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Max Hospital studies outcome of COVID-19 infection in liver transplant recipients under immunosuppression

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The study was conducted on adult patients who had undergone liver transplantation at the Centre for Liver & Biliary Sciences since 2006 and were on regular follow-up

An independent study conducted by Department of Gastroenterology and Hepatology and Centre for Liver & Biliary Sciences, Max Super Speciality Hospital, Saket under Prof (Dr) Subhash Gupta, Chairman, Centre for Liver & Biliary Sciences, Max Super Speciality Hospital, Saket has suggested that uncomplicated liver transplant recipients without comorbidities, who get affected by Coronavirus/SARS-CoV-2 do not have poor outcome.

Typically, COVID-19 is associated with higher mortality among patients who have comorbidities or pre-existing medical conditions such as obesity, diabetes, coronary artery disease, chronic kidney disease and non-alcoholic fatty liver disease. The study was conducted on 2,182 adult Indian patients who had undergone liver transplantation at the Centre for Liver & Biliary Sciences since 2006 and on regular follow-up.

Commenting on the reason behind conducting the study, Dr Gupta said, “It is an established fact that patients who have undergone liver transplantation (LT) are on long-term immunosuppressive medications which predispose them to infections. The study is significant because the data regarding impact of SARS-CoV-2 infection in post LT patients is conflicting, and risk factors for outcome are also not well defined. While initial studies suggested that patients on immunosuppressive medications, such as liver transplant recipients, are at increased risk of severe COVID-19 and mortality, subsequent evidence did not support this finding. Since India is one of the worst affected countries in this pandemic, our study, approved by the MAX HEALTHCARE institute’s ethical committee, shares the clinical characteristics, demographics and outcomes of SARS-CoV-2 infection in our post LT population.”

Elaborating on the inclusion and exclusion criteria, Dr Gupta said, “All post–liver transplant recipients (age >18 year at time of transplant) on regular follow-up since 2006 including those who tested positive for COVID-19  between 1st April 2020 and 31st May 2021 were included in the study. Under the supervision protocol, severity of COVID-19 was classified, and patients divided into three groups based on interval from liver transplantation till SARS-CoV-2 infection.

Of the 3096 patients who underwent liver at the centre since 2006, 2182 adult recipients were under regular follow-up and in communication with the centre during the pandemic.

Of these, 88 patients (3.71%) reported SARSCoV-2 infection, six adults and a child were excluded from the analysis, and 81 patients were included.

The average age of SARS-CoV-2–infected patients in the study was 51.3 years, and 74 patients (91.4%) were males. 21 (25.9%) patients infected with SARS-CoV-2 underwent liver transplant within one year. 36 (44.4%) patients received transplant between one and five years while 24 (29.6%) patients were transplanted more than 5 year ago.

A totol of COVID infected 81 patients received transplant for Alcohol-related liver disease (29.6%) patients, NASH related cirrhosis (27.2%), cryptogenic cirrhosis (18.5%) and HBV-related cirrhosis. (9.9%).

22 patients i.e. 27.1% of the SARS-CoV-2 infected patients had diabetes mellitus (DM) as the most common comorbidity while hypertension was present in 3.7% patients, and 7.4% patients had DM2 with hypertension. Four of them had chronic kidney disease (CKD) along with DM2, of which one had stage 2 CKD and other three patients had stage 3 CKD.

59 or 72.8% were on two immunosuppressants – CNIs and mycophenolate mofetil. 10 or 12.3% of them were receiving three immunosuppressive drugs calcineurin inhibitors (CNIs), mycophenolate mofetil and prednisolone. 11 or 13.5% patients were taking single immunosuppressive medication (tacrolimus) only. One patient was on steroids with tacrolimus and everolimus due to a recent rejection episode.

The most common symptom experienced by the patients for SARS-CoV-2 was fever, seen in 76.5% of the patients. Cough was the second most common symptom experienced by 52.2% patients and seventeen or 25.8% patients had shortness of breath at presentation of the disease. Only 7 or 10.6% of them had diarrhoea. 44 or 54.3% patients had mild disease only. Moderately severe disease was seen in 14 or 17.3% patients while 23 or 28.4% patients had severe disease. Of the 81 patients, 35 or 43.2% received in hospital care. Patients with mild disease and some of those with moderately severe disease managed on OPD basis with home isolation. 28 or 34.6% patients received ICU care and 17 of them needed mechanical ventilation. Overall, 14 (17.3%) out of 81   patients died because of COVID-19 infection. All COVID-19 related deaths occurred secondary to ARDS and respiratory failure. None of them had liver failure, graft rejection, or thromboembolic complication during the course of COVID-19.

Based on the duration since liver transplant, patients who were infected with SARS-CoV-2 were divided into three groups. Group A had 21 patients who got the disease within one year of liver transplant, Group B had 36 patients who got LT 1–5 years ago and group C had 24 patients who got LT more than 5 years ago.

Of these groups, only one or 4.8% patient died in group A as compared to 6 or 16.7% and 7 or 29.2% in group B and C respectively. Although mortality was higher in group C, the difference was not statistically significant (P = 0.102).

In the study group, 35 or 43.2% of the patients had one or more comorbidities. Eleven or 31.4% patients died because of COVID-19 in this group. Only 3 or 6.5% patients’ death occurred due to SARS-CoV-2 infection among transplant recipients without any comorbidity. (P = 0.003). On logistic regression analysis, advanced age and presence of comorbidities were independent predictors of death due to COVID-19.

In the observational study of 81 liver transplant recipients with SARS-CoV-2 infection, 14 (17.3%) patients died because of COVID-19. Most of the patients had mild disease only and recovered completely. Eighty-one (3.71%) adult liver transplant recipients reported SARS-CoV-2 infection as compared to the 2.06% prevalence of laboratory confirmed cases in general population.

However, true seroprevalence in general population is likely to be much higher due to undertesting and large proportion of asymptomatic cases. Deaths were more common in patients with comorbidities and advance age. Presence of DM2 and chronic kidney disease has been strongly associated with poor outcomes in individuals with SARS-CoV-2 infection. Thus, rather than the post–liver transplantation status, it was the presence of comorbidities, or other risk factors such as advanced age which may have been responsible for mortality.”

Talking about the conclusion of the study, Dr Gupta said, “In our study, all patients except one who died had received a liver transplant more than a year ago. After 1-year of transplantation, dose of immunosuppressive medication is usually significantly reduced and therefore the cytokine storm may not be ameliorated. In our study population, COVID-19–related mortality was 17.3% which is comparable to the 18.2 % mortality seen in older patients with co-morbidities. Our study suggests that uncomplicated liver transplant recipients who acquire SARSCoV-2 do not necessarily have a higher mortality as compared to similar non transplanted population. However, more studies are needed with larger patient population and matched control groups to reach a firm conclusion.”

Discussing the limitations of the study, Dr Gupta said, “Although testing for SARS-CoV-2 infection was liberal in our country, it may still be underdiagnosed in our study population as asymptomatic and mildly symptomatic patients who recovered swiftly may have avoided testing. We did not compare mortality in our liver transplant recipients with immunocompetent matched COVID-19 patients. That could have provided better understanding of role of immunosuppressants in COVID-19–related immune dysregulation. This should be addressed in future studies. We could not study the impact of individual comorbidities on mortality due to limited number of patients. In addition, details of inflammatory markers and serum level of immunosuppressive medications were not included in the study as only 43% patients were hospitalized, and remaining patients were managed at home.”

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