Discussion
In this cohort study, we reported the clinical characteristics, risk factors, and clinical outcomes of critically ill patients with COVID-19 infection. Some patients developed MODS after being admitted to the ICU, while some progressed to death. The Chinese Centre for Disease Control reported that most of the confirmed cases were classified as mild or moderate, 13.8% as severe, and only 4.7% as critically ill8. This was consistent with the WHO report 1. In recent years, due to the SARS and Middle East respiratory syndrome (MERS) outbreaks, the emergence of the COVID-19 epidemic has caused people to pay attention. The pathogenesis of the highly pathogenic human coronavirus is still not completely understood. Cytokine storm and viral evasion of cellular immune responses are thought to play important roles in disease severity 9. The severity of lung damage was found to be correlated with extensive pulmonary infiltration of neutrophils and macrophages, and the higher numbers of these cells in the peripheral blood of patients with MERS10. Some patients with SARS-CoV, MERS-CoV, or COVID-19 infections maybe asymptomatic in the early stages until severe pneumonia, dyspnoea, renal insufficiency, and even death occurs in the later stages11. Lymphocytes are essential for the immune responses against viral infections due to their regulatory effect on the positions of leukocytes in the host organs. White blood cell (WBC) counts (×109/L) were elevated in most patients (11.7±5.5), while the lymphocyte percentages in these patients were even lower than data in previous studies12,13. Therefore, spectral changes in the activities of lymphocytes may lead to severely maladjusted immune responses.
According to the recent reports on the characteristics of COVID-19 patients who required management in the ICU, advanced age (>60 years), the male sex, and underlying co-morbidities (particularly hypertension) were found to be risk factors for severe COVID-19 infection and death14,15. Considering that older age is associated with a decline in immune competence, the results of the present study showed that older age was associated with both MODS and death. Therefore, this relation might be due to the less robust immune response in older patients16. The overall fatality rate for the confirmed COVID-19 cases was found to be higher in male patients than in female patients, with an increased risk of death for advanced age in both sexes. The highest fatality rate was observed in patients aged 80 years and above14. The 88 critically ill patients with a median age of 70.7(62.3-78.25) years present an extremely high mortality rate (80.7%).
In this study, hypertension (43.2%) was the most frequent underlying co-morbidity, as seen in older patients. At the time of admission, compared to other patients, patients of the\(\ \leq\)7 days category showed greater impairment of consciousness, as per the GCS scores(11.0±2.9, P <0.01), indicating that higher GCS score predicted greater possibility of survival. Most of the critically ill patients developed leukocytosis and extremely low lymphocyte percentages, but high levels of CRP and PCT, indicating that a large proportion of the critically ill patients might have developed secondary bacterial infection, which could be strongly associated with death, after early COVID-19 infection. Deceased patients, compared with patients of the >14 days category, showed persistent and severe lymphopenia, suggesting that a state of lymphocyte immune deficiency was associated with poor prognosis. Although development of respiratory complications was also strongly associated with poor outcome in patients with COVID-19 infection, only 12% of the patients presented with chronic lung co-morbidities in this study. Considering one major ascribed cause of mortality, we found that respiratory failure was the most common complication (49.3%), suggesting that the high risk of respiratory failure could not be entirely ascribed to co-existing chronic lung disease. Moreover, cardiovascular event (32.4%) was the second most common cause of mortality, indicating that COVID-19 infection could induce acute cardiac injury and injury to other organs.
To date, no vaccine or specific antiviral treatment for COVID-19 infection has proven to be effective; hence, supportive therapy that eases the symptoms and protects the important organs may be most beneficial. Studies demonstrated that administration of methylprednisolone appeared to reduce the risk of death in patients with ARDS17,18. Consequently, methylprednisolone treatment may be beneficial for those COVID-19 patients who developed ARDS with the progression of the disease. However, Tsai et al. declared that early treatment and high dosing of corticosteroids was associated with significantly increased hospital-related mortality in adult patients with influenza-associated ARDS19. Critically ill patients who have an increased risk of death may develop MODS, including ARDS, sepsis, acute kidney injury, shock, acute cardiac injury, and DIC, which was found to be less frequent (1.4%) in the present study. Apart from respiratory failure, acute kidney injury was observed in 25% of the total patients and 45.2% of the patients of the ≤7 days category, indicating that acute kidney injury could be a major contributing factor to the risk of fatality of COVID-19 patients, regardless of history of previous kidney disease. Considering the prevalence of MODS in critically ill patients, corticosteroid therapy must be investigated further. In addition, ECMO can be used to maintain oxygenation, improve ventilation, adequately allow the injured lungs to rest, and avoid complications associated with sedation, intubation, and mechanical ventilation. However, ECMO does not provide direct support to the other organs beyond increasing systemic oxygen delivery and mitigating ventilator-induced lung injury20,21. Development of respiratory, renal, and cardiac complications, and DIC was also strongly associated with poor outcome of patients with COVID-19 infection22,23. Indeed, the survival time of patients who received ECMO was obviously prolonged in our study. Five cases of ECMO were performed, but still one patient died with 14 days.
Taken together, COVID-19 induced injuries of multiple organs, increasing the disease severity and worsening the outcomes24. Understanding the clinical features and immune conditions of patients with COVID-19 infection will not only provide a greater insight into the pathogenesis of COVID-19, but will also identify therapeutic targets11. Although specific antiviral agents are currently being developed in several countries, the use of antiviral agents alone may not be sufficient to stop multiple organ injuries in patients who present with symptoms in the later stages of the infection. According to the present situation, combined therapies, including Chinese traditional medicines, to protect organ functions and target lymphocyte immunomodulation in order to reduce the inflammation storm, may be used to ameliorate organ injuries and eventually improve mortality25,26. However, a limitation of this study is that some laboratory tests were not performed in all patients, and hence, missing data might have led to bias of the statistical analysis. Additionally, the 28-day duration was relatively short.
In conclusion, this is a retrospective single-centre clinical study on a unique population of critically ill patients with COVID-19 infection. The primary immune response of lymphocytes against the COVID-19 infection was severely destroyed. Higher GCS score predicted greater possibility of survival. However, acute kidney injury may be an indicator of worse outcome. These patients presented with fatal clinical manifestations and high risk of mortality, and this helped us in understanding the pathophysiology of COVID-19 infection better. Further studies on the viral factors that drive immune dysregulation and COVID-19 pathogenesis and induce MODS are of great importance for the development of vaccines and specific antiviral agents for the clinical management of the COVID-19 infection.