Successful Management of Severe COVID-19 in a Kidney Transplant Recipient Safe Co-Administered Tacrolimus and Ensitrelvir: A Case Report

1. Introduction and Clinical Significance

The novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2)(Cov-2), has been spreading globally from one city in Hubei Province, China, to the whole world since December 2019 [1] The COVID-19 pandemic ended as a Public Health Emergency of International Concern (PHEIC) in May 2023, as declared by the World Health Organization (WHO) [2] . However, in reality, the measures are insufficient, and the infection is spreading here and there [3]. Age is the strongest risk factor for severe COVID-19 outcomes. Patients with one or more underlying medical conditions are also at higher risk [4]. One reason for this is the use of corticosteroids or other immunosuppressive medications.

In transplant patients, TAC and Mycophenolate mofetilmycophenolate（MMF） are used to prevent post-transplant rejection. TAC acts by binding to the immunophilin FKBP-12 (FK506-binding protein) to form a new complex and reduce peptidyl-prolyl isomerase activity, thereby inhibiting both T lymphocyte signaling and IL-2 transcription [5]. MMF is known to suppress lymphocyte proliferation and the expression of T cell surface antigens, and to suppress rejection reactions in peripheral blood T cells [6]. Thus, solid organ transplant recipients are particularly vulnerable to severe acute respiratory syndrome coronavirus 2 (CoV-2) infection (COVID-19) due to their long-term immunosuppressive therapy [7]. However, some argue that the disease is at risk of severe complications. At the same time, the use of calcineurin inhibitors (CNI) or mycophenolic acid derivatives may be a strategy to reduce viral replication. However, it also notes that there is no clinical evidence on the potential benefits of these immunosuppressive drugs in transplanted patients with COVID-19 [8]. Antiviral therapy is generally recommended for COVID-19 patients at high risk of severe disease [9]. However, calcineurin inhibitors such as TAC are key drugs in post-transplant management, but are highly susceptible to pharmacokinetic interactions via the cytochrome P450 (CYP) 3A pathway. For this reason, administration of oral or intravenous nucleic acid analogs to solid organ transplant recipients with COVID-19 is limited. If these are ineffective, the disease progresses to a severe stage. In such cases, it remains unclear whether immunosuppressive therapy should be continued, whether additional steroid administration is appropriate, and what antiviral medication should be selected [10]. Encitrervir (ESV), an oral SARS-CoV-2 3CL protease inhibitor, has attracted attention as a potential treatment for COVID-19. However, because it inhibits CYP3A, its effect on TAC trough levels is unknown due to pharmacokinetic interactions, and clinical experience in transplant patient populations is still limited [11]. Here, we report a case of severe COVID-19 in a kidney transplant patient who had acute respiratory distress syndrome after SARS-CoV-2 infection and was placed on invasive ventilation. The TCA dose was successfully adjusted under intensive monitoring, and treatment with ESV was successful.

2. Case Presentation

A 74-year-old Japanese man was admitted with fever and acute hypoxemic respiratory failure. His medical history included living-donor kidney transplantation at 67 years of age for Nephrosclerosis, percutaneous coronary intervention, and prior endoscopic surgery for early-stage gastric cancer at a hospital specializing in Kidney Transplantation. He was a non-smoker and consumed alcohol occasionally.

2.1. Medications

After transplant treatment, his maintenance immunosuppression consisted of TAC (2.5 mg/day), prednisolone (PSL 5 mg/day), and mycophenolate mofetil (1000 mg/day). The blood trough level of TAC was stable at 4.34-6.61ng/ml over the past year. Concomitant medications included aspirin, nifedipine, olmesartan, and atorvastatin for cardiovascular disease.

2.2. Present Illness 2.3. Physical Examination

Seven years after transplantation, the patient developed cough and rhinorrhea and tested positive for COV2 by antigen testing at a nearby hospital. He initially received molnupiravir for five days; however, his condition continued to deteriorate even after 14 days. He visited again and tested positive again of COV2, with pneumonia found on his X-ray. His fever (39.0 °C) and cough have not improved at all, even though he has taken the prescribed antibiotics (Lascufloxacin 75mg). Therefore, he returned to the same hospital four days later for a third time, and his COV2 antigen test came back positive. His condition deteriorated, and he was emergently transferred to our hospital with high-grade fever (38.5 °C) and respiratory failure, requiring high-flow oxygen supplementation. His oxygen saturation (SpO2) was 90% on a non-rebreather mask(NRM) at 15 (L/min). On admission, he appeared acutely ill. Lung auscultation revealed coarse crackles bilaterally, tachycardia (110 beats/min), blood pressure of 160/65 mmHg, and respiratory rate of 20 breaths/min.

