Design and analysis of outcomes following SARS-CoV-2 infection in veterans.

BACKGROUND: Understanding how SARS-CoV-2 infection impacts long-term patient outcomes requires identification of comparable persons with and without infection. We report the design and implementation of a matching strategy employed by the Department of Veterans Affairs' (VA) COVID-19 Observational Research Collaboratory (CORC) to develop comparable cohorts of SARS-CoV-2 infected and uninfected persons for the purpose of inferring potential causative long-term adverse effects of SARS-CoV-2 infection in the Veteran population. METHODS: In a retrospective cohort study, we identified VA health care system patients who were and were not infected with SARS-CoV-2 on a rolling monthly basis. We generated matched cohorts within each month utilizing a combination of exact and time-varying propensity score matching based on electronic health record (EHR)-derived covariates that can be confounders or risk factors across a range of outcomes. RESULTS: From an initial pool of 126,689,864 person-months of observation, we generated final matched cohorts of 208,536 Veterans infected between March 2020-April 2021 and 3,014,091 uninfected Veterans. Matched cohorts were well-balanced on all 39 covariates used in matching after excluding patients for: no VA health care utilization; implausible age, weight, or height; living outside of the 50 states or Washington, D.C.; prior SARS-CoV-2 diagnosis per Medicare claims; or lack of a suitable match. Most Veterans in the matched cohort were male (88.3%), non-Hispanic (87.1%), white (67.2%), and living in urban areas (71.5%), with a mean age of 60.6, BMI of 31.3, Gagne comorbidity score of 1.4 and a mean of 2.3 CDC high-risk conditions. The most common diagnoses were hypertension (61.4%), diabetes (34.3%), major depression (32.2%), coronary heart disease (28.5%), PTSD (25.5%), anxiety (22.5%), and chronic kidney disease (22.5%). CONCLUSION: This successful creation of matched SARS-CoV-2 infected and uninfected patient cohorts from the largest integrated health system in the United States will support cohort studies of outcomes derived from EHRs and sample selection for qualitative interviews and patient surveys. These studies will increase our understanding of the long-term outcomes of Veterans who were infected with SARS-CoV-2.

Comparison of Moderna versus Pfizer-BioNTech COVID-19 vaccine outcomes: A target trial emulation study in the U.S. Veterans Affairs healthcare system.

Background: mRNA COVID-19 vaccines manufactured by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) have been shown to be efficacious but have not been compared in head-to-head clinical trials. Methods: We designed this observational study to emulate a target trial of COVID-19 vaccination by BNT162b2 versus mRNA-1273 among persons who underwent vaccination in the national U.S. Veterans Affairs (VA) healthcare system from 11/12/2020 to 25/03/2021 using combined VA and Medicare electronic health records. We identified the best matching mRNA-1273 recipient(s) for each BNT162b2 recipient, using exact/coarsened-exact matching (calendar week, VA integrated service network, age buckets and Charlson comorbidity index buckets) followed by propensity score matching. Vaccine recipients were followed from the date of first vaccine dose until 25/08/2021 for the development of SARS-CoV-2 infection, SARS-CoV-2-related hospitalization or SARS-CoV-2-related death. Findings: Each group included 902,235 well-matched vaccine recipients, followed for a mean of 192 days, during which 16,890 SARS-CoV-2 infections, 3591 SARS-CoV-2-related hospitalizations and 381 SARS-CoV-2-related deaths were documented. Compared to BNT162b2, mRNA-1273 recipients had significantly lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0.736, 95% CI 0.696-0.779) and SARS-CoV-2-related hospitalization (aHR 0.633, 95% CI 0.562-0.713), which persisted across all age groups, comorbidity burden categories and black/white race. The differences between mRNA-1273 and BNT162b2 in risk of infection or hospitalization were progressively greater when the follow-up period was longer, i.e. extending to March 31, June 30 or August 25, 2021. These differences were more pronounced when we analyzed separately the outcomes that occurred during the follow-up period from July 1 to August 25, 2021 when the Delta variant became predominant in the U.S. (aHR for infection 0.584, 95% CI 0.533-0.639 and aHR for hospitalization 0.387, 95% 0.311-0.482). SARS-CoV-2-related deaths were less common in mRNA-1273 versus BNT162b2 recipients (168 versus 213) but this difference was not statistically significant (aHR 0.808, 95% CI 0.592-1.103). Interpretation: In conclusion, although absolute rates of infection, hospitalization and death in both vaccine groups were low regardless of the vaccine received, our data suggests that compared to BNT162b2, vaccination with mRNA-1273 resulted in significantly lower rates of SARS-CoV-2-infection and SARS-CoV-2-related hospitalization. These differences were greater with longer follow-up time since vaccination and even more pronounced in the Delta variant era. Funding: U.S. Department of Veterans Affairs, grant numbers COVID19-8900-11 and C19 21-278.

