Fever, cough and shortness of breath are the classic symptoms of COVID-19, but there may be gastrointestinal symptoms, such as nausea and diarrhea, that are getting missed, according to a new Stanford Medicine study.
Researchers found that, in addition to upper respiratory symptoms, a significant number of those sick with the new virus also suffered from loss of appetite, nausea, vomiting and diarrhea.
The study, one of the earliest on U.S. patients with the coronavirus, was published online April 10 in Gastroenterology. Gastroenterology fellows George Cholankeril, MD, and Alexander Podboy, MD, share lead authorship. Aijaz Ahmed, MD, professor of gastroenterology and hepatology, is the senior author.
“COVID-19 is probably not just respiratory symptoms like a cough,” Podboy said.
“A third of the patients we studied had gastrointestinal symptoms. It’s possible we may be missing a significant portion of patients sick with the coronavirus due to our current testing strategies focusing on respiratory symptoms alone.”
Unique situation
As the coronavirus pandemic hit the San Francisco Bay Area in early March, hospitals began canceling elective surgeries and postponing nonemergency patient visits to make room for a surge of coronavirus patients.
With their clinics closed and other projects on hold, a group of gastroenterology fellows had time to work together on a project, Podboy said.
“George recognized early on that since Stanford was among the first hospitals to get COVID-19 patients in the U.S., that any type of early experience would be important,” he said.
“We were in a unique position to look into this subject of gastrointestinal symptoms among coronavirus patients at Stanford.”
The researchers were aware of a growing body of research out of China and Singapore that showed a prevalence of GI symptoms in COVID-19 patients, but could find no data on the topic from patients in the United States.
They decided to conduct their own study by examining the charts of the earliest group of patients treated for the virus at Stanford Health Care.
Study results
Researchers analyzed data collected from 116 patients who tested positive for the coronavirus at Stanford Health Care from March 4-24. The majority were treated and released from a hospital emergency room or a clinic.
A total of 33 were hospitalized, eight of those in an intensive care unit.
The median age of the patients was 50, and 53% of them were men. Only one death was reported within the group.
Gastrointestinal symptoms were reported by 31.9% of the patients.
The majority of that group described the symptoms as mild.
Twenty-two percent said they experienced loss of appetite, 22% had nausea and vomiting, and 12% had diarrhea, the study said.
“We also noticed that 40% of patients had elevated levels of an abnormal liver enzyme, and that those with high levels required more hospitalization,” Cholankeril said.
Testing recommended
The researchers suggest that while this data is early and from only a single institution, the results do raise the possibility that people exposed to the coronavirus who are experiencing gastrointestinal symptoms — not just those with respiratory symptoms — should also be tested.
“In our current cohort of patients, all patients had respiratory symptoms prior to the development of gastrointestinal symptoms,” Podboy said.
“No patients had gastrointestinal symptoms prior to the development of respiratory symptoms or as their only manifestation of COVID-19.”
He added, “However, that may be a product of who we were testing. Currently, testing is only offered for patients that meet specific criteria — criteria that often require the presence of pulmonary symptoms.”
The researchers plan to study the role of GI symptoms in COVID-19 and their implication on disease severity and hospitalization outcomes, Cholankeril said. They also plan to continue working as a team.
“We had six fellows working together and we were able to go through these charts pretty quickly,” Cholankeril said.
“It was a terrific collaboration between colleagues to be able to join forces to study this new disease. We think that by looking at patients here at Stanford, it can help improve our understanding of this emerging disease.”
Other Stanford co-authors are gastroenterology fellows Vasiliki Aivaliotis, MD, Branden Tarlow, MD, PhD, Edward Pham, MD, PhD, and Sean Spencer, MD, PhD; research scholar Donghee Kim, MD, PhD; and Ann Hsing, PhD, professor of medicine at the Stanford Prevention and Research Center.
Funding: The study was supported by the National Institutes of Health (grant T32DK007056
Mechanisms of gastrointestinal tract involvement
Evidence from previous SARS studies indicated that coronavirus has a tropism to the gastrointestinal tract. The SARS-CoV RNA could be readily detected in stool specimens of SARS patients 34, and electron microscopy on biopsy and autopsy specimens showed active viral replications in both small and large intestines 22.
Similarly, enteric infection could occur with MERS-CoV, as human intestinal epithelial cells were highly susceptible to the virus and could sustain robust viral replication 35. This gastrointestinal tropism may explain the frequent occurrence of diarrhoea in coronavirus infection. This faecal
source can lead to fomite transmission, especially when infective aerosols are generated from the toilet plume 36.
Although at a lower frequency compared to SARS, some Covid-19 patients do develop diarrhoea during their disease course. This suggests the possible tropism of SARS-CoV-2 to the gastrointestinal tract.
Genome sequences showed that SARS-CoV-2 shared 79.6% sequence identity to SARS-CoV, both encoding and expressing the spike (S) glycoproteins that could bind to the entry receptor ACE2 to enter human cells 37-39. The receptor binding domain on SARS-CoV-2 could bind to human ACE2 with high affinity, correlating with the efficient spread of the virus among humans 40, 41.
While ACE2 is highly expressed in type II alveolar cells (AT2) in the lungs, the receptor is also abundantly expressed in the gastrointestinal tract, especially in the small and large intestines 7, 8. Staining of viral nucleocapsid protein was visualized in cytoplasm of gastric, duodenal and rectal epithelium 27.
These data have provided valuable insights into the receptor-mediated entry into the host cells, and provided basis for its possible transmission route through the faecal contents.
