Multicentric Castleman's Disease Research Articles

Evaluation of two commercial diagnostic methods for HHV-8 viral load assessment

ObjectivesHuman herpesvirus-8 (HHV-8) can cause Kaposi's sarcoma or B lymphoproliferative disorders such as multicentric Castleman disease. Patient follow-up is based on assessing the HHV-8 viral load, which is usually achieved using real-time polymerase chain reaction (PCR). The HHV-8 Premix r-gene kit (BioMérieux) was used by some laboratories in the past, but BioMérieux ceased the production and distribution of this kit in 2021-2022. Other kits need to be tested so that they can be used for diagnostic purposes. Here we evaluated two commercial kits: HHV8 ELITe MGB Kit (ELITech) and Quanty HHV-8 (Clonit) and compared them with the HHV-8 Premix r-gene kit. MethodsWe used whole blood samples that had previously been tested with the HHV-8 Premix r-gene kit for diagnostic purposes. Overall, 46 samples (37 HHV-8-positive and 9 HHV-8-negative) were tested with the ELITe MGB Kit and 37 (29 HHV-8-positive and 8 HHV-8-negative) with the Quanty HHV-8 kit. The different methods were compared using Bland-Altman and Passing-Bablok tests with Analyse-it software. ResultsQualitative results were concordant except for one HHV-8 low-positive sample that was found to be negative by the ELITe MGB Kit. The quantitative results were also concordant; both kits showed mean differences of 0.58 log10 copies/ml and 0.73 log10 copies/ml, respectively, compared to the Premix r-gene kit. ConclusionsBoth the methods tested produced acceptable results and could be used for diagnostic purposes. It should be remembered that there is no international standard for HHV-8 quantification and that patients should always be followed using the same method.

Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study.

Refractory/relapsed idiopathic multicentric Castleman disease (R/R iMCD) has limited treatment options. With studies showing increased mTOR activation in iMCD patients, sirolimus becomes an attractive and promising therapy for R/R iMCD. Here we report the results of a retrospective study involving 26 R/R iMCD patients treated with sirolimus-containing regimen. The median age at sirolimus initiation was 40.5 years (23-60), with a median prior treatment line of 2 (1-5). 18 patients (69.2%) achieved symptomatic and biochemical response, with a median time to at least overall partial remission of 1.9 months (0.5-14.6). The median follow-up time from sirolimus initiation was 11.7 months (1.6-50.7) and the median time to next treatment (TTNT) was 46.2 months. No patients died at the end of follow-up. Most of the patients in the cohort are in ongoing responses and continue sirolimus therapy. Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

Can We Differentiate Between Primary Sjögren Syndrome and Idiopathic Multicentric Castleman Disease Based on the Characteristics of Pulmonary Cysts?

To identify radiological characteristics that could help differentiate cystic lung diseases between primary Sjögren syndrome (pSS) and idiopathic multicentric Castleman disease (iMCD). Patients with pSS or iMCD who had cysts were enrolled. Cyst characteristics (number, size, morphology, and distribution) and other accompanying manifestations (nodules, ground-glass opacities, calcification, and thickening of the bronchovascular bundles and interlobular septa) were compared between them. Eleven patients with pSS and 25 patients with iMCD were eligible for our study. Eleven patients with pSS (100.0%) and 23 patients with iMCD (92.0%) had round or oval cysts. None of the patients with pSS had irregular cysts, but 21 (84.0%) patients with iMCD had irregular cysts ( P = 0.005). Smooth-walled cysts were present in 11 patients with pSS (100.0%) and 18 patients with iMCD (72.0%). Only 1 patient with pSS (9.1%) exhibited non-smooth-walled cysts, whereas 23 patients with iMCD (92.0%) had non-smooth-walled cysts ( P = 0.003). The presence of nodules was common in both groups ( P = 1.000). However, the nodules were more likely to be larger and more numerous in patients with iMCD ( P < 0.001). Cysts with mural nodules (52.2%) and central nodules (47.8%) were only observed in iMCD ( P = 0.007). Although regular and smooth-walled cysts were common in the 2 diseases, irregular and non-smooth-walled cysts were more often associated with iMCD than pSS. Nodules in iMCD tended to be larger and more numerous, and a close positional relationship between nodules and cysts was only observed in iMCD.

