Mycophenolate mofetil/prednisone/tacrolimus

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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 study 5700 patients who treated between 14 March 2020 to 19 April 2020 in USA, five patients (4 men and 1 woman), aged 45−68 years, were described, who developed coronavirus disease 2019 (COVID-19) during immunosuppressive treatment with mycophenolate mofetil, prednisone or tacrolimus [routes and times to reactions onsets not stated].

Patient 01 (a 45-year-old man): The man was admitted to a hospital in March 2020 for the heart transplantation. He had a history of systemic hypertension. The post-transplant maintenance immunosuppressive treatment included mycophenolate mofetil 2000mg, prednisone 30mg and tacrolimus 6mg. During the course of admission, he showed symptoms of cough and dyspneoa. Vital signs on presentation included body temperature 36.6°C, BP 117/58mm Hg, HR 85 beats/minute, respiratory rate 18 breaths/minute, oxygen saturation 95%. Laboratory tests on presentation included WBC count 18.2 K/µL, absolute lymphocyte count 850/μL, serum creatinine 1.4 mg/dL, eGFR 60 mL/min/1.73m ², AST/ALT 14/16 U/L, albumin 3.4 g/dL, C-reactive protein 3.4 mg/L, D-dimer 2534 ng/mL (D-dimer unit), LDH 504 U/L, ferritin 163 ng/mL, troponin T high sensitivity 892 ng/L and tacrolimus trough level 20.4 ng/mL. Chest imaging showed bilateral ground-glass opacities. Given the laboratory result, he was diagnosed with moderate COVID-19 secondary to immunosuppressive treatment. In response to COVID-19, mycophenolate mofetil was discontinued, the dose of tacrolimus was reduced and therapy with prednisone was continued. He was treated with remdesivir and off-label therapy with hydroxychloroquine. After 2 week of COVID-19 diagnosis, histopathology study showed a mild acute cellular rejection. After 27 days of prolonged hospitalization, he was discharged home with clinically uneventful course depicted through peak serum creatinine concentration 2 mg/dL and peak C-reactive protein 9.2 mg/L.

Patient 02 (a 68-year-old woman): The woman was admitted to a hospital in 2020 for the heart transplantation. She showed a history of systemic hypertension. The post-transplant maintenance immunosuppressive treatment included mycophenolate mofetil 500 mg and tacrolimus 6mg. During the course of admission, she showed symptoms of fever, cough, diarrohea and rigors. Vital signs on presentation included body temperature 36.9°C, BP 111/72mm Hg, HR 102 beats/minute, respiratory rate 18 breaths/minute, oxygen saturation 100%. Laboratory tests on presentation included WBC count 4.5 K/µL, absolute lymphocyte count 870 /μL, serum creatinine 1.3 mg/dL, eGFR 41 mL/min/1.73 m2 (acute kidney injury), AST/ALT 26/14 U/L, albumin 4.3 g/dL, C-reactive protein 2.4 mg/L, LDH 180 U/L, procalcitonin 0.1 ng/mL, ferritin 89 ng/mL, and tacrolimus trough level 7.7 ng/mL. Chest imaging showed bilateral ground-glass opacities. Given the laboratory result, she was diagnosed with moderate COVID-19 secondary to immunosuppressive treatment. In response to COVID-19, mycophenolate mofetil was discontinued and the dose of tacrolimus was reduced. Treatment course included off-label therapy with hydroxychloroquine. After 6 days of prolonged hospitalization, she was discharged home with clinically uneventful course depicted through peak serum creatinine concentration 1.3 mg/dL and peak C-reactive protein 3.1 mg/L.

Patient 03 (a 67-year-old man): The man was admitted to a hospital in 2020 for the heart transplantation. He showed a history of systemic hypertension, ischaemic cardiomyopathy, hyperlipidaemia, obesity, post-transplant renal insufficiency. The post-transplant maintenance immunosuppressive treatment included mycophenolate mofetil 1000 mg and tacrolimus 10mg. During the course of admission, he showed symptoms of fever, cough, diarrohea and rigors. Vital signs on presentation included body temperature 39.3°C, BP 126/88mm Hg, HR 109 beats/minute, respiratory rate 23 breaths/minute, oxygen saturation 100%. Laboratory tests on presentation included WBC count 4.7 K/µL, absolute lymphocyte count 1260 /μL, serum creatinine 1.7 mg/dL, eGFR 49 mL/min/1.73 m2 (acute kidney injury), AST/ALT 16/14 U/L, albumin 4 g/dL, C-reactive protein 10.7 mg/L, LDH 222 U/L, procalcitonin 0.2 ng/mL and tacrolimus trough level 8 ng/mL. Chest imaging showed bilateral ground-glass opacities. Given the laboratory result, he was diagnosed with moderate COVID-19 secondary to immunosuppressive treatment. In response to COVID-19, mycophenolate mofetil was discontinued and the therapy with tacrolimus was ongoing. Treatment course included off-label therapy with hydroxychloroquine. After 23 days of prolonged hospitalization, he was discharged home with clinically uneventful course depicted through peak serum creatinine concentration 1.9 mg/dL and peak C-reactive protein 10.7 mg/L.

