EBV+ and Kaposi’s Sarcoma Herpesvirus‐Associated Multicentric Castleman Disease in a Patient With HIV Infection: A Case Report

Renal Involvement in Multicentric Castleman Disease With Glomeruloid Hemangioma of Skin and Plasmacytoma

Idiopathic multicentric Castleman's disease: a systematic literature review

Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome is a rare multi-systematic disorder of uncertain etiology, if associated with multicentric Castleman's disease, it can lead to a more serious condition. We here presented a case of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome in a 37-year-old male patient who initially presented with progressive lower limb weakness accompanied by pain, low skin temperature, and hyperpigmentation. He was admitted with increasingly serious dyspnea and lower leg edema. Fluid of serous cavities in the patient were also indicated in ultrasonic inspection and X-ray. Furthermore, biopsy of a left axillary lymph node showed mixed hyaline-vascular and plasma cell type of multicentric Castleman's disease. Administration of bortezomib (Velcade) (1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle) combined with thalidomide (100 mg/day and 21-day cycle) dramatically improved the condition of this disease. Of note, in our study, combination therapy of bortezomib and thalidomide successfully improved the condition of the patient with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome associated with multicentric Castleman's disease, suggesting that the combination therapy may be an effective therapeutic strategy for the intractable polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome associated with multicentric Castleman's disease.

Highly active antiretroviral therapy alone may be an effective treatment for HIV-associated multi-centric Castleman's disease

We report a case of multicentric Castleman’ s disease (MCD), in an HIV-infected patient successfully treated with anti CD-20 monoclonal antibody Mabthera (rituximab), an agent used for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma [1]. In December 2001, a 61-year-old man was admitted to our hospital because of high-grade fever, profound malaise, fatigue weight loss and, night sweats. Two months before admission the diagnosis of HIV infection and MCD was made at another hospital. The patient started steroids and highly active antiretroviral therapy (HAART) and discharged feeling well. Physical examination revealed cervical lymphadenopathy. Laboratory tests showed a mild Coombs negative normocytic anaemia, a slight lymphocytosis, elevated erythrocyte sedimentaion rate, diffuse hypergammaglobulinaemia, increased serum C-reactive protein and lactate dehydrogenase, and negative PRC test for human herpes virus type 8 (HHV-8) infection. Bone marrow examination revealed the presence of dysplastic myeloid cells and increased proportions of polytypic plasma cells (6%). An abdominal computed tomography scan revealed several homogenous enlarged lymph nodes in the retroperitoneal mesenteric and pelvic region and a chest high resolution computed tomography (HRCT) disclosed several lymph nodes with a diameter greater than 1 cm in the mediastinum and axillary region intraparenchymal nodules and in the subpleural area. Biopsy of a supraclavicular lymph node established once again the diagnosis of MCD. The patient was treated with steroids and discharged 3 weeks later in a good condition. During the next months, the patient presented with generalized pruritus associated with a papulomacular rash, and a steroid induced myopathy for which he refused to continue any treatment. In September 2002, he was readmitted to our department with the same symptomatology as above – high-grade fever, sweats, malaise, fatigue, weight loss and lymphadenopathy. The patient was commenced on rituximab at 375 mg/m2 once a week for 4 consecutive weeks. No adverse reactions were observed. At the end of the first week the patient's condition was significantly improved, all his symptoms had subsided and he was able to restart his HIV medication. The patient received a second course of therapy with rituximab as above 3 months later. At the end of any course the patient was evaluated with a computed tomography scan of the chest and the abdomen. A significant decrease in the lymph nodes size was noted. MCD, also known as multicentric lymphoid angio-follicular hyperplasia, is a distinct lymphoproliferative disorder characterized by polyclonal lymphoid proliferation associated with vascular hyperplasia and plasma cell infiltration [2]. The condition may present either as isolated MCD or as MCD combined with Kaposi's sarcoma or non-Hodgkin's lymphoma [2,3]. Virtually all MCD patients are symptomatic. Systemic signs include fever of varying degree, malaise, fatigue, weight loss, sweating, pulmonary symptoms, skin rash, peripheral oedema, generalized lymphadenopathy and hepato-splenomegaly as in our patient [2,4]. MCD is a rare condition in HIV-infected patients and the outcome is often fatal in the absence of treatment. Treatment options include steroids, chemotherapeutic agents, and monoclonal antibodies neutralizing human interleukin-6 [4,5]. In HIV-infected patients, MCD is frequently associated with Kaposi's sarcoma related to HHV-8 infection. B-cell lymphoma is also found with increased incidence in HIV related MCD [5–7]. Recently, a long-term remission of Kaposi's sarcoma-associated HHV-8 related MCD was reported in an HIV-infected patient with the administration of a chimeric anti-CD20 monoclonal antibody, Rituximab [8]. HIV-related MCD has been considered as a distinct type of MCD associated with the presence of HHV-8 positive Epstein–Barr virus-negative plasma cells in the lymphoid organs. It has been suggested that these cells derive from naive B-cells expressing λ-heavy and λ-light chains (IgMλ) and form sheets of cells in the mantle and interfollicular zones [6,7]. This cell population may proliferate to form non-Hodgkin's lymphoma, or may be controlled by the immune system or low-dose chemotherapy or administration of rituximab. It is notable that MCD may develop and progress in HIV infected patients as in our case, as an independent disorder despite undetectable viral load and high CD4 cell count resulting from HAART [8]. In conclusion, rituximab is effective in the treatment of MCD in HIV-infected patients and should be added to the list of therapeutic means for the otherwise fatal disorder. In our patient, clinical manifestations were completely resolved, and a remarkable reduction in the size of enlarged lymph nodes was documented. No relapse of the disease was noted 1 year after the cessation of treatment. Importantly, the beneficial effect of the drug was documented as early as 1 week after the first course of treatment.

