Brigham and Women's Hospitals

Gastroenterology

Updated: May 14, 2020

Viral shedding in feces

Overview:

  1. Prevalence
  1. About 50-55% of hospitalized adult patients have detectable levels of SARS-CoV-2 RNA in the stool, though estimates of prevalence have been reported to be as low as 25% in some studies and as high as 80% in other studies (Young et al, JAMA, 2020; Xiao et al, Gastroenterology, 2020; Wu et al, Lancet, 2020; Amirian, Internal Journal of Infectious Diseases, 2020; Wu et al, Travel Medicine and Infectious Disease, 2020).
  1. Stool positivity has been common in pediatric infection as well (Fan et al, Pediatric Investigation, 2020; Tan et al, CJCP, 2020; Donà et al, The Pediatric Infectious Disease Journal, 2020; Xu et al, Nature, 2020; Xing et al, Journal of Microbiology, Immunology and Infection, 2020; Zhang et al, J Med Virol, 2020).
  1. Pathophysiology
  1. The virus likely enters the gastrointestinal tract via its receptor, ACE2, which is expressed by enterocytes in the ileum and colon (Qi et al, Biochem and Biophys Res. Com., 2020; D'Amico et al, Clin Gastroenterol Hepatol, 2020). Biopsies from the GI tract in COVID-19 infection are limited. There is one report of positive immunofluorescent staining for the viral nucleocapsid protein in glandular epithelial cells of gastric, duodenal, and rectal biopsies (Xiao et al, Gastroenterology, 2020).
  2. To date, there are at least three reports of culture of viable virus from stool samples of adult patients (Amirian, Internal Journal of Infectious Diseases, 2020; Wang W et al, JAMA, 2020; Xiao et al, Gastroenterology, 2020; Zhang Y et al, China CDC Weekly, 2020).

Clinical significance

  1. Correlation with symptoms:
  1. Viral shedding in the stool does not appear to correlate with gastrointestinal symptoms or diarrhea. SARS-CoV-2 RNA has been detected in the stool of patients who had gastrointestinal symptoms early in the course of illness; in patients who had gastrointestinal symptoms later in the course of illness; and in patients who did not experience gastrointestinal symptoms at all during the course of illness (Amirian, Internal Journal of Infectious Diseases, 2020; Zhang et al, J Med Virol, 2020; Young et al, JAMA, 2020; Wu et al, Lancet Gastroenterol Hepatol, 2020; Chen et al, J Med Virol, 2020).
  2. The duration of viral shedding in the respiratory tract appears to be similar in those with and without viral shedding in the stool (Wu et al, Lancet Gastroenterol Hepatol, 2020).
  3. Clinical characteristics, laboratory findings (including indices of inflammation), and radiologic findings appear to be similar in those with and without viral shedding in the stool. Neither the presence of viral shedding in stool nor the duration of such shedding appears to be correlated with the severity of pulmonary disease (Zhang et al, J Med Virol, 2020; Chen et al, J Med Virol, 2020; Ling et al, Chin Med J, 2020).
  1. Duration of shedding in the stool:
  1. Viral shedding in stool may cease after just a few days or persist for up to 2-4 weeks (Wu et al, Lancet, 2020), even in those who have clinically recovered from illness (Amirian, Internal Journal of Infectious Diseases, 2020; Ling et al, Chin Med J, 2020).
  1. Shedding in the stool is prolonged in patients taking glucocorticoids. In one study, stool samples remained positive for 20 days in patients treated with glucocorticoids vs 11 days in patients not treated with glucocorticoids (Ling et al, Chin Med J, 2020).
  1. The onset of viral shedding in respiratory tract (as detected by nasopharyngeal swabs) appears to precede the onset of viral shedding in the stool (Wu et al, Lancet Gastroenterol Hepatol, 2020; Lo et al, Int J Biol Sci, 2020). Among inpatients with at least one positive fecal test during admission, respiratory positivity preceded the onset of fecal positivity in 93%, while only 7% had both positive respiratory and fecal tests upon initial test (Wu et al, Lancet Gastroenterol Hepatol, 2020).
  2. The clearance of the virus from the stool appears to lag behind the clearance of the virus from the respiratory tract (as detected by nasopharyngeal swabs). Stool samples may remain positive for more than a week (mean estimates of 6-11 days, range of 3-20 days) after nasopharyngeal swabs samples have become negative (Wu et al, Lancet, 2020; Chen et al, J Med Virol, 2020). Among inpatients with at least one positive fecal test during admission, fecal positivity persisted after clearance of respiratory samples in 80% (and in 30%, there was actually no overlap between initial respiratory positivity and subsequent fecal positivity) (Wu et al, Lancet Gastroenterol Hepatol, 2020). Other studies have demonstrated similar findings in adult populations (Ling et al, Chin Med J, 2020; Xiao et al, Gastroenterology, 2020; Zhang et al, Emerg Microbes Infect, 2020; Lei et al, Travel Medicine and Infectious Disease, 2020; Chen et al, J Med Virol, 2020). Multiple case series suggest that persistent and prolonged shedding in the stool, even after nasopharyngeal clearance, may be particularly prominent in the pediatric population (Xu et al, Nature, 2020).
  1. Stool infectivity:
  1. The infectivity of RNA-positive stool remains unclear (Amirian, Internal Journal of Infectious Diseases, 2020), but is an important area of research (Jin et al, Gut, 2020).
  2. Until proven otherwise, stool should be assumed to be infectious (Amirian, Internal Journal of Infectious Diseases, 2020).
  1. Healthcare workers should use appropriate PPE while handling feces and disposing of material contaminated by feces.
  2. Frequent and extensive cleaning of bathrooms is important, especially health care facilities and shared living spaces.
  1. Testing for COVID-19 in stool:
  1. We recommend against the addition of stool testing to nasopharyngeal testing for the purpose of diagnosing COVID-19, as respiratory shedding usually precedes stool shedding (Wu et al, Lancet Gastroenterol Hepatol, 2020).
  1. This may change in the future, as concurrent testing of nasopharyngeal swabs and stool samples may improve the positive detection rate when there is a high pretest probability of infection (Yun et al, Clinica Chimica Acta, 2020; Lo et al, Int J Biol Sci, 2020). There are now several case reports of patients with COVID-19 who have tested persistently positive in stool and persistently negative nasopharyngeal swabs (Jiang et al, J Med Virol, 2020; Chen et al, AJG, 2020).
  1. We do not currently test fecal samples for clearance, though this may change in the future, as stool samples often remain positive after respiratory samples have cleared (Wu et al, Lancet Gastroenterol Hepatol, 2020).

