general population and describe the characteristics of the affected individuals. Methods We mapped patient-level data from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). More than 3,000 data quality checks were performed to assess the readiness of the database for research. Subsequently, to summarise the COVID-19 population captured, we established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or positive test results for SARS-CoV-2, hospitalisations with COVID-19, and COVID-19 deaths during follow-up, which went up until 30th June 2021. Findings Mapping data to the OMOP CDM was performed and high data quality was observed. The mapped database was used to identify a total of 5,870,274 individuals, who were included in the general population cohort as of 1st March 2020. Over follow up, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation with COVID-19, 5,642 had an ICU admission with COVID-19, and 11,233 had a COVID-19 death. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised in general and those who died. Interpretation We have established a comprehensive dataset that captures COVID-19 diagnoses, test results, hospitalisations, and deaths in Catalonia, Spain. Extensive data checks have shown the data to be fit for use. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19 outcomes over time were described. Funding Generalitat de Catalunya and European Health Data and Evidence Network (EHDEN).

“Association between COVID-19 vaccination, infection, and risk of Guillain-Barre syndrome, Bell’s palsy, encephalomyelitis and transverse myelitis: a population-based cohort and self-controlled case series analysis” (preprint)

ABSTRACT OBJECTIVE We aimed to study the association between COVID-19 vaccines, SARS-CoV-2 infection, and the risk of immune-mediated neurological events. METHODS Design Population-based historical rate comparison study and self-controlled case series (SCCS) analysis. Setting Primary care records from the United Kingdom. Participants Individuals who received the first dose of ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A cohort with a first positive RT-PCR test for SARS-CoV-2 between 1 September 2020 and 28 February 2021 was used for comparison. Main outcome measures Outcomes included Guillain-Barre syndrome (GBS), Bell’s palsy, encephalomyelitis, and transverse myelitis. Incidence rates were estimated in the 28 days post first-dose vaccine, 90 days post-COVID-19, and between 2017 to 2019 for the general population cohort for background rates. Indirectly standardised incidence ratios (SIRs) were estimated. Adjusted incidence rate ratios (IRR) were estimated from the SCCS when sufficient statistical power was reached. Results We included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees; 299,311 people infected with COVID-19; and 2,290,537 from the general population. SIRs for GBS were 1.91 [95% CI: 0.86 to 4.26] after ChAdOx1, 1.29 [0.49 to 3.45] after BNT162b2, and 5.20 [1.95 to 13.85] after COVID-19. In the same cohorts, SIRs for Bell’s palsy were 1.34 [1.05 to 1.72], 1.15 [0.88 to 1.50], and 1.23 [0.80 to 1.89], and for encephalomyelitis 1.62 [0.61 to 4.31], 0.86 [0.22 to 3.46], and 11.05 [5.27 to 23.17], respectively. Transverse myelitis was too rare to analyse (n<5 in all cohorts). SCCS analysis was only conducted for Bell’s palsy due to limited statistical power. We found no association between either vaccine and Bell’s palsy, with an IRR of 1.10 [0.81 to 1.46] and 1.15 [0.87 to 1.49] for BNT162b2 and ChAdOx1, respectively. Conclusions We found no consistent association between either vaccine and any of the studied neuroimmune adverse events studied. Conversely, we found a 5-fold increase in risk of GBS and an 11-fold of encephalomyelitis following COVID-19.

Thromboembolic Events and Thrombosis With Thrombocytopenia After COVID-19 Infection and Vaccination in Catalonia, Spain (preprint)

