Publications by authors named "Fredrik Nyberg"

103 Publications

Severe COVID-19 among patients with asthma and COPD: a report from the Swedish National Airway Register.

Ther Adv Respir Dis 2021 Jan-Dec;15:17534666211049738

The OLIN-unit, Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.

Background: Patients with obstructive lung diseases may be at risk of hospitalization and/or death due to COVID-19.

Aim: To estimate the frequency of severe COVID-19, and COVID-19-related mortality in a well-defined large population of patients with asthma and chronic inflammatory lung disease (COPD). Further to assess the frequency of asthma and COPD as registered comorbidities at discharge from hospital, and in death certificates.

Methods: At the start of the pandemic, the Swedish National Airway Register (SNAR) included 271,404 patients with a physician diagnosis of asthma and/or COPD. In September 2020, after the first COVID-19 wave in Sweden, the database was linked with the National Patient Register (NPR), the Swedish Intensive Care Register and the Swedish Cause of Death Register, which all provide data about COVID-19 based on International Classification of Diseases (ICD-10) codes. Severe COVID-19 was defined as hospitalization and/or intensive care or death due to COVID-19.

Results: Among patients in SNAR, 0.5% with asthma, and 1.2% with COPD were identified with severe COVID-19. Among patients  < 18 years with asthma, only 0.02% were severely infected. Of hospitalized adults, 14% with asthma and 29% with COPD died. Further, of patients in SNAR, 56% with asthma and 81% with COPD were also registered in the NPR, while on death certificates the agreement was lower (asthma 24% and COPD 71%).

Conclusion: The frequency of severe COVID-19 in asthma and COPD was relative low. Mortality for those hospitalized was double as high in COPD compared to asthma. Comorbid asthma and COPD were not always identified among patients with severe COVID-19.
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http://dx.doi.org/10.1177/17534666211049738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8512278PMC
October 2021

Swedish Covid-19 Investigation for Future Insights - A Population Epidemiology Approach Using Register Linkage (SCIFI-PEARL).

Clin Epidemiol 2021 30;13:649-659. Epub 2021 Jul 30.

Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: In response to the Covid-19 pandemic, we designed and initiated a nationwide linked multi-register, regularly updated, observational study for timely response to urgent scientific questions.

Aim: To describe the SCIFI-PEARL (Swedish Covid-19 Investigation for Future Insights - a Population Epidemiology Approach using Register Linkage) linked database encompassing essentially all known diagnosed Swedish Covid-19 patients plus a large general population comparison cohort and outline its utility in the current and future phases of the pandemic.

Methods: Individuals with Covid-19 from the entire country are identified on a regularly updated basis, from different sources: all individuals from SmiNet, the national database of notifiable diseases, with positive SARS-CoV-2 polymerase chain reaction (PCR) test results; patients identified in the healthcare system by condition (ICD-10) or procedure codes in the National Patient Register or Cause-of-Death Register; patients identified through several disease-specific national quality registers (NQRs); and in two regions additionally patients identified in primary care. A comparison population was obtained by stratified random sampling from Swedish national population registers. Data from all these registers plus the National Prescribed Drug Register, the Cancer Register, national sociodemographic registers, some additional NQRs, the National Vaccination Register, and further data sources, are then linked to all study subjects (Covid-19 cases and population cohort). New cases in the study population and all data for all subjects are updated every few months, as required.

Conclusion And Utility: The SCIFI-PEARL study cohort captures Swedish residents with Covid-19 on an ongoing basis, includes a representative general population comparison cohort, and links to a broad range of national and regional healthcare data for a comprehensive longitudinal view of the Covid-19 pandemic. By combining high-quality national registers with short time delay and continuous repeated linkage and updating, the project brings timely and internationally relevant data for epidemiological research on SARS-CoV-2. Our efforts provide an example and important learnings for similar efforts internationally in the future.
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http://dx.doi.org/10.2147/CLEP.S312742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8331198PMC
July 2021

Characteristics and Outcomes of Over 300,000 Patients with COVID-19 and History of Cancer in the United States and Spain.

Cancer Epidemiol Biomarkers Prev 2021 10 16;30(10):1884-1894. Epub 2021 Jul 16.

Tennessee Valley Healthcare System, Veterans Affairs Medical Center, Nashville, Tennessee.

Background: We described the demographics, cancer subtypes, comorbidities, and outcomes of patients with a history of cancer and coronavirus disease 2019 (COVID-19). Second, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza.

Methods: We conducted a cohort study using eight routinely collected health care databases from Spain and the United States, 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 to 2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes.

Results: We included 366,050 and 119,597 patients diagnosed and hospitalized with COVID-19, respectively. Prostate and breast cancers were the most frequent cancers (range: 5%-18% and 1%-14% in the diagnosed cohort, respectively). Hematologic malignancies were also frequent, with non-Hodgkin's lymphoma being among the five most common cancer subtypes in the diagnosed cohort. Overall, patients were aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 2% to 14% and from 6% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza ( = 67,743) had a similar distribution of cancer subtypes, sex, age, and comorbidities but lower occurrence of adverse events.