Trends Over Time in the Risk of Adverse Outcomes Among Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: We aimed to describe trends in adverse outcomes among patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and September 2020 within a national healthcare system. METHODS: We identified enrollees in the national United States Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 28 February 2020 and 30 September 2020 (n = 55 952), with follow-up extending to 19 November 2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death. RESULTS: Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms, and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU, or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%), vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%), and remdesivir (1.7% to 45.4%) among hospitalized patients. CONCLUSIONS: The risk of adverse outcomes in SARS-CoV-2-positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.

Factors associated with early receipt of COVID-19 vaccination and adherence to second dose in the Veterans Affairs healthcare system.

BACKGROUND: We aimed to determine factors independently associated with early COVID-19 vaccination and adherence to two-dose regimens. METHODS: Among persons receiving care in the Veterans Affairs (VA) healthcare system (n = 5,766,638), we identified those who received at least one dose of COVID-19 vaccination through the VA, during the first ~3months following emergency use authorization, from December 11, 2020 to March 9, 2021 (n = 1,569,099, or 27.2%, including 880,200 (56.1%) Moderna, 676,279 (43.1%) Pfizer-BioNTech and 12,620 (0.8%) Janssen vaccines). RESULTS: Follow-up for receipt of vaccination began on December 11, 2020. After adjustment for baseline characteristics ascertained as of December 11, 2020, factors significantly associated with vaccination included older age, higher comorbidity burden, higher body mass index category, Black (vs. White) race (adjusted hazard ratio [AHR] 1.19, 95% CI 1.19-1.20), Hispanic (vs. non-Hispanic) ethnicity (AHR 1.12, 95% CI 1.11-1.13), urban (vs. rural) residence (AHR 1.31, 95% CI 1.31-1.31), and geographical region, while AI/AN race (vs. White), was associated with lower vaccination rate (AHR 0.85, 95% CI 0.84-0.87). Among persons who received both doses of Moderna or Pfizer-BioNTech vaccines, 95.3% received the second dose within ±4 days of the recommended date. Among persons who received the first vaccine dose, only 3.2% did not receive the second dose within 42 days for Pfizer versus 4.0% for Moderna (p<0.001). Factors independently associated with higher likelihood of missing the second dose included younger age (10.83% in 18-50 yo vs. 2.72% in 70-75 yo), AI/AN race, female sex, rural location, geographical region and prior positive test for SARS-CoV-2. CONCLUSIONS: We identified sociodemographic and clinical factors that may be used to target vaccination efforts and to further improve adherence to second vaccine dosing.

Risk Factors for Testing Positive for Severe Acute Respiratory Syndrome Coronavirus 2 in a National United States Healthcare System.

BACKGROUND: Identifying risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could help health systems improve testing and screening strategies. The aim of this study was to identify demographic factors, comorbid conditions, and symptoms independently associated with testing positive for SARS-CoV-2. METHODS: This was an observational cross-sectional study at the Veterans Health Administration, including persons tested for SARS-CoV-2 nucleic acid by polymerase chain reaction (PCR) between 28 February and 14 May 2020. Associations between demographic characteristics, diagnosed comorbid conditions, and documented symptoms with testing positive for SARS-CoV-2 were measured. RESULTS: Of 88 747 persons tested, 10 131 (11.4%) were SARS-CoV-2 PCR positive. Positivity was associated with older age (≥80 vs <50 years: adjusted odds ratio [aOR], 2.16 [95% confidence interval {CI}, 1.97-2.37]), male sex (aOR, 1.45 [95% CI, 1.34-1.57]), regional SARS-CoV-2 burden (≥2000 vs <400 cases/million: aOR, 5.43 [95% CI, 4.97-5.93]), urban residence (aOR, 1.78 [95% CI, 1.70-1.87]), black (aOR, 2.15 [95% CI, 2.05-2.26]) or American Indian/Alaska Native Hawaiian/Pacific Islander (aOR, 1.26 [95% CI, 1.05-1.52]) vs white race, and Hispanic ethnicity (aOR, 1.52 [95% CI, 1.40-1.65]). Obesity and diabetes were the only 2 medical conditions associated with testing positive. Documented fevers, chills, cough, and diarrhea were also associated with testing positive. The population attributable fraction of positive tests was highest for geographic location (35.3%), followed by demographic variables (27.1%), symptoms (12.0%), obesity (10.5%), and diabetes (0.4%). CONCLUSIONS: The majority of positive SARS-CoV-2 tests were attributed to geographic location, demographic characteristics, and obesity, with a minor contribution of chronic comorbid conditions.

