Real-life use of mTOR inhibitor-based therapy in adults with autoimmune cytopenia highlights strong efficacy in relapsing/refractory multi-lineage autoimmune cytopenia.

Data on mTOR inhibitors (mTORi) in autoimmune cytopenia (AIC), in adults are scarce. We retrospectively analysed 30 cases of refractory or relapsing AIC treated with an mTORi-based therapy. Eleven warm autoimmune hemolytic anaemia, 10 autoimmune thrombocytopenia, 6 acquired pure red cell aplasia, 3 autoimmune neutropenia were included. Twenty were multilineage AIC (67%) and 21 were secondary AIC (70%). mTORi were associated with other therapies in 23 AIC (77%). Twenty-two AIC (73%) responded to mTORi-based therapy: 5 reached a partial response (17%) and 17 a complete response (57%). Survival without unfavourable outcome (failure, requirement of a new therapy, or death) was longer in multilineage AIC compared to single-lineage AIC (p = 0.049) with a median event-free survival of 48 versus 12 months. Median event-free survival was 48 months in secondary AIC and 33 months in primary AIC (p = 0.79). mTORi were discontinued in 4 patients (15%) for safety reasons and in 3 patients for patient's choice (12%). In conclusion, mTORi could be considered as an alternative or an add-on therapy in refractory or relapsing AIC in adult patients, especially in multilineage AIC.

Characteristics of circulating KSHV-infected viroblasts during active KSHV+ multicentric Castleman disease.

Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder that mainly occurs in immunocompromised hosts. The diagnosis relies on lymph node biopsy demonstrating KSHV-infected cells located in the mantle zone with a marked interfollicular plasma cell infiltration. Infected cells are large cells positive for immunoglobulin M (IgM), λ light chain, and CD38, described initially as infected plasmablasts. We show that IgM+λ+CD38high cells were also detectable in the peripheral blood of 14 out of 18 (78%) patients with active KSHV-MCD and absent in 40 controls. Using immunofluorescence and flow-fluorescence in situ hybridization, we demonstrate that these cells are KSHV infected and express both latent and lytic KSHV transcripts. These KSHV-infected viroblasts (KIVs) harbor a distinct phenotype compared with conventional plasmablasts. We also identified several putative mechanisms of immune escape used by KSHV, because KIVs displayed an overall decrease of costimulatory molecules, with a remarkable lack of CD40 expression and are interleukin-10-producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements to the understanding of KSHV-MCD but also raises new questions that need to be clarified.

Lymphoma as an Exclusion Criteria for CVID Diagnosis Revisited.

PURPOSE: Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia. METHODS: Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed. RESULTS: A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype. CONCLUSION: Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.

Human adenoviral (HAdV) chronic arthritis expands the infectious spectrum of primary agammaglobulinemia.

Inborn errors of immunity (IEI) are a heterogeneous entity with an increasing number of late diagnoses. Besides infections, inflammatory manifestations are a growing part of the clinical landscape of IEI. These complications are of unknown causes and often lead to the prescription of immunosuppressive agents that worsen the underlying immune defect. We here report the case of an adult patient diagnosed with chronic Human Adenovirus C-1 arthritis in the setting of primary agammaglobulinemia. Metagenomic next-generation sequencing led to the correct diagnosis and high-dose intravenous immunoglobulins resulted in complete recovery. This observation gives new insights into adenoviral immunity and underlines the importance of metagenomics in the diagnosis of inflammatory manifestations in immunocompromised patients.

Leg-type form of idiopathic multicentric Castleman disease associated with severe lower extremity chronic venous/lymphatic disease.

Idiopathic multicentric Castleman disease (iMCD) is a lymphoproliferative disease of unknown etiology. Deciphering mechanisms involved in CD pathogenesis may help improving patients' care. Six cases of stereotyped sub-diaphragmatic iMCD affecting lower limb-draining areas and associated with severe and often ulcerative lower extremity chronic dermatological condition were identified in our cohort. Pathological examination revealed mixed or plasma-cell type MCD. In three patients, shotgun metagenomics failed to identify any pathogen in involved lymph nodes. Antibiotics had a suspensive effect while rituximab and tocilizumab failed to improve the condition. This novel entity requires a specific approach and exclusion of potentially harmful immunomodulation.

First Extensive Analysis of 18F-Labeled Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in a Large Cohort of Patients With HIV-Associated Hodgkin Lymphoma: Baseline Total Metabolic Tumor Volume Affects Prognosis.