Conclusions: Patients with a history of cancer and COVID-19 had multiple comorbidities and a high occurrence of COVID-19-related events. Hematologic malignancies were frequent.

Impact: This study provides epidemiologic characteristics that can inform clinical care and etiologic studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0266DOI Listing
October 2021

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

Int J Obes (Lond) 2021 Nov 15;45(11):2347-2357. Epub 2021 Jul 15.

Data Science to Patient Value Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Background: A detailed characterization of patients with COVID-19 living with obesity has not yet been undertaken. We aimed to describe and compare the demographics, medical conditions, and outcomes of COVID-19 patients living with obesity (PLWO) to those of patients living without obesity.

Methods: We conducted a cohort study based on outpatient/inpatient care and claims data from January to June 2020 from Spain, the UK, and the US. We used six databases standardized to the OMOP common data model. We defined two non-mutually exclusive cohorts of patients diagnosed and/or hospitalized with COVID-19; patients were followed from index date to 30 days or death. We report the frequency of demographics, prior medical conditions, and 30-days outcomes (hospitalization, events, and death) by obesity status.

Results: We included 627 044 (Spain: 122 058, UK: 2336, and US: 502 650) diagnosed and 160 013 (Spain: 18 197, US: 141 816) hospitalized patients with COVID-19. The prevalence of obesity was higher among patients hospitalized (39.9%, 95%CI: 39.8-40.0) than among those diagnosed with COVID-19 (33.1%; 95%CI: 33.0-33.2). In both cohorts, PLWO were more often female. Hospitalized PLWO were younger than patients without obesity. Overall, COVID-19 PLWO were more likely to have prior medical conditions, present with cardiovascular and respiratory events during hospitalization, or require intensive services compared to COVID-19 patients without obesity.

Conclusion: We show that PLWO differ from patients without obesity in a wide range of medical conditions and present with more severe forms of COVID-19, with higher hospitalization rates and intensive services requirements. These findings can help guiding preventive strategies of COVID-19 infection and complications and generating hypotheses for causal inference studies.
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http://dx.doi.org/10.1038/s41366-021-00893-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281807PMC
November 2021

Thirty-Day Outcomes of Children and Adolescents With COVID-19: An International Experience.

Pediatrics 2021 09 28;148(3). Epub 2021 May 28.

Data Science to Patient Value Program, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Objectives: To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children and adolescents diagnosed or hospitalized with coronavirus disease 2019 (COVID-19) and to compare them in secondary analyses with patients diagnosed with previous seasonal influenza in 2017-2018.

Methods: International network cohort using real-world data from European primary care records (France, Germany, and Spain), South Korean claims and US claims, and hospital databases. We included children and adolescents diagnosed and/or hospitalized with COVID-19 at age <18 between January and June 2020. We described baseline demographics, comorbidities, symptoms, 30-day in-hospital treatments, and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome, multisystem inflammatory syndrome in children, and death.

Results: A total of 242 158 children and adolescents diagnosed and 9769 hospitalized with COVID-19 and 2 084 180 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were more common among those hospitalized with versus diagnosed with COVID-19. Dyspnea, bronchiolitis, anosmia, and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital prevalent treatments for COVID-19 included repurposed medications (<10%) and adjunctive therapies: systemic corticosteroids (6.8%-7.6%), famotidine (9.0%-28.1%), and antithrombotics such as aspirin (2.0%-21.4%), heparin (2.2%-18.1%), and enoxaparin (2.8%-14.8%). Hospitalization was observed in 0.3% to 1.3% of the cohort diagnosed with COVID-19, with undetectable ( < 5 per database) 30-day fatality. Thirty-day outcomes including pneumonia and hypoxemia were more frequent in COVID-19 than influenza.

Conclusions: Despite negligible fatality, complications including hospitalization, hypoxemia, and pneumonia were more frequent in children and adolescents with COVID-19 than with influenza. Dyspnea, anosmia, and gastrointestinal symptoms could help differentiate diagnoses. A wide range of medications was used for the inpatient management of pediatric COVID-19.
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http://dx.doi.org/10.1542/peds.2020-042929DOI Listing
September 2021

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study.

BMJ 2021 05 11;373:n1038. Epub 2021 May 11.

Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, South Korea.

Objective: To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents.

Design: Multinational network cohort study.

Setting: Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea.

Participants: 303 264 patients admitted to hospital with covid-19 from January 2020 to December 2020.

Main Outcome Measures: Prescriptions or dispensations of any drug on or 30 days after the date of hospital admission for covid-19.