IntroductionHuman herpes virus 8 (HHV-8) is mainly responsible for the development of Kaposi's sarcoma and multicentric Castleman's disease in immunocompromised patients with untreated human immunodeficiency virus. Positive viral loads have been described in cases of Kaposi's sarcoma and multicentric Castleman's disease, with higher values found in the latter. We describe the case of a patient with HIV in whom a high level of HHV-8 replication was detected and who contracted an opportunistic disease other than multicentric Castleman's disease or Kaposi's sarcoma.Case presentationA 25-year-old man of West African origin with HIV complained of asthenia, weight loss, fever, and abdominal pain. Physical examination revealed that the patient had adenopathies and hepatosplenomegaly, but no skin or mucosal lesions were seen. Our first presumptive diagnosis was disseminated tuberculosis. However, since the cultures (sputum, bronchoalveolar lavage, blood, urine and lymph node biopsies) for mycobacteria were negative, the diagnosis was expanded to include multicentric Castleman's disease which was supported by high HHV-8 viral loads in the patient's blood: 196,000 copies/ml in whole blood, 39,400 copies/ml in plasma and 260 copies/10E5 in peripheral blood mononuclear cells. However, the histology and positive polymerase chain reaction assay for Mycobacterium tuberculosis complex of a second lymph node biopsy enabled us to conclude that the patient had disseminated tuberculosis and we started the patient on antituberculosis treatment.We analyzed the HHV-8 deoxyribonucleic acid in two other plasma samples (one from six months earlier and the other was 10 days after the positive test) and both yielded negative results. A search for latent and lytic HHV-8 antibodies confirmed that the patient was seropositive for HHV-8 before this episode.ConclusionWe describe the case of a patient with HIV who tested positive for asymptomatic HHV-8 replication during an opportunistic disease suggestive of multicentric Castleman's disease. The initial analysis was nullified by the diagnosis of a disease that was unrelated to HHV-8. This case report underlines the need to clarify the full clinical meaning and implication of a positive HHV-8 viral load in patients with AIDS. The diagnosis of multicentric Castleman's disease needs to be studied further to determine its sensitivity and specificity. Finally, when faced with the dilemma of urgently starting chemotherapy on a patient whose condition is deteriorating and whose clinical presentation suggests multicentric Castleman's disease, high HHV-8 viral loads should be interpreted with caution and histological analysis of lymph nodes or liver biopsies should be obtained first.

Synergistic Risks: The Impact of HIV on Kaposi Sarcoma and Lymphoma Incidence in Castleman's Disease

HHV-8-Negative, Idiopathic Multicentric Castleman Disease (iMCD): A Description of Clinical Features and Therapeutic Options through a Systematic Literature Review

HHV8 Associated Multicentric Castleman's Disease In a HIV Negative Patient Responding to Treatment with Bortezomib and Gancyclovir- A Novel Therapy for An Orphan Disease

Castleman's Disease's Clinical Course and Management: A Study of 20 Cases

The pulmonary manifestations of HIV disease in 2005 can be divided into two sets of presentations. For patients who do not have access to care, and who are not taking antiretroviral or chemoprophylactic drugs, opportunistic infections and neoplasms continue to occur. Pulmonary disease caused by Streptococcus pneumoniae, Pneumocystis carinii (now known as Pneumocystis jiroveci pneumonia; PCP), Mycobacterium tuberculosis, lymphoma, and Kaposi’s sarcoma present much as they did in the 1980s. Management has improved in terms of new diagnostic, therapeutic, and preventive strategies, as reviewed in guidelines issued jointly by the National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Disease Society of America (available online at http://www.aidsinfo.nih.gov).

