Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma with poor prognosis. Lymphoma cells are always infected with human herpesvirus-8 (HHV-8) and in most cases coinfected with Epstein-Barr virus. In classic presentation, PEL is characterized by body cavity effusions with or without mass lesions. A variant with only extracavitary localization has also been described. We report on a large single-center series of patients with PEL in the era of combined antiretroviral therapy (cART). The main objective was to compare the characteristics and the outcome of patients with classic (n = 34) and extracavitary (n = 17) variant PEL. At PEL diagnosis, no major difference was observed between the two groups in terms of demographic and HIV characteristics. Extracavitary localizations were exclusively nodal in six patients and involved various organs in 11 patients. Another HHV-8-associated disease was observed in 31 patients, Kaposi sarcoma in 25, and multicentric Castleman disease in 18 patients, without difference between the two groups. Thirty-two patients were treated with CHOP associated with high-dose methotrexate, 13 were treated with CHOP-derived regimen alone, and six patients received low-dose/no chemotherapy. Complete remission was achieved in 21 (62%) and seven (41%) patients of the classic and extracavitary groups, respectively. The median overall survival (OS) was 10.2 months. Despite a higher disease-free survival in the extracavitary group, there was no difference in OS between the two variants. Based on this series, characteristics of classic and extracavitary variants were very close. Although prognosis of PEL remains very severe in cART era, the median survival compares favorably with earlier series.
Le Lupus Erythemateux dissemine (LED) est un ensemble de maladies auto-immunes caracterisees par la presence d'anticorps anti-nucleaires. La pathogenese du lupus est inconnue a ce jour et les mecanismes de la maladie pourraient etre multiples. Dans ce travail nous reportons l'identification de variants autosomaux recessifs, pertes de function, dans le domaine kinase de ACK1 et BRK respectivement, chez des patients atteints de LED de 2 familles non apparentees. Utilisant des macrophages derives d'iPSCs similaires aux macrophages residents exprimant TIM4, nous montrons que la forme sauvage de ACK1 et BRK n'est pas requise pour la phagocytose de bacteries et de champignons, mais est necessaire pour une efferocytose efficace, incluant la phagocytose mediee par l'actin de cellules apoptotiques par des macrophages humains et l'expression precoce de gene anti-inflammatoire induit par STAT3 et AKT et declenche par l'exposition a des cellules apoptotiques. Ces resultats indiquent que l'activite kinase de ACK1 et BRK sont necessaires pour la clearance immunologiquement silencieuse des cellules apoptotiques par les macrophages. Enfin ces donnees definissent un sous-groupe de patients atteints de LED avec un deficit genetique d'efferocytose qui pourrait beneficier de therapie ciblee dans le future.
ABSTRACT Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages. One sentence summary Loss of function variants of human ACK1 and BRK kinase underlie systemic lupus erythematosus in young patients from multiplex families and disrupt the anti-inflammatory response of macrophages to apoptotic cells.
Introduction In resource limited settings, patients entering an antiretroviral therapy (ART) program comprise ART naive and ART pre-treated patients who may show differential virological outcomes. Methods This retrospective study, conducted in 2010–2012 in the HIV clinic of Calmette Hospital located in Phnom Penh (Cambodia) assessed virological failure (VF) rates and patterns of drug resistance of naive and pre-treated patients. Naive and ART pre-treated patients were included when a Viral Load (VL) was performed during the first year of ART for naive subjects or at the first consultation for pre-treated individuals. Patients showing Virological failure (VF) (>1,000 copies/ml) underwent HIV DR genotyping testing. Interpretation of drug resistance mutations was done according to 2013 version 23 ANRS algorithms. Results On a total of 209 patients, 164 (78.4%) were naive and 45 (21.5%) were ART pre-treated. Their median initial CD4 counts were 74 cells/mm3 (IQR: 30–194) and 279 cells/mm3 (IQR: 103–455) (p<0.001), respectively. Twenty seven patients (12.9%) exhibited VF (95% CI: 8.6–18.2%), including 10 naive (10/164, 6.0%) and 17 pre-treated (17/45, 37.8%) patients (p<0.001). Among these viremic patients, twenty-two (81.4%) were sequenced in reverse transcriptase and protease coding regions. Overall, 19 (86.3%) harbored ≥1 drug resistance mutations (DRMs) whereas 3 (all belonging to pre-treated patients) harbored wild-types viruses. The most frequent DRMs were M184V (86.3%), K103N (45.5%) and thymidine analog mutations (TAMs) (40.9%). Two (13.3%) pre-treated patients harbored viruses that showed a multi-nucleos(t)ide resistance including Q151M, K65R, E33A/D, E44A/D mutations. Conclusion In Cambodia, VF rates were low for naive patients but the emergence of DRMs to NNRTI and 3TC occurred relatively quickly in this subgroup. In pre-treated patients, VF rates were much higher and TAMs were relatively common. HIV genotypic assays before ART initiation and for ART pre-treated patients infection should be considered as well.