Results: Of the 303 264 patients included, 290 131 were from the US, 7599 from South Korea, 5230 from Spain, and 304 from China. 3455 drugs were identified. Common repurposed drugs were hydroxychloroquine (used in from <5 (<2%) patients in China to 2165 (85.1%) in Spain), azithromycin (from 15 (4.9%) in China to 1473 (57.9%) in Spain), combined lopinavir and ritonavir (from 156 (<2%) in the VA-OMOP US to 2,652 (34.9%) in South Korea and 1285 (50.5%) in Spain), and umifenovir (0% in the US, South Korea, and Spain and 238 (78.3%) in China). Use of adjunctive drugs varied greatly, with the five most used treatments being enoxaparin, fluoroquinolones, ceftriaxone, vitamin D, and corticosteroids. Hydroxychloroquine use increased rapidly from March to April 2020 but declined steeply in May to June and remained low for the rest of the year. The use of dexamethasone and corticosteroids increased steadily during 2020.

Conclusions: Multiple drugs were used in the first few months of the covid-19 pandemic, with substantial geographical and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed drugs. 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.
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http://dx.doi.org/10.1136/bmj.n1038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111167PMC
May 2021

COVID-19 in patients with autoimmune diseases: characteristics and outcomes in a multinational network of cohorts across three countries.

Rheumatology (Oxford) 2021 10;60(SI):SI37-SI50

Real-World Evidence, Trial Form Support, Barcelona, Spain.

Objective: Patients with autoimmune diseases were advised to shield to avoid coronavirus disease 2019 (COVID-19), but information on their prognosis is lacking. We characterized 30-day outcomes and mortality after hospitalization with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza.

Methods: A multinational network cohort study was conducted using electronic health records data from Columbia University Irving Medical Center [USA, Optum (USA), Department of Veterans Affairs (USA), Information System for Research in Primary Care-Hospitalization Linked Data (Spain) and claims data from IQVIA Open Claims (USA) and Health Insurance and Review Assessment (South Korea). All patients with prevalent autoimmune diseases, diagnosed and/or hospitalized between January and June 2020 with COVID-19, and similar patients hospitalized with influenza in 2017-18 were included. Outcomes were death and complications within 30 days of hospitalization.

Results: We studied 133 589 patients diagnosed and 48 418 hospitalized with COVID-19 with prevalent autoimmune diseases. Most patients were female, aged ≥50 years with previous comorbidities. The prevalence of hypertension (45.5-93.2%), chronic kidney disease (14.0-52.7%) and heart disease (29.0-83.8%) was higher in hospitalized vs diagnosed patients with COVID-19. Compared with 70 660 hospitalized with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2-4.3% vs 6.32-24.6%).

Conclusion: Compared with influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality.
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http://dx.doi.org/10.1093/rheumatology/keab250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989171PMC
October 2021

Unraveling COVID-19: a large-scale characterization of 4.5 million COVID-19 cases using CHARYBDIS.

Res Sq 2021 Mar 1. Epub 2021 Mar 1.

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. 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 11 June 2020 and are iteratively updated via GitHub [4]. We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical 886,193 , and 113,627 . 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/. 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.
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http://dx.doi.org/10.21203/rs.3.rs-279400/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941629PMC
March 2021

Implementation of the COVID-19 Vulnerability Index Across an International Network of Health Care Data Sets: Collaborative External Validation Study.

JMIR Med Inform 2021 Apr 5;9(4):e21547. Epub 2021 Apr 5.

Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea.

Background: SARS-CoV-2 is straining health care systems globally. The burden on hospitals during the pandemic could be reduced by implementing prediction models that can discriminate patients who require hospitalization from those who do not. The COVID-19 vulnerability (C-19) index, a model that predicts which patients will be admitted to hospital for treatment of pneumonia or pneumonia proxies, has been developed and proposed as a valuable tool for decision-making during the pandemic. However, the model is at high risk of bias according to the "prediction model risk of bias assessment" criteria, and it has not been externally validated.

Objective: The aim of this study was to externally validate the C-19 index across a range of health care settings to determine how well it broadly predicts hospitalization due to pneumonia in COVID-19 cases.

Methods: We followed the Observational Health Data Sciences and Informatics (OHDSI) framework for external validation to assess the reliability of the C-19 index. We evaluated the model on two different target populations, 41,381 patients who presented with SARS-CoV-2 at an outpatient or emergency department visit and 9,429,285 patients who presented with influenza or related symptoms during an outpatient or emergency department visit, to predict their risk of hospitalization with pneumonia during the following 0-30 days. In total, we validated the model across a network of 14 databases spanning the United States, Europe, Australia, and Asia.

Results: The internal validation performance of the C-19 index had a C statistic of 0.73, and the calibration was not reported by the authors. When we externally validated it by transporting it to SARS-CoV-2 data, the model obtained C statistics of 0.36, 0.53 (0.473-0.584) and 0.56 (0.488-0.636) on Spanish, US, and South Korean data sets, respectively. The calibration was poor, with the model underestimating risk. When validated on 12 data sets containing influenza patients across the OHDSI network, the C statistics ranged between 0.40 and 0.68.

