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.

Circovirus Hepatitis Infection in Heart-Lung Transplant Patient, France.

In March 2022, a 61-year-old woman in France who had received a heart-lung transplant sought treatment with chronic hepatitis mainly characterized by increased liver enzymes. After ruling out common etiologies, we used metagenomic next-generation sequencing to analyze a liver biopsy sample and identified an unknown species of circovirus, tentatively named human circovirus 1 (HCirV-1). We found no other viral or bacterial sequences. HCirV-1 shared 70% amino acid identity with the closest known viral sequences. The viral genome was undetectable in blood samples from 2017-2019, then became detectable at low levels in September 2020 and peaked at very high titers (1010 genome copies/mL) in January 2022. In March 2022, we found >108 genome copies/g or mL in the liver and blood, concomitant with hepatic cytolysis. We detected HCirV-1 transcripts in 2% of hepatocytes, demonstrating viral replication and supporting the role of HCirV-1 in liver damage.

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.

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.

Metagenomic next-generation sequencing restores the diagnosis of a rare infectious complication of B cell depletion.

A 45-year-old female patient receiving rituximab for B cell non-Hodgkin follicular lymphoma presented unexplained recurrent fever, abdominal discomfort, and pollakiuria. We performed shotgun metagenomic sequencing from peri-kidney collection that identified a co-infection with Mycoplasma hominis and Ureaplasma urealyticum. The patient recovered with sequelae after appropriate antibiotic treatment was given.

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.

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).

Orbital mass in ANCA-associated vasculitides: data on clinical, biological, radiological and histological presentation, therapeutic management, and outcome from 59 patients.

OBJECTIVE: Orbital mass is a rare and sight-threatening manifestation of ANCA-associated vasculitides, which remains a therapeutic challenge. We aimed to describe the presentation, therapeutic management and outcome of ANCA-associated vasculitides-related orbital mass. METHODS: We conducted a French nationwide retrospective study of patients with orbital mass in the setting of ANCA-associated vasculitides according to ACR criteria and/or Chapel Hill Consensus Conference definitions. RESULTS: Fifty-nine patients [33 women, median age 46 (range 7-90) years] were included. Fifty-six (95%) patients had granulomatosis with polyangiitis, two eosinophilic granulomatosis with polyangiitis and one microscopic polyangiitis. Orbital mass was unilateral in 47 (80%) cases, and seemed to develop from ENT involvement in most cases. Orbital mass biopsy was available in 32 (54%) patients, showing lymphoplasmacytic infiltration in 65%, fibrosis in 55%, granulomas in 48% and vasculitis in 36%. All patients but one received glucocorticoids as first-line therapy associated with immunosuppressive agents in 82%, mainly cyclophosphamide. Response to therapy was noted in 52% of patients treated with cyclophosphamide compared with 91% of those treated with rituximab. Twenty-seven (46%) patients required a second-line therapy because of relapse (59%) or refractory course (41%). Sequelae included visual impairment in 28%, with definitive blindness in 17%. Refractory course was associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis. CONCLUSION: Orbital mass is associated with refractory course and high frequency of sequelae, especially blindness. Refractory course is associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.