COVID-19, nausea, and vomiting

Abstract

Exclusion of nausea (N) and vomiting (V) from detailed consideration as symptoms of COVID-19 is surprising as N can be an early presenting symptom. We examined the incidence of NV during infection before defining potential mechanisms. We estimate that the overall incidence of nausea (median 10.5%), although variable, is comparable with diarrhea. Poor definition of N, confusion with appetite loss, and reporting of N and/or V as a single entity may contribute to reporting variability and likely underestimation. We propose that emetic mechanisms are activated by mediators released from the intestinal epithelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) modulate vagal afferents projecting to the brainstem and after entry into the blood, activate the area postrema (AP) also implicated in anorexia. The receptor for spike protein of SARS-CoV-2, angiotensin 2 converting enzyme (ACE2), and transmembrane protease serine (for viral entry) is expressed in upper gastrointestinal (GI) enterocytes, ACE2 is expressed on enteroendocrine cells (EECs), and SARS-CoV-2 infects enterocytes but not EECs (studies needed with native EECs). The resultant virus-induced release of epithelial mediators due to exocytosis, inflammation, and apoptosis provides the peripheral and central emetic drives. Additionally, data from SARS-CoV-2 show an increase in plasma angiotensin II (consequent on SARS-CoV-2/ACE2 interaction), a centrally (AP) acting emetic, providing a further potential mechanism in COVID-19. Viral invasion of the dorsal brainstem is also a possibility but more likely in delayed onset symptoms. Overall, greater attention must be given to nausea as an early symptom of COVID-19 and for the insights provided into the GI effects of SARS-CoV-2.

Keywords: ACE2; COVID-19; SARS-CoV-2; angiotensin II; angiotensin converting enzyme 2; dexamethasone; diarrhea; enteroendocrine cells; nausea; vomiting.

Figure 1

The incidence of nausea and/or vomiting and diarrhea from 41 clinical studies, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , : nausea, n = 34; vomiting, n = 39; diarrhea, n = 39. Values for individual studies are shown together with the median and 95% confidence intervals. No distinction was made between nausea and vomiting in 10 studies, so the same incidence was used in both categories. The total number of patients in the studies was 12 239. Five studies (data indicated by triangles) reported only data on children (1.5 months to 17 years)., , , ,

Figure 2

Diagram summarizing the potential mechanisms by which SARS‐CoV‐2 could induce nausea and vomiting. The left‐hand panel shows the routes by which virus can enter the body to access the airways and digestive tract. Air can enter the digestive tract during swallowing. The presence of high levels of angiotensin converting enzyme 2 receptor in the airways and digestive tract is indicated by red lines. The middle panel shows the potential mechanisms (based on evidence discussed in the text) for the interaction of the virus with the digestive tract epithelium leading to release of neuroactive agents from enteroendocrine cells and inflammatory mediations which act either by stimulating/sensitizing abdominal vagal afferent terminals and/or act on the area postrema in the dorsal medulla where the blood brain and blood cerebrospinal fluid barriers are relatively permeable. In addition, angiotensin II levels may increase and have central actions together with virus, which may enter the circulation from damaged lungs and digestive tract epithelia. The right hand panel summarizes the consequences of vagal afferent and area postrema activation to induce nausea and vomiting by projection of information to higher brain regions (nausea and anorexia) and vomiting by motor pathways in the ventral brainstem and spinal cord. 5‐HT, 5‐hydroxytryptamine; ACE 2, angiotensin converting enzyme receptor 2; AP, area postrema; CCK, cholecystokinin; DMVN, dorsal motor vagal nucleus; EEC, enteroendocrine cells in the digestive tract; GLP‐1, glucagon‐like peptide‐1; IL‐6, interleukin‐6; NTS, nucleus tractus solitarius; TMPRSS2, transmembrane protease serine 2; VRG, ventral respiratory group of neurones. [Color figure can be viewed at wileyonlinelibrary.com]