Abstract Introduction and aims Eosinophils are hallmark cells of type 2 (TH2) immune responses, but their pathogenic role in skin disorders remains unclear. In atopic dermatitis (AD) and drug reaction with eosinophilia and systemic symptoms (DRESS), clinical data suggest contrasting involvement, possibly reflecting distinct endotypes. Conventional biomarkers, such as eosinophil counts, do not indicate whether these cells actively drive disease or act as bystanders. This study aimed to characterize transcriptomic programmes of circulating eosinophils in cutaneous TH2-mediated diseases to identify activation pathways and disease-specific signatures. Methods Fifteen adult individuals [DRESS, AD and healthy controls (HCs); n = 5 per group] were recruited. Pure populations of negatively isolated eosinophils were subjected to bulk RNA sequencing. Eosinophils stimulated with interleukin (IL)-3, IL-5 or granulocyte-macrophage colony-stimulating factor defined reference transcriptomic datasets for use in in silico deconvolution (CIBERSORT). Comparative analyses included public data from asthma and chronic obstructive pulmonary disease. Results HC, AD and DRESS eosinophils showed distinct transcriptomic clustering, but DRESS transcriptomes showed more heterogeneity with significantly greater Euclidian distances (P < 0.01). DRESS showed many more differentially expressed genes (DEGs) as compared with both HC and AD, and these were similar, indicating profound transcriptomic reprogramming in DRESS but AD eosinophils remain close to homeostatic states. Key upregulated DRESS DEGs included PRG2, MT1E/MT1F, GPR42 and FAM19A2. The DRESS transcriptome was shown to be significantly driven by IL-5 compared with AD (P = 0.008) and asthma (P = 0.016) and to a lesser extent IL-3 (vs. AD, P = 0.032; asthma, P = 0.01). The 351 genes underpinning deconvolution mirrored whole-transcriptome clustering. Pathway ontology analysis in DRESS showed enriched adhesion/activation pathways and downregulated migration/chemotaxis. Conclusions Eosinophils exhibit distinct transcriptomic programmes in cutaneous TH2 diseases, supporting these as eosinophil-driven vs. bystander conditions. DRESS represents a highly activated phenotype, contrasting with AD. These findings warrant deeper characterization of eosinophil subsets with tissue-resident spatial analysis to define their role in skin disease pathophysiology.

Besides their largely specific and abundant toxic granule proteins, their Charcot-Leyden crystals, DNA traps, and the release of leukotrienes, human eosinophils are often seen as affecting the immune response and tissue remodeling due to the release of numerous types of cytokines and growth factors. However, the extent of release and the functionality of such mediators, particularly from human eosinophils, remains uncertain. We review the literature focused on cocultures of human eosinophils with other cell types to identify possible cytokines and growth factors secreted by eosinophils and their function(s) on epithelial cells, fibroblasts, lymphocytes, and endothelial cells. Models of coculture include direct cell-to-cell contact, separation with filters, and the use of eosinophil-conditioned media. These models identified cytokines and growth factors as potential eosinophilic factors affecting the behavior of other cell types. In multiple published transcriptome data sets, the expression of these factors in eosinophils was confirmed using human blood and tissue eosinophils, which also allowed us to identify additional potentially important eosinophilic products. The findings in this review support the idea that human eosinophils remain effector cells via their release of toxic proteins (ie EPX/eosinophil peroxidase, RNASE3/eosinophil cationic protein, PRG2/eosinophil major basic protein), Charcot-Leyden crystals of galectin-10, DNA, and leukotrienes, and they produce and release a set of cytokines and growth factors to affect their surroundings.

