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.