Discussion
Up to now, this is the first meta-analysis to explore severe Covid-19
associated clinical, laboratory and imaging factor when compared with
non-severe Covid-19. By systemically and comprehensively reviewed the
current evidence published, 14 studies with a total of 2,566 individuals
(771 in Severe group and 1,795 in Non-severe group) were eligible for
this meta-analysis[14-27], which retrieved the largest sample size
when compared with studies on the same topic. Overlapping patient was
checked by examining the first author of article and the origin of
patients, since we recognized that different articles might report of
the same patients.
Currently, the National Health Commission (NHC) issued the China
Guidelines for the Diagnosis and Treatment Plan of Novel Coronavirus
(COVID-19), which defined the degree of severity of Covid-19 (i.e.,
mild, common, severe and critical). As we all know, treatment algorithm
of Covid-19 depended on illness severity. Most severe and critical
patients required oxygen therapy and a minority of the patients needed
invasive ventilation or even extracorporeal membrane oxygenation.
Moreover, there were some patient who developed worsening respiratory
failure and acute respiratory distress syndrome (ARDS) rapidly that
required intubation[36]. According to epidemiological investigation,
severe illness occurred in 15.7% of the Covid-19 patients after
admission to a hospital. As the clinical spectrum of COVID-19 ranges
widely from mild illness to ARDS with a high risk of mortality, there is
an urgent need for research to identify early markers of disease
severity, which is of great value for clinician to diagnosis of the
severity of Covid-19 rapidly and exactly.
Though statistical analysis, it was demonstrated that patients in Severe
Covid-19 group were older and had a greater number of comorbid
conditions (e.g., hypertension, diabetes and heart disease) than
Non-severe group. Compromised respiratory status on admission (e.g.,
COPD) was also associated with severe illness. This suggests that age
and comorbidity may be risk factors for poor outcome. Meanwhile, severe
2019-nCoV infection is more likely to affect males. These data was
consistent with the recent report that showed 2019-nCoV infection is
more likely to affect males [37]. What’s more, our outcome did not
support that smoking was associated with severity of COVID-19 illness.
Consistently, Lippi et al conducted a meta-analysis of current evidence
and concluded that active smoking does not apparently seem to be
significantly associated with enhanced risk of progressing towards
severe disease in Covid-19, which further confirmed our outcome[38].
Common symptoms of Covid-19 at onset of illness were fever, dry cough,
expectoration, myalgia, fatigue, and dyspnea [1]. However, some
patients presented initially with atypical symptoms, such as diarrhea
and nausea [39, 40]. By statistical synthesis the data on common
sign and symptoms, the incidence of fever, expectoration, headache,
fatigue, myalgia and dyspnea were more common in Severe group than in
Non-severe group. However, only the incidence of dyspnea was
statistically different across groups. Thus, patient presented with
dyspnea should gain more caution for which might be severe Covid-19. And
this outcome was consistent with outcome found in ICU patient[41].
Accumulating evidence suggests that a subgroup of patients with severe
COVID-19 might have a cytokine storm syndrome[42]. In our study,
compared with non-severe patients, severe Covid-19 patients had numerous
laboratory abnormalities. By meta-analysis of current evidence,
depressed total lymphocytes were observed in this article. These
abnormalities suggest that 2019-nCoV infection may be associated with
cellular immune deficiency. And these laboratory abnormalities are
similar to those previously observed in patients with MERS-CoV and
SARS-CoV infection[43].
Individuals with severe Covid-19 might present with bilateral (95.8%)
or unilateral (30.5%) lung pathological changes, ground-glass opacities
(100%), consolidation (76.9%) and bronchial wall thickening (56.4%)
in chest CT. However, no statistical difference was revealed when
compared with Non-severe group. Although reticulation (30.8%),
intrathoracic lymph node enlargement (20.5%) and pleural effusions
(30.8%) were relatively rarely seen, meta-analysis revealed that
patients with reticulation, intrathoracic lymph node enlargement and
pleural effusions in chest CT were associated with more likelihood to be
a severe Covid-19. The outcome was further confirmed in a study carried
by Yuan eta al which investigated the association of radiologic findings
with mortality of patients infected with Covid-19[16].
The results should be viewed with recognition of limitations inherent in
this study. Firstly, although a broad review scope provides us with a
larger sample size and finally adequate statistical power to detect a
risk factor, three articles reporting data comparing clinical
characteristic between severe Covid-19 and non-severe Covid-19 was
excluded for overlapping patients [3, 35, 44]. One article that did
not reported the origin of patient was also excluded from this
meta-analysis [29], which resulted in relative small sample size.
However, their outcome further confirmed our conclusion.
Secondly, all eligible studies came from China, since first Covid-19 was
identified in Wuhan, China. Data in other country was not acceptable
right now. Thus, the outcome of our study could not be considered
conclusive on this topic. An update of this article is necessary when
needed.
Thirdly, more and more articles on Covid-19 were published every day.
There might be lots of article evaluating the clinical difference across
severe and non-severe Covid-19 unpublished. And funnel plot of this
meta-analysis revealed that publication bias might exist. Thus, it is
necessary for clinicians to interpret our outcome carefully.
In conclusion, it was demonstrated that older males manifested with
dyspnea whose blood routine test revealed lymphopenia should gain more
caution for which might be severe Covid-19. Patients with comorbidity,
such as hypertension, diabetes and heart disease were more susceptible
to severe Covid-19. Compromised respiratory status on admission (e.g.,
COPD) was also associated with severe illness. Specially, although
reticulation, intrathoracic lymph node enlargement and pleural effusions
were relatively rarely seen, meta-analysis revealed that patients with
such presentations in chest CT were associated with more likelihood to
be a severe Covid-19.
Although lots of risk factors were filtrated in this article,
exploration of predicted value of these factors in severe Covid-19
patients was impossible with aggregated data extracted from published
studies. Further diagnostic article evaluating how to differentiate
severe from non-severe Covid-19 with the manifestation in chest CT and
study evaluating the relation across clinical characteristic and
severity of Covid-19 with the help of logistic regression analysis is
needed.