A Multicentric Experience on Living Donor Liver Transplantation in Coronavirus Disease 2019 Hotspots in India

Abbreviations

ACLF

acute‐on‐chronic liver failure

ALF

acute liver failure

CLD

chronic liver disease

CO‐RADS

COVID‐19 Reporting and Data System

COVID‐19

coronavirus disease 2019

D0

Day of surgery

HRCT

high‐resolution computed tomography

ICU

intensive care unit

LDLT

living donor liver transplantation

LT

liver transplantation

LTICU

Liver Transplant Intensive Care Unit

MAFLD

metabolic dysfunction–associated fatty liver disease

MELD

Model for End‐Stage Liver Disease

NA

not applicable

PCR

polymerase chain reaction

PELD

Pediatric End‐Stage Liver Disease

RT‐PCR

real‐time polymerase chain reaction

SARS‐CoV‐2

severe acute respiratory syndrome coronavirus 2

TO THE EDITOR:

As of August 2020, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has affected more than 213 countries, leading to more than 18 million cases and 690,000 deaths. India is the second most affected country, with the majority of cases in metropolitan cities such as Mumbai, New Delhi, Chennai, and Bengaluru. There is limited literature on the outcomes and safety of performing living donor liver transplantation (LDLT) in coronavirus disease 2019 (COVID‐19) epicenters.

Patients and Methods

We conducted a multicenter, prospective cohort study that recruited consecutive LDLT recipients from 4 major transplant centers in Mumbai, Chennai, Hyderabad, and Bengaluru. The coordinating center was Gleneagles Global Health City in Chennai. This study conformed to the Declaration of Helsinki and was approved by the institutional ethics committee. Written informed consent was obtained from all patients. Both adult and pediatric recipients undergoing LDLT between April and July 2020 were included in the study. Recipient and donor data, including demographic variables, perioperative clinical and laboratory parameters, and postoperative outcome variables, were recorded. The overall survival rate at the end of 1 month post liver transplantation (LT) was recorded and analyzed.

COVID‐19 Safety Measures

COVID‐19 safety measures for LDLT were divided into the following 3 standard operating protocols: patient related, staff related, and environment/equipment related. Emphasis was given to make the protocols safe and sustainable. A COVID‐19–free transplant pathway was designed (Fig. 1). During the liver transplant intensive care unit (ICU) stay, donors and recipients were allowed to talk to their attenders through video calling. Caregivers underwent SARS‐CoV‐2 polymerase chain reaction (PCR) screening before coming into the liver unit. Home collection of blood samples and video consultations with the LT team were the primary modalities of follow‐up. If needed, patients came back to the dedicated liver unit, where all the emergency/elective queries were directed.

FIG. 1.

Preoperative COVID‐19 screening for LT recipients, donors, and staff members.

Statistical Analysis

Descriptive statistics were expressed as median (interquartile range) or number (percentage). Comparisons of continuous variables were done by Wilcoxon rank sum test, and categorical variables were compared by the Fisher’s exact test or Pearson chi‐square test. One‐way and 2‐way tables were computed. A P value of <0.05 was considered significant. Data were analyzed from Excel (Microsoft, Redmond, WA) sheets using Medcalc Software (Oostende, Belgium) statistical software.

Results

A total of 31 LDLTs were conducted during the study period. Of these, 21 (67.7%) were adults and 10 (32.2%) were children. The demographic characteristics of donors and recipients and their clinical details are included in Table 1. In adults, ethanol‐related chronic liver disease (CLD) was the predominant etiology followed by metabolic dysfunction–associated fatty liver disease (MAFLD). Of the children, 2 had progressive familial intrahepatic cholestasis presenting as secondary biliary cirrhosis, and 3 underwent LDLT for hepatoblastoma. Notably, 1 child presented with acute liver failure. The median postoperative ICU stay was 7 days in adults compared with 5 days in children (P = 0.02). Of the adults, 2 patients died as a result of bacterial sepsis. Of the 7 adult recipients with postoperative morbidity, 4 had septicemia. One patient each developed bile leak, hepatic artery thrombosis, or polytetrafluoroethylene graft thrombosis respectively, all of which were managed successfully. One pediatric recipient had acute cellular rejection, which was managed by pulse steroid therapy. One adult recipient was diagnosed with COVID‐19 infection after discharge from the hospital, 46 days after surgery. The patient presented with fever and hypoxemia and had deranged transaminases. Chest computed tomography showed ground‐glass opacities with COVID‐19 Reporting and Data System (CO‐RADS) 4 grading, and the PCR nasopharyngeal swab for COVID‐19 was positive. Mycophenolate mofetil was discontinued, and the doses of steroid and tacrolimus were optimized. Antivirals were avoided because of hepatitis. The patient is currently in the hospital and recovering without ventilatory support. Notably, none of the donors, recipients, or transplant team members acquired nosocomial COVID‐19 infection.