Gastrointestinal symptoms

Overview

  1. Incidence:
  1. The reported prevalence of gastrointestinal symptoms in COVID-19 has been variable across studies, ranging from <5% to 60% (Huang et al, The Lancet, 2020; Zhou et al, Gastroenterology, 2020; Wang et al, JAMA, 2020; Luo et al, Clin. Gastro, 2020; Pan et al, The Am. J. Gastroenterol, 2020; Redd et al, Gastroenterology, 2020).
  1. This variability may be due to differences in study populations, biases in patient or provider reporting, and/or differences in definitions. In particular, the incidence of gastrointestinal symptoms varies based on whether or not anorexia is included as such a symptom. In one study of 204 patients with COVID-19, 103 patients (51%) were reported to have a gastrointestinal symptom on presentation; however, when lack of appetite was excluded from the analysis, only 38 patients (19%) had a gastrointestinal-specific symptom (i.e. diarrhea, vomiting, abdominal pain) on presentation (Pan et al, The Am. J. Gastroenterol, 2020).
  1. Similarly, the reported prevalence of specific gastrointestinal symptoms has also been variable across studies, but in general, anorexia is the most common gastrointestinal symptom followed by diarrhea and then nausea. Vomiting and abdominal pain are not as common (Luo et al, Clinical Gastroenterology and Hepatology, 2020; Pan et al, The Am. J. Gastroenterol, 2020; Redd et al, Gastroenterology, 2020).
  1. In an analysis of the presenting symptoms and clinical outcomes of 318 adult patients with COVID-19 who were admitted to 9 hospitals across Massachusetts, 61% reported at least one gastrointestinal symptom (35% reported anorexia, 34% reported diarrhea, and 26% reported nausea) (Redd et al, Gastroenterology, 2020).
  1. Clinical course:
  1. Gastrointestinal symptoms have been reported as the initial presenting symptoms in 14% of patients and the predominant presenting symptoms in 20% of patients (Redd et al, Gastroenterology, 2020).
  1. Most patients who present with gastrointestinal symptoms will develop respiratory symptoms later in the course of their illness (sometimes as quickly as 1-2 days later) (Wang et al, JAMA, 2020; Amirian, International Journal of Infectious Diseases, 2020; Pan et al, The Am. J. Gastroenterol, 2020; Hajifathalian et al, World J Gastroenterol, 2020)
  2. Very few patients have gastrointestinal symptoms only throughout the course of their illness, but such presentations have been reported (Pan et al, The Am. J. Gastroenterol, 2020; Hosoda, Infect Control Hosp Epidemiol, 2020).
  1. Even when patients present with only or predominantly gastrointestinal symptoms, the majority (about 90% in one study) already show characteristic features of COVID-19 infection on labs (leukopenia, elevated CRP, and mild AST and ALT elevations) and imaging (abnormal chest imaging) (Luo et al, Clinical Gastroenterology and Hepatology, 2020).
  1. In addition, there appear to be no significant differences in leukocyte count, coagulation factors, liver enzymes, cardiac markers, ferritin, D-dimer, or CRP between those with and without gastrointestinal symptoms at presentation (Redd et al, Gastroenterology, 2020).
  1. Gastrointestinal symptoms are often mild (mean of 3-4 bowel movements per day), but may continue for several days to more than a week (mean of 4 days) (Han et al, AJG, 2020; Pan et al, The Am. J. Gastroenterol, 2020; Jin et al, Gut, 2020). High volume or clinically severe diarrhea is not common.
  1. Prognostic implications:
  1. Patients with gastrointestinal symptoms often present for care later than those with respiratory symptoms (Han et al, AJG, 2020; Pan et al, The Am. J. Gastroenterol, 2020). However, the presence of gastrointestinal symptoms does not appear to be a prognostic factor or marker of severity. While some studies have shown an association between the presence of gastrointestinal symptoms and the severity of respiratory disease (D'Amico et al, Clin Gastroenterol Hepatol, 2020), other studies have found no association between the presence of gastrointestinal symptoms and the duration of admission, need for intensive care or mechanical ventilation, duration of stay in intensive care, or overall mortality (Pan et al, The Am. J. Gastroenterol, 2020; Hajifathalian et al, World J Gastroenterol, 2020; Redd et al, Gastroenterology, 2020).
  1. Pathophysiology:
  1. Several potential mechanisms for gastrointestinal symptoms include:
  1. Direct damage to the intestinal mucosa via viral infection (see subsection on viral shedding).
  2. Hypercoagulable state leading to bowel ischemia via a) microthrombi in the lamina propria and submucosa; or b) less commonly, large vessel thrombosis. There are two case reports from France of patients with evidence of bowel ischemia on imaging leading to laparotomy; subsequent examination of the excised necrotic bowel showed microthrombi in the lamina propria and submucosa. One of these two patients also had large-vessel thrombosis (PVT and SMV thrombosis), but this patient had evidence of baseline hypercoagulability and prior PVT (Ignat et al, Surgery, 2020). However, there is at least one case report from Wuhan of a patient with no known medical history who had bowel ischemia associated with PVT, SMV thrombosis, and SMA thrombosis on imaging (de Barry et al, Radiol Case Rep, 2020).
  3. Indirect alterations in mucosal immunity via the “gut-lung axis”. The “gut-lung axis” refers to the idea that the digestive tract and respiratory tract share a common mucosal immune system. As such, inflammation or microbial alterations in the gut can invoke a mucosal immune response that in turn affects the lungs and vice versa (Pan et al, The Am. J. Gastroenterol, 2020; Dang et al, Nature, 2019)
  4. Adverse medication effects or secondary infections, especially if symptoms arise later in the course of disease.
  5. Secondary effects of anosmia and ageusia (especially with respect to anorexia) (Redd et al, Gastroenterology, 2020).

