EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Coronavirus disease 2019, Immunosuppressant, Kidney transplantation, Severe acute respiratory syndrome coronavirus 2

The novel virus SARS-CoV-2 caused a severe outbreak that rapidly spread worldwide. SARS-CoV-2 has a high infectivity and may cause an acute respiratory infection that leads to pneumonia and progresses to severe acute respiratory distress syndrome. This life-threatening disease, COVID-19, has led to >3 million global deaths, unprecedented since the advent of the field of transplantation. Hydroxychloroquine, lopinavir/ritonavir, remdesivir, tocilizumab, and various other agents have been used to treat pathogenic viruses; however, there is as yet no optimal management for COVID-19 that can reduce the high mortality.¹

Older age and the presence of comorbidities have been identified as risk factors for severe COVID-19.² Renal transplant recipients are classified as having a high risk of serious COVID-19 infection and have been shown to have a greater degree of pneumonic infiltration and higher mortality than the general population.³ The chronic immunosuppressive status of transplant recipients is believed to impair the defense mechanism against viral replication and to contribute to the worse prognosis of patients with COVID-19. However, despite these adverse effects, immunosuppressants are not unconditionally discontinued in transplant recipients with COVID-19, because such a discontinuation critically increases the risk of allograft rejection. In addition, previous studies have suggested that immunosuppressants prevent the devastating cytokine injuries during the course of COVID-19 and alleviate inflammatory responses in various organs.⁴ Therefore, immunosuppressive treatment plays conflicting roles in terms of producing beneficial and harmful effects, and this complexity is a main concern for the management of COVID-19 in renal transplant recipients.

The combination of calcineurin inhibitors, mycophenolate mofetil, and corticosteroids is the most commonly used regimen in renal transplant recipients. Previous reports have demonstrated the experiences and strategies on how these immunosuppressants are modified as the number of COVID-19 cases has increased.^4,5 However, information about sirolimus treatment is rarely reported, and the relevant complications or clinical outcomes are not well understood. Here, we report the successful treatment of COVID-19 with maintenance of sirolimus-based immunosuppressants in a renal transplant recipient.

A 59-year-old man was admitted with fever and sudden aggravation of dyspnea. He was previously diagnosed with end-stage renal disease due to immunoglobulin A nephropathy and underwent living related donor kidney transplant 18 years prior. The donor was a younger sister. His maintenance immunosuppressive regimen included 6 mg/day sirolimus and 5 mg/day prednisolone. He had hypertension, diabetes, and dyslipidemia as comorbid medical conditions. His latest serum creatinine level and estimated glomerular filtration rate before admission were 1.84 mg/dL and 40.2 mL/min/1.73 m², respectively, which were measured 2 months prior.

He complained of mild cough and sputum production and tested positive on real-time polymerase chain reaction assay for COVID-19. His body temperature was 38.0 °C, and oxygen saturation was 96% with 2 L/min oxygen administered via a nasal cannula. Laboratory tests showed decreased lymphocyte count, increased C-reactive protein (CRP) level, and elevated serum creatinine (Table 1). Chest radiography showed infiltrative patch opacities in both lung fields. Chest computed tomography demonstrated bilateral multifocal ground-glass opacities that were consistent with COVID-19 pneumonia (Figure 1).

We started lopinavir/ritonavir (400 mg/100 mg daily) for COVID-19 pneumonia and ceftriaxone (2 g daily) for prophylactic antibiotics. We maintained sirolimus and prednisolone at the same doses. Two days later, the patient’s fever persisted, hypoxemia continued, and CRP level increased considerably; however, over the next 3 days, his fever rapidly resolved, lymphocyte rate increased, and serum creatinine and CRP levels decreased. The multifocal consolidation on chest radiography was nearly resolved at day 5. The results of the polymerase chain reaction assay for COVID-19 were negative 4 consecutive times from hospital day 6. However, laboratory tests showed an increase in aspartate aminotransferase (647 U/L), alanine aminotransferase (357 U/L), alkaline phosphatase (439 U/L), and total bilirubin (5.41 mg/dL) on day 5 (Figure 2).

We evaluated the potential causes of hepatitis. The tests for viral hepatitis infection markers yielded negative results, and liver ultrasonography did not show any abnormal findings to explain the increased hepatic enzyme levels. Sirolimus trough level abruptly increased to 122.9 ng/mL. We suspected sirolimus-induced hepatitis and discontinued lopinavir/ritonavir because of the potential interaction with sirolimus. We also reduced the sirolimus dose to 2 mg/day. The sirolimus trough levels decreased, and the liver enzymes began to normalize. We maintained prednisolone administration during the entire hospitalization. Finally, the patient was discharged on day 22 of hospitalization.

Several risk factors for worse prognosis have been identified with the accumulation of a large number of studies on COVID-19.⁶ Our patient had well-known poor prognostic factors, including older age, hypertension, diabetes, dyslipidemia, and acute kidney injury, at the time of admission. In this patient, the COVID-19 condition worsened for 2 days after the diagnosis. Dyspnea occurred with increasing oxygen demand, and an abrupt progression of pneumonia was observed in both lung fields. However, his symptoms and oxygen saturation rapidly improved, and the pulmonary infiltration resolved in the next 3 days. In addition, transfer to the intensive care unit was not required and he did not develop respiratory distress, so there was no need for ventilator support. On the basis of these findings, our patient had a substantially favorable clinical course compared with the original poor prognosis.

The judicious adjustment of immunosuppressive drugs in renal transplant recipients is required during COVID-19 treatment. Immunosuppressants prevent an overwhelming cytokine response and hyperactivation of the T-cell immune system, a combination that can lead to fatal pneumonia.^7,8 In particular, the mechanistic target of rapamycin (mTOR) pathway offers valuable targets for control of the hyperimmune response, and there is an ongoing registered clinical trial on the use of sirolimus to prevent the severe progression of COVID-19.^9,10 In addition, a previous study has reported that mTOR signaling is markedly activated in SARS-CoV-2-infected cells and mTOR inhibition results in a considerable reduction in viral replication.¹¹ Several studies have suggested sirolimus could be repurposed as an inhibitor of viral particle synthesis.^12-14 Based on these reports, we suspect that sirolimus treatment may help prevent immune hyperactivation and promote the rapid resolution of COVID-19 pneumonia in patients similar to our patient. We propose that sirolimus potentially optimizes the care of renal transplant recipients with COVID-19.

Our patient showed extremely high levels of sirolimus with lopinavir/ritonavir treatment, and drug-induced hepatitis unexpectedly occurred. The metabolism of lopinavir/ritonavir is mediated by cytochrome P450 3A isozyme and P?glycoprotein, suppresses the metabolic breakdown of sirolimus, and increases the sirolimus blood level. Previous studies have demonstrated that lopinavir/ritonavir also has pharmacologic interactions with calcineurin inhibitors, which are a common treatment for renal transplant recipients.¹⁵ Therefore, we recommend careful monitoring of the blood level of sirolimus and calcineurin inhibitors when combined lopinavir/ritonavir therapy is used for COVID-19 treatment in renal transplant recipients.

We reported the successful treatment of COVID-19 pneumonia while maintaining sirolimus treatment in a renal transplant recipient. Sirolimus is an effective treatment option for renal transplant recipients with COVID-19, and pharmacologic interactions between immunosuppressants and lopinavir/ritonavir should be carefully monitored.

Volume: 19 Issue: 9 September 2021

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