Conclusions: Our results show that the discriminative performance of the C-19 index model is low for influenza cohorts and even worse among patients with COVID-19 in the United States, Spain, and South Korea. These results suggest that C-19 should not be used to aid decision-making during the COVID-19 pandemic. Our findings highlight the importance of performing external validation across a range of settings, especially when a prediction model is being extrapolated to a different population. In the field of prediction, extensive validation is required to create appropriate trust in a model.
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http://dx.doi.org/10.2196/21547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023380PMC
April 2021

Incidence of ICD-Based Diagnoses of Alcohol-Related Disorders and Diseases from Swedish Nationwide Registers and Suggestions for Coding.

Clin Epidemiol 2020 31;12:1433-1442. Epub 2020 Dec 31.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aim: To improve consistency between register studies in Sweden and ensure valid comparisons of possible changes in alcohol-related disorders and diseases (ARDDs) over time, we propose a definition of ARDDs. Based on this definition, we examined Sweden's incidence rates of ARDDs from 1970 to 2018 in non-primary healthcare settings (inpatient and outpatient).

Methods: Swedish Society of Epidemiology members were invited to give feedback on the International Classification of Disease (ICD) codes with a potential link to alcohol use. We then calculated age-standardised and age-specific incidence of ARDDs over time according to the National Patient Register, and the lifetime prevalence of ARDDs diagnosed in adults alive in Sweden on Dec 31, 2018.

Results: Sweden's estimated incidence of ARDDs increased substantially after introducing the new ICD-9 codes in 1987. In the past 10 years (2009-2018), the incidence of ARDDs has been stable (males: 110/100,000 person-years, females: 49/100,000 person-years). Requiring at least two ICD records for diagnosed ARDDs led to a somewhat lower incidence of ARDDs (males: 71 per 100,000 person-years, females: 29 per 100,000 person-years). In Sweden, the lifetime prevalence of diagnosed ARDDs in adults on Dec 31, 2018, was 1.9% (95% CI=1.9-1.9).

Conclusion: In this nationwide study, we found an incidence of ARDDs of 50-100/100,000 person-years. In 2018, 1 in 52 adults in Sweden had been diagnosed with ARDDs in the National Patient Register.
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http://dx.doi.org/10.2147/CLEP.S285936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781026PMC
December 2020

Incidence of ICD-Based Diagnoses of Alcohol-Related Disorders and Diseases from Swedish Nationwide Registers and Suggestions for Coding.

Clin Epidemiol 2020 31;12:1433-1442. Epub 2020 Dec 31.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aim: To improve consistency between register studies in Sweden and ensure valid comparisons of possible changes in alcohol-related disorders and diseases (ARDDs) over time, we propose a definition of ARDDs. Based on this definition, we examined Sweden's incidence rates of ARDDs from 1970 to 2018 in non-primary healthcare settings (inpatient and outpatient).

Methods: Swedish Society of Epidemiology members were invited to give feedback on the International Classification of Disease (ICD) codes with a potential link to alcohol use. We then calculated age-standardised and age-specific incidence of ARDDs over time according to the National Patient Register, and the lifetime prevalence of ARDDs diagnosed in adults alive in Sweden on Dec 31, 2018.

Results: Sweden's estimated incidence of ARDDs increased substantially after introducing the new ICD-9 codes in 1987. In the past 10 years (2009-2018), the incidence of ARDDs has been stable (males: 110/100,000 person-years, females: 49/100,000 person-years). Requiring at least two ICD records for diagnosed ARDDs led to a somewhat lower incidence of ARDDs (males: 71 per 100,000 person-years, females: 29 per 100,000 person-years). In Sweden, the lifetime prevalence of diagnosed ARDDs in adults on Dec 31, 2018, was 1.9% (95% CI=1.9-1.9).

Conclusion: In this nationwide study, we found an incidence of ARDDs of 50-100/100,000 person-years. In 2018, 1 in 52 adults in Sweden had been diagnosed with ARDDs in the National Patient Register.
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http://dx.doi.org/10.2147/CLEP.S285936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781026PMC
December 2020

Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis.

Lancet Digit Health 2021 02 17;3(2):e98-e114. Epub 2020 Dec 17.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension.

Methods: In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.

Findings: Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84-1·14) or combination use exposure (1·01, 0·90-1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68-1·21; with heterogeneity of >40%) or combination use (0·95, 0·83-1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79-0·99) and non-significant for monotherapy (0·85, 0·69-1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons.

Interpretation: No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.

Funding: Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.
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http://dx.doi.org/10.1016/S2589-7500(20)30289-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834915PMC
February 2021

Use of dialysis, tracheostomy, and extracorporeal membrane oxygenation among 842,928 patients hospitalized with COVID-19 in the United States.

medRxiv 2021 Feb 12. Epub 2021 Feb 12.