Analysis of the interaction between the ORF42 and ORF55 proteins encoded by Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease. The tegument is a structure that is unique to herpesviruses that includes host and viral proteins, including the viral ORF42 and ORF55 proteins. Alphaherpesvirus tegument proteins have been well studied, but much is unknown regarding KSHV. Here, we report an interaction between the ORF42 and ORF55 proteins. ORF55 interacted with and recruited ORF42 from the nucleus to the cytoplasm. When ORF42 and ORF55 were expressed simultaneously in cultured cells, the expression level of these two viral proteins was higher than when either was expressed independently. ORF55, but not ORF42, was polyubiquitinated, suggesting that an unidentified regulatory mechanism may be present. A recombinant virus with an ectopic stop codon in ORF42 exhibited normal replication of genomic DNA, but fewer virus particles were released with the recombinant than with the wild-type virus. A unique R136Q mutation in ORF42, which is found in a KSHV strain that is prevalent on Miyako Island, Okinawa Prefecture, Japan, further increased the expression of ORF42 and ORF55 when these proteins were expressed simultaneously. However, the ORF42 R136Q mutation did not affect the localization pattern of ORF42 itself or of ORF55. In addition, experiments with a recombinant virus possessing the ORF42 R136Q mutation showed lower levels of production of the mutant virus than of the wild-type virus, despite similar levels of genome replication. We suggest that the R136Q mutation in ORF42 plays an important role in ORF55 protein expression and virus production.

Idiopathic multicentric Castleman disease and its rare association with peripheral neuropathy and stroke

Idiopathic multicentric Castleman disease and its rare association with peripheral neuropathy and stroke

Radiological Imaging Findings of Adrenal Abnormalities in TAFRO Syndrome: A Systematic Review.

This systematic review article aims to investigate the clinical and radiological imaging characteristics of adrenal abnormalities in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome. We searched the literature in PubMed, the Cochrane Library, and the Web of Science Core Collection. Ultimately, we analyzed 11 studies with 22 patients plus our 1 patient, totaling 23 patients. The mean age was 47.0 ± 12.6 years. There were 20 male and 3 female patients, respectively. The histopathological analysis of lymph nodes was conducted in 15 patients (65.2%), and the diagnosis was consistent with TAFRO syndrome in all 15 patients. Among the 23 patients, 11 patients (18 adrenal glands) showed adrenal ischemia/infarction, 9 patients (13 adrenal glands) showed adrenal hemorrhage, and 4 patients (7 adrenal glands) showed adrenomegaly without evidence of concurrent ischemia/infarction or hemorrhage. One patient demonstrated unilateral adrenal hemorrhage and contralateral adrenomegaly. In patients with adrenal ischemia/infarction, the adrenal glands displayed poor enhancement through contrast-enhanced computed tomography (CT). In patients with adrenal hemorrhage, the adrenal glands revealed high attenuation through non-enhanced CT and hematoma through magnetic resonance imaging. Adrenomegaly, with or without adrenal ischemia/infarction or hemorrhage, was observed in all patients (23/23, 100%). The subsequent calcification of the affected adrenal glands was frequently observed (9/14, 64.3%) when a follow-up CT was performed. Abdominal pain was frequent (15/23, 65.2%), all of which occurred after the disease's onset, suggesting the importance of considering TAFRO syndrome as a cause of acute abdomen. Given the absence of evidence of adrenal abnormalities in non-TAFRO-idiopathic multicentric Castleman disease (iMCD), they may serve as diagnostic clues for differentiating TAFRO syndrome from non-TAFRO-iMCD.

