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In February, 麻豆传媒 published a story on the presence of gastrointestinal (GI) symptoms in the first case of COVID-19 in the U.S., and how these GI symptoms may be overlooked. Below we report on what has happened since.

In the early days of the SARS-CoV-2 outbreak, clinicians focused on respiratory symptoms and transmission, but soon identified the GI/fecal/oral route as another avenue of spread for this imperialistic virus.

"The biggest revelation over the year has been that the oral route is a point of entry into the body and the digestive tract is a primary organ system for the virus to multiply, replicate, and potentially spread," Brennan Spiegel, MD, of Cedars-Sinai Medical Center in Los Angeles, told 麻豆传媒.

Experts were quick to warn that, as with the original SARS coronavirus, extra-pulmonary complications in the GI tract might be more common than thought and should not be missed in the differential diagnosis of the 2019 version. Furthermore, GI symptoms, which appeared to affect 5% to 15% of patients, often persisted after the acute phase of the infection and sometimes signalled poorer patient outcomes, perhaps because they indicate the virus's penetration into more systems of the body.

Evidence Mounts

In addition to the February report, U.S. and Chinese researchers pointed to digestive symptoms as a possible hallmark of COVID-19 infection in some patients, and advised doctors to evaluate all patients with GI complaints for the virus. And earlier in March, mounting evidence of such symptoms in as many as 50% of patients led several U.S. GI societies to issue a on clinical precautions for providers of endoscopy and other gastroenterology care.

Also in March, 麻豆传媒 highlighted a Chinese study showing that in a subgroup of COVID-19 patients with mild disease, digestive problems, such as nausea and diarrhea, might be the only symptoms of infection, with no sign of the more typical fever or respiratory symptoms, and hence should be part of the differential diagnosis.

In early May, New York clinicians published figures showing that 22% of hospital-assessed COVID-19 patients had diarrhea, 7% had abdominal pain, 16% had nausea, and 9% had vomiting. In all, 33% of patients had at least one GI manifestation, and 62% of patients had biochemical evidence of liver injury.

Additionally, a Chinese group released results showing that 50.5% of COVID-19 patients presenting at hospitals had at least one digestive tract symptom and in almost half of these, a digestive problem was the main complaint. GI involvement spelled longer hospital stays and worse outcomes, with only 34.3% of those with digestive symptoms recovering versus 60% of patients without digestive symptoms discharged as recovered.

By July, with the pandemic in full swing, reported that COVID-19 patients treated in-hospital had lingering symptoms, including troublesome GI manifestations, for up to 2 months after recovering from the acute phase. And a California study linked the use of a stomach acid-suppressing proton pump inhibitor (PPI) to an increased risk of COVID-19 positivity.

Similar studies followed: August saw the publication of research revealing that the virus can present as acute idiopathic pancreatitis and Black and Hispanic patients with existing pancreatitis were more prone to COVID-19 infection.

With the arrival of fall, Chicago clinicians presenting at the 2020 American College of Gastroenterology (ACG) virtual meeting observed that GI symptoms at initial presentation were independently associated with a poor prognosis. In particular, diarrhea at presentation was tied to more severe disease and poor prognosis, according to a review and meta-analysis also outlined at the ACG.

Subsequently, the North American Alliance for the Study of Digestive Manifestation of COVID-19 reported that while severe GI complications in COVID-19 admitted to the ICU were uncommon -- at only 5.1% -- they were associated with a death rate of 55.6%.

While the study showed a low incidence of intestinal ischemia, Emad Qayed, MD, MPH, of Emory University in Atlanta, and colleagues warned that COVID-19 is "a hypercoagulable disorder that is associated with a higher incidence of venous thromboembolism." And since it can infect the endothelial cells of different vascular beds in the heart, small bowel, and lungs, endotheliitis caused by COVID-19 can lead to microthrombus formation and organ ischemia.

In agreement with this warning, Brett Williams, MD, of Chicago's Rush University Medical Center told 麻豆传媒, "We know this virus has a propensity to cause endotheliitis, which can obviously involve any organ. Patients with GI symptoms quite possibly have direct viral invasion of the GI mucosa, liver, and pancreas, though in sepsis-type syndromes, it's difficult to know how much the inciting pathogen, hypoperfusion, and inflammation each contribute to pathology in any one organ system."

Williams said that at his center, elevated lipase levels in COVID-19 patients were relatively common -- at 16.8% of those patients checked -- and elevated lipase levels were strongly associated with ICU admission and intubation. "And there appear to be receptors for the virus in the pancreas, as well as in mature enterocytes," he said.

Research from New York rounded out the year with the December publication of a finding that 3% of COVID-19 inpatients had GI bleeding, which was associated with higher mortality.

Most implicated in GI involvement are receptors for angiotensin-converting enzyme 2 (ACE-2), which abound in the intestines as well as the stomach and liver and to which the virus readily binds.

According to Spiegel, the respiratory virus sheds into saliva from the shared upper airways and the salivary glands. When swallowed, the viral-laden saliva passes through the acid layer using the ACE2 receptors to enter epithelial cells lining the intestine, where it replicates rapidly. Although gastric acid can inactivate most viruses, "if the virus hits before your first meal of the day when acid levels are low, or if you're taking a PPI or get a particularly large inoculum of virus, enough can get through to make it past," he told 麻豆传媒.

Impact on GI Practice

As the pandemic led to office shut-downs, a switch to telemedicine, and the reassignment of strained medical resources to COVID-19 care, there was a dramatic drop in routine procedures such as screening colonoscopies and elective surgeries, according to Hashem B. El-Serag, MD, MPH, president of the American Gastroenterological Association.

"Such procedures suffered in the early months of the pandemic and again each time there was a surge," El-Serag, of Baylor College of Medicine in Houston, told 麻豆传媒. "Gastroenterologists should be on the lookout for adverse events tied to delayed investigations."

El-Serag added that the lingering long-haul effects of COVID-19, such as chronic diarrhea and nausea, are intensifying pre-existing GI conditions including irritable bowel syndrome (IBS) and other chronic problems. "The virus disturbs the gut microbiome and exacerbates the mental anguish that these patients already feel," he explained.

The virus may also trigger new-onset post-viral IBS, said Spiegel, noting that his group is monitoring population data looking for any uptick in IBS or other GI disorders.

Perhaps the virus's greatest impact on practice has been to improve safety, stated Reem Z. Sharaiha, MD, of Weill Cornell Medicine/NewYork-Presbyterian Hospital in New York City. "We had to address how to protect ourselves and realized we were very lax in doing so pre-COVID," he said. "Societies have met to discuss importance of, and the meaning of, universal precautions. For GI specifically, the main thing has been the role of personal protective equipment."

As the GI checklist for COVID-19 symptoms strengthens, along with newer symptoms such as COVID-associated clinicians will have an increasing number of indicators to raise the index of suspicion and guide the diagnostic process in the coming year.

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