Bayer Pharmaceuticals, Sant Joan Despi, Spain.

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: Seven databases from the United States containing routinely-collected patient data: HealthVerity, Premier, IQVIA Hospital CDM, 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: 842,928 patients hospitalized with COVID-19 were included (22,887 from HealthVerity, 77,853 from IQVIA Hospital CDM, 533,997 from IQVIA Open Claims, 36,717 from Optum EHR, 4,336 from OPTUM SES, 156,187 from Premier, and 10,951 from VA-OMOP). Across the six databases, 35,192 (4.17% [95% CI: 4.13% to 4.22%]) patients received dialysis, 6,950 (0.82% [0.81% to 0.84%]) had a tracheostomy, and 1,568 (0.19% [95% CI: 0.18% to 0.20%]) patients underwent ECMO over the 30 days following hospitalization. Use of ECMO was more common among patients who were younger, male, and with fewer comorbidities. Tracheostomy was broadly used for a similar proportion of patients regardless of age, sex, or comorbidity. While dialysis was generally 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.
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http://dx.doi.org/10.1101/2020.11.25.20229088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709172PMC
February 2021

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.

medRxiv 2020 Nov 27. Epub 2020 Nov 27.

Real-World Evidence, Trial Form Support, Barcelona, Spain.

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.

What Is Already Known About This Topic: Patients with autoimmune conditions may be at increased risk of COVID-19 infection andcomplications.There is a paucity of evidence characterising the outcomes of hospitalised COVID-19 patients with prevalent autoimmune conditions.

What This Study Adds: Most people with autoimmune diseases who required hospitalisation for COVID-19 were women, aged 50 years or older, and had substantial previous comorbidities.Patients who were hospitalised with COVID-19 and had prevalent autoimmune diseases had higher prevalence of hypertension, chronic kidney disease, heart disease, and Type 2 diabetes as compared to those with prevalent autoimmune diseases who were diagnosed with COVID-19.A variable proportion of 6% to 25% across data sources died within one month of hospitalisation with COVID-19 and prevalent autoimmune diseases.For people with autoimmune diseases, COVID-19 hospitalisation was associated with worse outcomes and 30-day mortality compared to admission with influenza in the 2017-2018 season.
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http://dx.doi.org/10.1101/2020.11.24.20236802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709171PMC
November 2020

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.

medRxiv 2020 Oct 30. Epub 2020 Oct 30.

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. International network cohort. Real-world data from European primary care records (France/Germany/Spain), South Korean claims and US claims and hospital databases. Diagnosed and/or hospitalized children/adolescents with COVID-19 at age <18 between January and June 2020; diagnosed with influenza in 2017-2018. 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. 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. 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.
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http://dx.doi.org/10.1101/2020.10.29.20222083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605587PMC
October 2020

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.

medRxiv 2020 Oct 27. Epub 2020 Oct 27.

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 3,316,107persons 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.
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http://dx.doi.org/10.1101/2020.10.25.20218875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605581PMC
October 2020

Exposure to traffic-related particle matter and effects on lung function and potential interactions in a cross-sectional analysis of a cohort study in west Sweden.

BMJ Open 2020 10 19;10(10):e034136. Epub 2020 Oct 19.

Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objectives: To investigate the long-term effects of source-specific particle matter (PM) on lung function, effects of Surfactant Protein A (SP-A) and glutathione S-transferase (GST) genes GSTP1 and GSTT1 gene variants and effect modification by single-nucleotide polymorphism (SNP) genotype.

Design: Cohort study with address-based annual PM exposure assigned from annual estimates of size (PM, PM and PM) and source-specific (traffic, industry, marine traffic and wood burning) dispersion modelling.

Setting: Gothenburg, Sweden.

Participants: The ADult-Onset asthma and NItric oXide Study had 6685 participants recruited from the general population, of which 5216 (78%) were included in the current study with information on all variables of interest. Mean age at the time of enrolment was 51.4 years (range 24-76) and 2427 (46.5%) were men.

Primary And Secondary Outcome Measures: The primary outcome was forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV). Secondary outcome measures were effects and gene-environment interactions of SP-A and GSTT1 and GSTP1 genotypes.

Results: Exposure to traffic-related PM and PM was associated with decreases in percent-predicted (% predicted) FEV by -0.48% (95% CI -0.89% to -0.07%) and -0.47% (95% CI -0.88% to -0.07%) per IQR 3.05 and 2.47 µg/m, respectively, and with decreases in % predicted FVC by -0.46% (95% CI -0.83% to -0.08%) and -0.47% (95% CI -0.83% to -0.10%). Total and traffic-related PM was strongly associated with both FEV and FVC by -0.53 (95% CI -0.94 to -0.13%) and -0.43% (95% CI -0.77 to -0.09%) per IQR, respectively, for FVC, and similarly for FEV. Minor allele carrier status for two GSTP1 SNPs and the GSTT1 null genotype were associated with decreases in % predicted lung function. Three SP-A SNPs showed effect modification with exposure to PM from industry and marine traffic.

