Immunosuppressants in Liver Transplant Recipients With Coronavirus Disease 2019: Capability or Catastrophe?—A Systematic Review and Meta-Analysis

Abstract

Background: The probable impact of a maintenance immunosuppressant (IS) on liver transplant (LT) recipients with coronavirus disease 2019 (COVID-19) remains unexplored. Our specific aim was to approximate the prognosis of LT recipients with COVID-19 on the standard maintenance IS.Method: We searched separate databases for the qualified studies in between December 2019 and June 25, 2021. Ultimately, a meta-analysis was carried out using a fixed-effect or random-effect model based on the heterogeneity.Results: In a total of eight studies and 509 LT recipients with COVID-19, the pooled rates of severity and mortality during all the combined immunosuppressive therapies were 22.4 and 19.5%, respectively. Our study sufficiently showed that an immunosuppressive therapy in LT recipients with COVID-19 was significantly associated with a non-severe COVID-19 [odds ratio (OR): 11.49, 95% CI: 4.17–31.65; p < 0.001] and the survival of the patients (OR: 17.64, 95% CI: 12.85–24.22; p < 0.001). Moreover, mammalian target of rapamycin inhibitor (mTORi) typically had the lowest rate of severity and mortality compared to other ISs such as calcineurin inhibitors (CNIs), steroids, and antimetabolites, i.e., severity (13.5 vs. 21.1, 24.7, and 26.3%) and mortality (8.3 vs. 15, 17.2, and 12.1%), respectively. Contrary to the general opinions, our meta-analysis showed comorbidities such as diabetes, hypertension, cardiopulmonary disorders, chronic kidney disease (CKD), age >60, the duration of LT to the diagnosis of COVID-19, primary disease for LT, and obesity were not significantly associated with the severity and mortality in LT recipients with COVID-19 under an immunosuppressive therapy. However, our pooled analysis found that LT recipients with COVID-19 and without comorbidities have a less severe disease and low mortality rate compared to those with both COVID-19 and comorbidities.Conclusions: In conclusion, LT recipients with COVID-19 undergoing immunosuppressive therapies are not significantly associated with the severity and mortality. Therefore, taking the risk of organ rejection into a key consideration, a complete withdrawal of the IS may not be wise. However, mycophenolate mofetil (MMF) might be discontinued or replaced from an immunosuppressive regimen with the CNIs- or mTORis-based immunosuppressive therapy in some selected LT recipients with COVID-19, depending upon the severity of the disease.

COVID-19 and liver disease

“…On the other hand, a protective role of tacrolimus (TAC) was advocated in the European experience of Belli et al ,108 where the use of TAC in the IS regimen had a positive independent effect on survival (HR 0.55; CI 95% CI 0.31 to 0.99). A meta-analysis on the available literature concluded discouraging a complete withdrawal of IS in LT recipients with COVID-19, and suggested instead to consider MMF discontinuation and replacement with other IS regimens in selected cases, based on the severity of the disease 109. However, data regarding immunosuppression should be confirmed by independent and contemporary cohorts.…”

Antiviral prophylaxis or preemptive therapy for cytomegalovirus after liver transplantation?: A systematic review and meta-analysis

“…Technically, immunosuppressants used in LT act as a double-edged sword. Regardless, it typically prevents graft rejection; it also increases the incidence of hypogammaglobulinemia in LT recipients, which is a known risk factor for various opportunistic infection along with CMV in an early post-transplant period ( 26 , 27 ). In regard to steroids, steroids on one hand can increase CMV load in the blood, on the other hand it also increases the risk of end organ disease due to CMV by reducing the viral load needed to cause the disease ( 28 , 29 ).…”

Diagnosis, treatment protocols, and outcomes of liver transplant recipients infected with COVID-19

“…These comorbidities included diabetes, hypertension, cardiovascular diseases, chronic kidney disease, age > 60, the length of LT prior to the detection of COVID-19, and obesity. This was explained by the higher proportion of patients with mild illness in the included studies or the potential protective effects of immunosuppression in LT patients[ 43 ].…”

“…Data on the effect of the interval between LT and COVID-19 diagnosis on the disease severity and mortality are conflicting. As LT recipients are on higher doses of immunosuppression in the 1 st year, which is slowly tapered as a maintenance dosage, it may contribute to an increase in viral load and a delayed recovery from COVID-19 in the 1 st year after LT. Secondly, the outcomes of LT recipients with COVID-19 can be adversely impacted by the increasing frequencies of comorbidities brought on by chronic immunosuppression[ 43 ].…”