Severe infectious complications in a patient treated with rituximab for idiopathic thrombocytopenic purpura
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- Fianchi, L., Rossi, E., Murri, R. et al. Ann Hematol (2007) 86: 225. doi:10.1007/s00277-006-0206-1
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Rituximab has been recently employed in the treatment of patients with refractory chronic idiopathic thrombocytopenic purpura (ITP). Rarely, infectious complications due to rituximab treatment in chronic ITP are registered [1, 2].
In a 39-year-old immunocompetent man, after treatment with Clopidogrel for an acute coronary syndrome, diagnosis of ITP [platelet count (Plt) 59 × 109/l] was established on April 2003. He did not receive any treatment for more than 1 year due to Plt > 30 × 109/l. In January 2005, he presented a progressive reduction of Plt until 13 × 109/l and gingival bleeding; he started treatment with high-dose dexamethasone 40 mg p.o. pulsed for 4 days every 2 weeks , obtaining after three courses a partial response (Plt between 30 and 50 × 109).
In June 2005, Plt dropped to 23 × 109/l. Low doses of prednisone p.o. (10 mg every other day) was started, achieving a Plt > 30 × 109/l. On November 2005, because of unstable Plt, the patient was candidate to a second-line treatment; cardiopathy was considered a relative contraindication to splenectomy, and the patient started therapy with rituximab. He received four courses of rituximab (375 mg/m2 i.v.) at weekly intervals achieving a partial response (Plt 64 × 109/l). After 2 weeks from the last rituximab administration, the patient had fever, cough and thorax pain, and he was admitted to the hospital. At admission, he presented a normal neutrophil value (3.8 × 109/l), a lymphocyte count lower than 0.4 × 109/l and a mild hypogammaglobulinaemia. Chest X-ray showed a basal pulmonary infiltrate, and broad-spectrum antibiotic therapy was started (piperacillin/tazobactam 4.5 g every 8 h). On the third day from admission, serological positivity (IgA) for Mycoplasma pneumoniae was evidenced, and clarithromycin was added. After 5 days on antibiotic treatment, fever persisted, the patient’s clinical condition rapidly worsened, and he was transferred to the ICU for respiratory failure necessitating mechanical ventilation. A chest computed tomography (CT) scan documented a pleura-based mass-like infiltrate with a surrounding halo of ground glass attenuation compatible with fungal infection. From microbiological and histological examinations of broncho-alveolar lavage fluid performed with brushing, Aspergillus niger was detected, and voriconazole i.v. therapy (two doses of 6 mg/kg then 4 mg/kg every 12 h) was started. After 3 days on antifungal therapy, fever and clinical condition improved. A new chest CT scan showed an improvement of the pulmonary lesions. A total of 15 days on i.v. voriconazole treatment was made, and then the patient was discharged from the hospital with oral voriconazole and clarithromycin. At 4 weeks from discharge, chest CT scan did not show any pulmonary parenchymal alterations, and the therapy was stopped.
Conventional treatment of ITP is based on the employment of corticosteroids, other immunosuppressive drugs (e.g. cyclosporin), immunoglobulin, danazole and splenectomy.
Debilitating side effects are common when long-term high-dose steroid therapy is required to maintain Plt, and serious infections have been observed in patients who have received daily prednisone treatment for only several weeks .
Modern treatments of autoimmune diseases add to conventional approaches to immunological therapies. Opportunistic infections are rarely reported during rituximab treatment for non-neoplastic conditions where the decrease in the neutrophil count is not clinically significant, and sustained neutropenia rarely occurs . Evidence for the use of antifungal drugs in patients not undergoing transplantation is poor to support prophylaxis, and at present, there are no evidence-based data for the use of antifungal prophylaxis in patients receiving monoclonal antibody treatments both for neoplastic and non-neoplastic conditions.
In our patient, immunosuppression of degree sufficient to permit the development of aspergillosis was probably the combined result of previous corticosteroids treatment and defect in cell-mediated and humoral immunity due to rituximab use. A. niger pneumonia is generally rare and is observed, above all, in neutropenic patients; it is characterized by a high mortality rate . In our case, the timely use of mechanical ventilation, an effective antifungal therapy and a normal neutrophil count justified the favourable outcome.
In the future, the increasing use of immunological therapies could lead to the rise in the proportion of “non-neutropenic” patients who might develop severe infectious complications.