**1. Introduction**

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has first been identified in Wuhan city, Hubei Province, China as the pathogen responsible for several cases of severe pneumonia during November 2019, subsequently defined by the World Health Organization (WHO) as Coronavirus disease 2019 (COVID-19). Typical symptoms of COVID-19 include fever, cough, dyspnea, fatigue, myalgia, gastrointestinal manifestations, and impairment of smell and/or taste [1–3]. The course of the disease ranges from asymptomatic or mild [4] to severe manifestations, mainly with respiratory features, leading to respiratory insufficiency, acute respiratory distress syndrome (ARDS), and in some cases to death. Age, male gender, and comorbidities have been established as risk factors for a more severe course of the disease and for mortality [5,6].

Since March 2020, COVID-19 has spread worldwide, has been declared a pandemic by the WHO, and has rapidly become a public health matter with several unmet issues. As of 16 July 2021, there were over 188 million confirmed cases and over 4 million reported deaths worldwide [7].

While knowledge on disease evolution, risk factors, clinical manifestations, and optimal management of affected individuals is progressively increasing, treatment guidelines are difficult to standardize when taking into account specific categories of patients. In this regard, solid organ transplant (SOT) recipients, and among them, liver transplant (LT) patients, may represent a potentially high-risk population. Concerns have been raised regarding immunosuppression therapy, including SARS-CoV-2-associated liver injury [8] and a possible impairment of the immunological response.

**Citation:** Becchetti, C.; Gschwend, S.G.; Dufour, J.-F.; Banz, V. COVID-19 in Liver Transplant Recipients: A Systematic Review. *J. Clin. Med.* **2021**, *10*, 4015. https://doi.org/ 10.3390/jcm10174015

Academic Editor: Pierluigi Toniutto

Received: 31 July 2021 Accepted: 1 September 2021 Published: 5 September 2021

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In December 2020, encouraging results on the safety and efficacy profile of the first anti-SARS-CoV-2 vaccines were published [9,10], paving the way for a large-scale vaccination campaign. However, most special populations were excluded from the pivotal studies of these vaccines, and therefore, real-life observations on efficacy and safety are necessary.

Data regarding the management of immunosuppression therapy in LT recipients affected by COVID-19, as well as information on the course of the disease, outcome, and immunological response both to the infection and vaccination, remain scarce.

The aim of this review was therefore to analyze and summarize the published literature concerning LT recipients with COVID-19.

#### **2. Materials and Methods**

A systematic literature review was conducted identifying PubMed English-language articles published between November 2019 and 30 May 2021.

We structured our search on three areas, using different MeSH terms. First, we aimed to analyze outcome and clinical course in LT recipients; second, we aimed to analyze immunological response after COVID-19 in LT recipients; and third, we aimed to analyze vaccination response.

For the first purpose, the MeSH terms used were "COVID-19" (and related terms: 2019 novel coronavirus, SARS-CoV-2 infection, 2019-nCoV infection) AND "liver transplant" (and related terms: orthotopic liver transplant (OLT), hepatic transplant, liver transplantation, solid organ transplant).

For the second purpose, the MeSH terms used were "COVID-19" (and related terms) AND "liver transplant" (and related terms) AND "humoral response" (and related terms: serology, immune response, T-cell response).

For the third purpose, the MeSH terms used were "liver transplant" (and related terms) AND "COVID-19 vaccines".

Original articles, case reports, case series, commentaries, letters to the editor, and review articles were considered. Additional articles were considered on the basis of the reference lists of the included studies. Two reviewers independently evaluated titles and abstracts for inclusion. Only well-characterized adult transplant recipients were included. Articles with known duplications were excluded. When feasible, information on LT recipients summarized in mixed cohorts of SOT patients were extracted and analyzed. Systematic selection was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [11]. Data extraction was conducted independently by two researchers (SGG and CB), using the text, tables, and figures of the original published articles. Independently, the overall quality was also evaluated and graded according to the Newcastle–Ottawa scale (NOS) for assessing the quality of the observational studies and converting the results to the Agency for Health Care Research and Quality (AHRQ) standards (good, fair, and poor) where applicable. When disagreement was present, an open discussion led to a final consensus. All the reported patients' demographic and clinical characteristics, baseline immunosuppressant medications and modifications during the course of the infection, need for intensive care unit (ICU) and/or mechanical ventilation (MV), and outcome were collected. A meta-analysis to investigate association between baseline characteristics, immunosuppression, and outcomes was not performed because of the lack of sufficient data and the high heterogeneity between the different studies. For the second and third aims, we collected the data regarding the type of assay used to assess immunity and the type of vaccines applied. The principal measures used were the median, mean, standard deviation, and incidence as pooled results.

