Multicentric Castleman's disease is a lymphoproliferative disorder manifesting with fever, lymphadenopathy, splenomegaly, raised inflammatory markers, and cytopenias. The clinical course ranges from indolent to fulminant [1,2]. The proliferation of polyclonal but often monotypic lymphoplasmocytoid cells is thought to be driven by human herpesvirus 8 [2–5]. Multicentric Castleman's disease can result in death by complex immune dysregulation leading to sepsis-induced and/or cytokine-induced multiorgan failure [2,6]. An optimal treatment algorithm for fulminant multicentric Castleman's disease is unknown because of the absence of controlled trials, and the outcome is usually fatal. We report on two patients who developed multicentric Castleman's disease-associated multiorgan failure. One of them achieved complete remission on treatment with corticosteroids and chemotherapy after failing to respond to rituximab monotherapy.
A 36-year-old man presented with a 4-month history of night sweats and fever. He had been diagnosed with HIV infection 3 years earlier and had been on highly active antiretroviral therapy (HAART); [most recently emtricitabine (200 mg), tenofovir (300 mg), and efavirenz (600 mg) daily] since diagnosis.
Examination revealed generalized lymphadenopathy and hepatosplenomegaly. Left inguinal lymph node excision biopsy showed plasma cell multicentric Castleman's disease (MCD) associated with perifollicular HHV8-positive cells. His HIV viral load on presentation was less than 50 copies/ml, the white blood cell count (WBC) was 8.4 × 109/l, and the CD4 count 280 × 106/l. HHV8 plasma viral DNA load was 26 400 copies/ml but it increased to 104 000 copies/ml in another measurement performed 7 days later.
He was commenced on rituximab 375 mg/m2. Four days later, he developed ascites, acute renal failure, cholestatic liver impairment, bilateral chest infiltrates with type I respiratory failure, and pancytopaenia. Haemofiltration was initiated, and the next day he suffered two asystolic cardiac arrests. He was successfully resuscitated but remained intubated and dependent on inotropic support. HAART medications were stopped due to worsening liver function and lactic acidosis. During the acute episode, the WBC and CD4 counts decreased to 1.3 × 109/l and 120 × 106/l, respectively, and the HIV viral load increased moderately to 2900 copies/ml. Treatment with prednisolone (100 mg daily) and reduced-dose ganciclovir (3 mg/kg daily) was started and the patient also received a single dose of vincristine (0.5 mg). As there was a marked improvement, he was extubated and discharged from intensive care unit. He continued chemotherapy with vincristine, bleomycin, rituximab, and ganciclovir (Fig. 1a). After recommencement of HAART [Kaletra (lopinavir/ritonavir) four capsules once daily], the CD4 count recovered to 490 × 106/l, the HIV viral load decreased to less than 50 copies/ml, and HHV8 viral load became undetectable. The patient remained well and without any MCD-related symptoms with a follow-up of 11 months.
A 32-year-old man diagnosed with HIV infection 6 years earlier presented with generalized body aches, lethargy, anorexia, and intermittent high fever. There was palpable hepatomegaly, splenomegaly, and generalized lymphadenopathy.
He had never been on HAART as his CD4 count had always been greater than 300 × 106/l despite a very high plasma HIV load in excess of 500 000 copies/ml. In the previous year, the CD4 count had been decreasing steadily from 680 × 106/l to 360 × 106/l, with WBC within the normal range.
Histology of a lymph node revealed the presence of HHV8-positive Kaposi sarcoma but this was not deemed to be a sufficient explanation for his problems and he went on to have a diagnostic splenectomy. Histological examination of the spleen and a hilar lymph node showed HHV8-positive plasma-cell MCD. His HHV8 load at this time was 96 000 copies/ml.
After the splenectomy, his HHV8 viral load decreased to 3600 copies/ml but he continued to have fever and fatigue. We started treatment with rituximab (375 mg/m2) weekly, ganciclovir (5 mg/kg) twice daily, and Kaletra (lopinavir/ritonavir) capsules once daily (Fig. 1b). However, his condition continued to deteriorate with thrombocytopenia and hypoalbuminaemia, and we decided to start vincristine (0.5 mg) and dexamethasone (16 mg) daily. On this therapy, he became afebrile, and peripheral blood cell counts and inflammatory markers normalized. However, the CD4 count continued to decrease to 130 × 106/l. The patient developed severe cachexia, became completely bed-bound, and died 1 month after the onset of fulminant MCD. Autopsy was not permitted by the family.
Rituximab has recently emerged as a promising agent for the treatment of MCD and is recommended as the first-line treatment in many centres. Despite its activity in relapsing MCD, rituximab alone may not be sufficient in fulminant MCD. In a report by Marcelin et al., the two patients who developed haematological failure died on treatment with rituximab alone. Our experience shows that the combination of nonmyelotoxic chemotherapy and high-dose corticosteroids together with intensive care support is capable of reversing MCD-associated multiorgan failure even in patients progressing on rituximab and should be considered as the next step in the treatment algorithm for fulminant MCD.
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