PURPOSE: 18F-labeled fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) data in HIV-associated Hodgkin lymphoma (HIV-HL) are scarcely reported. In addition to the description of the characteristics of both baseline and interim 18F-FDG PET-CT examinations (PET1 and iPET, respectively), the aim of this study was to assess the prognostic value of PET1 and previously identified clinical parameters in this population. PATIENTS AND METHODS: PET1 of 109 patients with HIV-HL, treated with doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy regimen since 2007, and 104 iPET were centrally reviewed. All the patients were enrolled in an ongoing prospective single-center cohort of HIV-associated lymphoma. RESULTS: Most patients had a disseminated disease according to the Ann Arbor classification (30% stage III and 43% stage IV), with especially bone marrow and liver as extranodal localizations. After a median follow-up of 6.7 years, 12 patients relapsed (11%) and 13 died (12%). Five-year progression-free survival (PFS) was 75.1%, and 5-year overall survival was 86.1%. Median total metabolic tumor volume (TMTV) was 121.4 cm3. The optimal TMTV cutoff identified for prognostic analysis was 527 cm3, with a 2-year PFS of 71% in the 20 patients with TMTV > 527 cm3, compared with 91% in the 89 patients with TMTV ≤ 527 cm3 (P = .004). On multivariate analysis, a high TMTV was the only parameter independently associated with PFS. CONCLUSION: In this large series of HIV-HL patients with a homogeneous management, high TMTV on PET1 examination was associated with a poor prognosis.

Characteristics of thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly syndrome: a retrospective study from a large Western cohort.

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.

A Comprehensive Clinicopathologic and Molecular Study of 19 Primary Effusion Lymphomas in HIV-infected Patients.

Primary effusion lymphoma (PEL) is associated with human herpesvirus 8 and frequently with Epstein-Barr virus (EBV). We report here a single-center series of 19 human immunodeficiency virus-associated PELs, including 14 EBV+ and 5 EBV- PELs. The objectives were to describe the clinicopathologic features of PELs, with a focus on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, to search for genetic alterations by targeted deep sequencing analysis, and to compare the features between EBV+ and EBV- cases. All the patients were male, and the median age at diagnosis was 47 years old (interquartile range: 40 to 56 y). Reflecting the terminal B-cell differentiation, immunophenotypic profiles showed low expression levels of B-cell markers, including CD19 (0/19), CD20 (1/19), CD79a (0/19), PAX5 (1/19), BOB1 (3/19), and OCT2 (4/19), contrasting with a common expression of CD38 (10/19), CD138 (7/19), and IRF4/MUM1 (18/19). We observed a frequent aberrant expression of T-cell markers, especially CD3 (10/19), and less frequently CD2 (2/19), CD4 (3/19), CD5 (1/19), and CD8 (0/19). Only 2 cases were PD-L1 positive on tumor cells and none PD-1 positive. With respect to immune cells, 3 samples tested positive for PD-L1 and 5 for PD-1. Our 36-gene lymphopanel revealed 7 distinct variants in 5/10 PELs, with either a single or 2 mutations per sample: B2M (n=2), CD58 (n=1), EP300 (n=1), TNFAIP3 (n=1), ARID1A (n=1), and TP53 (n=1). Finally, we did not observe any major clinical, pathologic, or immunohistochemical differences between EBV+ and EBV- PELs and the outcome was similar (2-y overall survival probability of 61.9% [95% confidence interval, 31.2-82.1] vs. 60.0% [95% confidence interval, 12.6-88.2], respectively, P=0.62).

Point-of-care ultrasound with handheld devices in hematology: a monocentric single-stage phase II study.

Point of care ultrasound (PoCUS) with pocket-size devices is an efficient and safe imaging modality that became a standard of care in various clinical settings. However, its implementation in hematology has never been evaluated so far. We conducted a prospective monocentric study aiming to harvest data on its usage and to assess its diagnostic and interventional performance in improving the accuracy of basic physical examination in hematological patients. After a focused training program, six hematologists were trained and conducted this study. Sixty-two patients were included. Only in 19 cases, further specialized imaging was required, whereas, in 43 patients PoCUS was sufficient to address the clinical inquiries. The use of PoCUS devices was assessed for its performance difficulty and usefulness perception with satisfactory outcomes. This study represents a proof-of-concept application of PoCUS in hematology, suggesting benefits over the physical examination.KEY POINTSPoCUS is particularly attractive in a hematological setting because able to improve the accuracy of physical examination.A hematology-focused training in PoCUS using handheld devices can allow hematologists to perform bed-side diagnostic and interventional US-based exams.

Persistent FDG/PET CT uptake in idiopathic retroperitoneal fibrosis helps identifying patients at a higher risk for relapse.

