Could GI Symptoms in COVID-19 Portend Better Prognosis?

Pro-inflammatory response and mortality appeared to be reduced in hospitalized COVID-19 patients with gastrointestinal manifestations, suggesting that the GI tract may mitigate SARS-CoV-2 inflammation, researchers reported.

In a three-cohort international study, SARS-CoV-2 was detected in small-intestine epithelial cells by immunofluorescence staining or electron microscopy in 14 of 16 patients in the final analysis of biopsied patients, according to Saurabh Mehandru, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

High-dimensional analyses of GI tissues in COVID-19 patients revealed low levels of inflammation, including down-regulation of key inflammatory genes such as IFNG, CXCL8, CXCL2, and IL1B, as well as reduced frequencies of pro-inflammatory dendritic cells compared with controls. Infected intestinal cells were predominantly goblet cells, they stated in Gastroenterology.

The findings run counter to previous research reporting that the presence of GI symptoms, especially diarrhea, may signal a higher viral load, more severe disease, and worse outcomes in COVID-19 patients. The abundance of angiotensin-converting enzyme-2 (ACE 2) receptors in the epithelial cells of the digestive tract are thought to facilitate viral entry.

Study Details

In one part of the study, Mehandru’s group examined intestinal biopsy tissues from 19 COVID-19 patients admitted to the hospital from April 1, 2020, to April 15, 2020, and from 10 uninfected controls using immunofluorescent microscopy, CyTOF analysis, and RNA sequencing. Patients also underwent such procedures as esophagogastroduodenoscopy, colonoscopy, or both.

They also looked at disease severity and mortality in patients with and without GI symptoms, analyzed with multivariate logistic regression, in two independent cohorts of hospitalized patients: 634 in the U.S. and 287 in Europe. COVID-19 cases and controls in the biopsy cohort were comparable for age, gender, rates of hospitalization, and relevant comorbid conditions, the authors stated.

Consistent with the tissue findings, they reported a significant reduction in disease severity and mortality in patients presenting with GI symptoms independent of gender, age, and comorbid illnesses, and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there were reduced levels of key circulating inflammatory cytokines in GI-affected COVID-19 patients.

“A potential role of the GI tract in attenuating SARS-CoV-2 associated inflammation needs to be further examined,” the authors wrote, adding that the findings were unexpected in light of the robust intestinal expression of ACE2.

They suggested that one of the possible reasons why SARS-CoV-2 induced less severe inflammation in the gut could be the induction of potent neutralizing immunoglobulin A antibodies, which are predominantly produced in the intestines and do not fix complement unlike immunoglobulin G antibodies induced mainly in the lungs.

“We were surprised to find that patients who initially reported GI symptoms, such as diarrhea, seemed to do much better. We can only hypothesize why,” Mehandru said in a news release. “It could be that the virus traveled into the GI tract and got neutralized by the significant enzyme activity or IgA immunoglobulin presence in the intestinal tract, and as a result did not unleash the extent of inflammation that we sometimes see in in the lungs.”

Acknowledging that the results differ from those in other reports suggesting increased COVID-19 severity in the presence of GI symptoms, the authors noted that previous associations with worse outcomes were likely attributable to the inclusion of abnormal liver function tests, which can correlate with poor outcomes.

Yet similar data came from a 2020 case-control study of 278 patients at Columbia University Hospital in New York City, Mehandru told MedPage Today. “Among COVID-19 patients with GI symptoms (diarrhea, nausea and vomiting), there was a non-significant trend towards lower rates of ICU admission and a significantly lower rate of death during short-term follow-up,” he said.

Mehandru and colleagues stated that their data revealed a dynamic remodeling of GI tissues by SARS-CoV-2, notably with a significant down-regulation of pathways associated with inflammation and antigen presentation in the lamina propria with a concomitant activation of antiviral response signaling genes in the epithelial compartment.

“In summary, our data detail the previously unappreciated GI tissue response to SARS-CoV-2 and provide the rationale for future mechanistic studies to understand a possible attenuation of SARS-CoV-2 pathogenicity by the intestinal environment,” they wrote.

“Looking ahead, our study points to the need to better understand how infection in the intestines relates to long COVID symptoms and the emergence of viral variants, which will require further investigation,” Mehandru said.

Study limitations included the performance of GI biopsies on patients undergoing clinically indicated procedures, not all of whom were in the acute phase of illness. Also, with only three patients in the biopsy cohort exhibiting GI symptoms, the authors were unable to perform comparisons between those with and without these manifestations. Finally, infectious virus could not be isolated from intestinal biopsies, possibly due to culture methods, low multiplicity of infection, or inactivation of virus following contact with enteric secretions.

‘Needs Major Confirmation’

Hashem B. El-Serag, MD, MPH, of Baylor College of Medicine in Houston, urged caution in interpreting the study. “In general it poses interesting questions, but it would need to be redone like a million times,” said El-Serag, who was not involved in the research.

He cited several methodological issues, such as the small number of biopsy patients; the unknown reasons for scoping them, which might have introduced selection bias; and the unknown phase of their disease.

“Symptoms were not captured symptomatically or quantitatively, so you ask ‘Did they happen before admission, at admission, or during hospitalization?'” El-Serag stated. “Anything, including medication, could have precipitated GI symptoms. Was it a bystander effect, a colonization, or a real infection?”

El-Serag added that the study was done in three different populations and no virus was isolated from intestines. More rigorous symptom capture and more gut testing might lead to greater generalizability, he noted.

“It’s a good hypothesis-generating study but it needs major confirmation,” he said.

Last Updated March 04, 2021