Introduction
The pandemic of respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, resulted in an ongoing pandemic. The World Health Organization (WHO) named this illness “coronavirus disease 2019” (COVID-19). It is reported to cause severe illnesses in a significant proportion of infected individuals, especially in the aged and those with underlying comorbid conditions.1–3 Infected individuals’ symptoms can range from mild respiratory illness to critical illness. According to a cohort of around 44,500 patient population, 80% of individuals present with mild pulmonary symptoms. However, approximately 19% develop progressive severe disease and progressive hypoxemia requiring hospitalization and in some cases intensive care admission.4 However, some have developed various fatal complications, including multiple organ failure, septic shock, pulmonary edema, severe pneumonia, stroke, blood coagulopathies, acute respiratory distress syndrome (ARDS), and death.5 The case fatality ranges from 0.9% to as high as 7.0%.6,7
Most infected individuals develop fever, cough, dyspnea, and cold-like symptoms, indicating that the novel coronavirus commonly infects respiratory epithelium.8,9 COVID-19 patients may also develop diarrhea, nausea, anorexia, abdominal discomfort, and dysgeusia.
The pathophysiology behind gastrointestinal (GI) manifestations is yet to be fully understood. The virus gains entry into the target cells of the host through ACE2 receptors.10,11 These receptors are predominantly found in the respiratory tract. Abundant receptors are also present in the intestinal epithelium and other areas such as the esophagus, oral mucosa, and liver.11–13 After the entry into the cells, RNA and proteins are produced with the help of host cell machinery. Several viral RNA copies, capsids, and proteins are synthesized and assembled to form new viral particles. These new viral particles lead to the release of various cytokines (Interleukin 2, 7, tumor necrosis factor-α, and other inflammatory mediators). These chemical mediators cause various GI manifestations. In COVID-19 patients, the viral nucleocapsid protein has been verified in the GI tract. Also, plasmacytic and lymphocytic infiltration and interstitial edema are found in various parts, including the stomach, duodenum, and rectum. Thus, the novel coronavirus may cause GI symptoms through direct invasion into the host cells and immune-mediated injury.14
Fecal–Oral Transmission
Respiratory transmission is the primary mode of transmission for SARS-CoV-2, and it is known to spread via the respiratory route and direct contact.15,16 However, the novel coronavirus is known to cause various GI symptoms, and the likelihood of fecal–oral transmission warrants consideration. Several studies suggested that the virus may be viable in the feces.
Previous studies before the emergence of the COVID-19 pandemic showed that the related coronaviruses are observed in the stool. During the MERS-CoV epidemic, 14.6% of the infected patients were found to have intact virus in stool samples at low viral loads.17 Likewise, in the SARS epidemic which occurred in 2012, individuals demonstrated viral shedding of SARS-CoV in the stool samples of infected individuals.18 Due to the genetic similarity between the other pathogenic coronaviruses and SARS-CoV-2 and their ability to survive at low temperatures (20–30°C) for long periods, it is possible that the novel coronavirus could remain viable outside the host cell for a few days, leading to fecal–oral transmission.19 Viral RNA has been detected in stool samples even in the clinical setting of negative nasopharyngeal PCR.20,21 Several investigators have identified the viral shedding in the alimentary canal, and the prevalence ranged from 36 to 53% of the confirmed COVID-19 cases.20–24 Although the presence of the viral RNA in the feces was detected, its infectivity is yet to be determined.
The tests for SARS-CoV-2 virus in stool samples were positive even after a negative throat swab test in some individuals.25 Thus, stool sample testing may be used as an alternative and an additional test for diagnosing COVID-19 infection. Furthermore, a study showed active viral replication in the stool samples of infected patients.22,26 Interestingly, another study revealed that the SARS-CoV-2 virus could remain viable in an external environment such as stainless steel and plastic materials.27 The detection of the viral RNA in the feces does not confirm the infectivity, but viral spreading through the fecal–oral route is possible. A few studies have attempted to determine the infectivity of the fecal–oral route, but the evidence is weak. Therefore, more evidence is required to confirm this hypothesis.22,28
Gastrointestinal Manifestations
GI manifestations are common in a substantial percentage of individuals. Around 10 to 30% of COVID-19 patients may present with GI symptoms.29,30 Most frequently presented symptoms are diarrhea, abdominal pain, anorexia, and nausea/vomiting31 (Fig. 9.1).