Conclusions: PM exposure, specifically traffic related, was associated with FVC and FEV reductions and not modified by genotype. Genetic effect modification was suggested for industry and marine traffic PM.
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http://dx.doi.org/10.1136/bmjopen-2019-034136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574932PMC
October 2020

Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study.

Nat Commun 2020 10 6;11(1):5009. Epub 2020 Oct 6.

Clinical Pharmacology Unit, Zealand University Hospital, Køge, Denmark.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.
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http://dx.doi.org/10.1038/s41467-020-18849-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538555PMC
October 2020

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

Lancet Rheumatol 2020 Nov 21;2(11):e698-e711. Epub 2020 Aug 21.

Janssen Research and Development, Titusville, NJ, USA.

Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis.

Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the value was less than 0·4.

Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]).

Interpretation: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment.

Funding: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.
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http://dx.doi.org/10.1016/S2665-9913(20)30276-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442425PMC
November 2020

Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking.

Arthritis Rheumatol 2021 01 4;73(1):61-68. Epub 2020 Dec 4.

Karolinska Institutet, Stockholm, Sweden.

Objective: The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure.

Methods: Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (OR ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status.

Results: Respiratory disease diagnoses were associated with risk of RA, with an OR of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (OR 2.1 [95% CI 1.5-2.9]) than for smokers (OR 1.2 [95% CI 0.9-1.5]).

Conclusion: Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.
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http://dx.doi.org/10.1002/art.41491DOI Listing
January 2021

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study.

medRxiv 2020 Jun 12. Epub 2020 Jun 12.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University, Oxford, UK.

Introduction: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results.

Methods: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) use to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments.

Results: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 - 1.14), nor any difference for mono/combination use (1.01; 0.90 - 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 - 1.05) and marginally significant for mono/combination users (0.88; 0.79 - 0.99). We observed, however, no significant difference between drug- classes for COVID-19 hospitalization or pneumonia risk across all comparisons.

Conclusion: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.
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http://dx.doi.org/10.1101/2020.06.11.20125849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310640PMC
June 2020

Deep phenotyping of 34,128 patients hospitalised with COVID-19 and a comparison with 81,596 influenza patients in America, Europe and Asia: an international network study.

medRxiv 2020 Jun 28. Epub 2020 Jun 28.

Background In this study we phenotyped individuals hospitalised with coronavirus disease 2019 (COVID-19) in depth, summarising entire medical histories, including medications, as captured in routinely collected data drawn from databases across three continents. We then compared individuals hospitalised with COVID-19 to those previously hospitalised with influenza. Methods We report demographics, previously recorded conditions and medication use of patients hospitalised with COVID-19 in the US (Columbia University Irving Medical Center [CUIMC], Premier Healthcare Database [PHD], UCHealth System Health Data Compass Database [UC HDC], and the Department of Veterans Affairs [VA OMOP]), in South Korea (Health Insurance Review & Assessment [HIRA]), and Spain (The Information System for Research in Primary Care [SIDIAP] and HM Hospitales [HM]). These patients were then compared with patients hospitalised with influenza in 2014-19. Results 34,128 (US: 8,362, South Korea: 7,341, Spain: 18,425) individuals hospitalised with COVID-19 were included. Between 4,811 (HM) and 11,643 (CUIMC) unique aggregate characteristics were extracted per patient, with all summarised in an accompanying interactive website (http://evidence.ohdsi.org/Covid19CharacterizationHospitalization/). Patients were majority male in the US (CUIMC: 52%, PHD: 52%, UC HDC: 54%, VA OMOP: 94%,) and Spain (SIDIAP: 54%, HM: 60%), but were predominantly female in South Korea (HIRA: 60%). Age profiles varied across data sources. Prevalence of asthma ranged from 4% to 15%, diabetes from 13% to 43%, and hypertensive disorder from 24% to 70% across data sources. Between 14% and 33% were taking drugs acting on the renin-angiotensin system in the 30 days prior to hospitalisation. Compared to 81,596 individuals hospitalised with influenza in 2014-19, patients admitted with COVID-19 were more typically male, younger, and healthier, with fewer comorbidities and lower medication use. Conclusions We provide a detailed characterisation of patients hospitalised with COVID-19. Protecting groups known to be vulnerable to influenza is a useful starting point to minimize the number of hospital admissions needed for COVID-19. However, such strategies will also likely need to be broadened so as to reflect the particular characteristics of individuals hospitalised with COVID-19.
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http://dx.doi.org/10.1101/2020.04.22.20074336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239064PMC
June 2020

Group IIA Secretory Phospholipase A, Vascular Inflammation, and Incident Cardiovascular Disease.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1182-1190

From the Center for Lipid Metabolomics, Division of Preventive Medicine (A.O.A., P.R.L., R.J.G., P.M.R., D.I.C., S.M.), Department of Medicine, Brigham and Women's Hospital, Boston, MA.