Patient 04 (a 62-year-old man): The man was admitted to a hospital in 2020 for the heart transplantation. He showed a history of systemic hypertension and hyperlipidaemia. The post-transplant maintenance immunosuppressive treatment included prednisone 15mg, mycophenolate mofetil 2000 mg and tacrolimus 2mg. During the course of admission, he showed symptoms of cough, dyspnea and diarrohea. Vital signs on presentation included body temperature 37.1°C, BP 105/78mm Hg, HR 90 beats/minute, respiratory rate 43 breaths/minute, oxygen saturation 86%. Laboratory tests on presentation included WBC count 7.4 K/µL, absolute lymphocyte count 270 /μL (lymphocytic lymphopenia), serum creatinine 1.9 mg/dL, eGFR 43 mL/min/1.73 m2 (acute kidney injury), AST/ALT 45/30 U/L, albumin 3.2 g/dL, C-reactive protein 18.7 mg/L, D-Dimer 6000 ng/mL (D-dimer units), LDH 579 U/L, procalcitonin 5.3 ng/mL, ferritin 417 ng/mL, troponin T high sensitivity 111 ng/L and tacrolimus trough level 24 ng/mL. Chest imaging showed bilateral ground-glass opacities. Given the laboratory result, he was diagnosed with severe COVID-19 secondary to immunosuppressive treatment. In response to COVID-19, mycophenolate mofetil was discontinued, the dose of tacrolimus reduced and prednisone dose increased. Treatment course included off-label therapy with convalescent-anti-SARS-CoV-2-plasma [convalescent plasma] and tocilizumab. Additionally, he was shifted to the ICU and provided with invasive mechanical ventilation due to acute respiratory failure secondary to acute respiratory distress syndrome. Peak serum creatinine concentration noted as 3.9 mg/dL and peak C-reactive protein 27.9 mg/L. Two days following treatment with tocilizumab, peak C-reactive protein reduced to 8.5 mg/L. He underwent tracheostomy to facilitate ventilator weaning and developed oliguric renal failure necessitating haemodialysis, though he has since demonstrated partial renal recovery and no longer dependent on haemodialysis. As of hospital day 38, he remained stable for prolonged periods (>24 hours) without ventilator support. He underwent repeat qualitative nucleic acid testing for SARS-CoV-2 on hospital day 34, at which point the viral RNA remained detectable.

Patient 05 (a 68-year-old man): The man was admitted to a hospital in 2020 for the heart transplantation. He showed a history of systemic hypertension, ischaemic cardiomyopathy, hyperlipidaemia, diabetes mellitus, obesity and post-transplant renal insufficiency. The post-transplant maintenance immunosuppressive treatment included prednisone 15mg, mycophenolate mofetil 2000 mg and tacrolimus 6mg. During the course of admission, he showed symptoms of fever, cough and diarrohea. Vital signs on presentation included body temperature 36.6°C, BP 117/69mm Hg, HR 78 beats/minute, respiratory rate 17 breaths/minute, oxygen saturation 98%. Laboratory tests on presentation included WBC count 7.8 K/µL, absolute lymphocyte count 200 /μL (lymphocytic lymphopenia), serum creatinine 1.6 mg/dL, eGFR 45 mL/min/1.73 m2 (acute kidney injury), AST/ALT 13/16 U/L, albumin 3.1 g/dL, C-reactive protein 16.9 mg/L, D-Dimer 1194 ng/mL (D-dimer units), LDH 365 U/L, procalcitonin 0.72 ng/mL, ferritin 512 ng/mL, troponin T high sensitivity 292 ng/L and tacrolimus trough level 17.9 ng/mL. Chest imaging showed bilateral ground-glass opacities. Given the laboratory result, he was diagnosed with severe COVID-19 secondary to immunosuppressive treatment. In response to COVID-19, mycophenolate mofetil was discontinued, the dose of tacrolimus reduced and therapy with prednisone continued. Treatment course included off-label therapy with convalescent-anti-SARS-CoV-2-plasma [convalescent plasma]. Additionally, he was shifted to the ICU and provided with invasive mechanical ventilation due to acute respiratory failure secondary to ARDS. He also developed Staphylococcus epidermidis bacteremia and required a sternal wound debridement with pectoral muscle flap advancement for management of a deep sternal wound infection. He also underwent tracheostomy, but showed respiratory improvement and required only minimal periods of ventilatory support. After 21 days of prolonged hospitalization, he remained inpatient, but showed clinical improvement. Peak serum creatinine concentration noted as 3 mg/dL and peak C-reactive protein 18.2 mg/L. He underwent repeat testing for SARS-CoV-2 on hospital days 36 and 37, and in both cases viral RNA was not detected.