COVID-19 disease severity in US Veterans infected during Omicron and Delta variant predominant periods

Patient characteristics

Our matched analysis dataset 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 men, and 82.4% were White. The majority of veterans in our cohort were multi-morbid, and more than 75% (34,492/45,682) had two or more preexisting 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 coarsened exact matching. Individuals were matched on age, sex, race, vaccination status at the time of infection, second vaccine dose administration date, Charlson Comorbidity Index, area deprivation score (as a marker of socioeconomic status), and VA medical center to account for local differences in SARS-CoV-2 transmission, testing, and hospital admission practices.

Among 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). Infection was diagnosed ≥14 days after the booster dose in 910 (4.0%) of those infected during the Omicron period and 403 (1.8%) of those infected during the Delta period.

Table 1 Baseline characteristics of propensity score-matched veterans infected during Omicron and Delta predominant periods.

Disease severity

Among those infected during the Omicron period, 20,681 (90.5%) had mild disease, whereas 1308 (5.7%) fulfilled moderate disease criteria, and 852 (3.7%) met severe/critical disease criteria. Among those infected during the Delta period, 19,356 (84.7%) had mild disease, 1467 (6.4%) fulfilled moderate disease, and 2018 (8.8%) severe/critical criteria, respectively. Overall, a significantly lower proportion of veterans met moderate or severe/critical disease criteria during the Omicron period than 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 had received a booster dose ≥14 days prior. Of the 3485 moderate or severe/critical infections during the Delta period, 58 (1.7%) occurred among individuals who had received a booster mRNA vaccine at least 14 days before their 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 multivariable logistic regression model, infection during the Omicron period was associated with lower odds 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 presented in Supplementary Table 2. Veterans with confirmed COVID-19 disease during the Omicron period were younger, and a higher proportion was female and non-White. Fewer veterans were unvaccinated during the Omicron period (33.5% vs. 48.8%), and a significantly higher proportion had received a booster vaccine (19.4% Omicron vs. 4.1% Delta).

We calculated the odds of the 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 vaccinated with 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 recipients of a booster dose ≥ 14 days before 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 recipients of a booster dose ≥ 14 days before infection, the unadjusted 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 are summarized in Supplementary Table 3. A significantly lower proportion of individuals in the Omicron variant period required supplemental low flow 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 incident renal replacement therapy and vasopressor support did not differ between Omicron and Delta predominant periods.

Sensitivity Analyses

We recalculated the proportion of persons in each disease severity category by applying a more stringent definition of variant predominance, limiting time periods when each variant constituted >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 pairs 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 sensitivity analyses and excluded 3861 patients who had received these treatments after a positive SARS-CoV-2 PCR test. Disease severity estimates of 21,231 matched pairs were similar to our primary analysis (Supplementary Table 5).

Similarly, we performed additional analyses 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 authorized beds does not necessarily equate to the number of staffed beds, i.e., beds with nursing and other staff available to accommodate patients. We had information about acute medical and surgical care beds in operation for 107 of 129 VA facilities included in our dataset before matching. The average number of daily admissions for these facilities was well below operating bed capacity and thus unlikely to confound our estimates. 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 sensitivity analysis on the matched data and calculated disease severity estimates for facilities with median daily Omicron: Delta admission ratios below and above the 50% percentile (<3.25 vs. ≥3.25). Results were similar in both strata, suggesting that acute care bed capacity did not affect our severity estimates substantially.

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