Interferon-α as first-line therapy for treatment of multicentric Castleman's disease

Background: Castleman disease (CD) is a very rare non-malignant lymphoproliferation of undetermined origin. CD diagnosis is difficult and often delayed because of insidious onset, low awareness and clinical heterogeneity. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis confirmation is based on histopathological findings on an involved lymph node. Objectives: We attempted to survey all cases of paediatric CD identified in France so far, in order to set up a national registry aimed to improve CD early recognition, treatment and follow-up, within the context of a new reference centre (http://www.castleman.fr). Methods: In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the French paediatric rheumatology society and the French Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory. Results: We identified 23 patients (12 girls and 11 boys) diagnosed with UCD (n=17) and MCD (n=6) between 1994 and 2018 in 14 centres. The average age at first symptoms was 11.5 years for UCD and 8.3 years for MCD. The mean diagnosis delay was 8.2 months for UCD and 5.2 years for MCD. In UCD, the initial symptoms were: isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7), fever was present in 3 patients. Patients with MCD presented with fever (n=5), abdominal lymph nodes (n=5), failure to thrive (n=3), hepatomegaly and/or splenomegaly (n=3), arthralgia (n=2), abdominal pain (n=2), fatigue (n=2), facial oedema (n=1), isolated lymphadenopathy (n=1), trunk rash (n=1), vascular hepatopathy with oesophageal varicose veins (n=1), diarrhea (n=1) or cholestasis (n=1). One patient had a Duchenne muscular dystrophy. No patients had HIV or HHV8 infection. In MCD cases, one patient with recurrent fevers, had a heterozygous mutation in MEFV gene and another had a homozygous mutation in TNFRSF1A gene (P75L). A UCD patient experienced fever episodes and pericarditis two years after surgery. Genetic tests revealed one heterozygous mutation in IL10RA gene (V406L) and one in IL36RN gene (S113L). Nevertheless, our patient did not have any psoriasis or inflammatory bowel disease. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatments of MCD were tocilizumab, rituximab, anakinra, steroids, chemotherapy and splenectomy. Overall survival after an average of 6 years of follow-up, was 100% for both unicentric and multicentric forms. Conclusion: Paediatric CD seems still underdiagnosed with a significant diagnosis delay specially for the MCD but new international criteria will help in future. In UCD, surgery is the main treatment. New drugs are used specially for the MCD, but more studies need to be conduct in children. The global survey is better in children than adults. Disclosure of Interests: Charlotte Borocco: None declared, Claire Ballot-Schmit: None declared, Oanez Ackermann: None declared, Nathalie Aladjidi: None declared, Jeremie Delaleu: None declared, Vannina Giacobbi-Milet: None declared, Sarah Jannier: None declared, Eric Jeziorski: None declared, Yves Perel: None declared, Francois Maurier: None declared, Christophe Piguet: None declared, Eric Oksenhendler: None declared, Isabelle Kone-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, Caroline Galeotti: None declared

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder characterized by lymph node histopathology and systemic symptoms. To our knowledge, there are no descriptions in the literature of long-term outcomes of human herpesvirus-8 (HHV-8)-associated MCD. We report a case of a 70-year-old male living with human immunodeficiency virus and a history of human herpesvirus-8 (HHV-8)-associated MCD. The patient reported having had low-grade fever for two weeks. Extensive workup revealed systemic lymphadenopathy without evidence of autoimmune disease or malignancy. Lymph node biopsy was consistent with HHV-8-negative idiopathic MCD (iMCD). The patient was subsequently scheduled for anti-interleukin-6 therapy. The present case is the first report of probable development of iMCD after long-term follow-up for HHV-8-associated MCD. The case illustrates the possible long-term consequences of MCD, suggesting the necessity of further research on the pathogenesis of CD. Given the uncertainty in the long-term outcomes of HHV-8-associated MCD, periodic surveillance of patients with a history of HHV-8-associated MCD is warranted. Prospective nationwide cohort studies comparing characteristics of HHV-8-associated MCD and iMCD would bring further insights. This is the first case describing the probable development of HHV-8-negative idiopathic MCD after HHV-8-associated MCD.Little is known of long-term outcomes of HHV-8-associated MCD and idiopathic MCD, necessitating periodic surveillance.HHV-8-negative idiopathic MCD patients are treated with siltuximab, an interleukin-6 inhibitor, unlike patients with HHV-8-associated MCD, who benefit most from rituximab.

Rituximab failure in fulminant multicentric HIV/human herpesvirus 8-associated Castleman's disease with multiorgan failure: report of two cases