COVID-19 and liver transplantation: Lessons learned from three reported cases.

coronavirus disease 2019

liver transplantation

severe acute respiratory syndrome‐associated coronavirus 2

To the Editor,

During the COVID‐19 pandemic, transplant recipients have been recognized as more susceptible to infection, to have greater severity of disease, and prolonged shedding of this highly transmissible virus. However, there is limited information on the impact of COVID‐19 in liver transplant (LT) recipients. We reviewed three reported cases with detailed treatment information from China to better understand the features and associated therapeutic strategies used in transplant recipients with COVID‐19. , ,

As summarized in Table 1, three patients all received immunosuppressive therapy after transplantation and were initially diagnosed as having mild disease and then progressed to severe illness. High fever (ie, >39°C) was common in the patients, which differed from previous reports that organ transplant recipients present with only low‐grade or no fever. Similar to the general population, lymphopenia was common, while multiple peripheral pulmonary ground‐glass opacities were the typical radiological findings during progressive infection.

Table 1

Characteristics of the three patients

	Case 1	Case 2	Case 3
Age (year)/sex	59/Male	50/Male	37/Male
Co‐morbidities	Obstructive jaundice	Nil	Nil
Indication for liver transplant	Hepatocellular carcinoma	Hepatitis B cirrhosis	Hepatocellular carcinoma
Duration of liver disease prior to transplant	Diagnosed HBV infection 25 y ago and hepatocellular carcinoma 3 y previously	Unknown	Diagnosed HBV infection 19 y ago and multiple hepatic masses 3 mo previously
Post‐transplant complications	Several episodes of jaundice after transplantation	Nil	Nil
Maintenance immunosuppression	Tacrolimus and mycophenolate (unknown dosage)	Tacrolimus (at a mean dose of 0.03 mg/kg/d) monotherapy	Tacrolimus and systemic glucocorticoids (unknown dosage)
Interval from transplant to onset of COVID‐19 symptoms	Two years and nine	Two and a half years	3 d before transplantation (during the perioperative period)
Interval from onset of symptoms to admission	3 d	6 d	4 d after admission (during the perioperative period)
Exposure history	Close contact with his wife who was diagnosed with COVID‐19	A resident of Wuhan, exposure history uncertain	A resident of Wuhan, exposure history uncertain (fever on the fourth day of admission)
Symptoms and signs on admission	Fever (up to 40°C), jaundice, splenomegaly, and ascites	Fever (up to 39.6°C)	Fever (up to 39°C) on day 4
Abnormal biochemical indicators on admission	White cell count: 3.2 × 109/L; Lymphocyte count: 0.7 × 109/L; C‐reactive protein: 35.1 mg/L; Total bilirubin: 83.9 μmol/L; ALT: 60 U/L; GGT: 1087 U/L	White cell count: 5.9 × 109/L; Lymphocyte count: 0.42 × 109/L; High sensitivity C‐reactive protein: 32.1 mg/L; Liver transaminases: normal	Neutrophil count: 7.51 × 109/L; Lymphocyte count: 0.64 × 109/L
Chest computed tomography (CT) scan	Day 1: Bilateral ground‐glass opacities; Day 12: Significant worsening of bilateral lung inflammation.	Day 1: Multiple peripheral patchy ground‐glass shadows in both lungs; Day 8: Mixed diffuse ground‐glass opacities with multifocal patchy consolidation involving both lungs and bronchiectasis in left lower lobe; Day 28: Bilateral peripheral distribution of small patchy consolidations and reticular fibrosis and exudative lesions—improved	Day 9: Bilateral hypostatic change and minor pleural effusion in the right thoracic cavity; Day 28: Multicentric subpleural ground‐glass opacification in the left lobe; Day 36: Resolution of the infiltrate in the left lobe and progression of pleural effusion in the right lung
Microbiologic cultures	Blood culture was positive for candida albicans, and alveolar lavage and pleural fluid were positive for pseudomonas aeruginosa (d12); Bile duct pus was positive for pseudomonas aeruginosa (d23)	Not mentioned	Sputum culture was positive for gram‐positive cocci and gram‐negative bacilli (d9)
Changes in patients' conditions during hospitalization	Developed respiratory failure (d4); multiple organ failure (d37)	Presented with progressive dyspnea (d5); clinical symptoms resolved (d24)	ALT and AST levels gradually elevated (d26); fever subsided (d33); and suspected acute cellular rejection (d40);
Immunosuppressants	Tacrolimus and mycophenolate were maintained	Discontinued tacrolimus for 4 wks (d2‐29);	Tacrolimus gradually titrated to lower doses (d19‐39);
Glucocorticoid	Standard methylprednisolone (d4)	Systemic methylprednisolone (d2)	Glucocorticoids were gradually titrated to lower doses (d19)
Antiviral agents	α‐interferon, arbidol and lopinavir/ritonavir	α‐interferon, umifenovir, and lopinavir/ritonavir	Oseltamivir
Antimicrobial agents	Piperacillin‐tazobactam (d1); cefoperazone‐sulbactam and caspofungin (d12); and meropenem and voriconazole (d23)	Cefoperazone (d1)	Cefdinir (d4‐6); imipenem and cilastatin (d7‐21); caspofungin (d7‐21); and linezolid (d8‐21)
Intravenous immunoglobulin	Yes	Yes	Yes
Repeat COVID‐19 RT‐PCR test	Negative on days 33 and 35	Two consecutive negative nucleic acid tests before discharge	Negative on days 34 and 52; Positive on day 53 and returned to negative on day 56
Outcome	Died on day 45	Alive and discharged on day 31	Alive and discharged on day 60