Workup

  1. COVID-19 testing is not currently recommended for patients presenting with mild GI symptoms in the absence of other COVID-19 symptoms.
  1. Patients should be educated that gastrointestinal symptoms may precede the onset of respiratory symptoms and be given strict return precautions (CDC COVID-19, accessed May 19, 2020).
  1. In patients with suspected or known COVID-19 disease, remember to consider non-COVID-19 etiologies as well as secondary complications from COVID-19 (such as portal / mesenteric thrombosis) in the differential for gastrointestinal symptoms.
  1. Workup will depend on the nature and severity of the symptoms:
  1. Basic laboratories are included in the workup described in Diagnostics.
  2. More extensive laboratory evaluation (such as lipase, amylase, lactate, Clostridium difficile testing) and more extensive imaging (such as CT abdomen / pelvis, abdominal US +/- dopplers, or pelvic US) may be indicated.
  1. Do not miss critical conditions due to concerns about transport to imaging.
  1. Surgical and/or gastroenterology consultation may be indicated.

Management

  1. The gastrointestinal manifestations of COVID-19 (such as diarrhea, loose stool, nausea, vomiting, abdominal pain) are generally mild and transient.
  1. Treat nausea and diarrhea symptomatically, replete electrolytes, and be judicious in the use of IV fluids to replace gastrointestinal losses.
  2. If symptoms are not mild and transient, consider alternative etiologies, including drug side effects, secondary infections, bowel ischemia, etc.

