Clinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in critically ill French patients with COVID-19

Abstract

Infection with SARS-CoV-2 variant Omicron is considered to be less severe than infection with variant Delta, with rarer occurrence of severe disease requiring intensive care. Little information is available on comorbid factors, clinical conditions and specific viral mutational patterns associated with the severity of variant Omicron infection. In this multicenter prospective cohort study, patients consecutively admitted for severe COVID-19 in 20 intensive care units in France between December 7th 2021 and May 1st 2022 were included. Among 259 patients, we show that the clinical phenotype of patients infected with variant Omicron (n = 148) is different from that in those infected with variant Delta (n = 111). We observe no significant relationship between Delta and Omicron variant lineages/sublineages and 28-day mortality (adjusted odds ratio [95% confidence interval] = 0.68 [0.35-1.32]; p = 0.253). Among Omicron-infected patients, 43.2% are immunocompromised, most of whom have received two doses of vaccine or more (85.9%) but display a poor humoral response to vaccination. The mortality rate of immunocompromised patients infected with variant Omicron is significantly higher than that of non-immunocompromised patients (46.9% vs 26.2%; p = 0.009). In patients infected with variant Omicron, there is no association between specific sublineages (BA.1/BA.1.1 (n = 109) and BA.2 (n = 21)) or any viral genome polymorphisms/mutational profile and 28-day mortality.

Fig. 1. Dynamics of infecting SARS-CoV-2 variants during the study period in patients requiring intensive care hospitalized in the 20 participating centers.

Delta lineages/sublineages are in green, Omicron lineages/sublineages are in orange/red. VOC: variants of concern; Source data are provided as a Source Data file.

Fig. 2. Severity of illness scores in patients infected with variant Delta (red; n = 111) and variant Omicron (blue; n = 148).

a SAPS II scores at ICU admission; b SOFA score at day 0 (admission at the ICU) and day 3 of hospitalization (by two-way ANOVA, there was a significant effect of the variant (p = 0.0269), no significant effect of time (p = 0.2784), and no significant interaction of both parameters (variant x time; p = 0.7668)). In (a) and (b), data distribution is represented using violin plots and horizontal bars show the median and quartiles 25 and 75; c Organ system components of the SOFA score at ICU admission. Data distribution is represented using box-and-whisker plots, displaying median values and quartiles 25 and 75 (i.e., lower and upper limits of the box), and 5 and 95% percentiles (circles). Two-sided p-values have been generated with the Mann–Whitney test or the Sidak post-hoc ANOVA test; n = 111 and 148 independent measurements in the Delta and Omicron groups, respectively. SOFA: Sequential Organ Failure Assessment; SAPS II: Simplified Acute Physiology Score II; Source data are provided as a Source Data file.

Fig. 3. Unsupervised analysis of the clinical and biological characteristics of the patients infected with variants Omicron and Delta by self-organized maps (SOMs).

Unsupervised analysis by SOM automatically located patients with similar clinical and paraclinical parameters within 1 of 40 small groupings (“districts”) throughout the map. The more similar the patients, the closer on the map. Each individual map shows the mean values or proportions per district for each characteristic: blue indicates the lowest average values, red the highest, with numbers shown for a selection of representative districts in each SOM. In the upper left area of the maps were located mostly Omicron-infected patients, as shown by the high prevalence rates (red colors) in this area of the Omicron map, whereas patients infected with variant Delta were distinctly located in the lower half area, as indicated by low Omicron prevalence rates (blue colors) in this area. Interpretation of the key characteristics associated with Omicron versus Delta patients can be drawn from the observation of the other maps: for instance, Omicron-infected patients in the upper left area also had higher immunosuppression rates and mean number of vaccination doses received as indicated by the red colors in the corresponding maps. WHO World Health Organization, SOFA Sequential Organ Failure Assessment, SAPS II Simplified Acute Physiology Score II, MV mechanical ventilation, Source data are provided as a Source Data file.

Fig. 4. Relationship between SARS-CoV-2 mutations/deletions and day-28 mortality in patients infected with variant Omicron.

Over the full-length viral genomes of 97 Omicron sample-related patients, we investigated amino acid modifications (substitutions or deletions) outside Spike protein found in at least 20 viral genomes of patients infected by Omicron (n = 11 positions) and analyzed the relationship between these mutations and day-28 mortality in univariable analysis. Two amino acid substitutions (ORF1a-K856R = NSP3 K38R and M-D3G) were significantly associated with day-28 mortality but this relationship was no longer significant after correction of p-values for test multiplicity using the Benjamini–Hochberg procedure. Day 28 mortality is displayed in red and day 28 survival in blue; p-values come from unadjusted logistic regression modeling. Horizontal bars represent percentages; Source data are provided as a Source Data file.

Fig. 5. Serum anti-spike (S) antibody titers in vaccinated and non-vaccinated, immunocompromised (light blue) and non-immunocompromised (deep blue) patients.

By two-way ANOVA, there was a significant effect of vaccination on anti-S titers (p = 0.0023), no significant effect of the immunocompromised status (p = 0.6023) and no significant interaction between both parameters (vaccination x immunocompromised status; p = 0.9824); Data distribution is represented using violin plots; Horizontal bars show median and quartiles 25 and 75; Displayed p-values have been obtained with the Sidak’s post-hoc test.; BAU Binding Antibody Units, Source data are provided as a Source Data file.