Eosinophilic disorders

Eosinophilic inflammatory responses occur in association with multiple disorders. Although the initial cause and the affected organs vary among the different eosinophilic disorders, there are only 2 major pathways that mediate eosinophilia: (1) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders), and (2) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Independent from the original trigger, the most common cause of eosinophilia is the increased generation of IL-5-producing T cells. In some cases, tumor cells are the source of eosinophil hematopoietins. The intrinsic eosinophilic disorders are characterized by mutations in pluripotent or multipotent hematopoietic stem cells leading to chronic myeloid leukemias with eosinophils as part of the clone. Here, we propose a new classification of eosinophilic disorders on the basis of these obvious pathogenic differences between the 2 groups of patients. We then discuss many known eosinophilic disorders, which can be further subdivided by differences in T-cell activation mechanisms, origin of the cytokine-producing tumor cell, or potency of the mutated stem cell. Interestingly, many subgroups of patients originally thought to have the idiopathic hypereosinophilic syndrome can be integrated in this classification.

[Anti-interleukin-5 therapy for eosinophilic diseases]

In a number of diseases with eosinophilia, elevated interleukin (IL)-5 levels are detected in the peripheral blood and/or tissues. IL-5 plays an important role in regulating the production, differentiation, recruitment, activation, and survival of eosinophils. Therefore, neutralizing IL-5 by blocking antibodies seems a promising approach in the treatment of eosinophilic diseases. Clinical trials have demonstrated that anti-IL-5 therapy results in a rapid decrease in peripheral blood eosinophil numbers. Moreover, improvement of symptoms in patients with lymphocytic variants of hypereosinophilic syndromes, in eosinophilic esophagitis and chronic rhinitis with nasal polyposis has been observed. In contrast, in patients with bronchial asthma or atopic eczema, anti-IL-5 therapy showed only moderate or no clinical effects. Future studies will have to identify those eosinophilic diseases in which anti-IL-5 antibodies are effective, perhaps with the help of newly developed biomarkers.

General laboratory diagnostics of eosinophilic GI diseases

Eosinophils and gastrointestinal tract interact in an intimate and enigmatic relationship. Under inflammatory conditions, eosinophil infiltration in the gastrointestinal tract is a common feature of numerous eosinophilic gastrointestinal disorders (EGIDs). EGIDs are disorders, for which the diagnosis is relatively difficult. Nevertheless, some common laboratory techniques are currently used for their diagnosis and disease monitoring. Besides eosinophils, mast cells and T cells have also been suggested to play a role in the pathogenesis of these disorders. Here, we review the pathogenesis and common laboratory approaches applied for their diagnosis, in particular eosinophil and mast cell markers.

Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients

BACKGROUND ; AIMS: Eosinophilic esophagitis is a rapidly emerging, chronic inflammatory disorder. Prolonged inflammation evokes structural alterations and a fragile esophageal wall prone to perforation/rupture and food impaction. This report assesses the risk of spontaneously arising and procedure-induced complications and proposes practical recommendations. METHODS: The Swiss Esophageal Esophagitis Database documented 251 confirmed cases. A chart review identified which patients had required endoscopic bolus removal and/or experienced transmural esophageal perforation/rupture. In addition, a MEDLINE search for "eosinophilic esophagitis" with "esophageal perforation" or "esophageal rupture" was undertaken. RESULTS: During an 18-year period, 87 patients (34.7%) experienced 134 food impactions requiring flexible (124, 92.5%) or rigid (10, 7.5%) endoscopic bolus removal. Transmural perforation occurred in 20% (2/10) of rigid procedures, and 1 esophageal rupture (Boerhaave's syndrome) was observed. CONCLUSIONS: Bolus removal by rigid endoscopy is a high-risk procedure and should be avoided in eosinophilic esophagitis patients who require a gentler approach. Whether food impaction and esophageal wall remodeling can be prevented with anti-inflammatory medication is still undetermined. All Boerhaave's syndrome cases should be evaluated for underlying eosinophilic esophagitis.

Esophageal strictures in adult eosinophilic esophagitis: dilation is an effective and safe alternative after failure of topical corticosteroids

Strictures are a frequent complication of eosinophilic esophagitis. The efficacy and safety of topical corticosteroids and of dilation of eosinophilic esophagitis-associated strictures have not yet been thoroughly clarified. We present a retrospective analysis of 10 adult patients with eosinophilic esophagitis who had symptomatic esophageal stenosis that was unresponsive to topical corticosteroids, and who were treated using bougienage. Eight patients had one single stricture, one patient had two, and another had three strictures; mean stricture length was 2.1 cm (range 1 - 6 cm). Bougienage led to prompt symptom relief. Apart from transient postprocedural odynophagia, no severe complications occurred. During the follow-up (mean 6 months; range 2 - 11 months), all patients enjoyed sustained treatment response.

A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

BACKGROUND: The Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) gene fusion is a common cause of chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES), and patients suffering from this particular subgroup of CEL/HES respond to low-dose imatinib therapy. However, some patients may develop imatinib resistance because of an acquired T674I mutation, which is believed to prevent drug binding through steric hindrance. METHODS: In an imatinib resistant FIP1L1-PDGFRA positive patient, we analyzed the molecular structure of the fusion gene and analyzed the effect of several kinase inhibitors on FIP1L1-PDGFRA-mediated proliferative responses in vitro. RESULTS: Sequencing of the FIP1L1-PDGFRA fusion gene revealed the occurrence of a S601P mutation, which is located within the nucleotide binding loop. In agreement with the clinical observations, imatinib did not inhibit the proliferation of S601P mutant FIP1L1-PDGFRA-transduced Ba/F3 cells. Moreover, sorafenib, which has been described to inhibit T674I mutant FIP1L1-PDGFRA, failed to block S601P mutant FIP1L1-PDGFRA. Structural modeling revealed that the newly identified S601P mutated form of PDGFRA destabilizes the inactive conformation of the kinase domain that is necessary to bind imatinib as well as sorafenib. CONCLUSIONS: We identified a novel mutation in FIP1L1-PDGFRA resulting in both imatinib and sorafenib resistance. The identification of novel drug-resistant FIP1L1-PDGFRA variants may help to develop the next generation of target-directed compounds for CEL/HES and other leukemias.