Liver injury

Overview

  1. Incidence:
  1. 15-50% of patients with COVID-19 have abnormal liver function tests (LFTs) (Zhang et al, Lancet Gastroenterol Hepatol, 2020; Xu et al, Liver International, 2020; Fan et al, MedRxiv, 2020).
  1. The variability in the incidence may be due to differences in disease severity, multiple etiologies hepatic injury (such as direct viral injury, indirect inflammatory injury, drug-induced injury), as well as non-hepatic sources of elevated transaminases.
  1. Pattern and severity of liver injury:
  1. The pattern of injury is predominately hepatocellular.
  1. Elevations in the following are seen:
  1. AST and ALT in 18-78% and 18-28% of patients, respectively. The AST/ALT ratio has been reported as 1.5.
  2. Total bilirubin in 5-6% of patients.
  3. Alkaline phosphatase is rare (seen in <4% of patients).
  4. GGT in 18-54% of patients.
  5. LDH in 35-98% of patients.
  6. CK in 5% of patients.
  7. Prothrombin time in 2% of patients.
  1. Low levels of albumin are very common and seen in 98.5% of patients.
  2. Sources: (Shi et al, Lancet Infect Dis, 2020; Guan et al, NEJM, 2020; Huang et al, Lancet, 2020; Xu et al, Liver International, 2020; Zhou et al, Lancet, 2020; Wu et al, JAMA Intern Med, 2020; Fan et al, MedRxiv, 2020; Wang et al, JAMA, 2020; Zhang et al, Lancet Gastroenterol and Hepatol, 2020; Hajifathalian et al, World J Gastroenterol, 2020)
  1. Liver injury is often mild, even in patients with severe disease, and is self- resolving (Guan et al, NEJM 2020; Huang et al, Lancet, 2020; Xu et al, Liver International, 2020; Zhou et al, Lancet, 2020; Wu et al, JAMA Intern Med, 2020, Bangash, Lancet Gastroenterol Hepatol, 2020; Shi et al, Lancet Infect Dis, 2020) In a study of 201 hospitalized patients (42% of whom developed ARDS and 22% of whom did not survive), the median (IQR) values of LFTs and other parameters in all subjects on presentation included: AST 33 (26-45) U/L with reference range of 15-40 U/L; ALT 31 (20-47) U/L with reference range of 9-50 U/L; total bilirubin 11.5 (9.0-14.8) mg/dL with reference range of 0-26 mg/dL; albumin 33 (29-35) g/L with reference range of 40-55 g/L; LDH 308 (232-389) U/L with reference range of 120-150 U/L; and PT 11.1 (10.2-11.9) seconds with reference range of 10.5-13.5 seconds (Wu et al, JAMA Intern Med, 2020). In a study comparing laboratory and imaging parameters with respect to time from symptom onset, there were no significant differences in AST levels at ≤1 week after symptom onset; at >1 to 2 weeks after symptom onset; and at >2 weeks to 3 weeks after symptom onset (Shi et al, Lancet Infect Dis, 2020).
  2. Acute liver failure has not been reported (Ong et al, BMJ, 2020), even in those who are severely ill (Bangash, Lancet Gastroenterol Hepatol, 2020; Chen et al, The Lancet, 2020) and in those with chronic liver disease (Xu et al, Liver International, 2020).
  1. Prognostic associations:
  1. Abnormal LFTs are more common in patients with symptomatic disease vs pre-symptomatic disease. In a study of 81 patients with COVID-19, patients who were diagnosed in a sub-clinical phase (i.e. found to have classic CT findings before symptom onset) had a lower incidence of AST abnormalities as compared to those who were diagnosed while symptomatic. Specifically, 27% of the pre-symptomatic patients had an elevated AST (defined as AST > 40 U/L) while 62%, 60%, and 53% of the patients at 1 week, 1-2 weeks, or >2 weeks after symptom onset had an elevated AST, respectively (Shi et al, Lancet Infect Dis, 2020).