Changes in the associations of race and rurality with SARS-CoV-2 infection, mortality, and case fatality in the United States from February 2020 to March 2021: A population-based cohort study.

BACKGROUND: We examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study. METHODS AND FINDINGS: In a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2-related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value <0.001), mortality (AOR 3.85 [95% CI 3.30 to 4.50], p-value < 0.001), and case fatality (AOR 2.56, 95% CI 2.23 to 2.93, p-value < 0.001) in February to March 2020, but these associations were attenuated and not statistically significant by November 2020 for infection (AOR 1.03 [95% CI 1.00 to 1.07] p-value = 0.05) and mortality (AOR 1.08 [95% CI 0.96 to 1.20], p-value = 0.21) and were reversed for case fatality (AOR 0.86, 95% CI 0.78 to 0.95, p-value = 0.005). American Indian/Alaska Native (AI/AN versus White) race was associated with higher risk of SARS-CoV-2 infection in April and May 2020; this association declined over time and reversed by March 2021 (AOR 0.66 [95% CI 0.51 to 0.85] p-value = 0.004). Hispanic (versus non-Hispanic) ethnicity was associated with higher risk of SARS-CoV-2 infection and mortality during almost every time period, with no evidence of attenuation over time. Urban (versus rural) residence was associated with higher risk of infection (AOR 2.02, [95% CI 1.83 to 2.22], p-value < 0.001), mortality (AOR 2.48 [95% CI 2.08 to 2.96], p-value < 0.001), and case fatality (AOR 2.24, 95% CI 1.93 to 2.60, p-value < 0.001) in February to April 2020, but these associations attenuated over time and reversed by September 2020 (AOR 0.85, 95% CI 0.81 to 0.89, p-value < 0.001 for infection, AOR 0.72, 95% CI 0.62 to 0.83, p-value < 0.001 for mortality and AOR 0.81, 95% CI 0.71 to 0.93, p-value = 0.006 for case fatality). Throughout the observation period, high comorbidity burden, younger age, and obesity were consistently associated with infection, while high comorbidity burden, older age, and male sex were consistently associated with mortality. Limitations of the study include that changes over time in the associations of some risk factors may be affected by changes in the likelihood of testing for SARS-CoV-2 according to those risk factors; also, study results apply directly to VA enrollees who are predominantly male and have comprehensive healthcare and need to be confirmed in other populations. CONCLUSIONS: In this study, we found that strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality observed early in the pandemic were ameliorated or reversed by March 2021.

Cirrhosis and Severe Acute Respiratory Syndrome Coronavirus 2 Infection in US Veterans: Risk of Infection, Hospitalization, Ventilation, and Mortality.

BACKGROUND AND AIMS: Whether patients with cirrhosis have increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the extent to which infection and cirrhosis increase the risk of adverse patient outcomes remain unclear. APPROACH AND RESULTS: We identified 88,747 patients tested for SARS-CoV-2 between March 1, 2020, and May 14, 2020, in the Veterans Affairs (VA) national health care system, including 75,315 with no cirrhosis-SARS-CoV-2-negative (C0-S0), 9,826 with no cirrhosis-SARS-CoV-2-positive (C0-S1), 3,301 with cirrhosis-SARS-CoV-2-negative (C1-S0), and 305 with cirrhosis-SARS-CoV-2-positive (C1-S1). Patients were followed through June 22, 2020. Hospitalization, mechanical ventilation, and death were modeled in time-to-event analyses using Cox proportional hazards regression. Patients with cirrhosis were less likely to test positive than patients without cirrhosis (8.5% vs. 11.5%; adjusted odds ratio, 0.83; 95% CI, 0.69-0.99). Thirty-day mortality and ventilation rates increased progressively from C0-S0 (2.3% and 1.6%) to C1-S0 (5.2% and 3.6%) to C0-S1 (10.6% and 6.5%) and to C1-S1 (17.1% and 13.0%). Among patients with cirrhosis, those who tested positive for SARS-CoV-2 were 4.1 times more likely to undergo mechanical ventilation (adjusted hazard ratio [aHR], 4.12; 95% CI, 2.79-6.10) and 3.5 times more likely to die (aHR, 3.54; 95% CI, 2.55-4.90) than those who tested negative. Among patients with SARS-CoV-2 infection, those with cirrhosis were more likely to be hospitalized (aHR, 1.37; 95% CI, 1.12-1.66), undergo ventilation (aHR, 1.61; 95% CI, 1.05-2.46) or die (aHR, 1.65; 95% CI, 1.18-2.30) than patients without cirrhosis. Among patients with cirrhosis and SARS-CoV-2 infection, the most important predictors of mortality were advanced age, cirrhosis decompensation, and high Model for End-Stage Liver Disease score. CONCLUSIONS: SARS-CoV-2 infection was associated with a 3.5-fold increase in mortality in patients with cirrhosis. Cirrhosis was associated with a 1.7-fold increase in mortality in patients with SARS-CoV-2 infection.

