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

A 59-year-old woman developed hepatotoxicity during treatment with azathioprine and methotrexate for granulomatosis with polyangiitis and anti-neutrophil cytoplasmic antibodies associated systemic vasculitis. Additionally, she developed neutropenia secondary to rituximab and coronavirus disease 2019 pneumonia secondary to rituximab and methylprednisolone for granulomatosis with polyangiitis and anti-neutrophil cytoplasmic antibodies associated systemic vasculitis [not all dosages, routes and outcomes stated; durations of treatments to reactions onsets not stated].

The woman, who had granulomatosis with polyangiitis and anti-neutrophil cytoplasmic antibodies associated systemic vasculitis, received induction therapy with cyclophosphamide (in a total dose of 6g) and unspecified glucocorticoids intravenously and internally. She also received oral methylprednisolone [Metipred] at the maximum dose of 24mg per day. Despite the ongoing treatment, a complete remission of the disease was not achieved. Subsequently, she received methotrexate and azathioprine; however, she developed intolerance to methotrexate and azathioprine in the form of hepatotoxicity. In December 2017, she received a total of 3.5g of rituximab resulting in remission of the disease. Consequently, methylprednisolone was stopped in March 2019. Due to the identified IgG deficiency, she had been repeatedly treated with IV immune globulin [human immunoglobulin] injection, most recently in April 2019. On 3 March 2020, against the background of a stable state and the absence of laboratory signs of inflammatory activity due to the appearance of CD19+ B cells in the circulation (0.8%), a maintenance course of IV rituximab 500mg and pre-medication with IV methylprednisolone 250mg was given. One month later (i.e. on 6 April 2020), she developed drowsiness, headache, chills, fever, sore throat and nasal congestion. Two days later, she further developed nausea, diarrhoea, abdominal discomfort, dizziness, dry cough and increased weakness. On 8 April 2020, when examining a swab from the nasopharynx for COVID-19, the result of the polymerase chain reaction (PCR) was negative. From the 5^th day of the disease, shortness of breath was noted with little physical exertion. On 11 April 2020, investigations revealed the following: erythrocyte sedimentation rate (ESR) 13 mm/h, leukocytes 4.5 × 10⁹/L, lymphocytes 1.6 × 10⁹/L, neutrophils 2.4 × 10⁹/L, stab leucocytes 1% and platelets 231 × 10⁹/L. On day 9 of illness (i.e. on 14 April 2020), her condition failed to improve and oxygen saturation was 98%. A multispiral CT of the chest organs was performed, which revealed multiple bilateral foci of pulmonary tissue compaction of ground glass appearance, ranging in size from 16 to 21mm with areas of consolidation in S10 on the right. Repeat examination of the nasopharyngeal smear resulted in a positive PCR result for COVID-19, which was also identified in the patient's family members. She received off-label therapy with azithromycin, levofloxacin and ambroxol. A diagnosis of COVID-19 pneumonia was made on 16 April 2020. Her COVID-19 pneumonia was attributed to methylprednisolone and rituximab, as well as to neutropenia induced by rituximab.

The woman additionally received off-label therapy with hydroxychloroquine 400 mg/day after the confirmation of COVID-19 pneumonia. Thereafter, she developed sub-febrile body temperature, shortness of breath, decreased oxygen saturation, dizziness, nausea, diarrhoea, severe weakness and aches in the body. Further investigations performed on 19 April 2020 showed the following CRP 6.8 mg/L, ESR 7 mm/h, leucocytes 2.8 × 10⁹/L, lymphocytes 0.9 × 10⁹/L and neutrophils 1.8 × 10⁹/L, platelets 195 × 10⁹/L and Hb 149 g/L. From 20 April 2020, methylprednisolone was added at 4 mg/day which was increased to 8 mg/day two days later without significant improvement. Fluconazole and off-label metronidazole were prescribed. On 23 April 2020, she was transferred to another hospital in a state of moderate severity. At that time, examination revealed the following: SpO₂ 96%, CRP 28.8 mg/L, IgG 4.5 g/L, leucocytes 4.6 × 10⁹/L, neutrophils 4.2 × 10⁹/L, lymphocytes to 0.3 × 10⁹/L, platelets 229 × 10⁹/L and Hb 150 g/L. The AST, ATL, γ-glutamyl transpeptidase and creatinine levels were within the normal limits. Repeat PCR analysis of the nasopharyngeal swab showed COVID-19 positivity. Repeat multispiral CT of the chest showed an increase in interstitial changes like ground glass with the appearance of new extensive zones of injury and linear areas of consolidation of lung tissue. At the same time, some foci of compaction underwent partial regression and the size of the previously identified small cavity in S6 on the right had not changed. Thereafter, she received off-label therapy with lopinovir/ritonavir, sulbactam/amoxicillin, levofloxacin, cotrimoxazole [Biseptol] and a total of 10g of IV immune globulin [human immunoglobulin]. Additionally, she received enoxaparin sodium [enoxaparin]. One week later, nasopharyngeal swab test showed COVID-19 positivity; however, there was a decrease in CRP level. She was discharged from the hospital due to regression of fever and diarrhoea along with improvement in her oxygen saturation to 97%. On the 30^th day from the onset of the disease, CRP and complete blood count were within the normal limits. On the 45^th day, slight dyspnoea persisted during exercise and subpleural reticular changes were observed in the multispiral CT of the chest.