  2. Abnormal LFTs are more common in patients with clinically severe disease vs non-severe disease (Zhang et al, Lancet Gastroenterol Hepatol, 2020; Guan et al, NEJM, 2020; Huang et al, Lancet, 2020; Cai, MedRxiv, 2020) and are associated with markers of systemic inflammation (such as higher fever, higher CRP levels, higher procalcitonin level, and lower lymphocyte counts) (Fan et al, MedRxiv, 2020). In a study of 1099 patients with COVID-19, AST was elevated in 39% of patients with severe disease, but only 18% of patients with non-severe disease; similarly, ALT was elevated in 28% of patients with severe disease, but only 19% of patients with non-severe disease (Guan et al, NEJM, 2020). In a study of 41 patients with COVID-19, AST was elevated in 62% of patients requiring ICU care as compared to 25% of patients not requiring ICU care (Huang et al, Lancet, 2020). In a study of 298 patients at a dedicated COVID-19 hospital (in which 80% had non-severe disease and 20% had severe disease), the incidence of liver injury was much higher in patients with severe disease (36%) as compared to those with mild disease (10%) (Cai, MedRxiv, 2020).
  3. Some studies have shown no difference in the incidence of abnormal LFTs between critically ill survivors and non-survivors (Yang et al, Lancet Respir Med, 2020), while others have found higher incidence of abnormal LFTs among non-survivors (Xu et al, Liver International, 2020). In one study, an elevated ALT (defined as >40 U/L) was associated with increased odds of in-hospital death in univariate analysis, but this association was not seen in multivariate analysis (Zhou et al, Lancet, 2020). In a study of 201 hospitalized patients (42% of whom developed ARDS and 22% of whom did not survive), AST, ALT, and total bilirubin were statistically higher in those who developed ARDS as compared to those who did not, although the absolute difference in these values between the groups was small (median AST 38 U/L, ALT 35 U/L, and T bili 12.9 mg/dL in patients with ARDS; median AST 30 U/L, ALT 27 U/L, T bili 10.5 mg/dL in patients without ARDS). AST and ALT were not significantly different between non-survivors and survivors; T bili was significantly higher in non-survivors (median 14.5 mg/dL) as compared to survivors (median 11.7 mg/dL). Bivariate cox analysis showed that AST, ALT, and T bili were associated with hazard ratios of 1.02 [1.01-1.03], 1.00 [1.00-1.01], and 1.05 [ 1.02-1.08], respectively, for the progression to ARDS and hazard ratios of 1.07 [1.02-1.12], 0.99 [0.98-1.01], and 1.00 [0.98-1.01] for progression to death. (Wu et al, JAMA Intern Med, 2020). It remains unclear if elevated liver enzymes are independent predictors of prognosis or if such abnormalities simply represent end-organ damage seen in patients with severe disease complicated by shock and need for mechanical ventilation (Hajifathalian et al, World J Gastroenterol, 2020).
  1. Pathophysiology:
  1. Non-hepatic causes of elevated ALT and AST:
  1. May reflect strain on skeletal muscles or myocardium. Elevated LDH, CK, myoglobin, and troponin are seen, especially in more severe disease. And elevated aminotransferase levels due to myositis have been seen in other viral respiratory illnesses, including influenza (Bangash et al, Lancet Gastroenterol Hepatol, 2020; Fan et al, MedRxiv, 2020).
  1. Indirect injury from inflammation:
  1. Immune-mediated hepatic inflammation and cytokine storm may cause elevated aminotransferases (Bangash et al, Lancet Gastroenterol Hepatol, 2020; Zhang et al, Lancet Gastroenterol Hepatol, 2020; Fan et al, MedRxiv, 2020) The induction of a dysregulated innate immune response and/or the activation of cytotoxic T cells may result in collateral liver damage, which would explain the associations between elevated aminotransferase levels, elevated inflammatory markers, and the severity of the disease (Bangash et al, Lancet Gastroenterol Hepatol, 2020; Zhang et al, Lancet Gastroenterol Hepatol, 2020; Fan et al, MedRxiv, 2020)
