Background: Most COVID-19 patients are moderate, and fever is the most common clinical manifestation and associated with poorer prognosis. Gut microbiota may also play important roles in COVID-19 pathogenesis. However, the association between gut microbiota and fever in individuals with moderate COVID-19 remains unclear.
Methods: We compared the clinical features and laboratory results of 187 moderate COVID-19 patients with fever and without fever and identified several inflammatory markers in patients with fever. Then, we performed gut metagenome-wide association study for 31 individuals to identify the microbes and their epitopes which have potential role in fever and hyperinflammation.
Results: Among 187 moderate COVID-19 patients, 127 (67.9%) patients presented with fever. Lymphocytes, CD3+ T cells, CD4+ T cells and the ratio of CD4+ T cells to CD8+ T cells were significantly reduced, while AST, LDH, CRP, IL-6 and IL-10 were significantly elevated in patients with fever. Gut microbiome composition was significantly altered in patients with fever compared with those with non-fever. Opportunistic pathogens such as Enterococcus faecalis  and Saccharomyces cerevisiae  were enriched in patients with fever. E. faecalis  was positively correlated with LDH and D-dimer and negatively correlated with CD8+T cells and IL-4, while S. cerevisiae  was positively correlated with diarrhea symptom. Furthermore, several species with anti-inflammatory and protective effects, such as Bacteroides fragilis  and Eubacterium ramulus , were enriched in patients with non-fever. B. fragilis  was positively correlated with lymphocytes, and E. ramulus  was negatively correlated with LDH, AST and IL-6. Finally, we found that several bacterial epitopes of GroEL, a homolog of human HSP60, were enriched in patients with fever and positively correlated with IL-6, IL-10, WBC, neutrophils, D-dimer, LDH, CRP, and E. faecalis .
Conclusion: Gut microbiota dysbiosis correlates with abnormal immune response in moderate COVID-19 patients with fever.
Keywords: moderate COVID-19, fever, shotgun metagenomic sequencing, gut microbiota, epitopes