Case report: CAR-T cell therapy-induced cardiac tamponade

CD19-specific chimeric antigen receptor T (CAR-T) cell therapy has recently been shown to improve the prognosis of refractory diffuse large B-cell lymphoma (DLBCL). However, CAR-T cells may induce numerous adverse events, in particular cytokine release syndrome (CRS) which is frequently associated with cardiovascular manifestations. Among the latter, acute pericardial effusion represents less than 1% of cases and cardiac tamponade has only been reported once. The management and outcome of these severe complications are not well established. We report here, a case of cardiac tamponade associated with CRS in a context of CAR-T cell therapy, which required urgent pericardiocentesis.Case summaryA 65-year-old man with refractory DLBCL was treated with CAR-T cell therapy. He had a history of dilated cardiomyopathy with preserved ejection fraction and transient atrial fibrillation. A pericardial localization of the lymphoma was observed on the second relapse. One day after CAR-T cell infusion the patient was diagnosed with grade 1 CRS. Due to hypotension, he was treated with tocilizumab and dexamethasone, and then transferred to intensive care unit (ICU). Echocardiography performed at ICU admission showed acute pericardial effusion with signs of right ventricular heart failure due to cardiac tamponade. It was decided to perform pericardiocentesis despite grade IV thrombocytopenia in a context of aplasia. Analysis of pericardial fluid showed a large number of lymphoma cells and 73% of CAR-T cells amongst lymphocytes, a level that was similar in blood. Hemodynamic status improved after pericardiocentesis, and no recurrence of pericardial effusion was observed. The presence of a high count of activated CAR-T cells in the pericardial fluid as well as the short interval between CAR-T cells injection and the symptoms appear as potential arguments for a direct action of CAR-T cells in the mechanism of this adverse event. The patient was discharged from ICU after two days and initially exhibited a good response to DLBCL treatment. Unfortunately, he died fifty days after starting CAR-T cell therapy due to a new DLBCL relapse.ConclusionPatients with a pericardial localization of DLBCL should be assessed for a risk of cardiac tamponade if receiving CAR-T cell therapy and presenting CRS. In this case, cardiac tamponade seems directly related to CAR-T cell expansion. Pericardiocentesis should be considered as a feasible and effective treatment if the risk of bleeding is well controlled, in association with anti-IL6 and corticosteroids

Diagnostics différentiels du PTT à l’admission‎ : étiologies et impact sur l'évolution des patients. Expérience du Centre de Référence Français des Microangiopathies Thrombotiques

Le purpura thrombotique thrombocytopénique (PTT) est défini par l’association d’une anémie hémolytique mécanique, une thrombopénie profonde, des souffrances viscérales et un dosage de l’activité ADAMTS13 indétectable. Ce dosage non disponible en urgence occasionne de ce fait des errances diagnostiques. L’objectif principal de cette étude est de décrire les caractéristiques des PTT associés à une erreur diagnostique initiale et analyser l’impact du retard diagnostique sur l’évolution des patients. Matériel et Méthodes : Tous les patients atteints d’un PTT acquis avec déficit sévère en ADAMTS13 (<10%) inclus de manière prospective entre mai 2000 et mai 2014 dans le registre français des microangiopathies thrombotiques ont été analysés dans l’étude. Une erreur diagnostique était retenue si le diagnostic initial posé n'était pas celui de PTT et si les patients ne recevaient pas d’échanges plasmatiques initialement. Résultats : Parmi les 423 patients PTT inclus, 84 (20%) ont eu une erreur diagnostique initiale et n’ont pas bénéficié du traitement spécifique adapté. Les principales erreurs diagnostiques étaient attribuées à des diagnostics de syndrome d’Evans et de purpura thrombopénique autoimmun dans 51% et 38% des cas respectivement. Le délai diagnostique médian par rapport à l’admission était dans le groupe erreur diagnostique de 5 [2-8] jours et de 1 [0-3] jour dans le groupe sans erreur diagnostique (p<0.001). A l’admission, comparativement aux patients sans erreur diagnostique, les patients du groupe « erreur diagnostique » avaient un taux de schizocytes faible ou indétectable plus élevé (57.5% vs 32%, p= 0.001), une hémoglobinémie plus élevée (8.4+/-1.3g/dl vs 7.7+/-1.2g/dl, p= 0.008), une fréquence d’anticorps antinucléaires positifs plus élevée (64.7% vs 50.8%, p=0.045), un test direct à l’antiglobuline positif plus fréquent (18% vs 4%, p=0.008) et un diagnostic de maladie auto-immune associée plus fréquent (23.8% vs 13.6%, p=0.017). De manière notable, 74% des patients du groupe erreur diagnostique avaient des atteintes d’organes à l’admission ou pendant la période d’errance diagnostique et 49% des atteintes jugées sévères. Un traitement par corticostéroïdes était plus fréquemment prescrit dans le groupe erreur diagnostique (96% vs 79%, p=0.002). Le délai de normalisation des plaquettes était plus long dans le groupe erreur diagnostique (22[10-34] jours vs 18[10-29] jours, respectivement, p=0.02). Les taux de mortalité, d’exacerbation et de rechute étaient identiques dans les 2 groupes. Cependant, les patients du groupe bon diagnostic initial avaient probablement une forme plus sévère de PTT, définie par une atteinte d’organe sévère plus élevée, 64% vs 49%, p=0.019. Conclusion : Dans un contexte d’hémolyse et de thrombopénie, un taux faible ou indétectable de schizocytes à l’admission, un test direct à l’antiglobuline positif ou la présence d’anticorps anti-nucléaires ne doit pas faire récuser le diagnostic de PTT, surtout en cas de souffrance d’organe. Une recherche répétée de schizocytes pourrait également réduire le risque d’erreur diagnostique. Un retard diagnostique peut entrainer un délai de normalisation du taux de plaquettes plus long