The first day of hospital admission was assumed as day 1 (d1).

Two patients (cases 1 and 2) of similar age with post‐transplant infections had opposite outcomes. The first patient (case 1) was infected by his wife. During hospitalization, immunosuppressive therapy with maintained with tacrolimus and mycophenolate. He also received standard methylprednisolone therapy. Despite antibacterial treatment, he succumbed to secondary bacterial and fungal infection. The second patient (case 2) was suspected of having opportunistic infections; treatment was subsequently changed to discontinuation of tacrolimus and addition of cefoperazone. After a month of treatment, he successfully recovered and was discharged. Unlike these two patients, the third (case 3) was infected with COVID‐19 during the perioperative period. Antimicrobial agents were started immediately following transplantation because of persistent fever. When COVID‐19 was confirmed, tacrolimus and glucocorticoids were titrated to lower doses. After 60 days of hospitalization, he was successfully discharged.

Current data suggest that an exaggerated innate immune response is important in instigating severe illness in patients with COVID‐19. In this context, the immunocompromised host may be protected by a weaker innate response against severe COVID‐19. However, this ignores the fact that recipients are more likely to develop secondary bacterial or fungal infections, which was found in all three of the cases.

Successful treatment of opportunistic infection is important in the context of transplantation. Insufficient immunosuppression might result in acute graft rejection, whereas excessive immune suppression can lead to secondary nosocomial infections. Thus, healthcare professionals need to carefully balance the risks and benefits of altering immunosuppressive regimens in LT recipients. Based on the cases presented, a reduction or temporary halt to immunosuppressive agents might be considered in patients with serious infections who have a low risk of rejection. According to the current literature, LT recipients with serious infections are rare in the context of acute graft rejection.

Previous experience from SARS indicated that treatment with high‐dose corticosteroids yielded little benefit in transplant recipients. Similarly, the WHO recommends avoiding the use of corticosteroids in the treatment of patients with COVID‐19.

Prevention is the best “treatment.” In epidemic hotspots with high risk of SARS‐CoV‐2 transmission, transplant recipients should practice social distancing even with family members in the same household.

CONFLICT OF INTERESTAQ7

The authors have no conflict of interest to declare.

AUTHORS' CONTRIBUTIONSAQ8

Feng Gao and Ming‐Hua Zheng conceived and designed the study. Fen Gao and Jin‐Yang Gu interpreted and analyzed the data. Feng Gao and Kenneth I. Zheng drafted the manuscript. Jacob George critically revised the manuscript for important intellectual content. Ming‐Hua Zheng supervised the study. All authors contributed to the manuscript for important intellectual contents and approved the submission.

Funding information

This work was supported by grants from The National Natural Science Foundation of China (81500665), High Level Creative Talents from Department of Public Health in Zhejiang Province, and Project of New Century 551 Talent Nurturing in Wenzhou.