New data from Chinese colleagues working at the forefront of the COVID-19 outbreak, and studies of earlier viral outbreaks, provide important insight into the hepatotoxic and gastrointestinal implications of this pandemic.
Respiratory symptoms are the most common presentation, but they're not the only early signs of COVID-19. Diarrhea, nausea, vomiting, and abdominal pain were well documented and often preceded respiratory symptoms in a subset of 138 consecutive hospitalized patients in Wuhan, China.
A recently published study also indicates that COVID-19 was detected in the stool of over 50% of infected hospitalized patients. Investigators found that the lamina propria of the stomach, duodenum, and rectum was edematous with infiltrating plasma cells and lymphocytes. Viral host receptor angiotensin-converting enzyme 2 (ACE2) and viral nucleocapsid protein stained positive in specimens, making gastrointestinal infection with COVID-19—and fecal-oral transmission—likely. Fecal shedding of viral RNA was also found in 20% of patients with COVID-19, despite real-time reverse transcriptase polymerase chain reaction testing from two sequential respiratory tract specimens collected at least 24 hours apart being negative. These results have a clear impact regarding transmission precautions, especially in hospitalized patients.
Liver impairment is another emerging concern with COVID-19, as it was with the similar novel coronavirus, severe acute respiratory syndrome (SARS). According to a 2004 report, up to 60% of patients with SARS had liver impairment, with liver biopsy specimens demonstrating viral nucleic acids and injury. These authors noted that this may have been the result of drug-induced liver injury, given that most of these patients were treated with high doses of potentially hepatotoxic antivirals, antibiotics, and steroids.
A recent publication observed that 54% of patients hospitalized for COVID-19 at a single center in China had elevated gamma-glutamyl transferase (GGT). ACE2 expression is enriched in cholangiocytes, suggesting that COVID-19 might actually cause a higher risk for biliary injury over hepatocyte injury, as supported by these observed GGT elevations
Implications of Hepatic Dysfunction in Severe COVID-19
Individuals at high risk for severe COVID-19 are typically of older age and/or present with comorbid conditions such as diabetes, cardiovascular disease, and hypertension. This is also the same profile for those at increased risk for unrecognized underlying liver disease, especially nonalcoholic fatty liverdisease. This could make them more susceptible to liver injury from the virus, medications used in supportive management, or hypoxia.
Immune system overreaction accompanies disease progression, which can also independently lead to organ failure. It is well established that liver enzymes rise during systemic infections. Seasonal influenza is not known to cause hepatitis. However, a retrospective study comparing cohorts infected with either seasonal influenza or the more pathogenic influenza A/H1N1 behind a 2009 pandemic found that the latter resulted in a greater degree of inflammation/C-reactive protein elevation. Influenza animal models suggest that hepatic oxidative stress leading to injury is the primary event, not viral replication, although injury from virus-specific CD8+T cells might also be at play.
In considering the clinical implications of these data, we need to have a high suspicion for COVID-19 in patients who present with gastrointestinal (not just respiratory) symptoms. Such patients should be tested and isolated similar to the procedure for both respiratory and fecal-oral infections until confirmatory tests return. Isolation might need to be prolonged beyond when respiratory tract specimens are negative, especially in those with gastrointestinal manifestations. In our attempts to accomplish social isolation, individuals with underlying liver disease, or risks for liver disease, should be treated similarly to other high-risk groups.
Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of HCVGuidelines.org, a Web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair for the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.
It's not news to tell you that the coronavirus, known as COVID-19, is a worldwide problem. The initial outbreak of this novel virus in Wuhan in the Hubei province of China, first described in December 2019, has since moved on to being declared a pandemic by the World Health Organization.
The classic description of COVID-19 is a respiratory illness that manifests with fever, dry cough, and dyspnea on exertion. However, we're starting to see the potential for gastrointestinal (GI) implications of COVID-19 as well. This was observed with similar viral respiratory illnesses, such as severe acute respiratory syndrome (SARS), which emerged in 2003, and the Middle East respiratory syndrome (MERS), which emerged in 2012. These infections were transmitted through contact and viral spreading via microdroplets transmitted from the respiratory tract, as is also alleged for COVID-19. A fair percentage of patients with MERS and SARS developed GI symptoms later in the course of the disease.
In a recently published single-center case series of 138 consecutive hospitalized patients with confirmed COVID-19, investigators reported that approximately 10% of patients initially presented with GI symptoms, prior to the subsequent development of respiratory symptoms. Common and often very subtle symptoms included diarrhea, nausea, and abdominal pain, with a less common symptom being nonspecific GI illness.
New studies are expanding our understanding of the possible fecal transmission of COVID-19. Assessment by polymerase chain reaction (PCR) has provided evidence of virus in the stool and the oropharynx outside the nasopharynx and respiratory tract. Virus in the stool may be evident on presentation and last throughout the course of illness resolution for up to 12 days after the respiratory virus evidence is gone.
When I say "virus evidence," it's because it does not necessarily correspond to infectivity. Studies from fecal transmission to infectivity have yet to be done. However, it's certainly suggestive that the virus is intact, at least as far as how the PCR assay for the respiratory definition is now being applied the same way for stool.
Why Possible Fecal Transmission Is Important
The Centers for Disease Control and Prevention recommends that after two negative respiratory tests separated by ≥ 24 hours, patients can be dismissed from having transmissibility infection risk for COVID-19. But we now know that these stools may lag up to 12 days after. In fact, in one of the most recent studies looking at 73 patients, approximately 24% remained positive in their stool for evidence of virus, though not necessarily infection, after showing negative in respiratory samples.