Anakinra for the Treatment of Hemophagocytic Lymphohistiocytosis: 21 Cases

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening cytokine storm syndrome. There are no definitive guidelines for the management of secondary HLH (sHLH). A recent report by a National Health Service (NHS) clinical panel has recommended anakinra as a treatment option. We aimed to analyse the efficacy and safety of anakinra for the treatment of all-cause sHLH. We conducted a multicentric retrospective study in two French University hospitals and included all patients who had a diagnosis of sHLH and who received anakinra. Among 21 patients (median age, 45 years), 13 were men. Anakinra was used as first-line therapy in 10 patients, and as monotherapy in 5 patients. We found that anakinra was effective in 19/21 patients (90.5%), with fever resolution in 19 patients (90.5%) within a median of 1.0 day (1, 2). At the Day 7 assessment, the mean CRP concentration decreased significantly (p p = 0.011). Anakinra was generally safe and well tolerated and was discontinued for side effects in only three patients (14.3%). Anakinra is an efficient and safe treatment to control sHLH of various causes. These data, together with the recent report of the NHS panel, call for the rapid conduct of prospective randomized clinical trials

Eculizumab in gemcitabine-induced thrombotic microangiopathy: experience of the French thrombotic microangiopathies reference centre

International audienceBackground: Gemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA). Methods: This study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016. Results: Twelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4-44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2-22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m 2 respectively in the eculizumab group and in the control group. Conclusions: These results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery

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

International audienceIdiopathic 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

High prevalence of pre-existing sarcopenia in critically ill patients with hematologic malignancies admitted to the intensive care unit for sepsis or septic shock

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Anti-C5 antibody treatment for delayed hemolytic transfusion reactions in sickle cell disease

International audienceDelayed hemolytic transfusion reaction (DHTR) is an unpredictable severe complication of transfusion in patients with sickle cell disease (SCD). It presents clinically as a vaso-occlusive crisis (VOC), often associated with the failure of one or more organs, after the transfusion of packed red blood cells (pRBC).1,2 Hyperhemolysis is encountered in the most severe forms. Both transfused and autologous red blood cells (RBC) are lysed.The mechanisms underlying DHTR remain unclear. Alloantibodies against RBC antigens were initially thought to underlie the pathophysiology, but no such antibodies are detected in about a third of the cases.3RBC degradation products, such as hemoglobin and heme, are released into the bloodstream during intravascular hemolysis. These elements and heme-loaded membrane microvesicles have recently been implicated in inflammation and organ injury in DHTR.4 Complement is activated via the classical pathway, by alloantibodies, and/or via the alternative pathway, by free heme.5 Hemedependent complement deposits on the endothelium contribute to organ damage.6 Due to these vascular lesions, hyperhemolysis often progresses to multiple organ failure and, in some cases, death

Clinical features and outcome of patients with acute respiratory failure revealing anti-synthetase or anti-MDA-5 dermato-pulmonary syndrome: a French multicenter retrospective study

