Immunosuppressants

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

In a case report, 4 men aged 24−61 years were described, who developed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection during immunosuppressive treatment with basiliximab, mycophenolate mofetil, tacrolimus, prednisone or methylprednisolone for autoimmunological hepatitis in Poland [not all dosages and routes stated].

Patient 1: A 61-year-old man developed SARS-CoV-2 infection during immunosuppressive treatment with basiliximab, tacrolimus, mycophenolate mofetil, methylprednisolone and prednisone. The man was admitted to the hospital and underwent kidney transplantation in 2020 after 18 months of haemodialysis. His medical history was significant for atrial fibrillation, arterial hypertension, overweight and type 2 diabetes treated with insulin. Post-transplant, he received induction immunosuppressive treatment with basiliximab followed by standard maintenance immunosuppressive treatment with tacrolimus 5.5mg twice daily, mycophenolate mofetil 750mg twice daily, oral prednisone 20mg and IV methylprednisolone during operation procedure and post-transplant day (POD) 1. On POD 2, the tacrolimus blood level was found to be 24.7 ng/mL, which was subsequently found to be 9.4 and 7.1 ng/mL on POD 5 and 7, respectively. On POD 6, he was found to have high fever (40°C) and CRP levels were significantly elevated. Therefore, meropenem was administered. On the following day (POD 7), he was positively tested for SARS-CoV-2. On POD 7, the serum creatinine concentration reached 1.1 mg/dL. The high-resolution CT scan showed mild patchy ground-glass shadows located in the upper pulmonary lobes. Therefore, his therapy with mycophenolate mofetil was stopped. During the following week, his general condition was still good, despite high CRP levels on POD 12. Therefore, levofloxacin was started. However, he did not receive any antiviral medications. Subsequently, his body temperature returned to the normal range. The serum creatinine concentration was also found to be stable. On POD 15, the body temperature again increased to 38.2°C. On the following day, his clinical condition deteriorated rapidly. The serum creatinine increased to 1.8 mg/dL, and systolic BP lowered to 100mm Hg with tachycardia. The CRP and procalcitonin levels further increased. Subsequently, he developed perigraft fluid collection and ileus with apparent symptoms of septic shock due to post-transplant complications (not related to SARS-CoV-2 infection). However, during the preparation for surgery, he died suddenly after cardiac arrest.

Patient 2: A 24-year-old man developed SARS-CoV-2 infection during immunosuppressive treatment with basiliximab, tacrolimus, mycophenolate mofetil and prednisone. The man, who had a history of right-side nephrectomy, vesico-ureteral reflux and arterial hypertension, diagnosed 5 years prior to haemodialysis treatment, was admitted to the hospital and underwent kidney transplantation in 2020. Post-transplant, he received induction immunosuppressive treatment with basiliximab followed by standard maintenance immunosuppressive treatment with tacrolimus 6mg twice daily, mycophenolate mofetil 750mg twice daily and prednisone. On POD 2, the tacrolimus blood level was found to be 5.8 ng/mL, which was subsequently found to be 8.5 and 9.9 ng/mL on POD 4 and 7, respectively. On POD 4, the maximum CRP level was found to be 62.5 mg/L. On POD 10, he was positively tested for SARS-CoV-2. However, his clinical condition was excellent. On POD 11, the serum creatinine concentration started to decrease and reached 2.7 mg/dL, and CRP level decreased to 8.9 mg/L. Due to the lack of information about mycophenolate mofetil blood level due to the temporary laboratory shutdown caused by COVID-19 epidemic, the dose of mycophenolate mofetil was reduced and maintained at 250mg twice daily. During his hospital stay of 35 days, no clinical or biochemical signs of infection were observed. The consecutive tacrolimus results were found in between 8 and 10 ng/mL. Subsequently, the dose of prednisone was reduced to 7.5 mg/day. However, he did not receive any antiviral medications. On POD 24, 31 and 38, his swab test was found to be positive for COVID-19. However, on POD 45 and 47, the swab test revealed negative results, and he was discharged home with serum creatinine concentration of 1.5 mg/dL.

Patient 3: A 42-year-old man developed SARS-CoV-2 infection during immunosuppressive treatment with basiliximab, tacrolimus, mycophenolate mofetil and prednisone and methylprednisolone for autoimmunological hepatitis. The man was diagnosed with arterial hypertension and advanced stage chronic kidney disease. During haemodialysis, autoimmunological hepatitis was diagnosed with clinical manifestations of pleural fluid and ascites. Therefore, he was successfully treated with methylprednisolone. In 2020, he was admitted to the hospital and underwent kidney transplantation. Post-transplant, he received induction immunosuppressive treatment with basiliximab followed by standard maintenance immunosuppressive treatment with tacrolimus 7mg twice daily, mycophenolate mofetil 750mg twice daily and prednisone. On POD 1, the tacrolimus blood level was found to be >30 ng/mL. The dose of tacrolimus was then adjusted, and the consecutive blood level was found to be 17.6 and 8.0 ng/mL, respectively. On POD 9, he was positively tested for SARS-CoV-2. The CRP level was found to be 23.7 mg/L. After the surgery, the serum creatinine decreased and reached to 2.0 mg/dL on POD 9. Therefore, mycophenolate mofetil was maintained at a reduced dose of 250mg twice daily. The subsequent tacrolimus blood levels were noted to be 17.5 and 23.7 ng/mL, which required further dose reduction to 1mg twice daily. During his hospital stay of 23 days, no clinical or biochemical signs of infection were observed. The dose of prednisone was further reduced to 7.5 mg/day. However, he did not receive any antiviral medications. On POD 21, his swab test was found to be positive for COVID-19. However, on POD 28 and 29, the swab test revealed negative results. Therefore, he was discharged home with serum creatinine of 1.4 mg/dL.

Patient 4: A 52-year-old man developed SARS-CoV-2 infection during immunosuppressive treatment with basiliximab, tacrolimus, mycophenolate mofetil and prednisone. The man, who was diagnosed with primary sclerosing cholangitis and ulcerative colitis, was referred for liver transplantation in 2020. However, his kidney function was normal. Post-transplant, he received induction immunosuppressive treatment with basiliximab followed by standard maintenance immunosuppressive treatment with tacrolimus 1.5mg twice daily, mycophenolate mofetil 250mg twice daily and prednisone concomitantly with fluconazole as standard antifungal prophylaxis. After the surgery, he was admitted to the ICU for 4 days. On POD 2 and 7, the tacrolimus blood level was found to be 6.7 and 6.0 ng/mL, respectively. On POD 8, he was positively tested for SARS-CoV-2. Therefore, his therapy with mycophenolate mofetil was stopped. During his hospital stay of 14 days, no clinical or biochemical signs of infection were observed. However, procalcitonin and CRP levels were found to be low. The consecutive tacrolimus results were noted to be 5.1 and 7.4 ng/mL. Subsequently, his dose of prednisone was reduced to 10mg. On POD 22 and 23, his swab tests revealed negative results for COVID-19. Therefore, he was ultimately discharged home.