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Summary: Idiopathic multicentric Castleman disease (iMCD) is a non‐clonal inflammatory lymphoproliferative disorder of unknown origin. Recently, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) emerged as a singular variant of iMCD in Asia and was associated with a severe course and a poor outcome. The present study describes the first large Western cohort of TAFRO syndrome patients (n = 25) meeting the All Japan TAFRO Syndrome Research Group diagnostic criteria. Characteristics of TAFRO patients were compared to iMCD‐not otherwise specified (iMCD‐NOS) patients used as a control group (n = 43). Our results show that despite baseline characteristics in accordance with previously reported series, Western TAFRO syndrome patients do not appear to present with a worse outcome than iMCD‐NOS patients. There were no significant differences between the two groups regarding treatment choice, response to rituximab (71% vs. 67%) or tocilizumab (69% vs. 91%) in TAFRO and iMCD‐NOS, respectively. The two‐year overall survival was above 95% in both groups. Limits of inclusion and exclusion criteria for TAFRO definition are also discussed. Our findings raise the question of the singularity of the TAFRO entity in Western countries. The data should promote further research using unsupervised models to identify markers of disease severity in Western cohorts of iMCD patients. [ABSTRACT FROM AUTHOR]

Summary: Among 143 patients with elastase, neutrophil‐expressed (ELANE)‐related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte‐colony stimulating factor (G‐CSF), on G‐CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem‐cell transplantation. During the disease's natural history period (without G‐CSF; 1913 person‐years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3), high lymphocyte count (>3000/mm3) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G‐CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism. [ABSTRACT FROM AUTHOR]

Summary: We report the off‐label use of bortezomib combined with dexamethasone in eight adults with severe and multi‐refractory warm auto‐immune haemolytic anaemia (wAIHA). After six cycles of induction therapy, 6 of the 8 patients achieved response (3 complete response, 3 response). Response was obtained after a median of 2 (1–4) cycles. After a median follow‐up of 14 (6–36) months, six patients maintained a response (bortezomib/dexamethasone maintenance, n = 4); five patients experienced at least one moderate adverse event, including peripheral neuropathy (n = 2). These results suggest that bortezomib/dexamethasone combination is a promising approach with acceptable toxicity for treating severe refractory wAIHA in adults. [ABSTRACT FROM AUTHOR]

Summary: We retrospectively analysed 71 cases of Unicentric Castleman disease, a rare, usually asymptomatic, benign lymphoproliferative disorder presenting as a unique nodal mass. Although surgery is considered as the gold standard therapy, only 38 patients (54%) underwent initial surgical resection and 95% were cured. An additional 9 patients had surgery after an attempt at medical reduction. Reduction therapy was used in 21 patients with a 55% response rate, but without evidence for an optimal regimen. Radiotherapy was limited to 8 patients because of associated toxicity. Watch and wait was considered in 13 asymptomatic patients and 11 of these remained stable for up to 17 years. [ABSTRACT FROM AUTHOR]

Objective: Angioimmunoblastic T‐cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear. Method: Angioimmunoblastic T‐cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio). Results: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein‐Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow‐up of 24 months (range 3‐155), 10 patients relapsed, all associated with AITL relapse. Conclusion: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B‐cell activation leading to subsequent autoimmunity. [ABSTRACT FROM AUTHOR]

Summary: The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria. Twenty of these patients with Castleman‐like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy). Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV‐8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV‐8 negative/idiopathic multicentric CD (iMCD). 2‐(18F)fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline‐vascular histopathological features, and most patients were asymptomatic. Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV‐8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV‐8+ MCD, particularly in HIV‐infected patients. [ABSTRACT FROM AUTHOR]

Purpose Multicentric Castleman disease ( MCD) is a distinct lymphoproliferative disorder characterized by inflammatory symptoms, lymphadenopathy, splenomegaly, and cytopenia. Kaposi's sarcoma-associated herpesvirus ( KSHV), also called human herpesvirus-8 ( HHV-8), is the cause of virtually all cases of MCD occurring in patients with HIV infection. MCD lesions characteristically contain HHV-8-infected polyclonal IgMλ plasmablasts. A high frequency of HHV-8-related non-Hodgkin lymphoma has been reported in these patients. Patients and methods We now report on three patients who presented with severe symptoms of MCD, extreme splenomegaly, and rapid expansion of B-cell lymphocytosis (44-81%) attributable to circulating HHV-8 positive plasmablasts. Results The circulating plasmablastic cells shared the phenotype (IgMλ, CD19+, CD20− CD138−) of HHV-8-infected cells from MCD lesions, mimicking the leukemic phase of large B-cell lymphoma occurring in HHV-8-related MCD. These patients displayed a very high HHV-8 viral load in blood (>7 logs HHV-8 DNA copies/ml) and high levels of serum vIL-6, the viral homolog of human interleukin 6. Serum IL-6 and IL-10 were also abnormally elevated. HHV-8-infected cells were demonstrated by immunoglobulin gene rearrangement analysis, to be polyclonal and likely represent an expansion of HHV-8-infected cells similar to those found in MCD lesions. Conclusion Thus, the spectrum of HHV-8-related plasmablastic lymphoproliferative disorders in patients with HIV infection is expanded to include HHV-8+ polyclonal IgMλ B-cell lymphocytosis. At onset, this lymphoproliferative disorder may mimic plasmablastic leukemia/lymphoma. Recognizing this unusual complication may have important implications in treatment decision avoiding unnecessary toxicity to the patients. [ABSTRACT FROM AUTHOR]

