French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes.

Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients' association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database.

A better understanding of immune-related adverse events is essential for the early detection and appropriate management of these phenomena. We conducted an observational study of cases recorded at the French reference center for hypereosinophilic syndromes and in the French national pharmacovigilance database. Thirty-seven reports of eosinophilia induced by treatment with immune checkpoint inhibitors (ICIs) were included. The median [range] time to the absolute eosinophil count (AEC) peak was 15 [4─139] weeks. The median AEC was 2.7 [0.8─90.9] G/L. Eosinophil-related manifestations were reported in 21 of the 37 cases (57%). If administered, corticosteroids were always effective (n = 10 out of 10). Partial or complete remission of eosinophilia was obtained in some patients not treated with corticosteroids, after discontinuation (n = 12) or with continuation (n = 4) of the ICI. The AEC should be monitored in ICI-treated patients. If required by oncologic indications, continuation of ICI may be an option in asymptomatic hypereosinophilic patients, and in corticosteroid responders.

"Idiopathic Eosinophilic Vasculitis": Another Side of Hypereosinophilic Syndrome? A Comprehensive Analysis of 117 Cases in Asthma-Free Patients.

BACKGROUND: The absence of asthma may rule out a diagnosis of eosinophilic granulomatosis with polyangiitis in patients with hypereosinophilic syndrome (HES) and features of vasculitis. OBJECTIVE: To describe eosinophilic vasculitis (EoV) as a possible manifestation of HES in asthma-free patients. METHODS: We screened our hospital database and the literature for patients with HES who met the following 4 criteria: (1) histopathological or clinical features of EoV (biopsy-proven vasculitis with predominant eosinophilic infiltration of the vessel wall and/or features of vasculitis with tissue and/or blood hypereosinophilia [absolute eosinophil count >1.5 G/L]); (2) no other obvious causes of reactive eosinophilia, organ damage, and vasculitis; (3) the absence of antineutrophil cytoplasmic antibodies; and (4) the absence of current asthma. RESULTS: Ten of our 83 (12%) asthma-free patients with HES and 107 additional cases in the literature met the criteria for EoV. After a critical analysis of the patients' clinical and laboratory characteristics and outcomes, we identified 41 cases of single-organ EoV (coronary arteritis, n = 29; temporal arteritis, n = 8; cerebral vasculitis, n = 4). Of the remaining 76 patients with EoV, the most frequent manifestations (>10%) were cutaneous vasculitis (56%), peripheral neuropathy (24%), thromboangiitis obliterans-like disease (16%), fever (13%), central nervous system involvement (13%), deep venous thrombosis (12%), and nonasthma lung manifestations (12%). Blood hypereosinophilia more than 1.5 G/L was observed in 79% of patients, and necrotizing vasculitis was observed in 44%. CONCLUSIONS: Our results suggest that idiopathic EoV (HES-associated vasculitis) can be classified as an eosinophilic-rich, necrotizing, systemic form of vasculitis that affects vessels of various sizes in asthma-free patients.

[Hypereosinophilic syndromes]. / Syndromes hyperéosinophiliques.

Hypereosinophilic syndromes. Hypereosinophilic syndromes (HES) is a protean condition defined by chronic blood eosinophilia ≥ 1.5 G/L (> 1 month) leading to eosinophilic-related organ damage. HES subtypes includes neoplastic (clonal) disorders (HESN, that comprises FIP1L1-PDGFRA- related chronic eosinophilic leukemia and myeloproliferative and myelodysplastic syndromes associated with eosinophilia) and reactive HES (HESR, that aggregates all conditions e.g. parasitic infections, adverse drug reactions, inflammatory or neoplastic diseases that lead to the production of Th2-related cytokines and thereby to non-clonal hypereosinophilia). HESR also includes the lymphoid variant of HES (HESL), a chronic clonal indolent T-cell lymphoproliferative disorder in which mature peripheral T cells secrete high amounts of IL-5, leading to the polyclonal expansion of eosinophils. Despite an extensive etiological workup, approximately 50% of HES remain of undetermined cause. HES-related clinical manifestations are highly diverse, but dermatological, respiratory and gastro-intestinal symptoms are the most frequent. The long-term prognosis is driven by cardiac involvement and, for patients with HESN and HESL, by the risk of acute transformation into high-grade hematological malignancies. Treatment of HESN relies on tyrosine kinase inhibitors (e.g. imatinib mesylate), while oral glucocorticoids are the usual the fist-line therapy for HESR (including SHEL). In this setting, second-line treatments include hydroxyurea and Peg-interferon alfa-2a. IL-5-targeted therapies are very promising (except for HESN). Yet, to date, their use is restricted to clinical trials and to a compassionate use program dedicated to severe and refractory patients.