TABLE 1.

Demographic and Clinical Details of Recipients and Donors

Study Group	Adult LDLT (n = 21, mean ± SD)	Pediatric LDLT (n = 10, mean ± SD)	P Value
Recipient characteristics
Age, years, median (range)	46 (18‐59)	9 (0.5‐17)	NA
Sex, male:female	18:3	5:5	0.03
Etiology of liver disease, n (%)	Ethanol related, 8 (38)	Wilson’s disease, 3 (30)
	MAFLD, 7 (33.3)	Post‐Kasai, 1 (10)
	Hepatitis B, 2 (9.5)	Hepatoblastoma, 3 (30)
	Autoimmune hepatitis, 1 (4.7)	Progressive familial intrahepatic cholestasis, 2 (20)
	Wilson’s disease, 3 (14.3)	Cholesteryl esterase deficiency, 1 (10)
Indication for LT, n (%)	ALF, 0	ALF, 1 (10)	NA
	ACLF, 3 (14.3)	ACLF, 6 (60)
	MELD >15, 18 (85.7)	Hepatoblastoma, 3 (30)
Comorbidity, n (%)	Diabetes mellitus, 4 (19)	Nil	NA
	Hypertension, 2 (9.5)
	Ischemic heart disease, 1 (4.7)
	Diabetes, hypertension, and morbid obesity, 1 (4.7)
MELD/PELD score	20.3 ± 7.9	24.8 ± 9.5	0.33
Donor characteristics
Age, years	39.1 ± 9.3	33.9 ± 7.7	0.14
Sex, male:female	9:12	0:10	0.02
Body mass index, kg/m2	25.3 ± 3.2	23.7 ± 3.1	0.20
Outcome variables
ICU stay, days, median (range)	7 (4‐28)	5 (3‐8)	0.02
Hospital stay, days, median (range)	19 (12‐51)	17 (10‐23)	0.06
Morbidity, n (%)	7 (33.3)	1 (10)	0.17
Mortality, n (%)	2 (9.5)	0	0.32

Discussion

Timely LT in a patient with progressively decompensating cirrhosis or in a patient who is critically ill with acute‐on‐chronic liver failure (ACLF) is potentially curative, with good long‐term survival. However, the COVID‐19 pandemic has raised many unanswered questions, including the risk and severity of perioperative COVID‐19 in transplant recipients, the safety of the donors, and the safety of the LT team. In a large, online, cross‐sectional survey^{( 1 )} from 109 European transplant centers, the overall incidence of symptomatic COVID‐19 and the crude death rate in transplant waitlist candidates versus LT recipients were 1.05% versus 0.3% and 18% versus 15%, respectively. The data from Mount Sinai Medical Center, New York, also showed similar results in 38 recipients infected with COVID‐19, with an overall mortality of 18% and an in‐hospital mortality of 29%.^{( 2 )} Therefore, if we select patients who need urgent transplants and would be at higher risk of dying from liver failure than from COVID‐19, LT could be safely performed with appropriate precautions.

During the study period, the average monthly incidence of COVID‐19 in the 4 cities ranged between 955 and 2274 new cases per million population. The average hospital admission for COVID‐19 in the 4 study centers ranged between 16% and 38% of the total available beds in each hospital. Despite this, because of stringent precautionary measures followed by the donor, recipient, and their accompanying caregivers; strict mitigation of the primary LT surgical, anesthesia, and supporting staff members from other duties to avoid unnecessary exposure; and the segregation of the donors and recipients in the liver transplant intensive care unit (LTICU), the chain of any possible transmission in the hospital was broken, and therefore nosocomial‐acquired COVID‐19 cases were avoided. Only those patients with urgent indications, such as high Model for End‐Stage Liver Disease (MELD) scores, acute liver failure (ALF), acute‐on‐chronic liver failure (ACLF), primary hepatic malignancies, and so on were considered for timely LDLT after explaining the risks of COVID‐19 and ensuring strict compliance to prevention protocols. Unfortunately, 1 adult recipient acquired COVID‐19 infection from the community after discharge but is recovering. Similar encouraging results have also been reported from centers in India^{( 3 )} and Korea.^{( 4 )}

The possible limitation in the study is the small size of the study group. Further studies with long‐term follow‐up of these patients and donors can give us more information about the risk and severity of COVID‐19 infections compared with the general population. In conclusion, this is the first multicentric study highlighting the perioperative safety and good outcomes in carefully timed LDLT, even in COVID‐19 hotspots, with stringent preventive protocols in place.