Introduction: Lymphocytic-variant of hypereosinophilic syndrome (L-HES) is a clonal T-cell disorder driven by an aberrant Th2 response, typically featuring CD3- CD4+ T-cell expansion, eosinophil-mediated tissue injury, most commonly skin lesions, and lymphadenopathy. Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma of follicular helper T-cell origin; it can present with similar clinical features such as lymphadenopathy, rash and eosinophilia. Histological and immunophenotypic features may also be common in both diseases, thus creating a diagnostic overlap. Case description: We report the case of a 53-year-old man with a medical history of allergic rhinitis who developed a diffuse, persistent maculopapular rash with pruritis. Physical examination revealed inguinal lymphadenopathy without organomegaly, laboratory investigations demonstrated marked eosinophilia, and hypergammaglobulinemia, while additional testing excluded any infectious or autoimmune aetiologies. Lymphocytic immunophenotyping on peripheral blood and skin biopsy revealed a high proportion of CD3-CD4+ cells exhibiting a classic TH2 phenotype, consistent with L-HES. However, lymph node histology demonstrated architectural remodelling with intrafollicular infiltration by atypical T lymphocytes showing a T-cell follicular helper phenotype, findings indicative of AITL. The coexistence of L-HES and AITL was established. The patient underwent polychemotherapy, resulting in rapid clinical improvement of skin lesions with sustained remission at 6 months of follow up. Conclusion: L-HES and AITL may coexist, or L-HES may precede overt lymphoma, suggesting clonal evolution within a shared biological spectrum. This case highlights diagnostic pitfalls and emphasizes the need for integrated clinical, pathological, flow cytometric and molecular evaluation.

BACKGROUND:Eosinophilic cellulitis (EC), also known as Wells' syndrome, is a rare, poorly studied inflammatory dermatosis. OBJECTIVE:To describe the clinical and histopathological spectrum, associated conditions, outcomes of EC, and treatment response rates. METHODS:Retrospective multicenter study including patients with biopsy-proven EC. Risk factors for unfavorable clinical course (defined as recurrence or persistent disease >6 months) were assessed using univariable and multivariable logistic regression models. RESULTS:A total of 114 patients (53% females; median age, 52 years) were included. The most frequent clinical presentation was papulonodular (52%), with lesions predominantly on the legs (69%). Disabling pruritus was common (83%), whereas systemic symptoms were rare. Histological findings did not differ between patients with or without triggering factors or associated diseases, or between those with or without blood eosinophilia. Triggering factors and associated conditions were identified in 30 (26%) and 24 (21%) patients, respectively. Arthropod bites or stings were the most common triggering factor, whereas hematological malignancies, antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis, and idiopathic hypereosinophilic syndrome were the most frequently associated conditions. Most frequently used treatments were topical (54%) and oral corticosteroids (35%), with complete response rates of 67% and 82%, respectively. Conventional synthetic disease-modifying antirheumatic drugs showed moderate efficacy (complete response ≤31%), whereas biologics targeting type 2 inflammation yielded promising results. In multivariable analysis, lesion size higher than 5 cm was the only variable independently associated with unfavorable clinical course (odds ratio, 3.79; 95% CI 1.42-10.10; P = .008). CONCLUSIONS:EC likely represents a disease spectrum encompassing conditions leading to eosinophil-mediated dermal toxicity. Lesion size larger than 5 cm is associated with unfavorable clinical course. Although corticosteroids achieve high remission rates, biologics targeting type 2 inflammation appear promising second-line options warranting further evaluation.

Life-threatening hypereosinophilic syndrome (HES) is a rare medical emergency with limited therapeutic options in corticosteroid-refractory cases. Preliminary reports suggest that Janus kinase inhibitors may be beneficial in eosinophil-associated disorders, including HES. We conducted a nationwide multicenter retrospective study to assess ruxolitinib. Thirteen patients with severe acute HES and organ- or life-threatening involvement were included, most requiring intensive care, with massive baseline absolute eosinophil counts (AEC, median 45 × 109/L) and major involvement including eosinophilic myocarditis, ischemic strokes, and vascular thromboses. Ruxolitinib was initiated after a median of 7 days of corticosteroids. A rapid decline in absolute eosinophil counts was observed after initiation of ruxolitinib, with hematologic response rates of 54%, 85%, and 92% at Days 7, 14, and 30. Clinical improvement was observed across organ systems. Adverse events were manageable, although three deaths occurred during follow-up, only one of which occurred on ruxolitinib.