Development of COVIDVax Model to Estimate the Risk of SARS-CoV-2-Related Death Among 7.6 Million US Veterans for Use in Vaccination Prioritization.

Importance: A strategy that prioritizes individuals for SARS-CoV-2 vaccination according to their risk of SARS-CoV-2-related mortality would help minimize deaths during vaccine rollout. Objective: To develop a model that estimates the risk of SARS-CoV-2-related mortality among all enrollees of the US Department of Veterans Affairs (VA) health care system. Design, Setting, and Participants: This prognostic study used data from 7 635 064 individuals enrolled in the VA health care system as of May 21, 2020, to develop and internally validate a logistic regression model (COVIDVax) that predicted SARS-CoV-2-related death (n = 2422) during the observation period (May 21 to November 2, 2020) using baseline characteristics known to be associated with SARS-CoV-2-related mortality, extracted from the VA electronic health records (EHRs). The cohort was split into a training period (May 21 to September 30) and testing period (October 1 to November 2). Main Outcomes and Measures: SARS-CoV-2-related death, defined as death within 30 days of testing positive for SARS-CoV-2. VA EHR data streams were imported on a data integration platform to demonstrate that the model could be executed in real-time to produce dashboards with risk scores for all current VA enrollees. Results: Of 7 635 064 individuals, the mean (SD) age was 66.2 (13.8) years, and most were men (7 051 912 [92.4%]) and White individuals (4 887 338 [64.0%]), with 1 116 435 (14.6%) Black individuals and 399 634 (5.2%) Hispanic individuals. From a starting pool of 16 potential predictors, 10 were included in the final COVIDVax model, as follows: sex, age, race, ethnicity, body mass index, Charlson Comorbidity Index, diabetes, chronic kidney disease, congestive heart failure, and Care Assessment Need score. The model exhibited excellent discrimination with area under the receiver operating characteristic curve (AUROC) of 85.3% (95% CI, 84.6%-86.1%), superior to the AUROC of using age alone to stratify risk (72.6%; 95% CI, 71.6%-73.6%). Assuming vaccination is 90% effective at preventing SARS-CoV-2-related death, using this model to prioritize vaccination was estimated to prevent 63.5% of deaths that would occur by the time 50% of VA enrollees are vaccinated, significantly higher than the estimate for prioritizing vaccination based on age (45.6%) or the US Centers for Disease Control and Prevention phases of vaccine allocation (41.1%). Conclusions and Relevance: In this prognostic study of all VA enrollees, prioritizing vaccination based on the COVIDVax model was estimated to prevent a large proportion of deaths expected to occur during vaccine rollout before sufficient herd immunity is achieved.

BMI and Outcomes of SARS-CoV-2 Among US Veterans.

OBJECTIVE: The purpose of this study is to examine the associations of BMI with testing positive for severe acute respiratory coronavirus 2 (SARS-CoV-2) and risk of adverse outcomes in a cohort of Veterans Affairs enrollees. METHOD: Adjusted relative risks/hazard ratios (HRs) were calculated for the associations between BMI category (underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity) and testing positive for SARS-CoV-2 or experiencing hospitalization, intensive care unit admission, mechanical ventilation, and death among those testing positive. RESULTS: Higher BMI categories were associated with higher risk of a positive SARS-CoV-2 test compared with the normal weight category (class 3 obesity adjusted relative risk: 1.34, 95% CI: 1.28-1.42). Among 25,952 patients who tested positive for SARS-CoV-2, class 3 obesity was associated with higher risk of mechanical ventilation (adjusted HR [aHR]: 1.77, 95% CI: 1.35-2.32) and mortality (aHR: 1.42, 95% CI: 1.12-1.78) compared with normal weight individuals. These associations were present primarily in patients younger than 65 and were attenuated or absent in older age groups (interaction P < 0.05). CONCLUSION: Veterans Affairs enrollees with higher BMI were more likely to test positive for SARS-CoV-2 and were more likely to be mechanically ventilated or die if infected with SARS-CoV-2. Higher BMI contributed relatively more to the risk of death in those younger than 65 years of age as compared with other age categories.