BACKGROUND: The aim of this study was to evaluate the prognostic value of persistent retroperitoneal fibrosis FDG uptake using FDG/PET CT in patients with idiopathic retroperitoneal fibrosis (IRF). METHODS: In this monocentric retrospective cohort study, all patients admitted for IRF from January 2009 to December 2017 underwent a FDG/PET CT at diagnosis and during follow up. Metabolic activity of IRF was assessed by retroperitoneal fibrosis FDG uptake measured as maximal standardized uptake value (SUVmax). The primary outcome was IRF relapse rate during follow-up. RESULTS: 23 consecutive patients (54.7 [36.9-89] years, 73.9% of men) diagnosed with IRF had FDG/PET CT imaging performed at diagnosis, 3.1 [1-8.7] months (i.e 1st evaluation) and 10.4 [4.9-17.5] months (i.e 2nd evaluation) after diagnosis. High FDG retroperitoneal fibrosis uptake was present in all patients at diagnosis (SUVmax 6.5 [3.8-11.9]) and persisted in 16 (69.6%; SUVmax 3.65 [2.1-5.4]) and 12 (52.2%; SUVmax 3.75 [2.7-7.8]) patients, at 1st and 2nd evaluation respectively. All but one patient had received steroids at IRF diagnosis and 21 (91.3%) were in complete remission at both 1st and 2nd evaluation. During a median follow-up period of 38.7 [3-106.9] months, 6 (26.1%) patients suffered IRF relapse that occurred 15.7 [9.2-42.8] months after diagnosis. Multivariate analysis showed that only persistent retroperitoneal fibrosis FDG uptake at 2nd evaluation was associated with IRF relapse (p = .046). CONCLUSIONS: In IRF, persistent retroperitoneal fibrosis FDG uptake during follow up is associated with clinical outcome. FDG/PET CT may help to better stratify the risk of relapse and target therapy in IRF.

Plasma exchange in the intensive care unit: Technical aspects and complications.

BACKGROUND: Data on plasma exchange therapy in the intensive care unit (ICU) setting are scarce. We aimed to describe the technical aspects and the adverse events associated with the procedure in critically ill patients. METHODS: All adult patients treated by plasma exchange in the medical ICU of the Saint-Louis university hospital between January 1, 2013 and March 31, 2015 were prospectively included. RESULTS: We report on 260 plasma exchange procedures performed in 50 patients. The centrifugation technique was used for 159 (61%) procedures and the filtration technique for the other 101 (39%) procedures. Both techniques had similar efficacy to treat hyperviscosity syndrome (n = 18). Seventy (26.9%) of the 260 plasma exchange procedures were reported with at least one adverse reaction. Centrifugation and filtration techniques had similar rates of adverse reactions (23.9 vs. 31.7%, P = .19). Hypotension was the most reported (n = 21, 8%) and correlates with a low hematocrit before therapy. Most complications were related to allergic reactions to the replacement fluids. Coagulation disorders depended on the type of replacement fluid. The post-exchange fibrinogen level was decreased by 54% [48;66] with albumin 5%, and 4% [-5;17] with plasma frozen within 24 h. Twenty-three (22.8%) of the 101 filtration procedures experienced filter clotting. Filter clotting was associated with a higher volume exchange prescribed when compared to procedures without filter clotting (4600 [4000;5000] ml vs. 3900 [3600;4800] ml, P < .01). CONCLUSION: Plasma exchange is a relatively safe and generally well-tolerated procedure in the ICU setting. Most adverse events are unpredictable and related to minor allergic reactions.

Exclusion of Patients with a Severe T-Cell Defect Improves the Definition of Common Variable Immunodeficiency.

BACKGROUND: In 2014, the European Society for Immune Deficiencies (ESID) revised the common variable immunodeficiency (CVID) diagnosis criteria by incorporating new clinical and biological markers. The new definition appeared more restrictive but had not yet been evaluated in a large cohort of patients. OBJECTIVE: The objective of this study was to evaluate the impact of this new definition in a large cohort of patients with primary hypogammaglobulinemia. METHODS: Evaluation of 3 different CVID definitions (ESID/Pan-American Group for Immunodeficiency [PAGID] 1999, ESID 2014, DEFI 2015) in 521 patients included in the French DEFI study with a diagnosis of primary hypogammaglobulinemia. RESULTS: Using the ESID/PAGID 1999 definition, 351 patients were classified as CVID. The new ESID 2014 definition excluded 62 (18%) patients. Most of them (n = 56; 90%) had a less severe disease, whereas 6 (10%) presented with a severe disease with major T-cell defect. We propose different criteria (occurrence of opportunistic infection or very low naive CD4+ T-cell count) to define this population with severe T-cell defect. Sixty-two patients fulfilled these criteria, represented 20% of the initial CVID population but accounted for 77% of the deaths, with a 5-year overall survival of 67.6% (95% confidence interval, 51.0-79.6), and were considered as late onset combined immunodeficiency (LOCID). CONCLUSIONS: The new ESID definition for CVID still fails to exclude a large number of patients with severe T-cell defect. We propose a new definition (DEFI 2015) that excluded more patients with a T-cell defect and consider these patients as LOCID. This population has a poor outcome and should be considered as a distinct group requiring specific care.