Reduction in the number of neutrophils in the broncho-alveolar aspirate is associated with worse prognosis in elderly patients with severe COVID-19

The mortality rate of patients enrolled in this study was 57% (Fig. 1A). In the survivor group, 80% were male and the median age was 56 ± 13 years old. In contrast, non-survivors were 62% male, and the median age was 70 ± 14 years (P = 0.066 compared to survivors). The frequency and number of neutrophils were reduced in the BAL of non-survivors (Fig. 1B, C). These results suggest an association between neutrophils in BAL and severity of COVID-19.

Fig. 1figure 1

Neutrophils are reduced in the BAL of non-survivors and patients over than 60 years with severe COVID-19. Curve of survival from COVID-19 patients under mechanical ventilation (A). Flow cytometry analysis of neutrophils frequencies (B) and numbers (C) in survivor group (n = 10) and non-survivor group (n = 13). Survival curve of patients younger (< 60 years of age) and older (> 60 years of age) (D). Flow cytometry analysis of the neutrophil frequencies (E) and numbers (F). Frequencies (G) and numbers (H) of neutrophils in younger survivors (n = 7), younger non-survivors (n = 3), older survivors (n = 3), and older non-survivors (n = 10). Flow cytometry analysis of MFI of IL-10 (I), IFN-γ (J) and TNF (K) expressed by neutrophils. CXCL8 concentration (L) in the BAL of younger and older patients with COVID-19. Horizontal lines represent geometric mean ± 95% CI. *P < 0.05, **P < 0.01, ***P < 0.001 by one-way ANOVA followed by Newman–Keuls multiple comparisons post-test or by a t-test, to compare medians of the two groups. Survival analysis was made by Log Rank test. Outliers were identified using the ROUT (Q = 2.0%) method of GraphPad Prism program version 9.0 and removed from the analysis

Since older age is a risk factor for COVID -19 mortality and neutrophil dysfunction [7], we investigated whether this factor could be related to neutrophil count in BAL and blood. Patients were divided into younger (< 60-year-old) and older (> 60-year-old) groups. In the older group, 62% were male and the mean age was 74 ± 8 years, significantly higher than in the younger group, 49 ± 8 years (P < 0.001) and 80% of male. The older group had higher mortality than the younger group (80% versus 25%, P < 0.05) (Fig. 1D). The number and frequency of neutrophils were reduced in the BAL of older patients (Fig. 1E, F). However, in blood, the frequency of neutrophils, but not their absolute number, was higher in the older group than in the younger group (Table 1). Interestingly, the younger patients who died of COVID-19 also had a lower frequency of neutrophils (Fig. 1G), but not in absolute numbers (Fig. 1H), in BAL compared to survivor younger patients.

Table 1 Neutrophil profile in blood and CXCL8 concentration in serum in patients with severe COVID-19

To determine the activation status of neutrophils, we examined the expression of cytokines. We found that IL-10 expression by BAL neutrophils was higher in the older group than in younger group (Fig. 1I), but no difference was observed in IFN- γ or TNF expression (Fig. 1J, K). No difference was observed in cytokine expression by blood neutrophils between the groups (Table 1).

Because our data indicated a disturbance of neutrophil migration in the older group (high neutrophil levels in blood and low levels in BAL), we examined CXCL8, a chemokine that regulates neutrophil traffic. BAL CXCL8 levels were similar in the older and the younger patients (Fig. 1L), but older patients had higher blood CXCL8 concentrations when compared to younger patients (Table 1).

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