Cyclophosphamide/prednisolone/rituximab

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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

A 25-year-old man developed nosocomial COVID-19 infection during immunosuppressive therapy with cyclophosphamide, prednisolone and rituximab for eosinophilic granulomatosis with polyangiitis (EGPA) [not all dosages and routes stated].

The man, who was diagnosed with EGPA in early January 2020, presented to the emergency room with asthma, sinusitis and life-threatening myocardial infarction. A pulmonary CT scan was unremarkable. He immediately started receiving immunosuppressive therapy with IV high-dose prednisolone and IV cyclophosphamide, which showed adequate response. At the end of January 2020, IV prednisolone was changed to oral prednisolone. He developed a serious relapse of the disease with peripheral neuropathy, pulmonary haemorrhage and a second myocardial infarction [aetiologies unknown]. Due to severity of the disease, he was continuously admitted from January to March 2020 and had received IV infusion of cyclophosphamide (CYCLOPS-protocol) at a cumulative dose of 4.76g, rituximab 4 × 375 mg/m² infusion and a long-term, slowly tapered high-dose prednisolone up to 1 g/day. On presumed day 0 of nosocomial COVID-19, while receiving ongoing oral prednisolone 60mg daily (nine days after the last five cyclophosphamide infusions and 19 days after the last four rituximab infusions), he reported catarrh and a mild cough. A SARS-CoV-2 real-time reverse transcription PCR (rt-PCR) from oropharyngeal swab was positive. Thus, a diagnosis of nosocomial COVID-19 secondary to cyclophosphamide, prednisolone and rituximab was made [exact duration of treatments to reaction onset not stated].

On day 3, the man started was treated with off-label hydroxychloroquine for 6 days and off-label lopinavir/ritonavir for 8 days for nosocomial COVID-19. Also, his daily prednisolone was reduced from 60mg to 15mg, and IV prednisolone and cyclophosphamide were stopped. He developed a sore throat, diarrhoea, hyposmia, myalgias and headaches. In spite of rhonchi/crackles on auscultation and a CT scan consistent with bilateral viral pneumonia, he only had mild dyspnoea. He had short term decrease of oxygen saturation to minimal SaO₂ 85% and required oxygen supplementation for 3 days with a low flow of 2 L/min (during hospitalisation). Laboratory test revealed spiking serum concentrations of CRP at 125.9 mg/L, procalcitonin at 0.56 ng/mL and interleukin-6 at 320 pg/mL. Also, his CD4+ and CD8+ T-cell counts decreased, and he developed fever with maximum temperature of 39.1°C on day 7. Anti-interleukin-6 treatment was considered; however, he steadily recovered and was free of COVID-19 symptoms 2 weeks after onset. The subsequent oropharyngeal swabs confirmed active SARS-CoV-2 infection with gradual decrease of viral RNA.

Relapsing neurological symptoms of EGPA led to re-administration of high-dose IV prednisolone and IV cyclophosphamide on days 14 and 20, respectively, without causing recurrence of COVID-19-related symptoms. Despite severe immunosuppression and complete peripheral B-cell depletion, SARS-CoV-2 RNA copy numbers in oropharyngeal swabs were below the threshold for reliable detection on days 25, 26 and 29. By day 46, there were no antibodies to SARS-CoV-2 spike protein detectable by ELISA. Also, interferon-γ release upon polyclonal T-cell stimulation was normal on day 36.