Discussion
To our knowledge, this is among the systematic review and meta-analysis of China-based studies comparing the clinical symptoms between patients with severe vs. non-severe form of COVID-19 pneumonia. We observed no gender difference, which is consistent with the latest report11,13,16,17. Although fever and cough are relatively common symptoms, we found the incidences of fever, dyspnea and diarrhea are all significantly higher in patients with severe COVID-19 pneumonia, suggesting they could be alarming symptoms that worth extra medical attention. Although our findings in dyspnea were similar to previous reports 10,11, we have to point out that certain discrepancy exists: for example, some reported no difference in the incidence of fever and diarrhea 10,11,13, or even dyspnea 13. One possible explanation is that in those reports, the sample size was relatively small and studies were reported at relatively early phase of this pandemic COVID-19 pneumonia.
The early symptoms/signs of COVID-19 pneumonia can be indistinguishable from those of other common respiratory infectious diseases, and could exhibit certain similarities to those of severe acute respiratory syndrome associated coronavirus (SARS-CoV) and middle East respiratory syndrome coronavirus (MERS-CoV) infections 29,30. However, patients with COVID-19 rarely had obvious signs and symptoms of upper respiratory tract (e.g. nasal obstruction, rhinorrhea, runny nose, sore throat). In addition, intestinal signs and symptoms such as diarrhea were less common in COVID-19 pneumonia patients (below 10% even in severe form), while about 20-25% of patients with MERS-CoV or SARS-CoV infection presented with diarrhea 30. It should be noted however that fever in COVID-19 pneumonia patients (10.8%) was more common than SARS-CoV (1%) and MERS-CoV (2%)31.
As COVID-19 pneumonia can have a full spectrum of clinical presentations, it is therefore crucially important to recognize alarming symptoms that signal progression to severe form 14, as such information will not only help us better triage our patients, but also wisely use our medical resources which are often in shortage during pandemic crisis. This study has clearly shown that fever, dyspnea and diarrhea could be such alarming symptoms that warrant timely medical attention. Meanwhile, as can be seen from our validation results, fever and dyspnea are more common in patients with severe COVID-19 pneumonia. However, there was no statistically significant difference between the two groups in gastrointestinal symptoms such as nausea, diarrhea or abdominal pain (p >0.05). However certain limitation exists in this study: 1) since most data are from retrospective studies and case reports, which intend to report successful management, selection bias could exist. However, considering some studies reported that most patients were still hospitalized at the time of publication (for example, 93.6% (1029/1099) in Article 1 and 61.6% (85/138) inArticle 2 , Fig. 2 ), the selection bias could have little impact; 2) the data collection in some cases is not complete, especially for rare symptoms such as hemoptysis and conjunctivitis, hence the statistical power should be carefully interpreted for those symptoms; 3) from data analysis perspective using published studies, although symmetry was observed, it is challenging to evaluate publication bias due to limited number of studies included. However, since COVID-19 is new disease entity, both positive and negative results will likely have the chance to be published, which should theoretically reduce the publication bias for future secondary analysis.