ImportanceWith a large proportion of the US adult population vaccinated against SARS-CoV-2, it is important to identify who remains at risk of severe infection despite vaccination.ObjectiveTo characterize risk factors for severe COVID-19 disease in a vaccinated population.Design, Setting, and ParticipantsThis nationwide, retrospective cohort study included US veterans who received a SARS-CoV-2 vaccination series and later developed laboratory-confirmed SARS-CoV-2 infection and were treated at US Department of Veterans Affairs (VA) hospitals. Data were collected from December 15, 2020, through February 28, 2022.ExposuresDemographic characteristics, comorbidities, immunocompromised status, and vaccination-related variables.Main Outcomes and MeasuresDevelopment of severe vs nonsevere SARS-CoV-2 infection. Severe disease was defined as hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either blood oxygen level of less than 94%, receipt of supplemental oxygen or dexamethasone, mechanical ventilation, or death within 28 days. Association between severe disease and exposures was estimated using logistic regression models.ResultsAmong 110 760 patients with infections following vaccination (97 614 [88.1%] men, mean [SD] age at vaccination, 60.8 [15.3] years; 26 953 [24.3%] Black, 11 259 [10.2%] Hispanic, and 71 665 [64.7%] White), 10 612 (9.6%) had severe COVID-19. The strongest association with risk of severe disease after vaccination was age, which increased among patients aged 50 years or older with an adjusted odds ratio (aOR) of 1.42 (CI, 1.40-1.44) per 5-year increase in age, such that patients aged 80 years or older had an aOR of 16.58 (CI, 13.49-20.37) relative to patients aged 45 to 50 years. Immunocompromising conditions, including receipt of different classes of immunosuppressive medications (eg, leukocyte inhibitor: aOR, 2.80; 95% CI, 2.39-3.28) or cytotoxic chemotherapy (aOR, 2.71; CI, 2.27-3.24) prior to breakthrough infection, or leukemias or lymphomas (aOR, 1.87; CI, 1.61-2.17) and chronic conditions associated with end-organ disease, such as heart failure (aOR, 1.74; CI, 1.61-1.88), dementia (aOR, 2.01; CI, 1.83-2.20), and chronic kidney disease (aOR, 1.59; CI, 1.49-1.69), were also associated with increased risk. Receipt of an additional (ie, booster) dose of vaccine was associated with reduced odds of severe disease (aOR, 0.50; CI, 0.44-0.57).Conclusions and RelevanceIn this nationwide, retrospective cohort of predominantly male US Veterans, we identified risk factors associated with severe disease despite vaccination. Findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision-making about patients most likely to benefit from preexposure prophylaxis and antiviral therapy.

Background Death within a specified time window following a positive SARS-CoV-2 test is used by some agencies for attributing death to COVID-19. With omicron variants, widespread immunity, and asymptomatic screening, there is cause to re-evaluate COVID-19 death attribution methods and develop tools to improve case ascertainment. Methods All patients who died following microbiologically-confirmed SARS-CoV-2 in the Veterans Health Administration (VA) and at Tufts Medical Center (TMC) were identified. Records of selected vaccinated VA patients with positive tests in 2022, and of all TMC patients with positive tests in 2021-22, were manually reviewed to classify deaths as COVID-19-related (either directly caused by or contributed to), focused on deaths within 30 days. Logistic regression was used to develop and validate a surveillance model for identifying deaths in which COVID-19 was causal or contributory. Results Among vaccinated VA patients who died within 30 days after a positive test in January-February, 2022, death was COVID-19-related in 103/150 (69%) of cases (55% causal, 14% contributory). In June-August, 2022, death was COVID-19-related in 70/150 (47%) of cases (22% causal, 25% contributory). Similar results were seen among the 71 patients who died at TMC. A model including hypoxemia, remdesivir, and anti-inflammatory drugs had PPV 0.82-0.95 and NPV 0.64-0.83. Conclusions By mid-2022, “death within 30 days” did not provide an accurate estimate of COVID-19-related death in two US healthcare systems with routine admission screening. Hypoxemia and use of antiviral and anti-inflammatory drugs – variables feasible for reporting to public health agencies - would improve classification of death as COVID-19-related.

Background. Death within 30 days of a positive test for SARS-CoV-2 infection is used by some agencies in definitions of death from COVID-19. With omicron variants predominating in 2022, widespread immunity, and routine screening of asymptomatic patients in some healthcare systems, there is cause to systematically evaluate the proportion of deaths within 30 days of a positive test are COVID-19-related. Methods. Nationwide records in the Veterans Health Administration were used to identify all patients who died within 30 days after positive tests for SARS-CoV-2. Randomly-selected records of previously-vaccinated patients with positive tests in January-February, 2022, or June-August, 2022, underwent review for classification of death as caused by or contributed to by COVID-19, focused on death within 30 days. Multivariable logistic regression was used to determine demographic and clinical variables associated with classification of death as COVID-related, which included cause or contribution. Results. Among vaccinated patients who died within 30 days of a positive test in January-February, 2022 (omicron BA.1 predominance), death was COVID-related in 103/150 cases (69%), as the cause in 55% and contributor in 14%. In June-August, 2022 (BA.5 predominance), death was COVID-related in 70/150 cases (47%), as the cause in 22% and contributor in 25%. Variables positively associated with COVID-related death included medications for COVID-19, hypoxemia, immune-suppressive drugs, and age, whereas advanced cancer, time since positive test, and June-August time period had negative associations. Conclusions. As of mid-2022, “death within 30 days” alone no longer provided an accurate estimate of deaths from COVID-19 in a US healthcare system with routine asymptomatic screening. Over time, the proportion of cases where SARS-CoV-2 was a contributor, rather than the primary cause of death, has increased.