Background: Thromboembolism and thrombocytopenia have emerged as potential adverse events associated with vaccines against SARS-CoV-2. We compared rates of thromboembolism and thrombocytopenia following vaccination with BNT162b2 and ChAdOx1 with expected rates. Rates for people with COVID-19 were estimated to provide context. Methods: Primary care data from Catalonia, Spain, informed the analysis. Study participants were vaccinated with BNT162b2 or ChAdOx1 (27/12/2020-19/05/2021), diagnosed with COVID-19 (1/09/2020-1/03/2021) or present as of 1/01/2017. Outcomes included venous thromboembolism (VTE), arterial thromboembolism (ATE), thrombocytopenia, and thrombosis with thrombocytopenia syndrome (TTS). Incidence rates were estimated in the 21 and 90 days after vaccination and COVID-19 diagnosis, respectively, and up to 31/03/2019 for background rates. Age indirectly standardised incidence ratios (SIR) were estimated. Findings: We included 945,941 BNT162b2 (778,534 with 2 doses), 426,272 ChAdOx1, 222,710 COVID-19, and 4,570,149 background participants. SIRs for VTE were 1.29 [95% CI 1.13-1.48] and 0.90 [0.76-1.07] after first- and second-dose BNT162b2, and 1.15 [0.83-1.58] after first-dose ChAdOx1. The SIR for VTE in COVID-19 was 8.04 [7.37-8.78]. SIRs for thrombocytopenia were 1.35 (1.30-1.41) and 1.19 (1.14-1.25) after first- and second-dose BNT162b2, 1.03 (0.93-1.14) after first-dose ChAdOx1 and 3.52 (3.39 to 3.67) for COVID-19. Rates of ATE were similar to expected rates for BNT162b2 and ChAdOx1, as were rates of TTS for BNT162b2, while fewer than 5 such events were seen for ChAdOx1. Interpretation: Safety profiles of BNT162b2 and ChAdOx1 were similar. A safety signal was seen for VTE after first-dose of BNT162b2. Although confidence intervals were wider, a similar estimate was seen for first-dose of ChAdOx1. The 1.3 fold increase in the rate of VTE after first-dose of BNT162b2 compared with an 8 fold increase after diagnosis of COVID-19. No safety signals were seen for ATE or TTS. Further research is needed to investigate the causality in the observed associations. Funding Information: This study was funded by the European Medicines Agency in the form of a competitive tender (Lot ROC No EMA/2017/09/PE). Declaration of Interests: DPA’s research group has received research grants from the European Medicines Agency, from the Innovative Medicines Initiative, from Amgen, Chiesi, and from UCB Biopharma; and consultancy or speaker fees from Astellas, Amgen and UCB Biopharma. Peter Rijnbeek works for a research institute who receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, GSK, Amgen, UCB, Novartis, Astra-Zeneca, Chiesi, Janssen Research and Development, none of which relate to the content of this work. Katia Verhamme works for a research institute who receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, GSK, Amgen, UCB, Novartis, Astra-Zeneca, Chiesi, none of which relate to the content of this work .All other authors have no conflicts of interest to declare.Ethics Approval Statement: This study was approved by the Clinical Research Ethics Committee of the IDIAPJGol (project code: 21/054-PCV).

Cancer and the risk of COVID-19 diagnosis, hospitalisation, and death: a population-based multi-state cohort study including 4,618,377 adults in Catalonia, Spain (preprint)

Objectives To investigate the associations between cancer and risk of outpatient COVID-19 diagnosis, hospitalisation, and COVID-19-related death, overall and by years since cancer diagnosis (<1-year, 1-5-years, >5-years), sex, age, and cancer type. Design Population-based cohort study Setting Primary care electronic health records including ∼80% of the population in Catalonia, Spain, linked to hospital and mortality records between 1 March and 6 May 2020. Participants Individuals aged ≥18 years with at least one year of prior medical history available from the general population. Cancer was defined as any prior diagnosis of a primary invasive malignancy excluding non-melanoma skin cancer. Main outcome measures Cause-specific hazard ratios (aHR) with 95% confidence intervals for each outcome. Estimates were adjusted by age, sex, deprivation, smoking status, and comorbidities. Results We included 4,618,377 adults, of which 260,667 (5.6%) had a history of cancer. Patients with cancer were older and had more comorbidities than cancer-free patients. A total of 98,951 individuals (5.5% with cancer) were diagnosed and 6,355 (16.4% with cancer) were directly hospitalised (no prior diagnosis) with COVID-19. Of those diagnosed, 6,851 were subsequently hospitalised (10.7% with cancer) and 3,227 died without being hospitalised (18.5% with cancer). Among those hospitalised, 1,963 (22.5% with cancer) died. Cancer was associated with an increased risk of COVID-19 diagnosis (aHR: 1.08; 95% confidence interval [1.05-1.11]); direct COVID-19 hospitalisation (1.33 [1.24-1.43]); and death following a COVID-19 hospitalisation (1.12 [1.01-1.25]). These associations were stronger for patients recently diagnosed with cancer, aged <70 years, and with haematological cancers. Conclusions Patients recently diagnosed with cancer, aged <70 years, or with haematological cancers are a high-risk population for COVID-19 diagnosis and severity. These patients should be prioritised in COVID-19 vaccination campaigns and continued non-pharmaceutical interventions. What is already known on this subject Prior studies addressing the relationship between cancer and COVID-19 infection and adverse outcomes have found conflicting results The majority of these studies had small sample sizes, were not population-based (i.e. restricted to hospitalised patients), thus increasing the risks of selection and collider bias. In addition, they used different definitions for cancer (i.e. some included only patients with active cancer, while others focused on specific cancer types, etc.), which limits the comparability of their findings, and only a few analysed the effect of cancer across different patient subgroups. What this study adds We conducted a population-based cohort study to analyse the associations between having a prior diagnosis of cancer and the risks of COVID-19 diagnosis, hospitalisation and COVID-19-related deaths from 1 March to 6 May 2020. In a population of 4,618,377 adults, we found that cancer was associated with an increased risk of COVID-19 diagnosis (aHR: 1.08; 95% confidence interval [1.05-1.11]); direct COVID-19 hospitalisation (1.33 [1.24-1.43]); and death following a COVID-19 hospitalisation (1.12 [1.01-1.25]). These risks were higher for patients recently diagnosed with cancer (within the last year), younger than 70 years, or with haematological cancers. We also found a particularly high risk of COVID-19 hospitalisation and death among patients with lung and bladder cancer.

