COVID-19: Gastrointestinal manifestations, liver injury and recommendations

Table 1 Gastrointestinal manifestations in coronavirus disease 2019

Gastrointestinal manifestations	Frequency %
Gastrointestinal involvement	11-79
Anorexia	34-67
Diarrhea	2-49.5
Vomiting	1-16
Nausea	1-16
Abdominal pain	2.7-9.2
Liver injury	15-53

Table 2 European Association for the Study of the Liver-European Clinical Microbiology and Infectious Diseases recommendations for liver transplantation[48]

EASL-ECCMID recommendations
Liver transplant recipients
Reduction of immunosuppressive therapy should only be considered under special circumstances such as drug-induced lymphopenia, superinfection in case of severe COVID-19
LT recipients have high anxiety for COVID-19, and therefore their follow-up and treatment compliance may be impaired
Drug levels of calcineurin inhibitors and rapamycin inhibitors should be closely monitored. Because drugs used COVID-10 treatment such as hydroxychloroquine or protease inhibitors may interact them
Early admission should be made for LT recipients with COVID-19 infection
LT recipients, who have underlying malignancy, sarcopenia, graft dysfunction and metabolic disease are at-risk group for a severe COVID-19 infection
All patients should receive vaccination for Streptococcus pneumonia, influenza and COVID-19
Liver transplant candidates
Patients on the LT waiting list with decompensated cirrhosis are at high risk of severe COVID-19
LT should be prioritized for patients with poor short-term prognosis including those with acute liver failure, ACLF, high MELD score (including exceptional MELD points), and HCC at the upper limits of the Milan criteria
All donors for should be screening for SARS-CoV-2 infection by PCR and recommend
Both LT donors and recipients should be questioned clinical history, performed chest radiology, and SARS-CoV-2 testing
To reduce the risk of SARS-CoV-2 infection in the peri-transplantation period, protection measures should be strictly applied. Inward of high disease burden, a COVID-19 free pathway through transplantation should be implemented, including strict social isolation for waiting list patients, telephone screening for symptoms and exposures before admission, and perioperative management in a designated clean intensive care unit and post-LT ward
Consent for transplantation should include the potential risk of nosocomial COVID-19
LT candidates should be informed that infection with SARS-CoV-2 in patients undergoing major surgery is associated with an increased risk of severe COVID-19 and death
Living-donor transplantations should be considered on a case-by-case basis and include careful risk stratification of donor and recipient, incorporating a combination of clinical history, chest radiology, and SARS-CoV-2 testing

EASL: European Association for the Study of the Liver; ECCMID: European Clinical Microbiology and Infectious Diseases; LT: Liver transplantation; ACLF: Acute-on-chronic liver failure; MELD: Model for end-stage liver disease; HCC: Hepatocellular carcinoma.

Table 3 Recommendations for gastrointestinal system tumors during coronavirus disease 2019 pandemic