VEXAS syndrome: A new mimicker of idiopathic multicentric Castleman disease

IntroductionIdiopathic Multicentric Castleman Disease (iMCD) is a complex and poorly understood pathophysiological entity, which encompasses a variety of conditions and can mimic or be associated with autoimmune/autoinflammatory diseases, making it challenging to diagnose and treat. Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder associated with hematological abnormalities and caused by acquired somatic mutations in the ubiquitin-like modifier activating enzyme 1 gene (UBA1) which shares several common clinical and biological signs with iMCD. In this article, we report a patient with VEXAS syndrome initially presenting as iMCD, questioning the link between these two entities. Case descriptionWe report here a patient initially presenting as iMCD, proved on lymph node histology, which turns out to have a mutation at the splice acceptor site of exon 3 of UBA1 exhibiting VEXAS syndrome with Castleman-like lymph node. ConclusionThis is only the second case of VEXAS syndrome presenting as iMCD. VEXAS syndrome should therefore be considered in the presence of iMCD suspicion, including in cases of compatible histology.

Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy

AbstractIdiopathic multicentric Castleman disease (iMCD) is an inflammatory disease associated with a cytokine storm, activation of the PI3K/AKT/mTOR pathway, coagulopathy, and increased risk of thrombosis. The mechanisms underlying these pathologic processes remain elusive. We studied novel markers of mTOR activation and thrombosis in 1 patient with typical features of iMCD with TAFRO (thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, and organomegaly) syndrome (iMCD-TAFRO). Plasma levels of SVEP1 (Sushi, von Willebrand factor type A, epidermal growth factor, and pentraxin domain–containing 1 protein), a newly identified mTOR activator associated with cardiovascular diseases and dementia, in addition to cytokines, chemokines and components of the coagulation cascade and complement system were evaluated by enzyme-linked immunosorbent assay (ELISA) and arrays. Compared with healthy controls, a 15-fold increase in SVEP1 was observed. High levels of factor VIIa/antithrombin and microparticles expressing functional tissue factor (TF) were detected. The anticoagulants thrombomodulin and soluble endothelial protein C receptor were elevated, indicating shedding from endothelial cells. Plasminogen activator inhibitor 1 was increased, consistent with hypofibrinolysis, whereas high levels of C3b and C5a are in keeping with complement activation. Furthermore, markers of endothelial cell activation (e.g. von Willebrand factor, angiopoietin-2), cell adhesion molecules, and angiogenesis mediators were upregulated. SVEP1 emerges as a potential mechanism of mTOR activation in iMCD-TAFRO, while multiple pathways influence coagulopathy. Immunothrombosis emerges as a potential therapeutic target for iMCD.

Prioritizing Mobilization with Multicentric Castleman's Disease Superimposed on Incomplete Spinal Cord Injury: A Case Report

Prioritizing Mobilization with Multicentric Castleman's Disease Superimposed on Incomplete Spinal Cord Injury: A Case Report

Hodgkin Lymphoma-related Inflammatory Modification-displayed Castleman Disease-like Histological Features and Positron Emission Tomography/Computed Tomography Usefulness for the Differential Diagnosis.

Hodgkin lymphoma (HL) and idiopathic multicentric Castleman disease (iMCD) are markedly different conditions. However, in some cases, histological similarities caused by elevated cytokines, including interleukin-6, can lead to a misdiagnosis of HL as Castleman disease (CD). We herein report a patient with HL who had been diagnosed with CD by an expert panel and for whom an additional biopsy was useful for determining the correct diagnosis. Furthermore, we analyzed the positron emission tomography/computed tomography findings at the diagnosis and found that the maximum standardized uptake value was useful for distinguishing HL from iMCD.

A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was theoverall response rate at Week 12according to theCastleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be consideredwith caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.

Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.

Castleman Disease Presenting in the Neck: A Report of 3 Cases and a Literature Review.

