Serum gasdermin D levels are associated with the chest computed tomography findings and severity of COVID-19

Abstract

Background: The role of programmed cell death, especially pyroptosis and apoptosis, in unfavorable immune responses in COVID-19 remains to be elucidated.

Methods: We conducted a cross-sectional analysis to investigate the association between the serum gasdermin D (GSDMD) levels, a pyroptotic marker, and caspase-cleaved cytokeratin 18 fragment (M30), an apoptotic marker, and the clinical status and abnormal chest computed tomography (CT) findings in patients with COVID-19.

Results: In this study, 46 patients diagnosed with COVID-19 were divided into the following three groups according to the disease severity: mild to moderate group (n = 10), severe group (n = 14), and critical group (n = 22). The serum GSDMD levels were higher in the critical group than in the mild to moderate group (P = 0.016). In contrast, serum M30 levels were lower in the critical group than in the severe group (P = 0.048). Patients who required mechanical ventilation or died had higher serum GSDMD levels than those who did not (P = 0.007). Area of consolidation only and of ground glass opacity plus consolidation positively correlated with serum GSDMD levels (r = 0.56, P < 0.001 and r = 0.53, P < 0.001, respectively).

Conclusion: Higher serum GSDMD levels are associated with critical respiratory status and the consolidation area on chest CT in patients with COVID-19, suggesting that excessive activation of pyroptosis may affect the clinical manifestations in patients with COVID-19.

Keywords: Apoptosis; COVID-19; Caspase-cleaved cytokeratin 18 fragment; Gasdermin D; Pyroptosis.

Fig. 1

Levels of serum gasdermin D and caspase-cleaved cytokeratin 18 fragment in the different severity and outcome groups. The box-and-whisker plots represent the serum GSDMD (A) and M30 (B) levels and the ratio of GSDMD to M30 levels (C) in the COVID-19 patients stratified into the mild to moderate group (no need for oxygen supplementation; n = 10), severe group (need for oxygen supplementation with no ventilation assistance; n = 14), and critical group (need for ventilation assistance, n = 22). The box-and-whisker plots represent the serum GSDMD (D) and M30 (E) levels and the ratio of GSDMD to M30 levels (F) in the COVID-19 patients classified into the group that did not require MV and survived (n = 13) and the group that required MV or died (n = 33). Data are shown as medians (A, C, D, F) or means (B, E), and error bars represent the 10–90 percentile range values. Statistical significance of differences between the three groups was calculated using the Kruskal–Wallis test for GSDMD levels (A) and ratio of GSDMD to M30 (C) and using ANOVA for M30 (B), followed by Holm correction for multiple comparisons. Statistical significance of the difference between the two groups was calculated using Mann–Whitney U test for GSDMD levels (D) and ratio of GSDMD to M30 (F) and using t-test for M30 (E). (ANOVA, analysis of variance; GSDMD, gasdermin D; MV, mechanical ventilation; M30, caspase-cleaved cytokeratin 18 fragment).

Fig. 2

Correlation between the serum gasdermin D levels and the baseline laboratory data and inflammatory cytokines. The levels of serum GSDMD, IL-1β, IL-6, and IL-18 were log-transformed. Data were analyzed using Pearson correlation coefficient. (GSDMD, gasdermin D; IL, interleukin; PaO₂/FIO₂, ratio of arterial oxygen partial pressure to fractional inspired oxygen).

Fig. 3

Abnormal chest computed tomography findings during the first visit in COVID-19 patients of different severity groups. Data of abnormal CT findings are presented as mean percentages ± standard errors (error bars) in the total patients and the three groups. ANOVA was used to compare the scores between the three groups, and Holm correction was used to test for multiple comparisons. Mild to moderate group, no need for oxygen supplementation; severe group, need for oxygen supplementation with no ventilation assistance; critical group, need for ventilation assistance. (ANOVA, analysis of variance; CT, computed tomography; GGO, ground glass opacity).

Fig. 4

Correlation between the area of abnormal chest computed tomography findings and the levels of serum gasdermin D (A) and caspase-cleaved cytokeratin 18 fragment (B) in patients with COVID-19. The percentage on the horizontal axis indicates the proportion of the area of abnormal CT findings to the total lung field. Data were analyzed using Pearson correlation coefficient. (CT, computed tomography; GSDMD, gasdermin D; GGO, ground glass opacity; M30, caspase-cleaved cytokeratin 18 fragment).

figs1

figs2