  1. Direct injury from a virus-induced cytopathic effect (i.e. viral hepatitis)
  1. ACE2 is expressed in cholangiocytes (and in hepatocytes, to a lesser extent) (Chai et al, BioRxiv, 2020), and in SARS, viral cytopathic effect appeared to play a role (liver biopsies from patients with SARS showed detectable SARS-CoV-1 RNA) (Chau et al, Hepatology, 2004; Ding, J Pathol, 2004; Xu et al, Liver International, 2020).
  2. However, there are also a number of arguments that suggest direct liver injury is unlikely. These include: a) discordance between the proposed mechanism of direct viral injury (via ACE2 receptors, which are more highly expressed on cholangiocytes than hepatocytes) and the resultant LFT abnormalities (which are characterized by a hepatocellular pattern of injury and only very rare elevations in ALKP) (Bangash et al, Lancet Gastroenterol Hepatol, 2020); b) relatively mild derangements in liver function; c) lack of correlation between the duration of symptoms and degree of liver function abnormalities (Shi et al, Lancet Infect Dis, 2020); d) only non-specific findings (moderate microvesicular steatosis and mild lobular and portal activity) on the post-mortem liver examination in a patient who died from COVID-19 (Xu et al, Lancet Respir Med, 2020); and e) similar elevations of liver biomarkers are seen in other respiratory viral illnesses and are mediated by the immune response (Bangash et al, Lancet Gastroenterol Hepatol, 2020).
  1. Hepatotoxic drugs
  1. Drug-induced liver injury does not explain the mild LFT abnormalities seen on presentation with COVID-19, but initiation of drugs (such as antibiotics, antivirals, etc) for the treatment of COVID-19 likely contributes to abnormalities arising later. (Bangash et al, Lancet Gastroenterol Hepatol, 2020; Xu et al, Liver International, 2020; Fan et al, MedRxiv, 2020).
  2. Hepatotoxicity of commonly used medications for COVID-19 are described below:
  1. Chloroquine and hydroxychloroquine. Chloroquine and hydroxychloroquine are not associated with significant elevations in serum aminotransferases. Clinically significant liver injury is very rare (except in patients with porphyria cutanea tarda) (Liver Tox (NCBI), 2018).
  2. Tocilizumab. Tocilizumab causes mild elevations in ALT (1-3 times ULN) in 10-40% of patients, but such elevations are asymptomatic, not associated with elevations in ALKP or bilirubin, and resolve in 4-8 weeks after infusion); rarely, these tocilizumab has been associated with clinically apparent liver injury with jaundice (usually after several months of therapy). Tocilizumab is an immunosuppressive agent, but has not been implicated in causing reactivation of hepatitis B. Safety in chronic hepatitis C is not well understood (Liver Tox (NCBI), 2015).
  3. Remdesivir. Recent results from the Gilead Phase 3 SIMPLE trial showed that 7% of patients developed grade 3 or higher liver enzyme elevations with 3% of patients discontinuing remdesivir treatment due to elevated liver tests (Gilead Press Release, 2020).
  1. Critical illness
  1. Common etiologies for liver injury in critically ill patients include: ischemic hepatitis (“shock liver”); hypoxic hepatitis; hepatic congestion (secondary to elevated right atrial pressures and impaired venous return); and cholestasis of sepsis (Bangash et al, Lancet Gastroenterol Hepatol, 2020; Hajifathalian et al, World J Gastroenterol, 2020).