Risk Factors for Hospitalization, Mechanical Ventilation, or Death Among 10 131 US Veterans With SARS-CoV-2 Infection.

Importance: Identifying independent risk factors for adverse outcomes in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can support prognostication, resource utilization, and treatment. Objective: To identify excess risk and risk factors associated with hospitalization, mechanical ventilation, and mortality in patients with SARS-CoV-2 infection. Design, Setting, and Participants: This longitudinal cohort study included 88 747 patients tested for SARS-CoV-2 nucleic acid by polymerase chain reaction between Feburary 28 and May 14, 2020, and followed up through June 22, 2020, in the Department of Veterans Affairs (VA) national health care system, including 10 131 patients (11.4%) who tested positive. Exposures: Sociodemographic characteristics, comorbid conditions, symptoms, and laboratory test results. Main Outcomes and Measures: Risk of hospitalization, mechanical ventilation, and death were estimated in time-to-event analyses using Cox proportional hazards models. Results: The 10 131 veterans with SARS-CoV-2 were predominantly male (9221 [91.0%]), with diverse race/ethnicity (5022 [49.6%] White, 4215 [41.6%] Black, and 944 [9.3%] Hispanic) and a mean (SD) age of 63.6 (16.2) years. Compared with patients who tested negative for SARS-CoV-2, those who tested positive had higher rates of 30-day hospitalization (30.4% vs 29.3%; adjusted hazard ratio [aHR], 1.13; 95% CI, 1.08-1.13), mechanical ventilation (6.7% vs 1.7%; aHR, 4.15; 95% CI, 3.74-4.61), and death (10.8% vs 2.4%; aHR, 4.44; 95% CI, 4.07-4.83). Among patients who tested positive for SARS-CoV-2, characteristics significantly associated with mortality included older age (eg, ≥80 years vs <50 years: aHR, 60.80; 95% CI, 29.67-124.61), high regional COVID-19 disease burden (eg, ≥700 vs <130 deaths per 1 million residents: aHR, 1.21; 95% CI, 1.02-1.45), higher Charlson comorbidity index score (eg, ≥5 vs 0: aHR, 1.93; 95% CI, 1.54-2.42), fever (aHR, 1.51; 95% CI, 1.32-1.72), dyspnea (aHR, 1.78; 95% CI, 1.53-2.07), and abnormalities in the certain blood tests, which exhibited dose-response associations with mortality, including aspartate aminotransferase (>89 U/L vs ≤25 U/L: aHR, 1.86; 95% CI, 1.35-2.57), creatinine (>3.80 mg/dL vs 0.98 mg/dL: aHR, 3.79; 95% CI, 2.62-5.48), and neutrophil to lymphocyte ratio (>12.70 vs ≤2.71: aHR, 2.88; 95% CI, 2.12-3.91). With the exception of geographic region, the same covariates were independently associated with mechanical ventilation along with Black race (aHR, 1.52; 95% CI, 1.25-1.85), male sex (aHR, 2.07; 95% CI, 1.30-3.32), diabetes (aHR, 1.40; 95% CI, 1.18-1.67), and hypertension (aHR, 1.30; 95% CI, 1.03-1.64). Notable characteristics that were not significantly associated with mortality in adjusted analyses included obesity (body mass index ≥35 vs 18.5-24.9: aHR, 0.97; 95% CI, 0.77-1.21), Black race (aHR, 1.04; 95% CI, 0.88-1.21), Hispanic ethnicity (aHR, 1.03; 95% CI, 0.79-1.35), chronic obstructive pulmonary disease (aHR, 1.02; 95% CI, 0.88-1.19), hypertension (aHR, 0.95; 95% CI, 0.81-1.12), and smoking (eg, current vs never: aHR, 0.87; 95% CI, 0.67-1.13). Most deaths in this cohort occurred in patients with age of 50 years or older (63.4%), male sex (12.3%), and Charlson Comorbidity Index score of at least 1 (11.1%). Conclusions and Relevance: In this national cohort of VA patients, most SARS-CoV-2 deaths were associated with older age, male sex, and comorbidity burden. Many factors previously reported to be associated with mortality in smaller studies were not confirmed, such as obesity, Black race, Hispanic ethnicity, chronic obstructive pulmonary disease, hypertension, and smoking.