The proportion of patients with the β-phenotype was small in all cohorts, ranging from 1 to 4% (Fig. 1A), which limits the interpretation of this particular phenotype. Phenotype distribution was very similar between the COVID-19 and non-COVID-19 viral pneumonia sepsis cohorts. In both bacterial sepsis cohorts (pulmonary and non-pulmonary), the proportion of patients with the δ-phenotype was greater than in the viral sepsis cohorts at the expense of the α- and, especially, the γ-phenotype. This was particularly apparent for patients with bacterial sepsis of non-pulmonary origin. The latter was also the only cohort where the proportion of the δ-phenotype was greater than that of the γ-phenotype. In COVID-19 patients, the introduction of dexamethasone as standard treatment was associated with an increased proportion of patients with the δ-phenotype (6% vs. 11% in the pre- and post-dexamethasone cohorts, respectively, p < 0.001), at the expense of the γ-phenotype (81% versus 72%, p < 0.001).
Characteristics of all five cohorts are described in Table 1, Fig. 1B, and Additional file 1: Tables 2–6. Disregarding the nonabundant β-phenotype, patients with the α-phenotype were the youngest, had the highest BMI, and had relatively few comorbidities across all cohorts. This phenotype also presented with the lowest creatinine levels and white blood cell counts, and the highest PaO2/FiO2 ratios. This translated into the lowest APACHE IV scores of all phenotypes in all cohorts. Overall, the δ-phenotype exhibited the greatest proportion of males as well as the oldest patients with most comorbidities, highest creatinine levels and white blood cell counts, and therefore the highest APACHE IV scores. Representing the majority of the patient population in most cohorts, the γ-phenotype falls in between the extremes of the above-described phenotypes, only displaying the highest temperature across all cohorts.
Outcome differences between phenotypes were most pronounced for the pre-dexamethasone COVID-19 cohort and least pronounced in the non-COVID-19 viral pneumonia sepsis cohort (Fig. 1A). In all cohorts, the α-phenotype displayed the lowest 90-day mortality, while patients with the δ-phenotype generally displayed the highest mortality. Of interest, survival of the δ-phenotype was markedly higher following the introduction of dexamethasone as standard therapy for COVID-19 (60% vs 41%, p < 0.001, Fig. 1A), whereas no relevant differences in survival were observed for the other phenotypes among COVID-19 patients. Furthermore, across all phenotypes, hospital length-of-stay was 10 days shorter among survivors following the introduction of dexamethasone for COVID-19 patients, whereas the opposite was the case for non-survivors (5 days longer, see Table 1). Hospital length-of-stay also clearly varied between phenotypes in the different cohorts. For survivors, the α-phenotype exhibited the shortest (22 [14–33], 16 [11–27], 9 [6–14], 9 [5–14], and 7 [4–14] days for the pre-dexamethasone, post-dexamethasone, non-COVID-19 viral pneumonia sepsis, bacterial pneumonia sepsis, and bacterial sepsis of non-pulmonary origin cohorts, respectively) and the δ-phenotype the most prolonged length-of-stay (34 [24–57], 23 [13–42], 15 [9–30], 15 [8–26], and 14 [8–25] days, respectively) across all cohorts. For non-surviving COVID-19 patients, there were clear differences in length-of-stay between phenotypes, with the α-phenotype displaying the most prolonged (pre-dexamethasone: 18 [14–29] days, post-dexamethasone: 25 [17–36] days) and the δ-phenotype the shortest length-of-stay (9 [5–16] and 17 [10–26] days). A similar pattern was observed for patients with sepsis of non-pulmonary origin (α: 11 [5–17] days, δ: 5 [2–13] days), whereas no major differences in length-of-stay of non-survivors between phenotypes were observed for the other sepsis cohorts (data not shown).