Workup

  1. Obtain liver biochemistries (including AST, ALT, ALKP, total bilirubin, direct bilirubin, albumin, total protein, and PT-INR - see Diagnostics for full lab chart):
  1. For all patients on admission
  1. Also recommend LDH, CK, and troponin to assess non-hepatic sources
  2. If abnormal, send serologic testing for hepatitis B and C (HBV surface antigen, HBV surface antibody, HBV core IgM antibody, HBV core total antibody, and HCV antibody)
  1. Daily:
  1. If initial LFTs are abnormal
  2. If the patient is in the ICU
  3. If they are on hepatotoxic medications (e.g. lopinavir-ritonavir, remdesivir, tocilizumab, chloroquine, hydroxychloroquine, or statins)
  1. Every other day in other inpatients
  1. Imaging:
  1. Parsimony is advised in ordering abdominal ultrasound (with or without dopplers). Order for bedside whenever possible to avoid transport.
  2. Advanced imaging (such as MRI/MRCP) should be ordered in conjunction with GI consultation to avoid unnecessary testing.

Management

  1. Review medications carefully for offending agents
  1. Discontinue where possible
  2. If the patient is on an investigational or off-label therapeutic, discuss with ID and pharmacy
  1. Consult GI / hepatology if:
  1. Hepatitis B or C positive
  2. Concern for significant underlying liver disease (see special populations in GI below)
  3. If LFT abnormalities are severe or significantly worsening, especially if concern for acute liver failure (defined as severe acute liver injury with encephalopathy and an INR of ≥1.5)
  1. Liver injury is most often mild and self-resolving
  1. No specific therapy is typically needed
  2. For patients with severe liver injury the risk / benefit of N-acetyl-cysteine (NAC) should be discussed with GI / hepatology, as it involves a significant volume load, which could worsen respiratory status.

Elevated pancreatic enzymes

Overview

  1. Incidence:
  1. Hyperlipasemia has been seen in 10-17% of patients, though only 2.8% developed lipase >3 times the upper limit of normal. No patients met diagnostic criteria for acute pancreatitis. (McNabb et al, Gastroenterology, 2020; Wang et al, Gastroenterology, 2020; Liu et al., Clin Gastroenterol and Hepatol, 2020)
  1. Clinical presentation:
  1. Gastrointestinal symptoms are common in patients with hyperlipasemia; 55.6% with nausea, 11-66.7% with anorexia, 33.3% with general abdominal discomfort, 11-55.6% with diarrhea (McNabb et al, Gastroenterology, 2020, Wang et al, Gastroenterology, 2020)
  1. Pathophysiology:
  1. ACE2, the receptor of SARS-CoV-2, is expressed in the pancreas, and pancreatic injury may be a consequence of COVID-19 (Liu et al., Clin Gastroenterol and Hepatol, 2020)
  2. Lipase elevations may not be related to pancreatic inflammation and could be secondary to luminal gastrointestinal pathology (Jin et al, Gastroenterology 2019; McNabb et al, Gastroenterology, 2020; de-Madaria et al, Gastroenterology, 2020).

Workup and Management

  1. If concern for true pancreatitis, consult GI

Special Populations in GI

Cirrhosis and other underlying liver diseases

  1. Clinical Course
  1. The SECURE-Cirrhosis and COVID-Hep registries are tracking data on patients (throughout the world) with cirrhosis, chronic liver disease, and liver transplant who are infected with COVID-19 (Weekly Update, last updated May 4, 2020):
  1. Among patients s/p liver transplant: 22% required ICU admission, 21% required invasive ventilation, and 22% died.
  2. Among patients with non-cirrhotic chronic liver disease: 18% required ICU admission, 17% required invasive ventilation, and 6% died.
  3. Among patients with cirrhosis: 24% required ICU admission, 15% required invasive ventilation, and 37% died.
  1. 38% experienced a decompensating event (either ascites or encephalopathy, very rarely variceal bleeding) during the course of illness
  2. Unfortunately, poorer outcomes in cirrhosis are not unexpected. Among patients with ARDS of any cause, cirrhotic patients are known to have poorer outcomes (increased 90-day mortality) as compared to non-cirrhotic patients (Gacouin et al, Shock, 2016).
  1. Limited data exists on patients with NAFLD, but it seems this may be a risk factor for poor outcomes (Zhou et al, Journal of Hepatology, 2020). The odds of progressive illness during hospitalization (as defined by clinical parameters of tachypnea and hypoxia or worsening CT imaging findings) were 6.4 higher among those with NAFLD as compared to those without NAFLD (Ji et al, Journal of Hepatology, 2020).
  1. Management
  1. The American Association for the Study of Liver Diseases (AASLD) has constructed a ‘living document’ on best clinical practices in hepatology during the COVID-19 pandemic. More detailed information can be found at: AASLD "Clinical Best Practice Advice for Hepatology and Liver Transplant Providers during the COVID-19 Pandemic," last accessed May 14, 2020.
  2. We recommend GI / hepatology consultation for all COVID-19 patients with:
  1. Decompensated cirrhosis
  1. Patients with cirrhosis who are admitted with encephalopathy should be ruled out for COVID-19, as this may be the presenting symptom in this patient population (see AASLD recommendations as above).
  1. Chronic HBV or HCV infection
  1. It is essential to carefully interpret hepatitis B serologies prior to initiation of immune modulating therapies (such as IL-6 antagonists tocilizumab or sarilumab), which can result in hepatitis B reactivation.
  1. Autoimmune hepatitis
  2. S/p orthotopic liver transplant (OLT)
  3. Active or recent immune checkpoint-inhibitor (ICI) hepatitis
  4. Other serious liver disease
  1. For COVID-19 patients with compensated cirrhosis (and no evidence of new decompensation in the setting of infection), the utility of a GI / hepatology consultation can be discussed with the consult team.

