Gastrointestinal involvement attenuates COVID-19 severity and mortality

Abstract

Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.

Evolution of antibody immunity to SARS-CoV-2

“…Residual protein in tissues represents another potential source of antigen. SARS-CoV-2 replicates in ACE2-expressing cells in the lungs, nasopharynx and small intestine [22][23][24][25] , and viral RNA has been detected in stool samples even after the virus is cleared from the nasopharynx [26][27][28] .…”

Evolution of Antibody Immunity to SARS-CoV-2

“…4c-d). Similarly, R346S pseudotyped viruses were resistant to C032, but a 6.2-month clonal derivative C080 neutralized this variant with an IC50 of 5.3 ng/ml ( SARS-CoV-2 replicates in ACE2-expressing cells in the lungs, nasopharynx and small intestine [20][21][22][23] , and viral RNA has been detected in stool samples even after the virus is cleared from the nasopharynx [24][25][26] . To determine whether there might be antigen persistence in the intestine after resolution of clinical illness, we obtained biopsies from the upper and lower gastrointestinal (GI) tract of 14 individuals, an average of 4 months (range 2.8-5.5 months) after initial SARS-CoV-2 diagnosis (Supplementary Table 7).…”

Mucosal immune responses in COVID19 - a living review

“…High RNA levels may correlate with infectious virus, which has been isolated from nasal swabs, sputum and faeces [ 7 , 9 ]. However, another study that used small intestine biopsy samples failed to isolate infectious virions [ 10 ]. It is also unclear whether any virus from the intestine is infectious once it is egested, or whether it is degraded in the intestine with remaining nucleic acid detectable by qPCR.…”

“…Viral infection of human enterocytes of the small intestine has been shown by microscopy in organoid systems [ 11 ] and biopsies [ 10 ], indicating that SARS-CoV2 can productively infect cells of the intestine. Around 20% of patients with COVID-19 experience gastrointestinal symptoms, but these are generally mild and include diarrhoea, nausea and vomiting [ 12 ].…”

“…The presence of diarrhoea in severe patients has been associated with a worse outcome in some studies [ 13 , 30 ], which could be related either to systemic immune activation or more widespread viral invasion of tissues. Interestingly, another study using three patient cohorts found an association between GI symptoms and reduced disease severity and mortality even when comorbidities were accounted for [ 10 ]. A few patients with GI symptoms who underwent endoscopic evaluation had no evidence of mucosal inflammation despite the epithelial infection.…”