#### **3. Results**

### *3.1. Study Selection*

For the first aim, 820 papers met the research criteria applied, of which 76 articles were considered suitable for evaluation. Preliminary reports subsequently published as extended analyses were considered duplications and therefore not included in the final analysis. In addition, data duplication for survey-based studies could not be completely ruled out. Therefore, we restricted our final selection to 35 articles, including a total of 1076 patients. No randomized control trials were found, and only two studies were prospectively designed; the remaining 33 articles were retrospective studies, case reports or case series, editorials, or letters to the editor. Five studies reached "good quality" according to the NOS converted in the AHRQ standards. One study reached "fair quality", and the other studies were rated as "poor quality". The selection process followed the PRISMA guidelines and is summarized in Figure 1.

**Figure 1.** Flow diagram of the systematic literature search according to the PRISMA statement.

For the second and the third aims, 18 and 19 papers met the research criteria applied, respectively. Of these, four and five articles respectively were considered suitable for evaluation. No randomized control trials were found. Only two studies were prospectively designed; the remaining articles were retrospective studies, case reports or case series, editorials, or letters to the editor.

#### *3.2. Study Population Characteristics, Clinical Course, and Management of Immunosuppression*

Overall, 1076 patients were pooled. Mean age was 54.5 ± 12.1 years, with male gender being prevalent (*n* = 553, 66.8%). Extensive information on comorbidities was available in 30 papers. Diabetes mellitus type 2, arterial hypertension, and obesity were present in 38.6%, 43.5%, and 16.0% of patients, respectively. A history of previous neoplasia was described in three reports, identifying 23 out of 832 patients (2.8%). In the majority of patients, infection with SARS-CoV-2 occurred 79.7 months after LT. The demographic characteristics and main outcomes are summarized in Table 1.



**Table 1.** General

190


**Table 1.** *Cont.*




**Table 1.** *Cont.*


**Table 1.** *Cont.*

Regarding the incidence of COVID-19 infections in LT recipients, only the SETH cohort provided data, showing that the incidence of COVID-19 in liver transplant recipients compared to the general population (837.41 cases/ 105 patients vs. 311.93 cases/ 105 people) was almost double [17].

On the other hand, the COVID-LT cohort recorded 57 confirmed SARS-CoV-2 infections out of 11,790 patients in regular follow-ups, resulting in an incidence of 483.46 cases/ 105 patients [13]. Another report from Germany documented, using either serology or PCR-swab test, present or past SARS-CoV-2 infection in 3.7% of their LT recipients during the study period (May and August 2020) [41].

The most frequently described clinical presentation was fever (61.4%), followed by cough (58.6%) and dyspnea (36.2%). Webb et al. [45] reported general "respiratory symptoms", which were experienced by the 77% of the LT recipients included in the study. Gastrointestinal symptoms including vomiting, diarrhea, nausea, and abdominal pain were strongly represented (159/569 patients, 27.9%). In the aforementioned study, the proportion of patients with gastrointestinal symptoms was higher among LT recipients compared to the nontransplant cohort (30% vs. 12%, *p* < 0.0001), whereas no significant difference was observed with respect to respiratory symptoms. On the same line, Belli et al. [14] found diarrhea as the presenting symptom in 55 LT recipients, corresponding to 22.6%.

Concerning immunosuppression therapy, data on basal immunosuppression (IS) therapy and on subsequent management during the course of infection was available for 33 and 29 studies, respectively. The data are summarized in Table 2.


**Table 2.** Information regarding immunosuppressant regimen and its modification in during COVID-19.


**Table 2.** *Cont.*


Abbreviations: AZA: azathioprine; CNI: calcineurin inhibitors; Cys: cyclosporine; TAC: tacrolimus; MMF: mycophenolate mofetil; mTORi: mammalian target of rapamycin inhibitor; SOT: solid organ transplantation; LT: liver transplant; NA: not applicable; MTX: methotrexate.

