Background: Castleman disease comprises a rare and heterogeneous cluster of disorders, characterized by lymphadenopathy with unique histological features and associated with cytokine-driven constitutional symptoms and biochemical disturbances. Unicentric CD (UCD) is curable with complete surgical excision, but its multicentric counterpart (MCD) is a diagnostic and therapeutic challenge. Monoclonal antibodies to interleukin-6 and its receptor allow more targeted disease-specific intervention. The incidence of human immunodeficiency virus (HIV) HHV-8 associated MCD is increasing. Because MCD presents often as a diagnostic dilemma in a systemically unwell individual, familiarity with MCD and its treatment are of benefit to infectious diseases subspecialists.

Objectives: We will review a challenging pediatric MCD case, present diagnostic workup and discuss current treatment approaches.
Case: A 14-year old boy developed chest pain, abdominal pain, shortness of breath and nausea. He was thought to have viral pericarditis and received colchicine with no benefit. He subsequently developed intermittent fevers, night sweats and increase in abdominal girth. Physical examination revealed moderate ascites, peripheral edema, lymphadenopathy and hepatosplenomegaly. His blood work showed elevation in inflammatory markers (CRP 258 mg/L, ESR 48 mm/hr), D-Dimer (> 10mg/L FEU), liver enzymes and creatinine. His hemoglobin was 80, platelets normal throughout, and his WBC fluxuated. His infectious workup was negative (EBV, CMV, Hepatitis, HIV, HTLV, Brucella, coxiella, parvovirus, mycoplasma, stronglyloides, schistosomaiasis, HHV8, TB). He developed features consistent with macrophage activation syndrome (MAS), and was initially treated with IVIG and IV methylprednisolone. He underwent lymphnode biopsy which was consistent with MCD. His chest and abdominal CT was negative for a malignancy.

Results: Once MCD was confirmed, he received Tocilizumab (IL -6 blocker). He had no response and Anakinra, an IL-1 blocker, was added with some improvement. Eventually, IL-6 receptor antagonist, Siltuximab was added, and other biologics were discontinued. After siltuximab, his, inflammatory markers and renal failure improved but his ascites persisted and he was eventually diagnosed with MCD related portal hypertension.

Conclusion: MCD is a serious condition, and should be considered in patients who present with multisystem disease with fever of unknown origin. In the presence of lymphadenopathy, a biopsy should be considered. Treatment can be challenging, and current guidelines suggest IL-6-blockade as the first line approach. However, patients may have various response rates to individual anti-IL-6 therapy and may require additional immunosuppressive therapy. It is important to investigate for infectious, malignant and autoimmune conditions, as MCD can be associated with each of these disease processes.


Dr. Paivi Miettunen is a paediatric rheumatologist at Alberta Children’s Hospital, and an associate professor at the Cumming’s School of Medicine, University of Calgary, Calgary, AB, Canada. She has been involved in local, national and international research focused on bone health in pediatric leukemia (osteonecrosis), treatment and imaging of chronic recurrent multifocal osteomyelitis (CRMO), and treatment of macrophage activation syndrome (MAS).
She is a part of EURO-FEVER, an international research network for rare autoinflammatory diseases. She has published widely on autoinflammatory conditions (MAS, CRMO, periodic fevers) and has lectured internationally on these diseases.