BACKGROUND Castleman's disease (CD) is a reactive lymph node hyperplasia initially identified by Castleman in 1956. CD predominantly affects individuals 20-50 years of age, with low incidence in children. This case report describes 3 cases of CD treated in our hospital and reviews the relevant literature. The purpose of this case report was to enhance clinical understanding and treatment of CD in the head and neck in children. CASE REPORT To enhance clinical understanding and improve treatment of CD in the head and neck region in children, we present the cases of 3 patients who were admitted to the hospital, primarily presenting with a neck mass. Preoperatively, the patients collectively exhibited non-specific findings. Surgical interventions were performed with Cases 1 and 3 undergoing left functional (radical) neck lymph node dissection, in contrast to Case 2, in which bilateral functional (radical) neck lymph node dissection was executed. Pathological examination confirmed the diagnosis of CD in each of the 3 patients. Following surgery, a follow-up period ranging from 3 months to 1 year revealed that all patients had successfully recovered, with no recurrence. CONCLUSIONS Castleman disease is a rare disease in children and difficult clinical diagnosis. Some patients with unicentric Castleman disease (UCD) can be treated with surgery, and those with multicentric Castleman disease (MCD) need chemotherapy, but at present there is no widely accepted treatment plan.

TAFRO Syndrome: A Syndrome or a Subtype of Multicentric Castleman Disease?

TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow/renal dysfunction, organomegaly) syndrome is a systemic inflammatory disorder of unknown etiology. It has been recognized as a subtype of idiopathic multicentric Castleman disease (iMCD), and the international diagnostic criteria for iMCD-TAFRO require a lymph node histopathology consistent with iMCD. Furthermore, TAFRO syndrome is defined as a heterogeneous clinical entity caused by underlying diseases such as malignancy, autoimmune diseases, or infections. However, the cases that led to the proposal of TAFRO syndrome lacked recognizable lymphadenopathy and were inconsistent with any other diseases, despite vigorous efforts in differential diagnosis. Irrespective of the presence or absence of Castleman disease (CD)-like histology, TAFRO syndrome exhibits homogeneous clinical, laboratory, and prognostic features, setting it apart from iMCD without TAFRO syndrome. Defining iMCD-TAFRO apart from TAFRO syndrome is deemed meaningless and confusing. MCD is a heterogeneous lymphoproliferative disorder consisting of several subtypes with different pathogenesis, clinical manifestations, and histological features. Typical MCD in Japan, characterized by the histology of plasma cell type and marked polyclonal hypergammaglobulinemia, is identical to idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Although IPL is classified into iMCD-NOS (not otherwise specified), it should be recognized as a distinct clinicopathological entity. Furthermore, we propose to separate TAFRO syndrome from the MCD category as a defined disorder.

HHV8-Positive Multicentric Castleman's Disease and Thrombotic Thrombocytopenic Purpura among HIV-Positive Patients.

Castleman's disease (CD) and thrombotic thrombocytopenic purpura (TTP) are rare diseases, and their association remains extremely uncommon.We report a case of multicentric CD (MCD) with TTP in a 53-year-old male patient with HIV.Only five patients, including ours, have been reported as having both MCD and TTP, with all five having HHV8 and four having HIV. Thus, coinfection with HHV8 and HIV may be a potential pivotal factor in the occurrence of MCD with TTP.

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease

Aims and methodsIdiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO)...

Pacritinib inhibits proliferation of primary effusion lymphoma cells and production of viral interleukin-6 induced cytokines

