key: cord-0958365-2fum00uh authors: McDermott, Carmen V.; Cox, Emily J.; Scanlan, James M.; Alicic, Radica Z. title: COVID-19 and Gastrointestinal Symptoms: Recognition, Containment, and Learning From the Past date: 2020-08-25 journal: Mayo Clin Proc DOI: 10.1016/j.mayocp.2020.08.023 sha: 089afcc70521bf6418a27daccf9a9989dc946631 doc_id: 958365 cord_uid: 2fum00uh nan © 2020 Mayo Foundation for Medical Education and Research. Mayo Clin Proc. 2020;95(x):xx-xx. United States, but globally it is the third coronavirus outbreak of the twenty-first century. Almost no data were available to guide the hospital medicine response to previous coronaviruses; however, for COVID-19, hospitalists can look to more than a decade of research conducted in the wake of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Data gathered from these outbreaks taught us that gastrointestinal (GI) symptoms were characteristic of both SARS and MERS. 1 The importance of GI transmission for these infections was not fully recognized until after a large community outbreak had been precipitated by an index patient with diarrhea, most likely via airborne transmission. 2 Thus, a lesson learned from these previous human coronavirus outbreaks is the importance of early recognition of GI signs -sometimes the only presenting symptoms -by clinicians and infection control professionals. Such recognition is critical to avoid delayed diagnosis and unintended transmission events in hospital settings. 3 Therefore, to inform patient care and hospital containment efforts, we summarize current data on the characteristics of GI symptoms for these recent coronavirus outbreaks, and describe practical measures for preventing transmission due to GI viral shedding in hospital settings. Fever and respiratory symptoms were highlighted early in the COVID-19 outbreak and are widely considered to be the main symptoms of COVID-19. As the outbreak has evolved, GI complaints (notably vomiting, diarrhea, anorexia, and abdominal pain) have emerged as prevalent symptoms, which sometimes occur in the absence of non-GI symptoms. Compared to SARS-CoV-1 (SARS) or MERS-CoV (MERS), for J o u r n a l P r e -p r o o f which GI symptoms occurred in approximately one quarter of infected patients, 1 rates of GI symptoms appear to be lower for SARS-CoV-2. Recent analyses describing pooled prevalence of GI symptoms are shown in Table 1 . Combined results of these two meta-analyses suggest that the "true" population rate of GI symptoms in COVID-19 patients is likely between 10%-20%. Characterizing the time course of GI symptom appearance (i.e., at presentation, upon admission, during hospitalization) is important, although often neglected and poorly documented, for the accurate recognition of COVID-19. One meta-analysis determined that GI symptoms were the presenting symptoms in 10% of COVID-19 cases analyzed, 4 but data on this remains lacking. In other recent cohorts, between 3-16% of patients presented with at least one GI symptom (nausea, vomiting, diarrhea and abdominal pain) without concurrent respiratory symptoms. 5, 6 Importantly, GI symptoms that emerge later in the disease course of COVID-19 could result from viral pneumonia or systemic inflammatory response syndrome (especially anorexia, abdominal pain, and nausea/vomiting), or from antibiotics or other therapeutic agents given during treatment (especially nausea/vomiting, and diarrhea). Interestingly, COVID-19 studies from Asia generally report somewhat lower prevalence of GI symptoms. Reasons for differences in prevalence rates could be due to tendency to focus on more immediately threatening respiratory symptoms, as these are more likely to cause clinical deterioration; lack of awareness of GI manifestations earlier in the pandemic; differences in classification of diarrhea; variability in screening protocols for GI symptoms; viral strain variability; and varying ethnic susceptibilities to viral GI infection. COVID-19 patients also demonstrate serologic evidence of liver dysfunction, most commonly a mild increase in alanine transaminase and aspartate transaminase and bilirubin, and low albumin, though severe liver injury has been reported. 6, 7 A recent review of COVID-19 and liver disease concluded that COVID-19 was frequently associated abnormal liver function tests, but that such results were generally mild and transitory. 