Brief Observations

Indolent course of a patient with hypereosinophilic syndrome associated with clonal T-cell proliferation

Lymphocytic variant is a rare subtype of hypereosinophilic syndrome (L-HES) secondary to overproduction of eosinophilopoietic cytokines by the underlying clonal T lymphocytes with abnormal immunophenotypes. Clinical profiles, treatment responses, and outcomes of L-HES are not well characterized given its rarity. We performed a systematic literature review to summarize cases identified in PubMed and Embase databases between January 1994 and July 2021. A total of 148 patients met the inclusion criteria with a median age at diagnosis of 46 years and 51.4% being male. Cutaneous manifestations (81.1%) predominated the clinical picture, while the characteristic cardiovascular involvement was seen in 11.5% of cases. The median eosinophil count at baseline was 5.3 × 10⁹/L and 109 patients (73.6%) had underlying clonal T lymphocytes harboring the classic CD3⁻CD4⁺ immunophenotype, which was associated with higher numbers of eosinophils and organ involvement at baseline. Corticosteroids were the most common first-line agent (88.1%), but most patients required additional treatment, leading to clinical or hematologic response in two-thirds. The 10-year overall survival was 81.6% (95% confidence interval [CI] 68.1–89.8). Transformation into malignant T cell lymphoma was observed in 19 patients, specifically in those with cardiovascular involvement (odds ratio [OR] 4.723, 95% CI 1.304–17.108, p = 0.018) and imatinib use (OR 4.284, 95% CI 1.191–15.404, p = 0.026). Taken together, a heavier disease burden was shown in L-HES patients with classic CD3⁻CD4⁺ lymphocytes but they were manageable with corticosteroids and sparing agents. There is an increased risk of lymphoma transformation that could be associated with certain clinical surrogates.

Hypereosinophilic syndrome (HES) or syndromes are disorders characterized by chronic peripheral blood hypereosinophilia with damage to various organs due toeosinophilic infiltration and release of mediators. HES is most accurately described as a collection of heterogeneous disorders, with some similarities in clinical features, but many differences. Based on recent advances in molecular and genetic diagnostic techniques and increasing experience with differences in clinical features and prognosis, some subtypes of HES have been defined, such as myeloproliferative variants, including chronic eosinophilic leukemia, and lymphocytic variants, but other subtypes remain undefined. Recent evidence suggests that, in addition to differences in clinical features, the range of complications, treatment options, and prognoses differs significantly among the myeloproliferative, lymphocytic, and undefined variants of HES.

A large body of evidence establishing the existence of an underlying T-cell disorder in a subset of patients fulfilling hypereosinophilic syndrome (HES) diagnostic criteria has accumulated over the past decade, resulting in the definition of a novel HES variant termed “lymphocytic” HES. Although end-organ complications of hypereosinophilia are generally benign, with predominant cutaneous manifestations, long-term prognosis is overshadowed by an increased risk of developing T-cell lymphoma, as a result of malignant transformation of aberrant T cells years after HES diagnosis. Therapeutic strategies should target pathogenic T cells in addition to eosinophils, but the practical implications remain largely unexplored.

Angioedema with hypereosinophilia syndrome has a dramatic clinical presentation that may result from T-cell dysregulation and/or eosinophil dysfunction. Symptoms may be either episodic or persistent and are usually responsive to systemic glucocorticosteroid therapy. This diabetic patient had a dramatically severe presentation, responsive to high-dose steroids but relapsing when prednisone was tapered. To decrease his risks from long-term steroids, a therapeutic trial of intravenous immunoglobulin (IVIG) was tried, and a slow taper off of glucocorticosteroids achieved a prolonged remission. A brief recurrence and subsequent remission of eosinophilia and symptoms were associated with changes in the IVIG preparation lot and source. We conclude that some cases of angioedema with hypereosinophilia syndrome may be highly responsive to IVIG therapy and, furthermore, that specific sources and/or lots of IVIG may have significantly different immunoregulatory properties.

L’interleukine 5 produite par les lymphocytes Th2 est impliquée dans diverses maladies s’accompagnant d’hyperéosinophilie. Plusieurs groupes ont identifié des cellules Th2 clonales avec un phénotype aberrant dans le sang de certains patients atteints du syndrome hyperéosinophilique idiopathique. La nature prémaligne de ces lymphocytes aberrants est suggérée par le développement occasionnel d’un lymphome T périphérique porteur du même phénotype. Dans notre série de cinq patients, les clones T avaient tous le phénotype CD3– CD4+. La production de cytokines Th2 et la prolifération de ces cellules en réponse à des cellules dendritiques in vitro étaient dépendantes de l’engagement des molécules CD2 et CD28, ainsi que d’une boucle autocrine IL-2/IL-2R. L’importante apoptose spontanée de ces cellules était fortement inhibée par l’IL-2 et l’IFN-α in vitro, suggérant que l’administration d’IFN-α à de tels patients pourrait favoriser l’expansion et l’éventuelle transformation maligne du clone. En revanche, le syndrome hyperéosinophilique pourrait représenter une indication inattendue des nouvelles molécules immunomodulatrices telles que le CTLA4-Ig et l’anti-IL-2R-α.

Interleukin-5 produced by Th2 lymphocytes is involved in the pathogenesis of a number of hypereosinophilic disorders. We and others have identified phenotypically abnormal clonal Th2 cells in peripheral blood of certain patients presenting the idiopathic hypereosinophilic syndrome (IHS). The pre-malignant nature of the aberrant lymphocytes is suggested by the occasional development of a peripheral T cell lymphoma bearing the same phenotype. In our series of five patients, the T cell clones all bore a CD3– CD4+ phenotype. The production of type-2 cytokines and the proliferation of these cells in response to dendritic cells in vitro were dependent on engagement of CD2 and CD28 molecules and on an IL-2/IL-2R autocrine loop. The high-level spontaneous apoptosis displayed by these cells in vitro was drastically inhibited by IL-2 and IFN-α, suggesting that administration of IFN-α to such patients could favour further expansion and eventual malignant transformation of the T cell clone. The hypereosinophilic syndrome may represent an unexpected application of new immunomodulatory molecules such as CTLA4-Ig and anti-IL-2R-α.