Recommendations for gastrointestinal system tumors[116]
Social distancing mandates that every in-person interaction between patients and the health care system be scrutinized and only essential physical contacts between patients and health care professionals occur to diminish the risk of viral exposure to patients. Thus, minimize blood tests, scans and routine tests. Telephone and telemedicine visits should replace routine face-to-face clinic visits whenever possible
Whenever COVID-19 is clinically suspected or confirmed, systemic treatments should be suspended, and surgery should be postponed unless an urgent procedure is necessary (EOR)
Whenever surgery is indicated, SARS-CoV-2 testing should be considered
There are insufficient data to recommend in favor or against an open versus minimally invasive approach. Proven benefits of minimally invasive surgeries of reduced length of stay and complications should be considered individually. Nevertheless, whenever minimally invasive surgeries are indicated, the use of devices to filter released CO2 for aerosolized particles or techniques to treat the intra-abdominal gas whenever it should be emptied, is strongly advised
Central venous catheter flushing intervals should be increased to every 60 (younger and fit patients) or every 90 (older, frail patients with multiple comorbidities) days (EOR)
For early stage (cT1/2 cN0) colorectal, biliary, hepatocellular, esophagus and gastric tumors, where neoadjuvant treatment is not standard, consider deferring surgical resection to up to 8 weeks. If delays beyond 8 wk are expected, repeat staging exams (EOR)
Radiation schedules should be hypofractionated, whenever possible
Follow-up imaging and appointments should be reserved for those with symptoms suggestive of disease relapse. Asymptomatic patients not on active treatment should avoid imaging and follow up appointments, delaying tumor markers and colonoscopies, for example, for until the pandemic is over (EOR). In such cases, if possible, telemedicine or telephone consultation is indicated
DYPD screening is indicated whenever possible, before the use of fluoropyrimidines
Adjuvant treatment for colon and other gastrointestinal tumors, when recommended, should start in 4 wk to 8 wk after primary tumor resection. Monitoring blood counts at every cycle can be done by telemedicine if patients are asymptomatic
Infusional 5FU should be substituted for capecitabine in the following regimens: FOLFOX, cisplatin and 5FU, monotherapy, or when combined with radiotherapy. Exceptions are patients with severe renal dysfunction (creatinine clearance ≤ 30 mL/min); in patients with moderate (30 mL/min to 50 mL/min) renal dysfunction when upfront dose reduction of 25% is recommended
In curative-intent treatments, we encourage to maintain dose-intensity with the use of colony-stimulating growth factor (CSGF), if needed (EOR)
In the metastatic setting, consider dose-reduce chemotherapy instead of adding CSGF, if the latter requires more hospital visits (EOR)
In the metastatic setting, omit bolus 5FU in FOLFOX or FOLFIRI regimens to minimize toxicity (EOR)
Whenever possible, chemotherapy holidays may be considered in patients with low-volume metastatic disease, who are responding or experiencing tumor stabilization and when there is no major risk of complications for site-specific progression (e.g., peritoneum, biliary obstruction). If maintenance is considered to be beneficial instead of chemo holidays (e.g., more aggressive disease), prefer capecitabine alone, without bevacizumab[116]
Standard second or further lines of anticancer therapies should be recommended for ECOG 0 or 1 patient. Preferably, when there is clinically relevant overall survival gain demonstrated by randomized phase III trials (e.g., second-line for colorectal cancer)
Anti-PD1 immune checkpoint inhibitors are recommended in second or further lines of treatment for all gastrointestinal malignancies with microsatellite instability, regardless of the diagnostic method
For those in which immunotherapy monotherapy is indicated, we recommend the 6 wks’ schedule with pembrolizumab
Multidisciplinary team discussions (MDT) by web conferencing systems are highly encouraged. We think MDT are key to help with decisions about risks and benefits of cancer-directed therapies during the COVID-19 pandemic
In all cases, clinical individual judgment is advised and decisions should be shared with patients. Additionally, the anticipated survival benefit for each patient versus the risks of exposure to the virus should be discussed with patients, taking into consideration the individual’s comorbidities and degree of frailty, as well as caregivers and family members at home
Clinical trial enrolment
Patients who are candidates for clinical trials should be encouraged to enroll in the following situations: studies testing orphan drug indications, experimental treatments where benefits are very likely to outweigh the risks (e.g., immunotherapy combo of ipilimumab and nivolumab for microsatellite unstable metastatic colorectal cancer (CheckMate 8HW-NCT 04008030) or rare tumors. However, institutions and principal investigators should discuss and align with sponsors and Institutional Research Ethical Boards about how to minimize hospital visits (e.g., all lab and image tests performed in one single day), implement telemedicine in certain moments of trial conduction (lab checks for fit patients who are tolerating well the trial therapy, for example), extend intervals between hospital visits, if possible
For patients already on trial, treatment should continue based on clinical judgement that should balance tolerance versus benefit
The same principles cited above to decrease hospital visits should be sought

EOR: Expert opinion recommendation; ECOG: Eastern Cooperative Oncology Group; 5FU: 5 Florouracil; FOLFOX: Folinic acid, 5-fluorouracil, oxaliplatin; FOLFIRI: Folinic acid, florourasil, irinotekan.