Since the beginning of 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world, and a wide clinical spectrum of coronavirus disease-19 (COVID-19) has also been observed in solid organ transplant recipients, in whom immunosuppressive therapy and comorbidities affect the severity of the infection.1
We report a case of a 50-year-old woman who underwent liver transplantation for secondary sclerosing cholangitis on January 31, 2020. Immunosuppressive regimens consisted in induction with basiliximab and steroid, followed by maintenance with tacrolimus and steroid. Due to the occurrence of refractory ascites with histological evidence of sinusoidal obstruction syndrome (SOS), tacrolimus was shifted to cyclosporine, on the basis of previously reported cases of tacrolimus-induced SOS,2 and mycophenolate (1000 mg/d) was introduced. On March 16, after a single episode of fever, SARS-CoV-2 infection was diagnosed by nasopharyngeal swab (viral load: 6.5 log copies/10 000RNAseP).3 The whole genome sequence revealed the infection by lineage B.1 containing the single-nucleotide polymorphism D614G in S, recently associated with high viral load in vivo.4 No respiratory symptoms were reported, nor was pneumonia observed at chest X-ray. Low-molecular-weight heparin (enoxaparin 4000 U/d) was started. Concomitantly, the progression of SOS and evidence of antibody-mediated graft rejection prompted the initiation of defibrotide (6.25 mg/kg every 6 h) and plasma exchange (PE) with human albumin replacement (followed by human immunoglobulin 5 g after each session). Figure 1 describes the kinetics of viral load in nasopharyngeal swab and of antibody response according to treatment. While total immunoglobulin (Ig)A and IgG (COVID-19 IgA and IgG enzyme immunoassay. DIA.PRO. Diagnostic Bioprobes srl) were detectable 1 week after the infection, anti-spike proteins 1/2 (S1/S2) antibodies (LIAISON SARS-CoV-2 S1/S2 IgG; Diasorin S.p.A.) were found to be raised 2.5 weeks later. Concomitantly to S1/S2 seroconversion, the viral load dropped of 3 log copies/10 000RNAseP, and then rose again to 6.1 log copies/10 000RNAseP. Given the persistence of SARS-CoV-2 with confirmed replication (subgenomic RNA detected) and the low anti-S1/S2 titer, at 4 weeks after infection, velpatasvir/sofosbuvir (a readily available RNA-dependent RNA-polymerase inhibitor) was introduced on the basis of predicted potential antiviral activity.5 Despite a stable anti-S1/S2 titer, a progressive reduction in viral load in nasopharyngeal swab was recorded, reaching undetectability after 8 weeks from infection. Velpatasvir/sofosbuvir was discontinued after 28 days (8 wk after infection). Progressive reduction in donor-specific antibodies and improvement in SOS were recorded during PE (9 sessions). Anti-S1/S2 antibodies remained at low titer (8 mAU/mL), and SARS-CoV-2 on nasopharyngeal swab was persistently undetectable at 6 months after infection. Immunosuppression was left unchanged.
Despite the prolonged exposure to the high load of SARS-CoV-2, known to be a risk factor for severe COVID-19,6 and the profound immunodeficiency, the patient never developed severe disease. A progressive reduction in viral load was observed after 4 weeks, just before velpatasvir/sofosbuvir was started; even though the decline became steeper after the antiviral was initiated, its efficacy is not clear.
Defibrotide may have prevented vascular damage by reducing endotheliopathy and prothrombotic state, which can be elicited directly and indirectly by SARS-CoV-2,7 given its capability to prevent the production of reactive oxygen species,8 to inhibit p38 MAPK activation with subsequently reduced expression of interleukin-6, tumor necrosis factor-alpha, and interleukin-1beta, reduce the expression of adhesion molecules (ie, vascular cell-adhesion molecule, intercellular adhesion molecule–1, P-selectin, E-selectin), and the release of cytokines by endothelial cells.9
PE appeared to be effective in advanced disease,10 but no data are available on the early stage of infection. Current evidence supports the efficacy of PE in reducing the levels of circulating cytokines10 and in improving thrombotic microangiopathy,11 both crucial factors in the pathophysiology of COVID-19-related acute respiratory distress syndrome.7 Nonetheless, concomitant removal of antibodies12 may have slowed viral clearance.13
Despite the ongoing infection by SARS-CoV-2, the patient received the appropriate immunosuppressive treatment for graft rejection without progression to severe COVID-19. In addition, early beginning of anti-inflammatory, antifibrotic, antithrombotic therapy, and PE might have hampered the development of cytokine storm and endothelial damage despite prolonged high viral replication, thus preventing clinical progression. Even though caution is warranted in severely immunocompromised patients, accurate monitoring and tailoring of immunosuppression allow appropriate treatment of graft rejection even in the setting of SARS-CoV-2 infection.
The authors thank Dr Silvia Renica and Dr Maria Antonello for their contribution in performing digital droplet polymerase chain reaction and Dr Federica Di Ruscio and Dr Livia Tartaglione for the serological analysis. They also want to thank Dr Andrea De Gasperi for his valuable contribution to clinical management.
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