The COVID-19 pandemic poses a great challenge to human society. Although case mortality for COVID-19 is relatively low, it has so far caused far more deaths than severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) combined [7, 8]. Becausemortality is very high inpatients with severe COVID-19 , it is essential to find reliable early predictors ofrisk for severe illness.
Previous studies in patients with severe COVID-19 have shownchanges in immune-inflammation parameters, e.g., low counts of lymphocytes and its subgroups, high neutrophil counts, high NLR, and elevated serum IL-6 level [4, 6, 9–11]; these changes were attributed to the severe and aberrant host immune response . In our study, we found similar changes in patients who developed severe disease versus those who had mild disease:lymphocytes and all its subsets were significantly lower in the SC group, while neutrophil, NLR, N8R, and IL-6 were significantly higher (all P < 0.05). Reduction in T lymphocyte counts may due to the direct invasion by SARS-CoV-2, similar to the mechanism reported in MERS-CoV infection . In addition, autoimmune antibodies triggered by the viruscould decrease production and differentiation of T lymphocytes and other lymphocytes viainhibition of growthand suppression of hematopoiesis[11, 14]. Elevation of neutrophil counts usually indicates an inflammatory response, while decrease in lymphocyte counts suggests damage to the immune system; therefore, as the results of our study suggest, high NLR and N8R can serve as diagnostic markers for severe COVID-19  and also be useful predictors of severe illness.
Huang et al.were the first to suggest that a cytokine storm could be associated with severe disease ; this was confirmed by subsequent studies [15, 16]. IL-6 is a multifunctional cytokine involved in cell signaling and regulation of immune cells, and usually shows more significant serum levels changes than other cytokinesin inflammatory disease [17, 18]. IL-6 reflects the intensity of inflammatory response in the body. Liu et al. and Zhe et al. have demonstrated that IL-6 plays a pivotal role in the severity of COVID-19 and thereforehas value for monitoring the progress of severely ill patients [4, 5]. In our study, we found the cumulative incidence of severe illnessto be related to the baseline IL-6 level. Patients in the higher IL-6 quartile groups were significantly more likely to develop severe illness (Fig. 2A) and to need longer hospitalization (Fig. 2B). Since the severity of the disease corresponded to the intensity of inflammation, former phenomena could be explained.
Comorbidities such as diabetes and cancer can affect baseline IL-6 level [19, 20]; we therefore used logistic regression models to adjust for the effect of potential confounders. However, the significant association between baseline IL-6 level andrisk of severe illnesspersisted even after adjustment for all potential confounders (Models1–3; Table 2).
Neutrophil count, NLR, N8R, and IL-6 level have all been previously shown to be useful prognostic indicatorsin severe COVID-19 [4–6, 9]. We performed ROC analysis to identify the variable with the best predictive value. The AUC of IL-6 was significantly larger than those of neutrophil count and N8R. The AUC of IL-6 was comparable to that of NLR, which is currently widely accepted as a predictor of outcome in patients with COVID-19. However, the sensitivity of IL-6 was much higher than that of NLR (91.67% vs.66.67%). For any predictive or screening index, sensitivity is more important than specificity;the higher the sensitivity, the fewer the false-negative results. Thus,in addition to being a useful parameter for monitoring progression of disease in patients with COVID-19, baseline IL-6 could be a powerful predictor of risk of severe disease.
This study had some limitations. First, this was a retrospective analysis of a small sample and some bias is inevitable. Second, because of inconsistencies in data recording between the two centers, some clinical parameters could not be included in the analysis.