To assess the relative frequency of the different causes of pompholyx evoked in the literature.Prospective survey.Clinical outpatient setting.A total of 120 consecutive patients with pompholyx referred to our department from 2000 through 2003.Systematic investigation of different causes of pompholyx: fungal intertrigo, hyperhidrosis, atopy, contact eczema, and internal reactions with systematic provocation tests to metals, balsam of Peru, and food allergen when suspected.The present study found the following causes of pompholyx in the 120 patients: mycosis (10.0%); allergic contact pompholyx (67.5%), with cosmetic and hygiene products as the main factor (31.7%), followed by metals (16.7%); and internal reactivation from drug, food, or haptenic (nickel) origin (6.7%). The remaining 15.0% of patients were classified as idiopathic patients, but all were atopic. (Percentages do not total 100 because of rounding.)Our data confirm the existence of reactional pompholyx to interdigital-plantar intertrigos and endogenous reactions to metals or other allergens, but they mainly point at the unexpected importance of a so-called contact pompholyx in which cosmetic and hygiene products play a preponderant role compared with metals. The great frequency of atopic conditions, even if idiopathic pompholyx is not inferred as an equivalent of atopy, should lead to further causative investigations before undertaking more expensive or extensive treatments of refractory pompholyx.
Use of edible insects as an alternative source of proteins in food and feed is increasing. These last years, numerous companies in Europe have started producing insects for food and feed purposes. In the European Union, the use of edible insects for human consumption falls within Regulation (EU) No. 2015/2283 on novel foods. For feed, Commission Regulation (EU) 2017/893 authorizes seven insect species as processed animal proteins for aquaculture. Methods of authentication are required to check the conformity of the products. In this study, we propose a real-time polymerase chain reaction (PCR) method for the specific detection of the lesser mealworm (Alphitobius diaperinus), one of the species included in the shortlist of authorized insects. The selected target is the cadherin gene with a single-copy (per haploid genome) illustrated by our experimental evidence. The PCR test amplified a 134-bp fragment of the cadherin gene. The qualitative method was assessed toward several performance criteria. Specificity was checked against 54 insect species next to other animal and plant species. The sensitivity, efficiency, robustness, and transferability of the PCR assay were also successfully tested. Finally, the applicability of the test was assessed on real-life processed samples (industrial meals) of A. diaperinus. The study also showed that there seems to be a huge confusion on the correct labeling of the marketed mealworms. We did not succeed to get Alphitobius laevigatus samples. They all appeared to belong to the A. diaperinus taxon.
Severe coronavirus disease 2019 (COVID-19), due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), may be associated with mild thrombocytopenia,1, 2 and some COVID-19-induced immune thrombocytopenia (ITP) cases have been reported.3, 4 Some reports suggest that patients with pre-existing ITP may experience a relapse5 in the case of SARS-CoV-2 infection that could be prevented by vaccination. However, a growing number of de novo ITP occurring after anti-SARS-CoV-2 vaccination are being reported with mRNA-based vaccines. In a recent series,6 20 patients who received either BNT162b2 (Comirnaty®) or mRNA-1273 (SpikeVax®) vaccines had new-onset thrombocytopenia after the first injection (median time: 5 days), usually associated with bleeding and low platelet counts (median: 2 × 109/l). The incidence of vaccine-induced thrombocytopenia remains difficult to assess precisely as no routine blood count is recommended after vaccination. However, it appears very low, with >20 million people vaccinated in the United States with at least one dose at the time this paper6 was submitted. However, whether patients with ITP have a risk of relapse after anti-SARS-CoV-2 vaccination remains a matter of debate. In France, the National Reference Centre for Adult Immune Cytopenia proposed that anti-SARS-CoV-2 vaccination should be considered in patients with ITP and that a platelet count should be obtained 1 week after each vaccine injection in order to detect ITP relapse. In the present study, we assessed the evolution of a cohort of patients with ITP that received anti-SARS-CoV-2 vaccination. We conducted an observational study in four French referral centres from January 2021 to June 2021. Inclusion criteria were patients aged >18 years with a previous ITP diagnosis (primary or secondary) according to international criteria7 and receiving at least one anti-SARS-CoV-2 vaccine injection. All these patients were already enrolled in the prospective CARMEN-France registry and were not opposed to real-world data collection about ITP management. All clinical and biological data used in the present study were already recorded in the registry (authorisation number 2012-438 from the French national agency regulating data protection). From January to June 2021, 92 adult patients with ITP (55 women, 59·8%), with a median [interquartile range (IQR), range] age of 69 [19, 24–90] years (Table SI) were selected. In all, 78 patients had primary ITP (85%), and two had a history of COVID-19-associated ITP 1 year previously. At the time of first vaccine dose, the median (IQR, range) ITP duration was 90 (164, 2–914) months and 38 patients (41%) had no ongoing treatment (Table SI). Patients received BNT162b2 (Comirnaty®; n = 78, 