Abstract Objectives Inborn errors of immunity are rare genetic disorders that cause dysfunction of the immune system. Among these, familial haemophagocytic lymphohistiocytosis (FHL) involves defects in the perforin/granzyme pathway, which is essential for regulating immune responses. These conditions predispose individuals to haemophagocytic lymphohistiocytosis, a life‐threatening hyperinflammatory syndrome. FHL has traditionally been described in paediatric patients with a fatal outcome in the absence of early haematopoietic stem cell transplantation. However, some patients harbouring missense mutations may present with atypical or late‐onset symptoms, for which management remains unstandardised. Among these reported variants, the pathogenicity of the A91V PRF1 mutation remains the most controversial in the literature. Method We report clinical, biological and cytometric characteristics of two patients with a homozygous PRF1 A91V mutation who developed clinical features consistent with FHL2. Discussion We discuss the latest 2024 classifications to better characterise this group of disorders and their underlying genetic basis, with particular emphasis on atypical presentations and the A91V mutation, which may pose diagnostic and therapeutic challenges. Conclusion A91V PRF1 variant appears to represent a risk factor for the development of atypical FHL manifestations under divers triggers.

Innate immune cells appear to have an important implication in the resolution and/or the aggravation of the COVID-19 pathogenesis after infection with SARS-CoV-2. To better appreciate the role of these cells during COVID-19, changes in blood eosinophil, the neutrophil and monocyte count, and levels of surface protein markers have been reported. However, analyses at several timepoints of multiple surface markers on granulocytes and monocytes over a period of one month after a SARS-CoV-2 infection are missing. Therefore, in this study, we performed blood eosinophil, neutrophil, and monocyte phenotyping using a list of surface proteins and flow cytometry during a period of 30 days after the hospitalization of patients with severe SARS-CoV-2 infections. Blood cell counts were reported at seven different timepoints over the 30-day period as well as measures of multiple mediators in serum using a targeted multiplex assay approach. Our results indicate a 95% drop in the blood eosinophil count by D1, with eosinophils displaying a phenotype defined as CD69/CD63/CD125high and CCR3/CD44low during the early phases of hospitalization. Conversely, by D7 the neutrophil count increased significantly and displayed an immature, activated, and immunosuppressive phenotype (i.e., 3% of CD10/CD16low and CD10lowCD177high, 6.7% of CD11bhighCD62Llow, and 1.6% of CD16highCD62Llow), corroborated by enhanced serum proteins that are markers of neutrophil activation. Finally, our results suggest a rapid recruitment of non-classical monocytes leaving CD163/CD64high and CD32low monocytes in circulation during the very early phase. In conclusion, our study reveals potential very early roles for eosinophils and monocytes in the pathogenesis of COVID-19 with a likely reprogramming of eosinophils in the bone marrow. The exact roles of the pro-inflammatory neutrophils and the functions of the eosinophils and the monocytes, as well as these innate immune cell types, interplays need to be further investigated.

Primary intestinal lymphangiectasia or Waldmann’s disease (ORPHA code: 90362) is a very rare disorder of unknown etiology, characterized by digestive lymphatic vessel dilations. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Centers for Rare Vascular diseases and Rare Digestive diseases, is available from the French Health Authority website. The latter allow lymph leakage (chyle) into the intestinal lumen that is responsible for protein-losing gastroenteropathy, combining hypoalbuminemia, lymphopenia and hypogammaglobulinemia. Diagnosis is usually made before the age of 3, but primary intestinal lymphangiectasia may be discovered in adults. Edema of the lower limbs is the main clinical sign and serous effusions (pleura, peritoneum, pericardium) are sometimes abundant. Exudative gastroenteropathy is confirmed by increased α1-antitrypsin clearance. Esophagogastroduodenoscopy finds milky lesions corresponding to lymphangiectasias; duodenal biopsies confirm the diagnosis. Endoscopic videocapsule may be useful to evaluate the extent of the disease and/or if esophagogastroduodenoscopy is not contributory. In rare cases, the disease may be complicated by digestive or extra-digestive B-cell lymphoma in adults. Management is mainly based on a strict fat-free diet, combined with supplementation with medium-chain triglycerides, essential fatty acids and fat-soluble vitamins. Octreotide, a somatostatin analogue, has inconsistent efficacy, in combination with the fat-free diet and the sometimes-prescribed mammalian target of rapamycin-receptor inhibitor sirolimus, occasionally achieving positive effects. Diuretics and albumin infusions may be useful in addition to the fat-free diet. Intestinal resections are proposed for rare, localized, segmental forms of the disease. Primary intestinal lymphangiectasia is a chronic disease requiring a prolonged restrictive and constraining strict low-fat diet supplemented with medium-chain triglycerides and fat-soluble vitamins. Its evolution can be complicated by more-or-less severe serous effusions and rare lymphoma. Life-long clinical and biological monitoring is required.