Objective- Inflammation is a causal risk factor for cardiovascular disease (CVD). sPLA-IIA (group IIA secretory phospholipase A) plays an integral role in regulating vascular inflammation. Although studies investigated sPLA-IIA in secondary prevention, we prospectively evaluated sPLA-IIA mass and genetic variants with CVD events in a primary prevention population with chronic inflammation. Approach and Results- The JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) randomized participants with LDL (low-density lipoprotein) <130 mg/dL and hsCRP (high-sensitivity C-reactive protein) ≥2 mg/L to high-intensity rosuvastatin versus placebo. Baseline and 1-year plasma sPLA-IIA mass was measured (N=11 269 baseline; N=9620 1 year). We also identified genetic variants influencing sPLA-IIA using genome-wide association and examined them with CVD. Three hundred thirteen incident CVD events occurred during follow-up. Baseline sPLA-IIA mass (median, 25th-75th percentile: 3.81, 2.49-6.03 ng/mL) was associated with increased risk of CVD: risk factor-adjusted hazard ratio (95% CI; P) per SD increment: 1.22 (1.08-1.38; P=0.002). This remained significant (1.18; 1.04-1.35; P=0.01) after incrementally adjusting for hsCRP. Similar estimates were observed in rosuvastatin and placebo groups ( P treatment interaction>0.05). The rs11573156C variant in PLA2G2A (encoding sPLA-IIA) had the strongest effect on sPLA-II: median (25th-75th percentile, ng/mL) for CC and GG genotypes: 2.79 (1.97-4.01) and 7.38 (5.38-10.19), respectively; and had nonsignificant trend for higher CVD risk (hazard ratio, 1.11; 95% CI, 0.89-1.38; P=0.34). Conclusions- In the JUPITER population recruited on chronic inflammation, sPLA-IIA mass was associated with CVD risk relating to vascular inflammation not fully reflected by hsCRP. Additional studies, including larger functional genetic and clinical studies, are needed to determine whether sPLA-IIA may be a potential pharmacological target for primary prevention of CVD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00239681.
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http://dx.doi.org/10.1161/ATVBAHA.118.311894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534275PMC
June 2019

Gefitinib exposure and occurrence of interstitial lung disease in Japanese patients with non-small-cell lung cancer.

Cancer Chemother Pharmacol 2019 05 14;83(5):849-858. Epub 2019 Feb 14.

Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: A prospective, multicenter, large-scale cohort with a nested case-control study (NCT00252759) was conducted to identify and quantify risk factors for interstitial lung disease (ILD) in Japanese patients with non-small-cell lung cancer who received gefitinib. This study reports the association between gefitinib exposure and the occurrence of ILD.

Methods: A total of 1891 gefitinib plasma concentrations from 336 patients were measured after first dose, at steady state, and at time of ILD occurrence. Influences of demographic and pathophysiological factors on pharmacokinetics were investigated by non-linear mixed-effect modeling. The exposure to gefitinib was compared between patients without and with ILD occurrence to explore risks associated with gefitinib-induced ILD. Intra-patient comparison of exposure was also conducted between times at ILD development and normal states.

Results: In the population pharmacokinetic analysis for gefitinib, α-acid glycoprotein (AGP), age, body weight, and concomitant use of cytochrome P450 3A4 inducers were significant covariates on oral clearance (CL/F). AGP and body weight were also identified as factors affecting the volume of distribution. CL/F was significantly lower at the time of ILD occurrence than normal states. Patients who developed ILD tended to show higher exposure to gefitinib than those without ILD; however, these differences were not statistically significant. On the other hand, exposure at the time of ILD occurrence was significantly elevated compared to the time of normal state within the same patients.

Conclusions: Significant elevation of exposure of gefitinib was observed at the time of ILD occurrence, suggesting reduction of CL/F could be associated with ILD-induced AGP elevation. Increase in exposure of gefitinib is unlikely to be a robust predictor of ILD and does not warrant any dose modifications.
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http://dx.doi.org/10.1007/s00280-019-03788-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458983PMC
May 2019

Prospective observational study in patients with obstructive lung disease: NOVELTY design.

ERJ Open Res 2019 Feb 1;5(1). Epub 2019 Feb 1.

School of Biological Sciences, University of Manchester, Manchester, UK.