Implications to patient care and infection control
The tropism of SARS-CoV-2 to the gastrointestinal tract, its positive detection in stool, and its associated gastrointestinal symptoms, have important implications to both patient care and infection control. Clinicians should be alert of the gastrointestinal symptomatology of Covid-19, especially as they may occur before the onset of pyrexia and respiratory symptoms.
More importantly, several studies have demonstrated the presence of viral RNA in stool or anal / rectal swabs of Covid-19 patients 2-6. In a study that evaluated 73 Covid-19 patients, 39 (53.4%) were tested positive for SARS-CoV-2 RNA in stool, with a duration of positive stool ranging from 1 to 12 days. Rather of concern, 17 (23.3%) patients remained positive with stool viral RNA after showing negative in their respiratory samples 7.
In another study that followed 10 paediatric patients and evaluated their nasopharyngeal and rectal swabs, eight children were persistently tested positive on rectal swabs even after nasopharyngeal clearance of the virus 3.
Moreover, two children had positive rectal swabs, despite after clearance with two consecutive negative rectal swabs separated by at least 24 hours apart 31. In contrast to the cycle threshold (Ct) value of 36-38 on illness day 7 stool sample from the first US case 4, the longitudinal Ct values in the paediatric patients were mostly below 35 3.
This suggested that viral shedding from the gastrointestinal tract may be abundant, and may last long after resolution of clinical symptoms. Indeed, a previous study of SARS-CoV indicated that viral RNA could still be detected after 30 days in stool of SARS patients 42.
Nevertheless, the viral dynamic of SARS-CoV-2 in the gastrointestinal tract is not known, and may not follow that of SARS- CoV as observed in the respiratory tract 25, 43.
The immediate implication of these data is certainly on the disease infectivity. A recent environmental study suggested that SARS-CoV-2 could remain viable in aerosols for hours, and could stay stably on plastic and stainless steel for at least 72 hours 44.
While more studies are needed to demonstrate its replication-competence, its abundance in stool and stability in environment would poise SARS-CoV-2 favourably to spread among human hosts.
This faecal source can lead to viral transmission especially when aerosols are generated, as with the major outbreak caused by toilet fume in Amoy Garden during the SARS epidemics in Hong Kong 36.
The gastrointestinal involvement of Covid-19 would necessitate a need to consider several clinical policies, such as incorporation of rectal swab testing before discharging patients 45, as well as our preparedness for personal protective equipment in the endoscopy setting 46, 47. These considerations will be important in our battle against Covid-19.
References
[1] Gu J, Han B, Wang J. COVID-19: Gastrointestinal manifestations and potential fecal- oral transmission. Gastroenterology. 2020.
[2] Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020; 9: 386-9.
[3] Xu Y, Li X, Zhu B, et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nature Medicine. 2020.
[4] Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020; 382: 929-36.
[5] Tang A, Tong ZD, Wang HL, et al. Detection of Novel Coronavirus by RT-PCR in Stool Specimen from Asymptomatic Child, China. Emerg Infect Dis. 2020; 26.
[6] Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020.
[7] Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020.
[8] Harmer D, Gilbert M, Borman R, Clark KL. Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett. 2002; 532: 107-10.
[9] Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395: 514-23.
[10] Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020.
[11] Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395: 507-13.
[12] Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497-506.
[13] Liu K, Fang YY, Deng Y, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020.
[14] Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020.
[15] Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020.
[16] Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.
[17] Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020; 368: m606.
[18] Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020.
[19] Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020.
[20] Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020.
[21] Lee N, Hui D, Wu A, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003; 348: 1986-94.
[22] Leung WK, To KF, Chan PK, et al. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology. 2003; 125: 1011-7.
[23] Cheng VC, Hung IF, Tang BS, et al. Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome. Clin Infect Dis. 2004; 38: 467-75.
[24] Liu CL, Lu YT, Peng MJ, et al. Clinical and laboratory features of severe acute respiratory syndrome vis-a-vis onset of fever. Chest. 2004; 126: 509-17.
[25] Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet. 2003; 361: 1767-72.
[26] Chan JF, Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015; 28: 465-522.
[27] Zhao D, Yao F, Wang L, et al. A comparative study on the clinical features of COVID- 19 pneumonia to other pneumonias. Clin Infect Dis. 2020.
[28] Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges.
Lancet Gastroenterol Hepatol. 2020.
[29] Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 2020.
[30] Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020.
[31] Ding Y, He L, Zhang Q, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004; 203: 622-30.
[32] Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-7.
[33] Tan YJ, Fielding BC, Goh PY, et al. Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway. J Virol. 2004; 78: 14043-7.
[34] Hung IF, Cheng VC, Wu AK, et al. Viral loads in clinical specimens and SARS manifestations. Emerg Infect Dis. 2004; 10: 1550-7.
[35] Zhou J, Li C, Zhao G, et al. Human intestinal tract serves as an alternative infection route for Middle East respiratory syndrome coronavirus. Sci Adv. 2017; 3: eaao4966.
[36] Yu IT, Li Y, Wong TW, et al. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med. 2004; 350: 1731-9.
[37] Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579: 270-3.
[38] Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020.
[39] Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395: 565- 74.
[40] Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020.
[41] Wrapp D, Wang N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020; 367: 1260-3.
[42] Chan KH, Poon LL, Cheng VC, et al. Detection of SARS coronavirus in patients with suspected SARS. Emerg Infect Dis. 2004; 10: 294-9.
[43] Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020; 382: 1177-9.
[44] van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020.
[45] Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020; 5: 335-7.
[46] Repici A, Maselli R, Colombo M, et al. Coronavirus (COVID-19) outbreak: what the department of endoscopy should know. Gastrointest Endosc. 2020.
[47] Repici A, Maselli R, Colombo M, et al. Coronavirus (COVID-19) outbreak: what the department of endoscopy should know. Gastrointestinal Endoscopy.
Source:
Stanford