A 41-year-old woman presented to the emergency room for long-term dysphagia, with a loss of eight kilos in two months. Myositis or inflammatory myopathies were suspected. A marked increase in troponin T concentration was observed.

Despite well-conducted replacement therapy with polyvalent immunoglobulins (IgRT), some patients with primary immunodeficiencies (PID) continue to experience recurrent or chronic infections. IgA and IgM, essential for mucosal and complement-mediated immunity, are absent or minimal in standard immunoglobulin products. The aim of this study is to evaluate the safety and clinical evolution profiles in PID patients with undetectable IgA/IgM levels and persistent infections despite standard IgRT, after introduction of an IgA- and IgM-enriched immunoglobulin preparation (IgGAM, Pentaglobin®). A compassionate use program (CUP) in France enrolled 20 PID patients with undetectable IgA/IgM levels, receiving IgGAM IV infusions every 7–14 days. Tolerance, infection frequency, hospitalizations, and biological markers (Ig levels, complement activation, salivary IgA) were analyzed prospectively. Twenty patients were included in the CUP at the time of analysis. No severe adverse event was reported. Half of the patients experienced mild to moderate hypersensitivity symptoms. Mean antibiotic courses dropped from 5.4 to 2.3/year (p = 0.0009) and mean number of hospitalizations decreased from 2.6 to 1.2/year (p = 0.01). Median serum IgA and IgM levels increased three months after IgGAM start. IgM and low levels of IgA were detected in saliva samples, suggesting at least a transient transfer of IgA/IgM from IgGAM into mucosal fluids. In patients with severe PID and undetectable IgA/IgM, IgGAM was associated with reduced infections and hospitalizations. Controlled studies are needed to confirm the benefit of IgA/M enriched immunoglobulin preparations in PID patients with persistent and/or recurrent respiratory or digestive infections.

BACKGROUND:The FIP1L1-PDFGRA (F/P)-associated hypereosinophilic syndrome (HES) is a rare condition. The F/P fusion gene testing is one of the first-line investigations in patients with unexplained eosinophilia and yields poor diagnostic performance. OBJECTIVE:To build and validate the factor interacting with PAPOLA and CPSF1 (FIP) score: a set of weighted criteria warranting testing for the F/P fusion gene. METHODS:We merged data from 151 patients with F/P-associated HES and 320 patients with either F/P-negative HES (n = 279) or hypereosinophilia of undetermined significance (n = 41). Training and validation cohorts (comprising, respectively, 90% and 10% of all patients) were randomly dichotomized. Variables with a P value less than .20 in univariate analysis were included in the multivariable forward-backward logistic regression model to assess their independent contribution to testing positive for the F/P fusion gene. Beta coefficients from multivariable logistic regression were used to assign points for the construction of the score. RESULTS:Age younger than 66 years, male sex, splenomegaly, lymphomatoid papulosis, absence of gastrointestinal involvement, high serum vitamin B12, high serum tryptase, and normal serum immunoglobulin E levels were the 8 variables retained in the model. The best cutoff value was greater than 48. The model yielded a sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve, respectively, of 88.3%, 93.7%, 87.1%, 94.4%, and 0.962 in the training dataset and of 85.7%, 97.0%, 85.7%, and 97.0%, 0.986 in the validation dataset. CONCLUSIONS:The FIP score highlights the need for closely selecting patients with hypereosinophilia for whom F/P fusion gene testing should be performed, resulting in medical time reduction and substantial cost-savings.

Background Subcutaneous immunoglobulin (SCIg) replacement therapy is indicated for patients with hypogammaglobulinemia caused by primary (PID) and secondary immunodeficiencies (SID). Objective To compare healthcare resource utilization (HCRU) and related direct medical costs of patients in France treated with weekly conventional SCIg (cSCIg) vs monthly hyaluronidase-facilitated SCIg (fSCIg). Methods This retrospective study of Ig-naïve patients with PID or SID newly receiving a SCIg between 2016 and 2018, extracted from the French National Healthcare reimbursement database (SNDS), analyzed the SCIg-related HCRU and reimbursed costs generated from in-hospital (hospitalizations and SCIg doses) or at-home (nurse visits [NV] and pump provider visits [PPV], drug doses) SCIg administration. Results Overall, 2,012 patients (PID:534; SID:1,478) were analyzed. The follow-up duration varied between 7.5 and 8.7 months according to sub-groups. Compared with fSCIg-treated patients, monthly mean rates of NV and PPV were respectively 2.5 and 3.1 times higher in PID, and 1.6 and 3.1 times higher in SID cSCIg-treated patients. Monthly mean rates for SCIg administration-related hospitalizations were lower overall, while their costs were 1.6 and 1.8 times higher for cSCIg than fSCIg subgroups, in PIDs and SIDs respectively; these results are due to more frequent hospitalizations with fSCIg being mainly shorter, without stayover. Total HCRU costs from the French NHI’s perspective were estimated to be lower with fSCIg vs cSCIg, in PIDs and SIDs. Conclusion This study provides real-world evidence of SCIg administration in a large French population. Patients with PID or SID treated with fSCIg had fewer at-home HCRU and lower overall costs for in-hospital or at-home SCIg administration compared with cSCIg-treated patients.