85%), ChadOx1nCoV-19 (VAXZEVRIA®; n = 9, 10%), and mRNA-1273 (SpikeVax®; n = 5, 5%) vaccines. First, we focussed on the 65 patients (70%) who had a platelet count at 7 ± 3 days after the first shot of vaccine (Fig 1). The last platelet count available (56/65 patients) in the 4 weeks before vaccination was a median (IQR, range) of 116 (137, 12–644) × 109/l, including two patients (3%) with platelet counts of <30 × 109/l, while the median (IQR, range) platelet count at 7±3 days after the first shot was 118 (133, 14–729) × 109/l, among which three patients (4·5%) had a platelet count of <30 × 109/l (one of them also had a platelet count of <30 × 109/l before vaccination; Fig 2). A total of 70 patients (76%) were fully vaccinated (two shots), all of them with the same vaccine (including 46 patients with a platelet count at 7±3 days after the first shot). Reasons for absence of the second injection were lack of follow-up (16 patients), SARS-CoV-2 infection before the second injection (four), patient refusal (one) and ITP relapse (one). Among the 53 patients (75·7%) who had a platelet count available at 7±3 days after the second dose, six (11·3%) had a platelet count of <30 × 109/l. During the follow-up [median (IQR, range) time: 59 (35, 15–126) days], after the first vaccination of the entire cohort of 92 patients (Fig S1), eight (8·7%) required a rescue therapy and/or a change of ITP therapy, including three patients with bleeding manifestations (Fig 1 and Fig S2). Among these eight patients, three had a previous stable disease, and platelet counts decreased only after vaccination (Fig S2A–C). One 69-year-old man with a history of ITP who had been in remission without any treatment for 7 years, had a decrease in platelet count from 177 × 109/l (18 days before) to 12 × 109/l on day 2 after vaccination with BNT162b2 (Fig S2A). The patient presented with bleeding and received dexamethasone, repeated intravenous immunoglobulin courses, romiplostim and vinblastine with a transient response. After 2 months, he received rituximab and eventually achieved a complete response in combination with romiplostim at 10µg/kg/week. He was not given a second vaccine dose. One 49-year-old woman with chronic ITP and long-term treatment with dapsone and low-dose corticosteroids had fluctuating platelet counts of between 30 and 60 × 109/l without bleeding. At 1 week after the second injection of mRNA-1273 vaccine she had mild purpura and 20 × 109/l platelets (Fig S2B). She achieved a complete response 5 days after a transient increase of her corticosteroids dose. One 46-year-old man with chronic ITP and long-term treatment with eltrombopag (Fig S2C) had a decrease in platelet count from 227 × 109/l at 11 days before to 23 × 109/l at 2 days after the second dose of BTN16B2, with no bleeding. He achieved a response (49 × 109/l) 5 days after an increase in the eltrombopag dose combined with a short course of prednisone. The five remaining patients had bleeding symptoms and treatment modifications within the 3 months preceding vaccination, with multiple relapses that were chronologically unrelated to vaccination (Fig S2D–H). Overall, we observed three clinically significant drops in platelet counts that could be attributed to anti-SARS-CoV-2 vaccine (3·3%). Interestingly, all ITP relapses occurred within the week after vaccination, as previously described for thrombocytopenia in patients with no pre-existing ITP6 and in a recent series,8 and in two out of three patients after the second dose. The low number of events did not allow the identification of risk factors, but one patient had ITP remission for several years, suggesting that ITP relapse may be unpredictable. One of the main limitations of our present study is the relatively few patients and limited follow-up. Furthermore, the proportion of patients who received non-RNA-based vaccines in our present study was too low (nine patients) to draw any definite conclusion on the safety of non-replicating adenovirus-based vaccines in patients with ITP. Overall, our present results suggest that ITP relapses after mRNA vaccines are rare and most often benign and support a routine assessment of platelet counts in the week after each vaccination. We thank Marine Cecchi and Odile Gosset for technical assistance. Etienne Crickx and Bertrand Godeau designed the study and analysed the data. Etienne Crickx, Guillaume Moulis, Matthieu Mahevas and Marc Michel wrote the manuscript. Other authors included patients in the study. Guillaume Moulis received meeting attendance grants from Amgen and Novartis, is coordinator of research studies granted by Amgen, CSL Behring, Novartis and Grifols. He participated to educational sessions funded by Amgen and Novartis, and to boards for Amgen, Argenx, Novartis and Sobi. Mikael Ebbo received meeting attendance grants from Novartis, Octapharma and Sobi, and participated to educational sessions for Amgen, Grifols, Novartis and to boards for Grifols and Novartis. Marc Michel participated to educational sessions and boards for Amgen, Argenx, Novartis, Sobi and UCB. Matthieu Mahevas received meeting attendance grants from Amgen and Novartis, is coordinator of research studies granted by GSK. He participated to educational sessions funded by Amgen and Grifols. Bertrand Godeau participated in educational sessions and boards for Amgen, Grifols, Novartis, Roche and Sobi. Louis Terriou participated in educational sessions and boards for Amgen, Novartis and Sobi. The other authors have no conflict of interest to declare. Fig S1. Platelet counts after vaccination. Fig S2. Patients with treatment modification during follow-up after first vaccine (day 0, dotted line). Table SI. Patients' characteristics. 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