Mild impact of SARS-CoV-2 infection on the entire population of liver transplant recipients: the experience of an Italian Centre based in a high-risk area.

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) outbreak ravaged Italy. Marche is the eight Italian region in terms of rate of disease [1]. Several cases of Coronavirus Disease 19 (COVID 19) in liver transplant recipients (LTRs) have been reported but there is no figure on the prevalence of the disease in the entire population of LTRs.

We investigated the clinical status of all currently alive LTRs transplanted in Ancona, a single centre based in a high-incidence area, between January 1, 2005 and March 31, 2020 (Table 1). Starting with a phone interview, we updated the clinical status focusing on symptoms related to COVID19 and further assessed.

Table 1

Baseline characteristics of liver transplant recipients that participated to the clinical survey, performed between April 15th and April 20th 2020

Baseline characteristics	Totaln = 343
Age (years)	55.0 (18–70)
Time from liver transplant (months)	70 (1–177)
Sex (M) %	257 (75.5)
Body mass index	26.22 (16.2–56.1)
Liver transplant primary indications (%)
Viral cirrhosis  Alcoholic cirrhosis  Non alcoholic steato hepatitis  Autoimmune  Others	176 (51.7) 80 (23.5) 15 (4.4) 25 (7.3) 44 (12.9)
Comorbidities (%)
Diabetes  Hypertension  Hypercholesterolemia  Hypertriglyceridemia	99 (29.1) 157 (46.1) 57 (16.7) 89 (26.1)
Hepatocellular carcinoma (%)	125 (36.7)
Type of immunosuppression (%)
Tacrolimus  Everolimus  Mycophenolate  Steroids  Ciclosporin  Combination  TACa + EVEb  TACa + MMFc  EVEb + MMFc  CsAd + MMFc	282 (82.9) 192 (56.4) 53 (15.5) 16 (4.7) 10 (2.9) 198 (58.2) 146 (42.9) 31 (9.1) 18 (5.2) 3 (0.8)
Tacrolimus (mg given)	2.0 (1.0–12.0)
Everolimus (mg given)	2.0 (1.0–6.0)
White blood cells (× 103 μ/L)	5.44 (1.57–13.3)
Neutrophils (× 103 μ/L)	3.12 (1.0–11.0)
Lymphocytes (× 103 μ/L)	1.48 (0.1–4.0)
Hemoglobin (g/dl)	13.20 (9.0–18.0)
ASTe (μ/L)	20 (6–280)
ALTf (μ/L)	22 (4–202)
GGTg (μ/L)	26 (6–709)
Cholesterol (mg/dl)	177 (48–340)
Triglyceride (mg/dl)	132 (41–601)
Last tacrolimus trough level (ng/mL)	4.6 (0.1–14.0)
Last everolimus trough level (ng/mL)	3.86 (0.1–11.0)
Last ciclosporin trough level (ng/mL)	75 (45–112)
Major symptoms (%)
Fever (> 37.5 °C)  Cough  Both	33 (9.7) 24 (7) 19 (5.6)
Minor symptoms (%)
Weakness  Sore throat  Headache  Muscle pain  Nasal symptoms	15 (4.4) 12 (3.5) 16 (4.7) 17 (5) 18 (5.2)
Duration of symptoms (days)	2 (1–14)

aTacrolimus

bEverolimus

cMycophenolate

dCsA ciclopsorin

eAspartate aminotransferase

fAlanine aminotransferase

gGamma glutamyl transpeptidase

Among the 343 LTRs, 3 suffered from SARS-CoV-2 infection confirmed by nasopharyngeal swab and 36 were classified as “suspected cases” for COVID 19 symptoms with a negative swab, according to World Health Organization guidelines [2]. Only one patient suffered from a severe infection. A 60-year-old male, liver transplantation 7 years earlier for a HCV-related cirrhosis, with no comorbidity, Body Mass Index 25 and immunosuppressed with Tacrolimus (TAC) monotherapy (blood level: 4.5 ng/mL). Forty days earlier, the patient had experienced fever, dry cough and diarrhea, which lasted for about 10 days and was treated with paracetamol alone. Due to the development of difficulty in breathing, he had been transferred to a peripheral hospital where radiological findings of bilateral severe interstitial pneumonia were detected at the chest X-ray. On admission, blood chemistry tests were as follows: aspartate aminotransferase 84 U/dl, alanine aminotransferase 30 IU/dl, Bilirubin 1.4 mg/dL, gamma-glutamyl transpeptidase 262 IU/L, creatinine 1.16 mg/dL. The patient died on the same day, soon after admission to the Intensive Care Unit.

The other two patients with a positive swab confirmed COVID 19 experienced mild disease with a single episode of fever and cough for one week. The immunosuppressive regime was a combination of TAC with Mycophenolate or Everolimus. Both patients had a normal liver function and were treated with Hydrossichlorochyne.

On 26 of these 36 (72.2%) “suspected cases”, we performed serological tests to detect anti-SARS-CoV-2 antibodies and no positivity for IgM and/or IgG was detected. Globally, in our population of LTRs, rate of SARS-CoV-2 infection and mortality were 0.87 and 0.29% respectively versus 0.44% and 0.06% of the general population in Marche region [1].

During the COVID 19 outbreak, only other three Italian liver transplant centres reported their experience: Bergamo, Istituto Tumori Milan and Ospedale Maggiore Ca’ Granda Policlinico Milan. D’Antiga et al. reported 200 LTRs with 3 tested positive patients for SARS-CoV-2, none developed a clinical pulmonary disease [3]. Bhoori et al. reported three deaths among 111 long-term adult liver transplant survivors (transplanted more than 10 years ago) following severe COVID-19 while 3 of 40 recently transplanted (ie, within the past 2 years) patients who were found SARS-CoV-2 positive experienced an uneventful course of the disease [4]. Donato et al. reported an incidence of confirmed COVID-19 infection of 1.25% in the population of LTRs of one Milan transplant centre of whom none developed such a severe disease to require invasive ventilation [5].

During the outbreak of COVID-19, in Marche region the infection rate of SARS-Cov-2 has been of 0.44% [1], similar to that observed in our LTRs population. A possible explanation of this mild impact of COVID-19 on LTRs is the relatively low mean age (55 years) and low exposure to immunosuppressant agents in the context of modern minimization protocols. Self-isolation either spontaneous or induced by the lockdown, imposed by the Italian Government in the early phase of the epidemia, may have also helped in limiting the spread of the infection.

Whereas the available literature has been mainly focused on describing those cases that had a poor outcome or a severe disease, the major point of strength of the present report is that a thorough investigation on the health status of all LTRs was carried out, and this minimizes the possibility of underestimation of the actual impact of SARS-COV-2 infection in this particular population.

We acknowledge that this LTRs series has some limitations, such as the small sample size and the necessity of further studies to achieve solid results and conclusions. However, according to our observation, we suggest that for liver transplant recipients, the risk of acquiring SARS-CoV-2 infection and, in particular, of developing COVID-19 is not as remarkably high as it could have been hypothesized.