BACKGROUND:Hypereosinophilic syndromes (HES) are a heterogenous group of eosinophilic disorders. To date, only retrospective studies of limited sample-size and/or follow-up duration are available. METHODS:The COHESion study is a national prospective multicenter multidisciplinary cohort recruiting both adults or children with the spectrum of eosinophilic disorders (including reactive HE/HES [HE/HES-R], idiopathic HES [HES-I], lymphocytic HES [HES-L], neoplastic HE/HES [HE/HES-N], HE of unknown significance [HE-US], as well as IgG4-related disease [IgG4RD] or ANCA-negative eosinophilic granulomatosis with polyangiitis [EGPA] overlaps). Patients are followed-up yearly. All data about final diagnosis, organ involvement assessments, and outcome profiles in HES-I were captured and analyzed centrally by HES expert centers. RESULTS:From May 2019 to November 2023, 779 patients were included. For this preliminary analysis, 550 cases were available for centralized review (mean ± SD age: 56 ± 18 years, 42% of female patients). The final diagnoses were HES-I (47%), HE/HES-R (16%), HE-US (15%), HE/HES-N (7%), HE/HES-L (6%), IgG4RD (2%), and ANCA-negative EGPA (7%). In the 258 HES-I patients, outcome profiles were classified as follows: 16.3% had a "single-flare" without further relapse, 28.3% had a "relapsing-remitting" disease when there was at least a 6-month period free of symptoms between two flares, 46.1% had a "persistent disease" requiring continuous treatment to avoid relapses (9.3% remained unclassified because of insufficient follow-up). CONCLUSIONS:The COHESion cohort is the first nationwide prospective multicenter study collecting data on the full spectrum of HE/HES disorders. This preliminary analysis confirms that idiopathic HES patients have various outcome profiles, suggesting different underlying pathophysiological mechanisms and the need of patient-specific management. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT04018118.

Atopic dermatitis and other type 2 immune response diseases are often linked to elevated eosinophil levels in the blood. Although the role of eosinophils in atopic dermatitis pathophysiology is suspected, it remains unclear. The development of new treatments targeting the type 2 response, particularly cytokines involved in eosinophil activation and chemotaxis, makes it necessary to identify potential eosinophil profiles in atopic dermatitis that may respond to these treatments. A prospective study was conducted comparing blood eosinophil phenotypes in patients with moderate to severe atopic dermatitis (n = 19) without recent systemic treatment to healthy individuals (n = 19). The primary outcome was the membranous phenotypic signature of eosinophils, assessed by flow cytometry. Most patients with atopic dermatitis (84%) had early onset in childhood, a severe disease (mean SCORing Atopic Dermatitis of 57.5), and elevated blood eosinophil counts (310 per mu L in atopic dermatitis vs 120 in healthy individuals, P < 0.0001). Patients with atopic dermatitis exhibited lower CRTH2 on eosinophils but higher levels of human leukocyte antigen-DR isotype and Siglec-8 compared to healthy individuals. Other surface proteins showed no significant differences. Clustering analysis confirmed increased Siglec-8 in patients with atopic dermatitis. Additionally, patients with atopic dermatitis had higher serum levels of type 2 immune response markers such as eotaxin-2, IL-5, IL-3, and TARC. Circulating eosinophils in patients with atopic dermatitis show a distinct phenotypic profile, suggesting a role in atopic dermatitis pathophysiology and potential involvement in differential treatment responses. [GRAPHICS] .