In this retrospective cohort study, we found that COVID-19 patients with ARDS were more likely to develop into death. Moreover, patients with elevated inflammatory-related indexes, decreased immune cell subsets, abnormal multiple-organ damage biomarkers and higher scores were more likely to develop ARDS and progress from ARDS to death. Specifically, in addition to previously reported risk factors such as neutrophils, IL-6, D-Dimer, leukocytes and platelet, we identified novel risk factors including elevated TNF-α, ALB and CK-MB as well as decreased CD8+ T cell and CD3−CD19+ B cells. Furthermore, we established a comprehensive risk prediction model by combining risk factors and scores which showed good prediction accuracy for ARDS development (AUC = 0.904) and ARDS death risk (AUC = 0.959). This model will be beneficial for early identification of development of ARDS and determination of effective treatments in COVID-19 patients.
Enrolled 796 COVID-19 patients with ARDS were statistically matched by age, sex, and comorbidities to those without ARDS. We noted that patients with ARDS presented excessive inflammation, dysregulated immune response and critical multiple organ damage. Moreover, SOFA, qSOFA, APACHE II and SIRS scores appeared to be higher in COVID-19 patients with ARDS as well as non-survivors. These findings provided supporting evidence that COVID-19 patients with ARDS were associated with higher risk of worse clinical outcomes.
Multivariable logistic regression models were performed to explore risk factors related to ARDS development and death in COVID-19 patients. In terms of inflammatory-related indexes, in addition to previous reported risk factors such as neutrophils, IL-6 and CRP, we found TNF-α was a novel risk factor of ARDS development and death in COVID-19 patients. Cytokine storm has been reported to mediate extensive lung inflammation and ultimately induce ARDS in COVID-19 patients through severe systemic secretion of pro-inflammatory cytokines.17,18 IL-6 induces various pro-inflammatory cytokines and chemokines through the regulation of STAT3 and activation of the NF-κB pathway, which ultimately causes pneumocyte and endothelial injury, vascular leakage and alveolar edema in cytokine storm.19–21 During pulmonary infections in COVID-19 patients, intracellular IL-6 acts in concert with CXCL1 and CXCL2 to recruit polymorphonuclear leukocytes to the lung, resulting in killing pathogens but generating fibrosis.22 TNF-α, a potential novel risk factor for the development of ARDS identified here, has been reported to mediate airway hyper-responsiveness through the induction of M2 muscarinic receptor dysfunction.23 In addition, TNF-α not only promotes the apoptosis of both lung epithelial cells and endothelial cells but also inhibits the generation of germinal center B cells by suppressing T cell helper functions. 24,25 An overproduction of TNF-α and IL-6 indicated the exuberant inflammatory responses during course of SARS-COV-2 infection. Collectively, these findings may partly account for the influence of pro-inflammatory cytokines on the high risk of ARDS development and death in COVID-19.