IF 3.771International audienceBackgroundAnti-synthetase (AS) and dermato-pulmonary associated with anti-MDA-5 antibodies (aMDA-5) syndromes are near one of the other autoimmune inflammatory myopathies potentially responsible for severe acute interstitial lung disease. We undertook a 13-year retrospective multicenter study in 35 French ICUs in order to describe the clinical presentation and the outcome of patients admitted to the ICU for acute respiratory failure (ARF) revealing AS or aMDA-5 syndromes.ResultsFrom 2005 to 2017, 47 patients (23 males; median age 60 [1st–3rd quartiles 52–69] years, no comorbidity 85%) were admitted to the ICU for ARF revealing AS (n = 28, 60%) or aMDA-5 (n = 19, 40%) syndromes. Muscular, articular and cutaneous manifestations occurred in 11 patients (23%), 14 (30%) and 20 (43%) patients, respectively. Seventeen of them (36%) had no extra-pulmonary manifestations. C-reactive protein was increased (139 [40–208] mg/L), whereas procalcitonine was not (0.30 [0.12–0.56] ng/mL). Proportion of patients with creatine kinase ≥ 2N was 20% (n = 9/47). Forty-two patients (89%) had ARDS, which was severe in 86%, with a rate of 17% (n = 8/47) of extra-corporeal membrane oxygenation requirement. Proportion of patients who received corticosteroids, cyclophosphamide, rituximab, intravenous immunoglobulins and plasma exchange were 100%, 72%, 15%, 21% and 17%, respectively. ICU and hospital mortality rates were 45% (n = 21/47) and 51% (n = 24/47), respectively. Patients with aMDA-5 dermato-pulmonary syndrome had a higher hospital mortality than those with AS syndrome (n = 16/19, 84% vs. n = 8/28, 29%; p = 0.001).ConclusionsIntensivists should consider inflammatory myopathies as a cause of ARF of unknown origin. Extra-pulmonary manifestations are commonly lacking. Mortality is high, especially in aMDA-5 dermato-pulmonary syndrome

DataSheet_1_Ophthalmic vascular manifestations in eosinophil-associated diseases: a comprehensive analysis of 57 patients from the CEREO and EESG networks and a literature review.pdf

IntroductionEosinophils have widespread procoagulant effects. In daily practice, eosinophil-related cardiovascular toxicity consists of endomyocardial damage, eosinophilic vasculitis and arterial or venous thrombosis. Here we aim to report on the clinical features and treatment outcomes of patients with unexplained ophthalmic vascular manifestations and eosinophilia.MethodsWe conducted a retrospective, multicenter, observational study and a literature review of patients with eosinophilia (≥0.5 x109/L) and concomitant ophthalmic vascular manifestations independent of the underlying eosinophilic disease but with no alternative cause for ophthalmic manifestations. ResultsFifty-seven patients were included (20 from the observational study and 37 from the literature review). Ophthalmic vascular features were the initial manifestation of eosinophil-related disease in 34 (59%) patients and consisted of 29 central retinal artery occlusions, six branch retinal artery occlusions, five central retinal vein occlusions, two branch retinal vein occlusions, seven retinal vasculitides, two retinal vasospasms, 12 Purtscher’s retinopathies, 13 anterior ischemic optic neuropathies and two posterior ischemic optic neuropathies. The median [IQR] absolute eosinophil count at onset of ophthalmic vascular manifestations was 3.5 [1.7-7.8] x109/L. Underlying eosinophil-related diseases included eosinophilic granulomatosis with polyangiitis (n=32), clonal hypereosinophilic syndrome (HES) (n=1), idiopathic HES (n=13), lymphocytic HES (n=2), adverse drug reactions (n=3), parasitosis (n=2), polyarteritis nodosa (n=1), IgG4-related disease (n=1), eosinophilic fasciitis (n=1) and primary sclerosing cholangitis (n=1). Other extra-ophthalmologic arterial or venous thromboses related to eosinophilia were reported in four (7%) and nine (16%) patients, respectively. Visual prognosis was poor: only eight (10%) patients achieved full recovery of ophthalmologic symptoms. After a median follow-up of 10.5 [1-18] months, one patient (3%) had a recurrence of an ophthalmic vascular manifestation, and three patients (10%) had a recurrence of other vascular symptoms (deep vein thrombosis in two and pulmonary embolism in one patient). At the time of recurrence, absolute eosinophil counts were above 0.5 x109/L in all cases (n=4). DiscussionThis study broadens the spectrum of vascular manifestations associated with hypereosinophilia by adding ophthalmic vascular manifestations. In patients with ophthalmological vascular manifestations and hypereosinophilia, aggressive treatment of the underlying pathology (and normalization of blood count) should be implemented.</p