Characteristics of Diarrhea
Diarrhea is a commonly presented symptom in COVID-19 patients.32 In most cases, it is not severe and is self-limiting.32 As it is subjective, the presentation is heterogeneous, and the estimates may vary. In most cases, patients present with watery diarrhea, but rarely, a few patients may present with bloody diarrhea. The presence of occult blood in the stool can be because of other underlying conditions like diverticulosis. Thus, other causes of GI bleeding such as hemorrhoids, inflammatory bowel disease (IBD), and medications must be ruled out before attributing the symptoms to COVID-related manifestations. Usually, the stools are without blood or WBC and are accompanied by nausea/vomiting. Diarrhea is associated with an increase in fecal calprotectin concentrations levels. From these findings, it is assumed that the diarrhea is mainly because of the secretory abnormal reabsorption of the fluid and electrolytes in conjunction with mild inflammatory colitis. Fecal calprotectin concentrations were elevated in COVID-19 patients with diarrhea than in those without diarrhea and have a tendency to be higher in patients with severe COVID-19 than in those with mild/moderate COVID-19.29,31
Nausea and anorexia are also very commonly reported GI symptoms in COVID-19 patients. However, nausea and anorexia can develop because of cytokine-mediated responses in inflammatory or infectious conditions. Thus, these symptoms may not be specific to the disease.33,34 Some patients can also present with GI bleeding, anosmia, and dysgeusia.30,35 Ageusia and dysgeusia are common symptoms. The prevalence of dysgeusia in COVID-19 patients can be as high as 70 to 80% and may persist throughout the disease course.36,37 Smell and taste disturbances can sometimes present as initial symptoms in some patients.36,37
In many patients, GI symptoms can portend COVID-19 as they may appear several days prior to admission, with a significant variability of symptoms appearing up to 20 days before admission. Data from one of the studies support the inclusion of GI symptoms among the COVID-19 features, allowing for earlier diagnosis and care particularly in individuals who do not have respiratory symptoms.38 This could be especially important given the high rate of transmission among close contacts, linked to GI viral infection and possible oral–fecal transmission, which could last even after nasopharyngeal and pulmonary viral clearance.11,39
Hepatic Manifestations
Hepatic injury is common in COVID-19 patients, and is associated with poor outcomes.40 Elevation of serum aminotransferases and impaired hepatic biomarkers were observed in greater than 50% of the patients with severe COVID-19.41–44 Injury is thought to be because of several mechanisms. It is observed that ACE-2 receptors are abundant in cholangiocytes compared to hepatocytes.45 Thus, viral infection impairs hepatic function by a cytopathic effect due to the intracellular replication of viral particles cells. The cytotoxicity induces apoptosis, pyroptosis, or necrosis in the host cell. Thus, hepatic manifestations are thought to be because of direct liver injury due to viral toxicity and viral entry through the hepatobiliary system due to the abundance of ACE-2 receptors. Interestingly, a recent study revealed that the peroxisome proliferator activated receptor signaling pathway and the renin-angiotensin system could enhance the infection. In addition, hypoxic injury due to compromised respiratory function and thrombosis may aggravate the ongoing disease process. Several experts suggested that bile duct cells are an important driver in hepatic immune dysregulation and inflammation.10 The antibiotics, antipyretics, and antiviral medications used in the treatment of COVID-19 may also cause liver injury.46
In Patients with Pre-Existing Liver Conditions
To date, there is a paucity of evidence on the impact of chronic liver disease on the clinical outcome of COVID-19. Based on few studies, it is understood that chronic liver diseases and on-admission liver-associated laboratory results predicted a worse clinical outcome in COVID-19 disease.47 It remains to be seen if COVID-19 disease exacerbates cholestasis in those with chronic cholestatic hepatobiliary disease with or without cirrhosis.6 One of the studies aimed to evaluate whether there is any association between metabolic dysfunction-associated fatty liver disease (MAFLD) and COVID-19 outcomes identified MAFLD is associated with a 2.6-fold increased risk of severe COVID-19 compared to those without MAFLD.48 One study demonstrated that in patients with MAFLD, a proinflammatory state potentially exacerbates the viral-induced cytokine storm.49 ICU utilization rate was increased in MAFLD when compared to non-MAFLD patients.50 However, the difference was statistically nonsignificant, but MAFLD still may adversely impact the clinical course of COVID-19. COVID-19 patients with MAFLD had a worse prognosis, twofold higher prevalence of deteriorating clinical disease course, increased viral shedding time, and more hepatic failure.50 The link between MAFLD and COVID-19 severity is undoubtedly multifactorial. Metabolic syndrome and its elements have already been linked to worse clinical outcomes in COVID-19.51 The presence of fibrosis in MAFLD patients is a superimposed risk factor for the severity of COVID-19, independently of metabolic syndrome comorbidities. The severity disease is substantially augmented with the extensiveness of liver fibrosis. Individuals with a FIB-4 score higher than 2.67 had the highest risk of developing severe COVID-19.52 Another interesting point was reported in a multicenter preliminary study, where patients with MAFLD under 60 years demonstrated a more than fourfold risk of severe COVID-19 compared to those without MAFLD suggesting younger patients with MAFLD are at increased risk of severe COVID-19.53 Neutrophil-to-lymphocyte ratio (NLR) is noted to be a recognized and commonly assessable prognostic marker in the early stage of viral infection.54 Superimposed MAFLD in conjunction with an NLR higher than 2.8 is associated with a higher risk of severe COVID-19 compared to patients without MAFLD and with normal NLR.49 Currently, there is no definitive data on COVID-19 and its effects on decompensated cirrhosis or those awaiting liver transplantation (LT).55