8 Patients with more severe cases of COVID-19 also showed a greater likelihood of liver injury. Relatively little data is currently available concerning COVID-19 in patients with pre-existing liver disease, such as cirrhosis and NAFLD. It is not yet known whether the etiology of liver injury is related to viral infection of hepatocytes, COVID-19 treatments, systemic inflammation due to the infection, or another causes. Taken together, however, these findings suggest that evidence of liver injury should be considered a GI manifestation of COVID-19. The pathophysiology underlying GI symptoms in COVID-19 cases is not completely clear, but active viral replication may take place in the GI tract, with initial viral entry occurring through the angiotensin-converting enzyme 2 (ACE2) receptor. Generally, ACE-2 receptors are highly expressed in the GI system, even more abundantly than in the lungs, and GI mucosa can therefore serve as a viral target site. Viral replication in the GI tract is supported by a report that identified intracellular viral nucleocapsid protein in biopsy results of gastric, duodenal, and rectal, epithelial cells; another report finding live SARS-CoV-2 in stool; and yet another showing high stool viral loads by PCR and intestinal cells expressing subgenomic viral mRNA in hospitalized patients. 9 These data parallel reports from the SARS and MERS literature, which show that these viruses probably infected the GI tract. J o u r n a l P r e -p r o o f While prevalence among patients from different geographical regions, racial/ethnic backgrounds, and age groups needs to be clarified, these findings challenge the assumption that the "typical" COVID-19 patient has exclusively respiratory symptoms and fever, or that COVID-19 infection is improbable in the absence of respiratory symptoms. Previous outbreaks can possibly shed light on transmission concerns for SARS-CoV-2. Fecal shedding and airborne transmission appear to have been pivotal in a notable super-spreading event for SARS, which involved an index patient with diarrhea and high viral loads in stool and urine. 2 The aerosolization of SARS-CoV-1 and transmission via the plumbing and ventilation systems have been argued to be the mechanisms that precipitated this event. As the GI presentations of COVID-19 bear similarity to those caused by SARS and MERS, the prevalence of GI symptoms in these patients and the shedding of virus in stool should raise parallel concerns. Already, GI transmission has been reported in a hospital spreading event for COVID-19, whereby one COVID-19 patient with GI symptoms infected several healthcare workers and other patients. 10 To prevent such events in hospital environments, the two primary considerations related to GI symptoms are (1) Furthermore, it is well established (though not well publicized) that toilet flushing has the potential to generate infectious droplets and aerosols resulting in contamination of the surfaces and air in some enteric pathogens, especially in viruses). Notably, as discussed, aerosolization of SARS-CoV-1 probably triggered a SARS superspreading event, 2 highlighting the importance of this transmission mode. For transmission via GI secretions to occur, live virus needs to be secreted in stool or vomit, and remain viable on surfaces or air, which is not yet fully understood for SARS-CoV-2. However, virus has been detected by PCR in stool of patients from numerous cohorts, and live virus was isolated from stool of patients without diarrhea in one small cohort. More research and validation from larger patient cohorts would be valuable to ascertain the infectiousness of fecal bio-aerosols, especially since the viability of SARS-CoV-2 in air has not been fully determined. To our knowledge, thus far there has been only one report of infectious virus being isolated from stool samples. 11 While reports remain inconclusive, it is prudent for any enclosed air facility with a dense population of COVID-19 patients, especially hospitals, to remember that this mode of transmission was an important factor in previous coronavirus outbreaks. 2, 3 Whether stool samples that test positive by PCR contain infectious virus remains to be determined, as does the sensitivity and specificity of stool PCR relative to clinical disease and infectiousness. As infectiousness is best measured in culture, and few studies have cultured stool, there is no consensus on whether stool samples generally contain live or dead virus. Moreover, while the ability of a sample to grow virus in culture should be the ultimate "gold standard" for the infectiousness of both respiratory and stool samples, this reference is rarely employed, because of J o u r n a l P r e -p r o o f lag time, inconvenience and the reluctance of laboratories to culture COVID-19 because of potential infection. Clearly, having a firm distinction between "PCR positive" and "likely to be infectious" would be very clinically useful. Infected persons may shed virus in all phases of illness, and