2.4. Laboratory and Imaging Findings

The patient’s laboratory testing (Table 1) showed elevated inflammatory markers, including C-reactive protein (CRP 19.85 mg/dL) and ferritin (550 U/L), with neutrophil-predominant leukocytosis and lymphopenia. Renal function was mildly impaired (creatinine, Cre 1.35 mg/dl). Chest radiography and computed tomography (CT) scan demonstrated bilateral pulmonary infiltrates consistent with severe COVID-19 pneumonia (Figure 1). Furthermore, the CT scan showed bilateral pleural effusions, ground-glass opacities (GGOs), and a Crazy-paving pattern around the consolidation in his left lung. In the right lung, significant consolidation was observed in segments 8 and 9. Polymerase chain reaction (PCR) testing and antigen testing of the patient’s nasopharyngeal swab confirmed CoV2 infection, while extensive testing for other viral, bacterial, and fungal pathogens was negative (Table 2). The PCR was performed using an assay targeting both the E and N genes of SARS-CoV-2. Cycle threshold (Ct) values for the E and N gene assay were 22.2 and 27.9, respectively. We decided to treat the patients as if they had critical conditions.

3. Discussion

In this report, we present a case in which simultaneous TAC and ESV therapy was initiated in a kidney transplant patient, resulting in good outcomes. To date, two cases have been reported in which ESV was used to treat SARS-CoV-19 infection in transplant or rheumatoid arthritis patients receiving TAC. However, in both cases, elevated TAC blood levels were observed, necessitating discontinuation of TAC treatment [11,12]. Based on these reports, we inferred that administering ESV increases TAC blood levels threefold and were able to treat critical COVID-19 cases by reducing the TAC dose and maintaining TAC blood levels within the therapeutic range. To our knowledge, this represents the first reported case of successful remission in a kidney transplant patient with severe COVID-19 treated with a combination of TAC and ESV.

ESV is a substrate of CYP3A and P-glycoprotein (P-gp) and an inhibitor of CYP3A, P-gp, breast cancer resistance protein (BCRP), and organic anion transporter 3 (OAT-3) [13]. However, the difference in the area under the blood concentration time curve (AUC) increase of midazolam (14.3-fold and 6.7-fold, respectively) between nirmatrelvir/ritonavir and ESV both 3CL protease inhibitors, when coadministered with midazolam, a pure CYP3A substrate, is likely due to the difference in the intestinal CYP3A inhibitory potency of NMV/RTV and ESV, with ESV’s inhibitory potency being considered weaker than NMV/RTV[11]. The impact on blood TAC concentrations varies depending on the concomitant medication [13]. In the case of ESV, it can be considered a viable option even when combined with TAC, provided the TAC dosage is reduced to 1/4 to 1/3 of the original dose [11,12]. The predicted increase in TAC AUC with concomitant use of ESV can be calculated based on pharmacokinetic considerations [14]. However, in actual clinical practice, TAC levels are affected by various factors, including the concomitant use of dexamethasone (a CYP3A4 inducer) [15] and proton pump inhibitors [16], as well as changes in liver function, hematocrit (Hct) levels, dietary intake, the presence of inflammatory conditions, and CYP3A5 genetic polymorphism[17,18,19]. Initially, we reduced the TAC dosage by 20%, anticipating a drug-drug interaction with ESV. However, the TAC trough level subsequently rose to 3 times baseline (pre-ESV). Previous reports indicate that the TAC dosage should be reduced to 1/3 or 1/4 of the original dose when combined with ESV [11,12], as in this case.

This was consistent with the present case. Therefore, when the TAC dose was reduced from 2.5 mg to 1 mg, the trough level approached the ideal target value. In this case, continuous monitoring of the TACs trough level enabled safe co-administration and prevented nephrotoxicity and rejection.

The patient initially presented with cold-like symptoms, but developed a fever on day 17 of onset. On day 20, the fever and respiratory status rapidly deteriorated, and abnormalities were detected on lung imaging. Due to the worsening respiratory condition, the patient was intubated and placed on a ventilator. Subsequently, the patient was placed in the prone position, and PEEP (positive end-expiratory pressure) was applied, leading to an immediate improvement in the P/F ratio. Compared with other reports, the time to onset of respiratory failure and the rapid improvement observed in this case differed from the clinical course of Acute Respiratory Distress Syndrome (ARDS), which is typically driven by decreased lung compliance due to increased vascular permeability.

