Ciclosporin/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 72-year-old man exhibited lack of efficacy during treatment with rituximab and developed COVID-19 during treatment with ciclosporin and rituximab for acquired amegakaryocytic thrombocytopenia [routes and dosages not stated ].

The man, who had a history of aplastic anaemia and chronic kidney disease stage III, presented to the hospital due to cough, fever and progressive fatigue. He was diagnosed with aplastic anaemia in 2014 and the anaemia controlled with antithymocyte-globulin, methylprednisolone and ciclosporin [cyclosporine A]. Nine months later, he had progession of anaemia that required treatment with antithymocyte-globulin, methylprednisolone and ciclosporin. Later, in 2019, he had progression of thrombocytopenia due to acquired amegakaryocytic thrombocytopenia. Hence, 4 doses of rituximab were administrated in 2020. However, no response noted to rituximab therapy. His further investigational findings were consistent with acquired amegakaryocytic thrombocytopenia. He also received ciclosporin. However, his pancytopenia persisted despite treatment with ciclosporin and he required platelet transfusions. His physical examination at the presentation showed mild tachycardia, fever and normal oxygen saturation. He had mild respiratory distress and laboratory tests showed severe lymphopenia and increased CRP and IL-6. Chest x-ray demonstrated a consolidation in the left midlung, suggestive of pneumonia. Based on these findings, COVID-19 secondary to immunosuppression therapy with ciclosporin and rituximab was suspected [duration of treatment to reaction onset not stated].

The man then received off label treatment with hydroxychloroquine. Azithromycin and ceftriaxone were commenced for possible community acquired pneumonia. Subsequently, he was admitted and his nasal swab for COVID-19 showed positive result on the admission day 0. During hospitalisation, he had persistent fever and required oxygen support intermittently. Thereafter, he had progression of pancytopenia that required packed RBCs and platelet transfusions. Due to neutropenia and persistent high fever, prophylactic antibacterial therapy with cefepime and meropenem was started. Additionally, posaconazole was commenced for antifungal prophylaxis. Eltrombopag and filgrastim [tbo-filgrastim] were initiated for thrombocytopenia and severe neutropenia. On hospitalisation day 9, he developed hypoxia and lethargy, which required increased oxygen supplementation. Repeat chest x-ray showed worsening of pulmonary infiltrates bilaterally. His lab test showed elevation of inflammatory markers including CRP and ferritin. He also had worsening of acute on chronic renal failure. Cytokine storm due to severe COVID-19 was considered and he received off label treatment with methylprednisolone injection and then tocilizumab on hospitalisation day 11. On the same day, his fever had resolved and he experienced mild hypothermia. Eventually, his temperature became normal and oxygen requirements gradually decreased. Lab tests showed decrease in the inflammatory markers and resolution of the renal failure. He had persistent pancytopenia that required transfusion. Owing to neutropenia, his prophylactic therapy was switched from meropenem to oral levofloxacin. On hospitalisation day 18, he had recurrence of the fever and X-ray of the chest showed new pulmonary infiltratation. Hence, cefepime was re-started. Additionally, voriconazole and vancomycin were commenced. However, he had hypotension that resolved after fluid resuscitation therapy. Thereafter, antibiotic therapy with meropenem and tobramycin were initiated. Eventually, he had improvement in his clinical condition and it was considered that his clinical deterioration was due to bacterial pneumonia. Subsequently, he completed antibiotic therapy with vancomycin and meropenem that led to resolution of fever and normalization of oxygen requirement. His IL-6 level on hospitalisation day 28 was found to be elevated. He was discharged from hospital on day 31. At the time of discharge, he remained pancytopenic requiring transfusions. His PCR test was positive for COVID-19 on hospitalization day 29. Later, 22 days post-discharge, his PCR for SARS-CoV-2 showed negative result.