Severity of COVID-19 disease in US veterans infected during the predominant periods of Omicron and Delta variants – Nature Communications

Patient characteristics

Our matched analysis data set consisted of 22,841 veterans infected during the Omicron period and 22,841 matched veterans infected during the Delta period. (fig. 1) The median age (IQR) was 62.0 years (49.0; 72.0), 91.9% were male, and 82.4% were Caucasian. The majority of veterans in our cohort were multimorbid and over 75% (34,492/45,682) had two or more pre-existing chronic health conditions. The median Charlson Comorbidity Index score was 3 (IQR 2.4).

fig. 1: Overview of study cohort derivation.
Figure 1

We constructed a 1:1 matched cohort by matching veterans infected during the Omicron variant period with veterans infected during the Delta variant period using random coarser exact matching. Individuals were matched for age, sex, race, vaccination status at time of infection, date of administration of the second vaccine dose, Charlson Comorbidity Index, area deprivation score (as a marker of socioeconomic status), and VA medical center to account for local differences in SARS levels. CoV-2 transmission, testing and hospitalization practices.

Of both groups, 7393 (32.4%) had received two doses of an mRNA vaccine and 990 (4.3%) had received an additional booster dose (Table 1† The infection was diagnosed ≥14 days after the booster dose in 910 (4.0%) of the infected during the Omicron period and in 403 (1.8%) of the infected during the Delta period.

Table 1 Baseline Characteristics of Propensity Scored Veterans Infected During Omicron and Delta Predominant Periods.

Severity of the disease

Of those infected during the Omicron period, 20,681 (90.5%) had mild disease, while 1,308 (5.7%) met criteria for moderate disease and 852 (3.7%) met criteria for severe/critical disease. Of those infected during the Delta period, 19,356 (84.7%) had mild disease, 1467 (6.4%) met moderate disease, and in 2018 (8.8%) met severe/critical criteria, respectively. Overall, a significantly lower percentage of veterans met moderate or severe/critical disease criteria during the Omicron period than in the Delta period (9.5% vs. 15.3%; p< 0.001; Table 2

Table 2 Summary of disease outcomes of the two SARS-CoV-2 variant groups.

Of the 2160 moderate or severe/critical infections during the Omicron period, 48 (2.2%) occurred in those who received a booster dose ≥ 14 days previously. Of the 3485 moderate or severe/critical infections during the Delta period, 58 (1.7%) occurred in subjects who received a booster mRNA vaccine at least 14 days prior to infection. †p< 0.001; Table 3

Table 3 Summary of disease outcomes of the two SARS-CoV-2 variant groups, stratified by vaccination status.

In the multivariate logistic regression model, infection during the Omicron period was associated with a lower probability of moderate or severe disease (unadjusted odds ratio: 0.58, 95% CI 0.55 to 0.62, p< 2 × 10−16† adjusted odds ratio (aOR): 0.56; 95% CI 0.53-0.59, p< 2 × 10−16

Additional analyses

Baseline characteristics of the entire cohort before matching (72,492 in the Omicron period and 35,848 in the Delta variant period) are shown in the Supplementary Table 2† Veterans with confirmed COVID-19 disease during the Omicron period were younger and a greater percentage were female and non-Caucasian. Fewer veterans were unvaccinated during the Omicron period (33.5% vs. 48.8%) and a significantly higher percentage received a booster vaccine (19.4% Omicron vs. 4.1% Delta).

We calculated the probability of disease severity, stratified by the predominant variant. Vaccination was associated with significant protection against moderate or severe/critical disease. The unadjusted OR was 0.99 (95% CI 0.89-1.09, p= 0.786), and the aOR was 0.51 (95% CI 0.46-0.57, p< 2 × 10−16) for Omicron variant infection among vaccinees with a 2nd dose ≥ 3 months before infection. The unadjusted OR was 0.68 (95% CI 0.51-0.87) and the aOR was 0.26 (95% CI 0.20-0.34, p< 2 × 10−16) for booster dose recipients 14 days prior to infection. The corresponding unadjusted and adjusted ORs for the Delta variant period were 0.85 (95% CI 0.78-0.92), p= 5.47 × 10−5 and 0.47 (95% CI 0.43-0.51, p< 2 × 10−16) for those vaccinated with a 2nd dose 3 months before infection, respectively. Accordingly, for booster dose recipients ≥ 14 days prior to infection, the uncorrected OR for severe/critical disease was 0.82 (95% CI 0.60-1.09; p= 0.177), and the aOR was 0.34 (95% CI 0.25–0.46, p= 3.46 × 10−12

The proportion of veterans requiring organ support measures during Omicron and Delta variant periods is summarized in the Supplementary Table 3† A significantly smaller proportion of individuals in the Omicron variant required low flow supplemental oxygen (36.3% vs 63.4%), high flow oxygen (8.8% vs 25.9%) and mechanical ventilation (6.5% vs. 10.0%). †p< 0.001 for all comparisons). The need for occasional renal replacement therapy and vasopressor support did not differ between the periods when Omicron and Delta predominate.

Sensitivity analyses

We recalculated the proportion of individuals in each disease severity category by applying a stricter definition of variance predominance, limiting the time periods in which each variant accounted for >98% of all reported variants (October 1 to December 4, 2021, for the Delta variant and January 2 to January 15, 2022, for the Omicron variant). Results from our sensitivity analysis of 19,874 matched couples were similar to our primary results (Supplementary Table) 4

To exclude a potential confounding effect of prior treatment with monoclonal antibodies or nitravelmir/ritonavir (paxlovid) on disease severity, we performed susceptibility analyzes and excluded 3861 patients who had received these treatments after a positive SARS-CoV test. 2 PCR test. Disease severity estimates of 21,231 matched couples were comparable to our primary analysis (Supplementary Table) 5

Similarly, we performed additional analyzes to exclude confounding due to different hospital bed capacities during Omicron and Delta periods. Assessing bed capacity in this context is challenging because the number of beds allowed is not necessarily equal to the number of staffed beds, i.e. beds with nurses and other staff available to accommodate patients. We had information on acute medical and surgical care beds in use for 107 of the 129 VA facilities included in our dataset before they were compared. The average number of daily admissions for these facilities was well below bed capacity, so our estimates are unlikely to be confused. The median number of admissions per day during the 24-day Omicron period was 1.62 (IQR 0.87, 2.67). In contrast, the median number of daily admissions during the 72-day Delta period was 0.49, IQR: 0.29, 0.76, resulting in a median daily admission ratio (Omicron: Delta) of 3.25 (IQR 1, 74, 5.25). We performed a sensitivity analysis on the matched data and calculated disease severity estimates for facilities with median daily Omicron:Delta uptake ratios below and above the 50% percentile (<3.25 vs. -3.25). The results were similar in both layers, suggesting that acute care bed capacity did not substantially affect our severity estimates.

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