Human primary immunodeficiencies (PIDs) are often thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leucocyte subsets and resulting in multiple, recurrent, opportunistic and fatal infections in infancy. We highlight here the rapidly growing number of exceptions to each of these conventional qualifications. Indeed, bona fide PIDs include common and sporadic illnesses and may present as dominant, or even polygenic traits; their pathogenesis may involve non haematopoietic cells, and they may result in single episode of illness, with a single or multiple morbid phenotypes, some of which may involve infection, in otherwise healthy adults. We need to increase awareness of the multitude of clinical presentations of human PIDs considerably and rapidly in the medical community. Human PIDs should be considered in a wide range of clinical situations. [ABSTRACT FROM AUTHOR]

The IL-12/IFN-γ axis is crucial for protective immunity to Mycobacterium in humans and mice. Our goal was to analyze the relative contribution of various human blood cell subsets and molecules to the production of, or response to IL-12 and IFN-γ. We designed an assay for the stimulation of whole blood by live M. bovis Bacillus Calmette-Guérin (BCG) alone, or BCG plus IL-12 or IFN-γ, measuring IFN-γ and IL-12 levels. We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF-κB essential modulator (NEMO), and IL-1 receptor-associated kinase-4 (IRAK-4). Patients with deficiencies in IL-12p40, IL-12 receptor β1 chain (IL-12Rβ1), IFN-γR1, IFN-γR2, and STAT-1 were used as internal controls. We showed that monocytes were probably the main producers of IL-12, and that NK and T cells produced similar amounts of IFN-γ. NEMO and IRAK-4 were found to be important for IL-12 production and subsequent IFN-γ production, while a lack of CD40L or HLA class II had no major impact on the IL-12/IFN-γ axis. The stimulation of whole blood by live BCG thus triggers the IL-12/IFN-γ axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. [ABSTRACT FROM AUTHOR]

IL-12 is the signature IFN-γ-inducing cytokine and, as such, is thought to be crucial for protective immunity against intracellular microorganisms. This concept is supported by results from experimental infections of knockout mice lacking IL-12 or the IL-12 receptor. The description of human patients with inherited IL-12 or IL-12-receptor deficiency challenges this view. Indeed, in natural conditions of infection and immunity - the hallmark of the human model - IL-12 was found to be redundant in defense against intracellular microorganisms other than Mycobacteria and Salmonella. More surprisingly, IL-12 was recently found to be redundant even in defense against primary intection by Mycobacteria and Salmonella in many patients, and against secondary infection by Mycobacteria but not Salmonella in most patients. [ABSTRACT FROM AUTHOR]

Summary: Individuals with inherited disorders of interferon-γ (IFN-&gamma)-mediated immunity appear to be specifically vulnerable to mycobacterial infections. The severity of clinical features of affected individuals differs between cases. Some patients die of mycobacterial infection in early childhood, whereas others have long asymptomatic periods in childhood and as adults. This rare syndrome also shows high allelic and non-allelic genetic heterogeneity. Mutations in IL12B, encoding the interleukin (IL)-12 p40 subunit, and in IL12RB1, encoding the β1 chain of the IL-12 receptor, result in impaired IFN-γ production. Mutations in IFNGR1 and IFNGR2, encoding the two IFN-γ receptor chains, and mutations in STAT1, encoding an essential signaling component, result in impaired cellular responses to IFN-γ. Different types of mutation define two types of complete and two types of partial IFN-γR1 deficiency. Complete and partial IFN-γR2 deficiency have also been described. We herein compare the genotypes, cellular phenotypes, and clinical phenotypes of healthy individuals and patients with the seven known genetic disorders impairing cellular responses to IFN-γ. Patients with defective IFN-γ production were not considered in this study. The mutations and clinical features of patients with IFNγR1, IFNγR2, and STAT-1 deficiency are reviewed. Selected cell lines from each of the eight groups were tested for their response to IFN-γ. We find that individuals may be classified into four broad groups based on genotype, cellular phenotype, and clinical phenotype (normal individuals and patients with... [ABSTRACT FROM AUTHOR]