First, while the time to worsening of COVID-19 clinical symptoms varies, changes in chest CT findings peaked 10 days after symptom onset [20]. Possible reasons why it took time for the symptoms to become severe in this case include in vitro studies indicating that calcineurin inhibitors and mycophenolic acid derivatives suppress viral replication[8]. Furthermore, it was suggested that, in immunosuppressed patients, this could be explained by the possibility that a weakened immune response plays a protective role[21]. On the other hand, immunosuppressed patients are considered at higher risk of severe COVID-19 [22]. Immunosuppression has been suggested to be involved in delayed symptom onset and increased severity of the disease.

The relationship between transplant patients and COVID-19 remains largely unresolved, with no conclusions being drawn at present, and should not be used as a guideline for patient management. Many aspects are still unclear. An expert panel from the American Association for the Study of Liver Diseases (AASLD) stated that while post-transplant immunosuppression has not been a risk factor for mortality as it was in SARS (2002–2003) and MERS (2012–present), it is premature to comment on its relationship with COVID-19[23]. The following reasons are considered for the rapid recovery despite the critical condition.

The pathophysiology of SARS-CoV-2-caused ARDS is similar to that of other causes of ARDS. A reduction in absolute CD4+ T cell counts and elevated IL-6 levels significantly correlated with pulmonary lesion volume in severe cases[24]. In this case, the level was also elevated to 19.85 MG/dL, which was a serious level [25]. Nevertheless, rapid remission is thought to result from the following mechanism.SARS-CoV-2 targets various cell types in the proximal airways and type II alveolar epithelial cells in the gas-exchange region of the distal lung, which may lead to a reduction in pulmonary surfactant[26]. Surfactant deficiency causes alveolar cell injury[27]. If this mechanism drives lung damage, COVID-19 patients under immunosuppression might recover without progressing to pulmonary fibrosis, distinguishing them from those with cytokine-storm-induced ARDS [28]. However, because persistent SARS-CoV-2 viremia causes cellular dysfunction, prompt elimination of the virus is essential to reverse this collapse. In immunocompromised patients, rapid and intensive viral suppression is required, even if initial symptoms are mild. In this case, the immunosuppressive agents likely delayed the onset of apparent pulmonary dysfunction. Furthermore, the low Ct values at admission suggest persistent high viremia, which ultimately led to the progression of severe disease.

Predicting the severity of COVID-19 is crucial for saving patient lives.

The biological response to COVID-19 involves numerous immune cells, including dendritic cells, T cells, B cells, and plasma cells, that contribute to the immune system’s ability to control SARS-CoV-2 infection. TAC is a potent calcineurin inhibitor that blocks the dephosphorylation of nuclear factor of activated T-cells (NFAT). This reduces the expression of cytokines such as interleukin-2 (IL-2) in the nucleus, thereby suppressing T-cell proliferation and differentiation[29]. Therefore, in COVID-19 patients who have received TAC, the immune response differs from that of normal patients, suggesting that predicting disease severity becomes more difficult. Recently, galectin-9/neutrophil axis was proposed to play a pivotal role in COVID-19 infection [30]. Gal-9 can be considered a new biomarker for evaluating rheumatoid arthritis activity and therapeutic effects, including TAC [31], as it is known to reflect the severity of COVID-19 [32]. The levels could also reflect the severity of COVID-19 under TAC treatment.

The patient received anti-IL-6 therapy, steroids, immunoglobulin, and antibiotics; however, the efficacy of steroids has not been established. In this case, the administration of steroids was considered, as it may address the deficiency of alveolar type II cells [33]. While tocilizumab has the potential to suppress cytokine storms in severe COVID-19 pneumonia, it has been reported that the drug does not significantly improve mortality or clinical outcomes in critically ill patients with lung injury requiring mechanical ventilation[34]. The use of antibiotics in COVID-19 pneumonia is also uncertain. Broad-spectrum coverage, including MRSA, is selected by healthcare providers as both directed and empirical therapy when faced with a severely ill inpatient and diagnostic uncertainty regarding potential bacterial co-infection [35]. In immunosuppressed patients in whom bacterial infection cannot be ruled out, it was thought that antibiotics could not be used until the causative bacteria were confirmed.

This paper reports a case of a kidney transplant recipient with COVID-19 who was treated with a combination of immunosuppressants and anti-SARS-CoV-2 drugs, resulting in a favorable outcome. The mechanism of ARDS may differ during immunosuppressant use; therefore, accumulating more cases is essential to establish optimal treatment strategies, including antibiotic and anti-inflammatory drug use.

4. Conclusions

ESV may represent a valuable therapeutic option for severe or refractory COVID-19 in kidney transplant recipients. However, significant drug–drug interactions with TAC can occur. Close therapeutic drug monitoring and prompt dose adjustment are essential to ensure safety. Further accumulation of case data is needed to establish standardized management strategies in this high-risk population.