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

Patient characteristics

Our matched analysis dataset included 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 white. The majority of veterans in our cohort were multimorbid and more than 75% (34,492/45,682) had at least two pre-existing chronic conditions. The median Charlson Comorbidity Index score was 3 (IQR 2.4).

Fig. 1: Overview of the derivation of the study cohort.
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 coarse exact matching. Individuals were matched on age, sex, race, vaccination status at time of infection, date of second dose of vaccine, Charlson comorbidity index, deprivation score area (as a marker of socioeconomic status) and VA medical center to account for local differences in SARS-CoV-2 transmission, screening, and hospital admission practices.

Of the two 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 the Omicron and Delta predominant periods.

disease severity

Of those infected during the Omicron period, 20,681 (90.5%) had mild disease, while 1,308 (5.7%) met the criteria for moderate disease and 852 (3.7%) met the criteria. severe/critical disease criteria. Of those infected during the Delta period, 19,356 (84.7%) had mild disease, 1,467 (6.4%) met moderate disease, and 2018 (8.8%) met severe/critical criteria, respectively. Overall, a significantly lower proportion of veterans met the criteria for moderate or severe/critical illness during the Omicron period compared to 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 people who received a booster dose ≥ 14 days previously. Of the 3,485 moderate or severe/critical infections during the Delta period, 58 (1.7%) occurred in people who had received an mRNA booster 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 a lower risk 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).

Complementary analyzes

The 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 higher proportion were female, not white. Fewer veterans were unvaccinated during the Omicron period (33.5% versus 48.8%), and a significantly higher proportion received a booster (19.4% Omicron versus 4.1% Delta).

We calculated disease severity ratings 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 infection with the Omicron variant in vaccinees with the 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 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 recipients of a booster dose ≥ 14 days prior to 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 the Omicron and Delta variant periods is summarized in the 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% versus 10.0%). (P< 0.001 for all comparisons). The need for incident renal replacement therapy and vasopressor support did not differ between the Omicron- and Delta-predominant periods.

Sensitivity analyzes

We recalculated the proportion of people in each category of disease severity by applying a stricter definition of variant predominance, limiting the time periods when each variant constituted >98% of all reported variants (October 1 through October 4). December 2021, for the Delta variant and in January 2 to 15 January 2022, for the Omicron variant). The results of 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 analyzes and excluded 3861 patients who had received these treatments after PCR testing. SARS-CoV-2 positive. Disease severity estimates of 21,231 matched pairs were similar to our primary analysis (Supplementary Table 5).

Similarly, we performed additional analyzes to exclude confounding due to different hospital bed capacities during the Omicron and Delta periods. Assessing bed capacity in this context is difficult because the number of authorized beds does not necessarily correspond to the number of staffed beds, i.e. beds with nursing and other staff available to accommodate the patients. Prior to matching, we had active medical and surgical bed information for 107 of the 129 VA facilities included in our dataset. The average number of daily admissions to these facilities was well below operating bed capacity and therefore unlikely to have biased 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 over 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 paired data and calculated disease severity estimates for facilities with median Omicron:Delta daily admission ratios below and above the 50% percentile (<3.25 vs. ≥3.25). The results were similar in both strata, suggesting that acute care bed capacity did not significantly affect our severity estimates.

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