Asthma and chronic obstructive pulmonary disease (COPD) have overlapping clinical features and share pathobiological mechanisms but are often considered distinct disorders. Prospective, observational studies across asthma, COPD and asthma-COPD overlap are limited. NOVELTY is a global, prospective observational 3-year study enrolling ∼12 000 patients ≥12 years of age from primary and specialist clinical practices in 19 countries (ClinicalTrials.gov identifier: NCT02760329). NOVELTY's primary objectives are to describe patient characteristics, treatment patterns and disease burden over time, and to identify phenotypes and molecular endotypes associated with differential outcomes over time in patients with a diagnosis/suspected diagnosis of asthma and/or COPD. NOVELTY aims to recruit real-world patients, unlike clinical studies with restrictive inclusion/exclusion criteria. Data collected at yearly intervals include clinical assessments, spirometry, biospecimens, patient-reported outcomes (PROs) and healthcare utilisation (HCU). PROs and HCU will also be collected 3-monthly internet/telephone. Data will be used to identify phenotypes and endotypes associated with different trajectories for symptom burden, clinical progression or remission and HCU. Results may allow patient classification across obstructive lung disease by clinical outcomes and biomarker profile, rather than by conventional diagnostic labels and severity categories. NOVELTY will provide a rich data source on obstructive lung disease, to help improve patient outcomes and aid novel drug development.
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http://dx.doi.org/10.1183/23120541.00036-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355976PMC
February 2019

Prevalence of cardiovascular disease and major risk factors in patients with rheumatoid arthritis: a multinational cross-sectional study.

Clin Rheumatol 2018 Sep 25;37(9):2331-2340. Epub 2018 Apr 25.

Corrona LLC, Southborough, MA, USA.

To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins.
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http://dx.doi.org/10.1007/s10067-018-4113-3DOI Listing
September 2018

Infection rates in patients from five rheumatoid arthritis (RA) registries: contextualising an RA clinical trial programme.

RMD Open 2017 10;3(2):e000498. Epub 2017 Oct 10.

Occupational and Environmental Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Objective: Patients with rheumatoid arthritis (RA) have an increased risk of serious infections. Comparing infection rates across RA populations is complicated by differences in background infection risk, population composition and study methodology. We measured infection rates from five RA registries globally, with the aim to contextualise infection rates from an RA clinical trials population.

Methods: We used data from Consortium of Rheumatology Research of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (Sweden), Norfolk Arthritis Register (UK), CORRONA International (multiple countries) and Institute of Rheumatology Rheumatoid Arthritis (Japan) and an RA clinical trial programme (fostamatinib). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data. Infection definitions were harmonised across registries. Sensitivity analyses to address potential confounding explored subcohorts defined by disease activity, treatment change and/or prior comorbidities and restriction by calendar time or follow-up. Rates of infections were estimated and standardised to the trial population for age/sex and, in one sensitivity analysis also, for Health Assessment Questionnaire (HAQ) score.

Results: Overall, age/sex-standardised rates of hospitalised infection were quite consistent across registries (range 1.14-1.62 per 100 patient-years). Higher and more consistent rates across registries and with the trial programme overall were seen when adding standardisation for HAQ score (registry range 1.86-2.18, trials rate 2.92) or restricting to a treatment initiation subcohort followed for 18 months (registry range 0.99-2.84, trials rate 2.74).

Conclusion: This prospective, coordinated analysis of RA registries provided incidence rate estimates for infection events to contextualise infection rates from an RA clinical trial programme and demonstrated relative comparability of hospitalised infection rates across registries.
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http://dx.doi.org/10.1136/rmdopen-2017-000498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652583PMC
October 2017

Patient perspectives on neuromyelitis optica spectrum disorders: Data from the PatientsLikeMe online community.

Mult Scler Relat Disord 2017 Oct 11;17:116-122. Epub 2017 Jul 11.

PatientsLikeMe Inc., 160 s Street, Cambridge, MA 02142, USA. Electronic address:

Background: Few studies have evaluated patient perspectives on neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD).

Objective: Describe patient-reported clinical and treatment experience in NMOSD and compare disease characteristics of NMOSD with those of multiple sclerosis (MS).

Methods: This retrospective, observational study included 522 members with NMO or NMOSD (hereafter collectively referred to as NMOSD) from PatientsLikeMe (PLM), an online patient community. Data describing member demographics, symptoms, and treatments were collected, analysed descriptively, and compared with data from PLM members with MS.

Results: Fatigue, pain, and stiffness/spasticity were each rated as moderate to severe by more than half of NMOSD members, and 59% reported that their health limited the type of work or other activities they could perform all or most of the time. Overall, symptom severity and disability levels were comparable between NMOSD and MS members; however, NMOSD members were more likely than MS members to attribute disability to vision-related symptoms and were less likely to report moderate to severe cognitive and emotional symptoms, including brain fog, depressed or anxious mood, and emotional lability.

Conclusion: This analysis underscores the challenges of living with fatigue, pain, stiffness/spasticity, and visual difficulties, prevalent NMOSD symptoms among members of the PLM community.
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http://dx.doi.org/10.1016/j.msard.2017.07.014DOI Listing
October 2017

Cohort Profile: The INTERGENE Study.

Int J Epidemiol 2017 12;46(6):1742-1743h

Section for Epidemiology and Social Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

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http://dx.doi.org/10.1093/ije/dyw332DOI Listing
December 2017
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