Hepatic Campylobacter jejuni infection in patients with Castleman-Kojima disease (idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome).

Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

Fatal case of TAFRO syndrome associated with over-immunosuppression: a case report and review of the literature.

TAFRO syndrome is a novel disease concept characterized by Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, Organomegaly, multiple lymphadenopathy and a histopathological pattern of atypical Castleman's disease. A 58-year-old man was diagnosed as TAFRO syndrome by clinical and histopathological findings. After receiving intensive immunosuppressive therapy, his thrombocytopenia and anasarca had not improved. He developed complications such as methicillin-resistant Staphylococcus aureus sepsis, gastrointestinal bleeding, peritonitis caused by Stenotrophomonas maltophilia, gastrointestinal perforation, and disseminated candidiasis resulting in death. Autopsy revealed disseminated candidiasis and hemophagocytic lymphohistiocytosis, with no evidence of TAFRO syndrome. During treatment, we regarded his lasting thrombocytopenia and anasarca as insufficient control of TAFRO syndrome. However, the autopsy revealed that thrombocytopenia was caused by secondary hemophagocytic lymphohistiocytosis caused by over-immunosuppression. We reviewed the published literature to identify indicators of adequate treatment, which suggested improvement of platelet count and anasarca several weeks after initial therapy. This indicated that we could not depend on the platelet count and anasarca in acute medical care after initial treatment. We should treat TAFRO syndrome based on patients' clinical status and obviate the risk of treatment-related complications caused by over-immunosuppression.

HIV-associated multicentric Castleman disease: a report of 4 cases and review of the literature.

BACKGROUND: Multicentric Castleman's disease (MCD) is a rare, non-clonal lymphoproliferative disorder characterized by constitutional symptoms, anaemia and generalised lymphadenopathy. Its incidence among the HIV-positive population seems to have increased during the past decades. AIM: The present study intends to compare demographic features, clinical presentation, laboratory studies, imaging results as well as treatment regimens and outcome in our MCD patients to those of larger reported series. METHOD: We reviewed the files of 920 HIV-1-infected patients from our AIDS Reference Centre. Data was collected from the operating software for the patients' medical records of our institution (Medical Explorer v3r3, Cliniques St Luc, 2008). RESULTS: We report a series of four cases of MCD among our HIV/AIDS patients' cohort. Three were of African origin. They were diagnosed after 2003, after a mean duration of 54 months of HIV-seropositivity (ranging from 7 to 120 months) All presented with characteristic clinical features and laboratory findings, and were started on HAART a few months before or upon MCD diagnosis. Three patients were treated with chemotherapy (ABV), and one with HAART only. One patient who was given ABV is in continuous remission after 3 years of follow-up. The remaining three are alive, with good symptom control, regardless of the treatment they received. CONCLUSION: MCD is a rare, but rising issue among HIV-infected patients. The clinical and paraclinical features of our series of four patients are in keeping with those of larger reported series. Currently, treatment is mainly chemotherapy-based, but a wide variety of protocols have been used, mainly because of the lack of available evidence. New approaches such as anti-CD 20 antibodies seem highly effective, and the role of HHV-8 needs to be further investigated, as it might be an important target for future treatment. In light of this review, we are looking forward to offer these opportunities to our patients, despite unhelpful regulations.

Kaposi's sarcoma-associated herpesvirus: from cell biology to pathogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is linked to the etiopathogenesis of Kaposi's sarcoma, a plasma-blastic variant of Castleman's disease and primary effusion lymphoma. KSHV is related to a number of non-human primate viruses. Only a limited number of KSHV proteins are expressed in tumor cells. Here we discuss the putative role of these proteins in KSHV pathogenesis.

[Detection of human herpesvirus 8 in patients with Kaposi's sarcoma or Castleman's disease associated with AIDS]. / Detección del herpesvirus humano 8 en pacientes con sarcoma de Kaposi o enfermedad de Castleman asociados al sida.

A new herpesvirus provisionally termed as KSHV or HHV-8 has been detected in lesions from AIDS-based Kaposi's sarcoma (KS) and from other KS clinical forms, and also in other tumors such as body cavity-based lymphomas or Castleman's disease (CD). We have assessed the presence of this novel herpesvirus in specimens from patients diagnosed with either AIDS and KS or AIDS and CD. DNA samples from skin lesions and peripheral blood obtained from 8 patients diagnosed with AIDS, seven with KS and one with multicentric CD were analyzed; skin specimens and peripheral blood samples from volunteer blood donors or from KS and CD free HIV seronegative patients were used as controls. Detection of the virus was done by PCR amplification of KS330 region, one of the HHV-8 sequences first reported. All skin lesions analysed tested positive for KS330; peripheral blood samples from 5 of the patients, including the one diagnosed with CD, showed also the virus sequence. All skin specimens and peripheral blood samples from controls were negative. From our results it can be concluded that the novel herpesvirus HHV-8 can also be detected in patients with AIDS-associated KS and AIDS-associated CD in Spain.

Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease.

Multicentric Castleman's disease (MCD) is an atypical lymphoproliferative disorder defined using clinical and pathologic criteria. A characteristic of the MCD is a close association with Kaposi's sarcoma (KS), which occurs during the clinical course of most human immunodeficiency virus (HIV)-associated MCD cases and also, but less frequently, in HIV-negative patients. Recently, sequences of a putative new Herpesvirus (KSHV) have been isolated and further detected in almost all the acquired immunodeficiency syndrome (AIDS) KS and in most of the non-AIDS KS samples. In this study, we searched for these Herpesvirus-like sequences in MCD samples of 31 patients. KSHV sequences were detected in 14 of 14 cases of HIV-associated MCD, including 5 cases without detectable KS. Moreover, KSHV was detected in 7 of 17 MCD cases in HIV-negative patients, including 1 case associated with a cutaneous KS. In 34 non-MCD reactive lymph nodes (follicular and/or interfollicular hyperplasia) in HIV-negative patients, KSHV was detected in only 1 case. In 1 HIV-negative case of MCD, KSHV was found in both the lymph node and peripheral blood samples. These data suggest that KSHV could play a role in the pathogenesis of MCD, especially in HIV-infected patients.

Disseminated persistent lymphoid hyperplasia containing Epstein-Barr virus and clonal rearrangements of DNA.

We describe the pathologic, molecular, and clinical features of a 52-year-old man who had a 7-year history of widely disseminated, persistent lymphoid hyperplasia. Exuberant follicular and interfollicular lymphoid hyperplasia with some histologic features of Castleman's disease were present at various times in the submental and cervical lymph nodes, lacrimal and parotid glands, right and left orbits, mediastinum, and hard palate of this patient. Flow cytometric and immunoperoxidase studies of two of the specimens indicated a slight predominance of cells expressing lambda-immunoglobulin light chain. In one specimen, there were clonal rearrangement of DNA coding for immunoglobulin heavy chain and for the T-cell beta-receptor. When DNA from this specimen was also examined by the polymerase chain reaction technique, Epstein-Barr viral DNA was detected. This case suggests that Epstein-Barr virus may be associated with an unusual form of aggressive and persistent lymphoid hyperplasia that contains clonal rearrangements of DNA.

Angiofollicular lymphoid hyperplasia (Castleman's disease) in two mice treated with polyoma virus or urethane.

Localized angiofollicular hyperplasia, otherwise known as Castleman's disease, is described in the lymph nodes of 2 mice of different strains, one inoculated with polyoma virus at birth and the other given urethane within 24 hr of birth. A plasma cell component in the lesion, suggestive of bone marrow stem cell involvement, was present in the mouse treated with polyoma virus but absent in the mouse given intraperitoneal urethane. Dysregulated interleukin 6 has recently been reported to produce the systemic variety of angiofollicular hyperplasia in mice, but the role of this cytokine in the localized variety described in this report is not known. This lesion appears to be rare in mice, but when present it could easily be missed or overlooked because the typical layering of follicle cells and the relatively large germinal centers seen in humans do not appear prominent in mice. Although there is, obviously, no proof of a causal relationship between the lesion and polyoma virus or urethane, it is suggested that this lesion be searched for in order to estimate its frequency and possible etiologic associations.

Clonal rearrangement for immunoglobulin and T-cell receptor genes in systemic Castleman's disease. Association with Epstein-Barr virus.

Castleman's disease is a morphologically and clinically heterogeneous lymphoproliferative disorder. Both a localized benign variant and an aggressive form with systemic manifestations have been described. To investigate the differences between these variants of Castleman's disease, the authors analyzed lymph node DNA from 4 patients with the localized type and 4 with the systemic type of Castleman's disease for immunoglobulin and T-cell receptor gene rearrangements. The role of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was also studied by viral genomic DNA probes. They detected clonal rearrangements in 3 of the 4 patients with the systemic variant of Castleman's; no patients with localized disease had rearrangements. Copies of EBV genome were also detected in 2 of the 3 patients with clonal rearrangements. These results suggest that systemic Castleman's disease is a disorder distinct from the classical localized variant in that it may evolve into a clonal lymphoproliferation.