notably continue to shed virus in stool during recovery phases, even after respiratory samples test negative for the virus. Consequently, individuals who have negative respiratory swab tests, thus appearing non-infectious, could still shed virus in stool. Infectivity is highly heterogenous among patients and between different viral strains, and until more data is available to understand infectivity in all phases, it is important for hospitals to consider the potential for transmission from viral shedding 3 during all illness phases, including asymptomatic and convalescent phases of illness. Hospital infection control responses to COVID-19 can directly extrapolate from lessons learned during the SARS and MERS outbreaks. Here, we suggest essential considerations for hospital containment strategies for human coronaviruses ( Table 2 ). patients and health care staff to receive education on how to recognize all possible initial presentations of COVID-19 patients including those who do not present with the typical fever and respiratory symptoms. 3 Currently, messages alert patients to notify staff of respiratory symptoms and fever upon entry to most healthcare facilities; however, these messages should be expanded to include GI symptoms. This elevated awareness would allow for immediate and rapid isolation upon presentation and timely testing for COVID-19, which was shown to likely prevent transmission in SARS. 3 Protocols for screening patients for COVID-19 symptoms should include questions about GI as well as respiratory symptoms. (including GI symptoms) should be immediately placed in isolation precautions until the disease is appropriately ruled out. Isolation measures should take in to account the potential for fecal-oral transmission. Future planning should encompass adequate facility measures to permit isolation for future infectious outbreaks in order to prevent nosocomial superspreading events. 3 3. Improve environmental controls: Aggressive environmental cleaning with disinfectants is critical. 3 Additionally prevention of airborne spread from toilets and plumbing should be considered. 3 All staff should know that toilets generate bio-aerosols when flushed, which can either enter the air or land on surfaces. Staff should also be aware that covering flushed toilets is the simplest way to block these aerosols (closing the toilet lid during flushing = 12-fold reduction in bio-aerosol spread). Where this is not possible, healthcare workers should be If recent coronavirus outbreaks are any indication, COVID-19 will probably not be the last coronavirus to move from animals to humans and pose a clinical and containment concern for clinicians and hospitals. Clinicians should be aware of gastrointestinal symptoms that are prevalent with COVID-19, and indeed other notable human coronavirus infections to date. Clinicians should also be aware that these symptoms can occur early in the disease and in the absence of respiratory symptoms. Infection control knowledge from previous outbreaks should guide the response to COVID-19 and any future coronaviruses. 3 In particular, lack of awareness of GI transmission and potential bio-aerosolization of the virus was an infection control gap with previous coronavirus outbreaks. 2 14 Cheung et al. 15 Tariq et al. 16 J o u r n a l P r e -p r o o f Insight into 2019 novel coronavirus -An updated interim review and lessons from SARS-CoV and MERS-CoV Evidence of airborne transmission of the severe acute respiratory syndrome virus Identifying and Interrupting Superspreading Events-Implications for Control of Severe Acute Respiratory Syndrome Coronavirus 2 Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis Don't Overlook Digestive Symptoms in Patients With 2019 Novel Coronavirus Disease (COVID-19) Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study Don't overlook digestive symptoms in patients with 2019 novel coronavirus disease (COVID-19) Review article: COVID-19 and liver disease-what we know on 1st Virological assessment of hospitalized patients with COVID-2019 Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan Detection of SARS-CoV-2 in Different Types of Clinical Specimens Airborne Transmission of SARS-CoV-2: Theoretical Considerations and Available Evidence Airborne Spread of SARS-CoV-2 and a Potential Role for Air Disinfection Prevalence of Gastrointestinal Symptoms and Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic Review and Meta-analysis Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples from the Hong Kong Cohort and Systematic Review and Meta-analysis Prevalence and Mortality of COVID-19 patients with Gastrointestinal Symptoms: A Systematic Review and Meta-analysis