Cancer and the Risk of COVID-19 Diagnosis, Hospitalisation, and Death: A Population-Based Multi-State Cohort Study Including 4,618,377 Adults in Catalonia, Spain (preprint)

Background: The relationship between cancer and COVID-19 infection and severity is poorly understood. We described the associations between cancer and risk of COVID-19 diagnosis, hospitalisation, and COVID-19-related death.Methods: Population-based cohort study between 1 March and 6 May 2020, using electronic health records from the SIDIAP database including ~80% of the population in Catalonia, Spain. Cancer was defined as any primary invasive malignancy excluding non-melanoma skin cancer. We estimated adjusted hazard ratios (aHRs) for the risk of COVID-19 (outpatient) clinical diagnosis, hospitalisation (with or without a prior COVID-19 diagnosis) and COVID-19-related death using Cox proportional hazard regressions. Models were estimated for the overall cancer population and by years since cancer diagnosis (<1-year, 1-5-years, >5-years), sex, age, and cancer type (haematological or solid); and adjusted for age, sex, smoking status, deprivation, and comorbidities.Findings: We included 4,618,377 adults, of which 260,667 (5.6%) had a history of cancer. Patients with cancer were older and had more comorbidities than cancer-free patients. A total of 98,951 individuals (5.5% with cancer) were diagnosed and 6,355 (16.4% with cancer) were directly hospitalised (no prior diagnosis) with COVID-19. Of those diagnosed, 6,851 were subsequently hospitalised (10.7% with cancer) and 3,227 died without being hospitalised (18.5% with cancer). Among those hospitalised, 1,963 (22.5% with cancer) died. Cancer was associated with an increased risk of COVID-19 diagnosis (aHR: 1.08; 95% confidence interval [1.05-1.11]); direct COVID-19 hospitalisation (1.33 [1.24-1.43]); and death following a COVID-19 hospitalisation (1.12 [1.01-1.25]). These associations were stronger for patients recently diagnosed with cancer, aged <70 years, and with haematological cancers.Interpretation: Patients recently diagnosed with cancer, aged <70 years, or with haematological cancers are a high-risk population for COVID-19 diagnosis and severity. These patients should be prioritised in COVID-19 vaccination campaigns and continued non-pharmaceutical interventions.Funding: This project was funded by the Health Department from the Generalitat de Catalunya with a grant for research projects on SARS-CoV-2 and COVID-19 disease organized by the Direcció General de Recerca i Innovació en Salut. This project has also received support from the European Health Data and Evidence Network (EHDEN) project. EHDEN received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 806968. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. The University of Oxford received a grant related to this work from the Bill & Melinda Gates Foundation (Investment ID INV-016201), and partial support from the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. ER was supported by Instituto de Salud Carlos III (grant number CM20/00174). DPA is funded through a National Institute for Health Research (NIHR) Senior Research Fellowship (Grant number SRF-2018-11-ST2-004). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: DPA reports grants and others from AMGEN; grants, non-financial support and other from UCB Biopharma; grants from Les Laboratoires Servier, outside the submitted work; and Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA's department and open for external participants. No other relationships or activities that could appear to have influenced the submitted work.Ethics Approval Statement: This study was approved by the Clinical Research Ethics Committee of the IDIAPJGol (project code: 20/070-PCV)

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.

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.

Body mass index and risk of COVID-19 diagnosis, hospitalisation, and death: a population-based multi-state cohort analysis including 2,524,926 people in Catalonia, Spain (preprint)

Objective: To investigate associations between body mass index (BMI) and risk of COVID-19 diagnosis, hospitalisation with COVID-19, and COVID-19-related death, accounting for potential effect modification by age and sex. Design: Population-based cohort study. Setting: Primary care records covering >80% of the Catalonian population (Spain), linked to regionwide testing, hospital, and mortality records from March to May 2020. Participants: People aged [≥]18 years with at least one measurement of weight and height from the general population and with at least one year of prior medical history available. Main outcome measures: Cause-specific hazard ratios (HR) with 95% confidence intervals for each outcome. Results: Overall, 2,524,926 participants were followed up for a median of 67 days. A total of 57,443 individuals were diagnosed with COVID-19, 10,862 were hospitalised with COVID-19, and 2,467 had a COVID-19-related death. BMI was positively associated with being diagnosed as well as hospitalised with COVID-19. Compared to a BMI of 22kg/m2, the HR (95%CI) of a BMI of 31kg/m2 was 1.22 (1.19-1.24) for COVID-19 diagnosis, and 1.88 (1.75-2.03) and 2.01 (1.86-2.18) for hospitalisation without and with a prior outpatient diagnosis, respectively. The relation between BMI and risk of COVID-19 related death was J-shaped. There was a modestly higher risk of death among individuals with BMIs[≤]19 kg/m2 and a more pronounced increasing risk for BMIs [≥]37 kg/m2 and [≥]40kg/m2 among those who were previously hospitalised with COVID-19 and diagnosed with COVID-19 in outpatient settings, respectively. The increase in risk for COVID-19 outcomes was particularly pronounced among younger patients. Conclusions: There is a monotonic association between BMI and COVID-19 infection and hospitalisation risks, but a J-shaped one with mortality. More research is needed to unravel the mechanisms underlying these relationships.

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.

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

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.