Primary effusion lymphoma (PEL) and a form of multicentric Castleman’s disease (MCD) are both caused by Kaposi sarcoma herpesvirus (KSHV). There is a critical need for improved therapies for these disorders. The IL-6/JAK/STAT3 pathway plays an important role in the pathogenesis of both PEL and KSHV-MCD. We explored the potential of JAK inhibitors for use in PEL and KSHV-MCD, and found that pacritinib was superior to others in inhibiting the growth of PEL cell lines. Pacritinib induced apoptosis in PEL cells and inhibited STAT3 and NF-κB activity as evidenced by reduced amount of phosphorylated moieties. Pacritinib also inhibits FLT3, IRAK1, and ROS1; studies utilizing other inhibitors of these targets revealed that only FLT3 inhibitors exhibited similar cell growth inhibitory effects. FLT3’s likely contribution to pacritinib’s cell growth inhibition was further demonstrated by siRNA knockdown of FLT3. RNA sequencing and RT-PCR showed that many key host genes including cyclins and IL-6 were downregulated by pacritinib, while KSHV genes were variably altered. Finally, pacritinib suppressed KSHV viral IL-6-induced human IL-6 and IL-10 production in peripheral blood mononuclear cells, which may model an important step in KSHV-MCD pathogenesis. These results suggest that pacritinib warrants testing for the treatment of KSHV-MCD and PEL.

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

TAFRO syndrome is associated with anti-SSA/Ro60 antibodies, in contrast to idiopathic castleman disease

TAFRO syndrome is an acute systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. There have been increasing reports that TAFRO is a disease distinct from idiopathic multicentric Castleman disease and that TAFRO patients may be positive for anti-SSA antibodies. To assess anti-SSA antibody positivity and the clinical characteristics of the two diseases, we retrospectively compared 7 TAFRO and 10 iMCD patients in our hospital. The mean age of onset of TAFRO and iMCD was 48.0 (interquartile range [IQR], 41–53) and 45.0 (IQR, 35–53) years, respectively. The TAFRO and iMCD groups had 6 (86%) and 4 (40%) male patients, respectively, and the following pretreatment laboratory values: platelet count, 3.8 (IQR, 2.2–6.4) and 35.5 (IQR, 22.2–42.8) × 104/μL, respectively; C-reactive protein, 10.2 (IQR, 6.8–21.4) and 9.5 (IQR, 6.2–13.6) mg/dL, respectively; IgG, 1431 (IQR, 1112–1815) and 4725 (IQR, 3755–5121) mg/dL, respectively. RNA immunoprecipitation (5 cases for anti-SSA) or protein array (5 cases for anti-SSA/Ro60) detected anti-SSA antibodies in six (86%) TAFRO patients but not in iMCD patients; it did not detect anti-SSB antibodies in any of the patients. None of the patients were diagnosed with Sjögren syndrome. All iMCD patients treated with tocilizumab (TCZ) responded well. Meanwhile, two of six TAFRO patients treated with TCZ showed inadequate responses; thus, both patients were switched to rituximab, following which they achieved remission. TAFRO and iMCD have different clinical features. TAFRO may be categorized as a severe phenotype of the anti-SSA antibody syndrome.

TAFRO syndrome associated with C3 nephropathy (an analysis of clinical experience)

Aim. To present a clinical case of TAFRO syndrome – a recently described subtype of idiopathic multicentric Castleman disease of unknown etiology, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis of the bone marrow and / or renal dysfunction, organomegaly associated with an increase in serum IL-6 secretion.Materials and methods. Herein, we report a young patient diagnosed with TAFRO combined with C3 nephropathy. The patient was treated with glucocorticoids (methylprednisolone), colchicine, sarilumab, rivaroxaban, and symptomatic treatment.Results. Key aspects of diagnosis, treatment and course of the syndrome were discussed. The possibility of the combined course of two rare pathologies – a subtype of idiopathic multicentric Castleman disease and C3 nephropathy is still unclear.Conclusion. The diagnosis of TAFRO syndrome can be considered after the exclusion of a number of infectious, paraneoplastic, systemic connective tissue diseases, POEMS syndrome, liver cirrhosis against the background of autoimmune hepatitis, autoimmune thrombocytopenic purpura, as well as hemolytic-uremic syndrome. Kidney damage in this category of patients, in most of the described clinical cases, is morphologically represented by thrombotic microangiopathy or mesangioproliferative glomerulonephritis. C3 nephropathy in that clinical case seems to be concomitant. Glucocorticoids in high and ultrahigh doses, cyclosporine, IL-6 type inhibitors, as well as anti-CD20 antibodies are used as therapy.