Inflammatory bowel disease

  1. Clinical Course
  1. The SECURE-IBD registry (SECURE-IBD Registry) is a joint collaboration between Mount Sinai and the University of North Carolina that launched in March 2020 to better understand the impact of COVID-19 on IBD patients.
  1. As of May 8, 2020, there were 1170 reported cases of COVID-19 in IBD patients (379 of which were in the US).
  1. Among the 1170 cases, 32% required hospitalization, 6% required ICU admission, 5% required mechanical ventilation, and 4% died.
  2. Among the 1170 cases, 58% were in remission. Among those in remission, 28% required hospitalization; 30% and 44% of those with mild and moderate-severe disease activity required hospitalization, respectively.
  1. Cohort studies from Italy and Spain suggest that patients with IBD (including those on biologics or immunomodulators) have an overall good prognosis (Norsa et al, Gastroenterology, 2020; Rodriguez-Lago et al, Gastroenterology, 2020).
  2. Patients on prednisone (> 20 mg daily) are likely at increased risk of COVID-19. It is unclear if the risk and severity of infection are increased in patients on thiopurines (azathioprine, 6-mercaptopurine), methotrexate, anti-TNF therapies (infliximab, adalimumab, certolizumab, golimumab), vedolizumab, ustekinumab, and the JAK inhibitor tofacitinib (Rubin et al, Gastroenterology, 2020).
  1. Management
  1. Recommendations from the International Organization for the Study for Inflammatory Bowel Disease on the management of IBD during the COVID-19 pandemic are now published (Rubin et al, Gastroenterology, 2020).
  2. We recommend GI / hepatology consultation for all COVID-19 patients with IBD.

Patients with Clostridium difficile infection

  1. Fecal Microbiota Transplant (FMT) for C. difficile in the COVID-19 era:
  1. The FDA has issued an alert recommending that stool used for FMT should have been donated prior to December 1, 2019 but does not prohibit FMT if deemed necessary (FDA Safety Alert).
  2. We currently recommend holding the use of FMT until further donor screening protocols as well as endoscopic safety and logistic considerations are in place for COVID-19.

Patients requiring endoscopic procedures

  1. Safety during endoscopic procedures:
  1. Both upper and lower endoscopy are considered aerosolizing procedures.
  2. Data on the efficacy of PPE during endoscopy has been reassuring thus far (Repici et al, Gastroenterology, 2020).
  1. Timing of endoscopic procedures:
  1. Recommendations for the timing of endoscopic procedures and PPE use during endoscopy are as follows:
  1. Guidance from the US GI societies (AGA, ACG, ASGE, AASLD) can be found here:
  1. Joint GI Society, Clinical Insights for Gastroenterologists, March 2020.
  2. Joint GI Society, Guidance on Endoscopic Procedures, March 2020.
  3. Joint GI Society Statement, Statement on the Use of PPE in Endoscopy, April 2020.
  1. Guidance from the European Society of Gastroenterology and Endoscopy Nurses and Associates can be found here:
  1. ESGE / ESGENA, Position Statement on Endoscopy, April 2020.
  1. A comparison of guidance from endoscopic societies worldwide, including Wuhan, Hong Kong, Australia, Canada, US, UK, and European societies, can be found here: Lui et al, JGH, 2020.
  1. Consult GI / hepatology for questions about decisions to proceed with or defer endoscopic procedures during the pandemic.