When we consider other disease states with fecal-oral transmission, the classic example that comes to mind is Clostridium difficile. We tell patients with C difficile–positive stool that when they use and flush the toilet, they can aerosolize these spores, which may then deposit on the surface areas in their bathroom. As we do with C difficile, we may need to consider recommending the implementation of a high-level disinfection and mechanical disruption approach for COVID-19.
The latest science indicating that persistence may last up to 12 days after resolution of their respiratory infection or evidence of virus raises concerns around timing. How long should these patients be isolated from other people? Fecal-oral transmission has a real possibility for enhancing community spread, for active infected individuals and also for those less active infected and maybe those with concomitant illness that they just dismiss.
Another concern is the extrapulmonary manifestations of COVID-19. The most recent data suggest that transaminase elevation may be evident in some of these patients, at least those seen in Wuhan. This same hepatotoxicity was previously seen with SARS and MERS. It's not yet clear whether it's a direct viral effect on the liver or whether it's a concomitant effect from drugs (eg, antivirals, steroids, antibacterials) in patients who are sick or in the ICU. There's certainly more to be said on that topic.
Take Precautions
The potential for fecal-oral transmission of COVID-19 needs to be strongly considered. We need to start to look at some of those same isolation precautions we employ with C difficile. The potential for fecal transmissibility has yet to be defined, but we know from a recent study that the virus has been evident in the stool of just over 50% of patients and remains in nearly 25% otherwise clear of respiratory evidence of virus.
There's certainly more to be learned and understood. But at present, there's also a lot we may want to keep in mind as potential implications and precautions. I hope this provides you with good guidance.
I'm Dr David Johnson. Thanks again for listening.
David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.
UPDATED March 19, 2020: This story has been updated to clarify the study findings. // Patients with gastrointestinal (GI) symptoms who were admitted to the hospital and were diagnosed with COVID-19 were more likely to have severe disease than patients who did not have GI symptoms, according to findings published March 18 in the American Journal of Gastroenterology.
However, the unexpectedly large proportion is due in part to the inclusion of anorexia, said Brennan M. R. Spiegel, MD, MSHS, co–editor-in-chief of theAmerican Journal of Gastroenterology.
"If you leave out anorexia, which is very nonspecific, the percentage of COVID-19 patients with GI symptoms is about 30%," Spiegel told Medscape Medical News.
Lei Pan, MD, PhD, of Binzhou Medical University Hospital in Binzhou, China, and colleagues in the Wuhan Medical Treatment Expert Group conducted a descriptive, cross-sectional, multicenter study on 204 patients who had polymerase chain reaction–confirmed COVID-19 at three hospitals in Hubei province from January 18, 2020, to February 28, 2020. The team considered clinical characteristics, laboratory data, and treatment.
Ninety-nine patients (48.5%) presented to the hospital with digestive symptoms as their chief complaint. Most of these patients did not have underlying digestive diseases. Their symptoms included anorexia (83.8%), diarrhea(29.3%), vomiting (0.8%), and abdominal pain (0.4%).
Like Spiegel, David A. Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine in Norfolk, says that the patients with anorexia should be excluded. A more realistic ― if high ― estimate is the 29% who presented with diarrhea, Johnson says.
"Other GI problems ― abdominal pain, nausea, and vomiting ― may raise the percentage slightly from the 29%," Johnson said.
For the overall study population, Pan and colleagues found that the average time from symptom onset to hospital admission was 8.1 days. However, it was 9.0 days for patients with GI symptoms, including those with anorexia, compared with 7.3 days for those who did not have digestive symptoms. Seven patients had digestive symptoms but no respiratory symptoms at admission.
Digestive symptoms appeared to be tied to worse outcomes. Whereas 60% of patients without digestive symptoms recovered and were discharged, only 34.3% of the patients with digestive symptoms recovered.
Spiegel explained how the digestive symptoms arise. "The virus enters human cells through the ACE2 receptor in the lungs but also in other body parts, including the GI tract. We think the virus gets into saliva and we swallow it, and then it passes through the acid layer in some patients and uses the ACE2 receptors to enter epithelial cells that line the intestine."
The virus replicates rapidly in the cells of the GI lining, enters the intestinal tract, and is shed, Spiegel said. "There is clear evidence from endoscopy that it can damage the stomach and the intestines. The fact that these patients do worse may be that more of the body is involved."
An explanation for the longer time between symptom onset and COVID-19 diagnosis might be that patients with only GI symptoms or mild respiratory complaints did not think that they could have the coronavirus.
"When the patients were admitted to the hospital, no one yet knew they had COVID-19. Almost half, when asked why they were there, mentioned a digestive problem. They may have also had a respiratory symptom, like a cough or shortness of breath, but that's not what they said was their main complaint," Spiegel told Medscape Medical News.
The authors conclude, "Clinicians should recognize that digestive symptoms, such as diarrhea, may be a presenting feature of COVID-19, and that the index of suspicion may need to be raised earlier in at-risk patients presenting with digestive symptoms rather than waiting for respiratory symptoms to emerge."
Spiegel points out that the Centers for Disease Control and Prevention has yet to include GI symptoms in their guidance, although recommendations are changing rapidly.
Spiegel urges caution in evaluating patients with only GI symptoms. "A large part of the population has diarrhea, abdominal pain, nausea, and vomiting regularly, so it's clearly impossible and irresponsible to start testing everyone with diarrhea for COVID-19. But if somebody has new fever and diarrhea and suspects they may have had contact with a patient or carrier, I'd want to test them."
Limitations of the study include a relatively small sample, the retrospective design, and not testing for SARS-CoV-2 RNA in stool.
Am J Gastroenterol. Published online March 18, 2020. Full text
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