Syndromes hyperéosinophiliques. Les syndromes hyperéosinophiliques sont définis par l'association d'une hyperéosinophilie sanguine supérieure ou égale à 1,5 G/L d'évolution chronique (> 1 mois) à des dommages tissulaires (quels qu'ils soient) en rapport avec l'infiltration éosinophilique. Il s'agit d'une entité hétérogène qui comprend notamment les syndromes hyperéosinophiliques néoplasiques « clonaux ¼ (SHEN) [dont la leucémie chronique à éosinophiles liée à la délétion FIP1L1-PDGFRA et les éosinophilies associées aux autres syndromes myéloprolifératifs et myélodysplasiques] et les syndromes hyperéosinophiliques réactionnels (SHER, entité hétérogène regroupant l'ensemble des situations (infections parasitaires, prise médicamenteuse, maladies inflammatoires ou néoplasiques) responsables de la production de cytokines Th2 conduisant à une hyperéosinophilie non clonale. Parmi les SHER, on distingue les SHE lymphoïdes (SHEL), où la production d'interleukine 5 (IL-5) est liée à la présence d'une lymphoprolifération T de bas grade de phénotype aberrant (généralement CD3-CD4+). Malgré un bilan causal exhaustif large, on estime qu'environ 50 % des SHE restent d'origine indéterminée. Les manifestations cliniques sont diverses et les atteintes dermatologiques, respiratoires et digestives sont les plus fréquentes. Le pronostic à long terme est surtout corrélé à l'atteinte cardiaque et, pour les SHEN et les SHEL, au risque d'acutisation en pathologie maligne de haut grade (leucémie aiguë myéloblastique et lymphome T périphérique respectivement). La prise en charge des SHEN repose sur les inhibiteurs de tyrosine kinase, notamment l'imatinib mésylate. Pour les SHER (y compris les SHEL), la corticothérapie est généralement efficace, et les thérapeutiques de deuxième ligne sont l'hydroxyurée et le peginterféron alpha-2a. Les biothérapies ciblant l'IL-5 sont très prometteuses (hors SHEN) mais leur utilisation est pour l'instant limitée aux essais thérapeutiques et à un protocole d'usage compassionnel pour les patients les plus sévères et réfractaires aux thérapeutiques de première ligne.

Disseminated Spiroplasma apis Infection in Patient with Agammaglobulinemia, France.

We report a disseminated infection caused by Spiroplasma apis, a honeybee pathogen, in a patient in France who had X-linked agammaglobulinemia. Identification was challenging because initial bacterial cultures and direct examination by Gram staining were negative. Unexplained sepsis in patients with agammaglobulinemia warrants specific investigation to identify fastidious bacteria such as Spiroplasma spp.

Antioxidant and anti-atherogenic activities of olive oil phenolics.

The aim of the current study was to investigate the antioxidant and cellular activity of the olive oil phenolics oleuropein, tyrosol, hydroxytyrosol, and homovanillic alcohol (which is also a major metabolite of hydroxytyrosol). Well-characterized chemical and biochemical assays were used to assess the antioxidant potential of the compounds. Further experiments investigated their influence in cell culture on cytotoxic effects of hydrogen peroxide and oxidized low-density lipoprotein (LDL), nitric oxide production by activated macrophages, and secretion of chemoattractant and cell adhesion molecules by the endothelium. Inhibitory influences on in vitro platelet aggregation were also measured. The antioxidant assays indicated that homovanillic alcohol was a significantly more potent antioxidant than the other phenolics, both in chemical assays and in prolonging the lag phase of LDL oxidation. Cell culture experiments suggested that the olive oil phenolics induce a significant reduction in the secretion of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (and a trend towards a reduced secretion of monocyte chemoattractant protein-1), and protect against cytotoxic effects of hydrogen peroxide and oxidized LDL. However, no influence on nitric oxide production or platelet aggregation was evident. The data show that olive oil phenolics have biochemical and cellular actions, which, if also apparent in vivo, could exert cardioprotective effects.