**Table 2.** *Cont.*

In the study by Colmenero et al. [17] patients receiving MMF or in whom an attempt was made to completely withdraw immunosuppression were more prevalent in the severe COVID-19 group (*p* = 0.014, and *p* = 0.016 respectively). Conversely, tacrolimus-based immunosuppression was more frequent in the nonsevere COVID-19 group, albeit without statistical significance (*p* = 0.113). Similar findings regarding calcineurin inhibitor (CNIs) based regimens were observed in the COVID-LT study, where the continuation of CNIs therapy after COVID-19 diagnosis was higher among survivors (64% vs. 42.8%) [47]. Indeed, in the study of Belli et al. [14], after multivariable analysis, the use of TAC was confirmed to be independently associated with a reduced mortality risk (HR, 0.55; 95% CI, 0.31–0.99). Additionally, in the Spanish cohort, survival curves illustrated the negative prognostic impact of MMF, particularly at doses higher than 1000 mg/day. In agreement with this finding, in patients receiving full-dose of MMF at baseline (i.e., 2000 mg/day), complete drug withdrawal showed a trend towards reduced severe COVID-19 (41.7% vs. 69.2%, *p* = 0.16) [17].

Overall, 375 out of 1064 (35.2%) patients were managed in an outpatient setting, whereas 64.8% were hospitalized. Of the hospitalized patients, 158/689 (22.9%) were admitted to an ICU. Death was reported in 135 cases. In the COVID-LT study, case fatality was estimated at 12% (95% CI 5–24%), which increased to 17% (95% CI 7–32%) among hospitalized patients [13], whereas Rabiee and coauthors found a 22.3% case fatality rate [40]. In the study by Webb and coauthors [45], case fatality was 19% (vs. the 27% reported for the comparison cohort, *p* = 0.046), with the propensity-score-matched analysis showing that LT did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1.4% (95% CI 7.7–10.4)). Colmenero et al. [17] described a mortality rate of 18% among LT patients.

In Webb et al., multivariate analyses showed that factors significantly associated with death were: increased age (OR 1.06 (95% CI 1.01–1.11) per 1 year increase, *p* = 0.031), presence of nonliver cancer (OR 18.30 (1.96–170.75); *p* = 0.011), and higher baseline serum creatinine (OR 1.57 (1.05–2.36) per 1 mg/dL increase) *p* = 0.028) [45]. Results derived from the multivariate analysis performed within the SETH cohort study identified the following independent predictors: Charlson comorbidity index (relative risk (RR) = 1.28 (95% CI 1.05–1.56), male gender (RR = 2.49; 95% CI 1.14–5.41), dyspnea at diagnosis (RR = 7.25; 95% CI 2.95–17.82), and baseline immunosuppression containing MMF (RR = 3.94; 95% CI 1.59–9.74) [17]. Belli et al. reported risk factors associated with worse prognosis including advanced age (>70 vs. <60 years, HR 4.16; 95% CI 1.78–9.73) and the use of TAC [14].

Despite theoretically higher levels of immunosuppression, only the report by Belli et al. [14] mentioned time since LT as an independent factor associated with poor outcome in univariate analysis. On the other hand, Colmenero et al. [17] showed that the time from LT had no impact on the risk of suffering from severe COVID, a finding that was confirmed by Webb et al. [45], who reported no association between death and time since LT.

Lastly, Rabiee et al. showed that the incidence of acute liver injury (defined by ALT 2-5x ULN) was not higher in LT recipients when compared to age- and gendermatched nontransplant patients with chronic liver disease and COVID-19 (47.5% vs. 34.6%; *p* = 0.037). The presence of liver injury during COVID-19 in LT recipients was significantly associated with mortality (OR 6.91 (95% CI: 1.68–28.48), *p* = 0.007) and ICU admission (OR 7.93 (95% CI: 1.75–35.69), *p* = 0.007) [40]. In the US study of Hadi et al., considering only LT recipients, only 18 patients (7.5%) experienced the composite outcome including mechanical ventilation and death at 30 days. This rate was lower when compared to that for recipients of other organ transplants [23].