Furthermore, we found that decreased immune cell subsets including T cells, B cells and NK cells, were correlated with the development risk of ARDS among COVID-19 patients and death risk among patients who developed ARDS. Notably, CD8+ T cells and CD3−CD19+ B cells were identified as novel risk factors. The dysregulated cellular immune responses by decreased lymphocytes are thought to be associated with severity and mortality in COVID-19 patients.26 CD8+ T cells play a critical role in mediating viral clearance after acute respiratory infections of respiratory syncytial virus, influenza A virus, and human metapneumovirus.27,28 In addition, CD8+ T cells are reported to suppress inflammatory immune response by secreting immunosuppressive cytokines and cytotoxic enzymes, and the decreased level of CD8+ T cells associated with the dysfunction of immune response and severe complications.29 CD3−CD19+ B cells inhibit proinflammatory cytokines and support regulatory T cells differentiation by secreting anti-inflammatory cytokine IL-10.30 Besides, CD3−CD19+ B cells act as a booster to the maintenance of immune homeostasis, which are associated with the poor clinical outcomes in patients with autoimmune diseases and viral infectious disease.31–33
In addition to elevated inflammatory-related indexes and decreased immune cell subsets, we found abnormal multiple-organ damage biomarkers were another risk factors for development of ARDS and progression from ARDS to death in COVID-19 patients. Previously reported risk factors of COVID-19, such as ALT, AST, hs-cTnI, NT-proBNP, eGFR, D-Dimer and FDP were also confirmed in our study. Furthermore, we identified novel risk factors including CK-MB and ALB. The systemic inflammatory response and immune system disorders during disease progression in patients with COVID-19 result in the high incidence of organ failure symptoms and dysregulated tissue damage biomarkers.34 Additionally, respiratory dysfunction and hypoxemia in patients with COVID-19 and ARDS caused damage to myocardial cells through the regulation of type 1 and type 2 T helper cells.35 Moreover, The high serum levels of CK-MB suggested myocardial damage in early-stage which were correlated with the severity and case fatality rate of COVID-19.36,37 ALB was reported to selectively suppress the expression of pro-inflammatory TNF-α by inhibiting the activation of NF-kB pathway.38 Additionally, the decreased levels of ALB contribute to inflammatory response and oxidative stress injury through the upregulating the levels of glutathione, which partly accounted for disease severity in MERS patients.38,39 However, it remains insufficient to explore the association between the multiple-organ damage and the pathogenesis of development of ARDS.
Previous researches have reported that SOFA, qSOFA, APACHE II, and SIRS scoring systems shows good prediction accuracy for evaluating septic shock, multi-organ failure and ICU mortality.7,8, 10–12,40,41 Here, we confirmed that those with higher SOFA, qSOFA, APACHE II or SIRS scores were more likely to develop ARDS and progress to death in COVID-19 patients. Moreover, we found that elevated inflammatory-related indexes, decreased immune cell subsets and abnormal multiple-organ damage biomarkers were associated with ARDS development and progression from ARDS to death in COVID-19 patients. In addition, the patients with increased levels of the biomarkers were more likely to develop complications such as heart failure, acute cardiac, kidney, liver injury and DIC. Therefore, the combined model integrating risk factors and scores showed the best predictive capacities of both development of ARDS and progression from ARDS to death in COVID-19 patients.
It is critical to recommend standardized and effective treatment protocols for SARS-COV-2 infection worldwide to improve poor clinical outcomes. Consistent with other studies, antibiotics and antivirals were widely used in COVID-19 treatment.13,42 Notably, COVID-19 patients with ARDS received more supportive therapy, such as ventilation treatments and glucocorticoid therapy. Preliminary evidence suggested the standard supportive care for ARDS patients was a protective ventilatory strategy, which might improve prognoses of patients with ARDS.43,44 Additionally, recent studies showed that corticosteroids could be an effective treatment. The administration of dexamethasone and methylprednisolone could decrease duration of mechanical ventilation and reduce the death risk of patients with COVID-19 who develop ARDS.45,46 In view of the excessive inflammation, dysregulated immune response and multiple organ damage in COVID-19 patients with ARDS, the current management of COVID-19 should be focused on inflammatory immune response, treatment of complications and supportive care, especially oxygen support.
Based on our study, several management strategies are warranted for COVID-19 patients with ARDS. First, inflammatory-related indexes and organ damage indexes should be monitored at different stages to prevent the development of ARDS in COVID-19 patients. Second, early application of systemic immune modulators such as intravenous immunoglobulin should be considered to reduce aberrant immune responses at the early stage of ARDS, which is helpful to prevent the progression of ARDS.47 Third, Supportive therapy such as ventilation treatment is also critical for COVID-19 patients with ARDS.
Our study has several limitations. First, this was a retrospective cohort study and not all laboratory tests were done in all patients. The missing data might affect the interpretation of the results. Second, the potential mechanisms of multiple organ damage and ARDS development and progression to death need to be further investigated and confirmed. Third, our study was performed in single-center hospital, which need be further confirmed in multi-center studies in the future. Finally, given that age and comorbidities, such as diabetes and hypertension, have been reported as the common risk factors of COVID-19 with ARDS, these factors were statistically matched between patients with ARDS and those without ARDS and were not included in this study.