Colitis in the Setting of COVID-19
Colitis in COVID-19 patients has been reported in a patient who, during recovery from SARS-CoV-2 pneumonia, developed diarrhea abdominal pain and marked distension.56 CT scan demonstrated pneumoperitoneum and almost entire distension of the large bowel, with perforation of the ascending colon. Intraoperative findings included a profuse amount of free air, distension of the entire colon, and cecal distension accompanied with cecal perforation. Neither obstruction was documented nor etiology of marked colonic distension was demonstrated.56 The physiopathology of an acute overdistension of the entire colon, without evidence of obstruction leading to diastatic colonic perforation, is unknown. It is presumed to be due to viral cytopathic injury to colonic cells. ACE2 has been located in many cell types in the GI system, suggesting the possible viral tropism for the GI tract potentially explaining these GI manifestations.11 Furthermore, viral RNA was mainly detected in the cytoplasm of GI epithelial cells indicating that the virus can infect cells of the GI tract.57 Another hypothesis was altered colonic motility viral neuronal invasion resulting in dysautonomia of the colonic innervation of the colon.58
In Patients with Inflammatory Bowel Disease
IBD is a disorder of immune dysregulation in the GI tract. Most patients presenting with moderate to severe symptoms are managed with immune-suppressing or -modifying agents. Many patients with IBD are prescribed immunosuppressants or immunomodulators, and the use of such compounds may interfere with host defense mechanisms. As IBD is an immune response and the therapy involves immunosuppression, there is an increasing concern regarding patients’ risk with IBD and prognosis in COVID-19 patients with IBD. However, despite the potential for increased exposure and risk, there is no current evidence to suggest an increased risk of infection with SARS-CoV-2 or the development of a severe clinical course of the COVID-19 in patients with IBD.59 Experts recommend continuation of the ongoing treatment for the patients with IBD who do not have an infection with SARS-CoV-2.60
Management
The management should be individualized based on the patient’s factors, the severity of the presentation, and associated COVID-19-related complications. Patients with new-onset GI symptoms should be considered for COVID-19 infection, especially in highly prevalent areas. Getting a detailed history regarding the clinical presentation, risk factors, location can help in identifying COVID-19-related GI symptoms. A thorough history of underlying GI disorders should be obtained. Clinical examination, laboratory, and imaging findings may help determine the cause of the presenting GI symptoms. In addition, assessment for volume depletion should be done (decreased skin turgor, dry mouth, postural hypotension) as diarrhea can cause fluid loss in the body. Clinicians should be aware of volume status and the risk of hypovolemia in patients presenting with GI symptoms associated with typical COVID-19 symptoms (fever and respiratory tract symptoms). Even after the COVID-19 diagnosis has been made, other entities should be ruled out. Similar conditions that overlap with the clinical spectrum of COVID-19 symptoms such as C. difficile infection, other viral infections, IBD should be ruled out. Additional testing may be needed based on the presentation. Stool testing for ova and parasites; stool cultures; antigen and molecular testing for the specific organism are needed to determine the pathogen.61
Several medications used in the management of COVID-19 are associated with GI side effects. Medications can sometimes cause several GI side effects. Diarrhea, nausea, and vomiting are noted side effects of Remdesivir, chloroquine, and hydroxychloroquine. Remdesivir has been associated with elevated transaminases.62 Clinicians should be aware of these side effects while using these medications.46
Currently, other than supportive care, there are no specific guidelines for the management of COVID-19-associated GI symptoms. Fluid and electrolyte monitoring and replacement are essential. For milder cases of diarrhea, fluids and electrolytes can be maintained by a sufficient intake of juices, soups, sports drinks, and other electrolyte solutions.63 Oral rehydration therapy is recommended for mild volume depletion. Intravenous fluids can be used in severe cases due to fluid loss.64 In addition to maintaining supportive care, symptoms can be managed with antidiarrheal and antiemetic agents. In patients who desire symptomatic therapy, diarrhea can be managed with antimotility drugs such as loperamide after ruling out other infectious causes.63,64 For patients who present with dysentery (bloody/mucoid stools), antimotility medications are usually avoided. Nausea and vomiting can be treated with antiemetics such as prochlorperazine and ondansetron.63,64 Several antibiotics and antivirals are being used in the management of COVID-19. Thus, these medications can alter the gut microbiota and cause diarrhea. So, replenishing gut microbiota can be a potential therapeutic option to preserve the intestinal microbiome balance.65 Patients should be monitored continuously for worsening symptoms like GI bleeding, severe vomiting, severe signs of dehydration, altered mental status.66 If the clinical condition worsens, the patients might need either hospitalization or referral to a gastroenterologist.66
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