Using a cohort of more than 450 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to identify and characterize novel subgroups of patients with eosinophilia. Although hypereosinophilic syndrome (HES) is most common in adults aged 20-50 years, it has been reported in children as young as 1 year old. Despite this, published data on the clinical presentation, ultimate diagnosis, treatment and prognosis of hypereosinophilia (HE) and HES in children is scarce. To address this issue, we conducted a retrospective analysis comparing pediatric (n=37) and adult (n=254) subjects referred for evaluation of unexplained HE (Williams et al. J Allergy Clin Immunol In Pract 2016). Overall, the differential diagnosis, clinical manifestations, corticosteroid responsiveness and overall prognosis were very similar between the two groups. These data suggest that the diagnostic and treatment algorithms for adult patients with HES are likely applicable to children. The availability of targeted sequencing has led to the identification of causative mutations in some patients with HES. We recently described a somatic gain-of-function mutation in STAT5b in two children with very similar clinical presentation characterized by a syndrome of early-onset non-clonal eosinophilia, urticaria, dermatitis and diarrhea (Ma et al. paper submitted). Functional studies of both patients T-cells confirmed a marked increase in STAT5b responsiveness to an array of cytokines. These findings are significant not only because of the description of a novel eosinophilic syndrome, but because of the implications for therapy targeting the JAK/STAT pathway. Other subgroups of eosinophilic subjects currently under study include families with autosomal dominant eosinophilia and patients with episodic angioedema and eosinophilia. Therapy for eosinophilic disorders remains a primary focus of our group. In the past year, we have reached near complete or complete enrollment in two clinical trials of targeted therapy for the treatment of HES. The first of these is a placebo-controlled, double-blind phase 2 trial of benralizumab (MedImmune/Astra Zeneca), an afucosylated antibody to IL-5 receptor alpha that has shown clinical efficacy in patients with eosinophilic asthma. The current trial stems, in part, from our prior pre-clinical work examining IL-5 receptor levels in patients with eosinophilia and/or mastocytosis (Wilson et al. J Allergy Clin Immunol 2011). To date, 18 of 20 planned subjects have been enrolled, of which 15 have entered the open-label phase of the study. The drug has been well-tolerated and early efficacy results are promising. The second trial is an open-label trial of dexpramipexole (Knopp Biosciences) in patients with steroid-resistant HES. Dexpramipexole was developed for the treatment of amyotrophic lateral sclerosis (ALS). Although it was well tolerated, dexpramipexole failed to show efficacy in a large phase 3 trial for this disease. It did, however, appear to selectively lower blood eosinophils, which prompted the current proof-of-concept open-label phase 2 trial in HES. All 10 planned subjects have been enrolled, of which 8 have reached the study endpoint. The drug has been well-tolerated and early efficacy results are encouraging. We have also completed enrollment in a new multicenter placebo-controlled, double-blind phase 3 clinical trial of mepolizumab (anti-IL-5 antibody) for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). This trial will be unblinded and analyzed in November 2016. In addition to the clinical trials described above, we continue to explore standard therapies for HES. We recently published a trial examining imatinib response in subjects with FIP1L1/PDGFRA-positive myeloproliferative neoplasm (FP), PDGFRA-negative HES with myeloproliferative features (MP) and steroid-resistant without myeloproliferative features (SR) (Khoury et al. Allergy 2016;71:803-10). Overall, imatinib response rates were 100% in the FP group (n= 16), 50% in the MP group (n=13) and 0% in the SR group (n=16). The presence of 4 myeloproliferative features was the sole predictor of response. After 18 months in complete remission, imatinib was tapered and discontinued in 8 FP and 1 MP subjects. Seven subjects (6 FP, 1 MP) remain in remission off therapy for a median of 29 months (range 14-36). We have also continued to enroll subjects in a double-blind clinical trial designed to assess the utility of a glucocorticoid challenge in determination of glucocorticoid responsiveness in HES and in a clinical trial of mepolizumab (humanized anti-IL-5 antibody) for treatment-refractory HES (Kuang et al. J Allergy Clin Immunol 2016; 137:AB 168). Finally, in collaboration with GlaxoSmithKline and ICON, we collected data for development of a PRO (patient-reported outcome measure) for use in clinical trials in HES. A total of 26 HES subjects from 14 US states were interviewed, including subjects with myeloproliferative and lymphocytic variant HES (Kovacs et al. J Allergy Clin Immunol 2016;137:AB167). As expected, patient-reported symptoms were extremely heterogeneous. The results of this study were used to inform data collection in an upcoming phase 3 multicenter trial of mepolizumab for HES. The therapeutic potential of novel antibodies with the potential to target eosinophils is an ongoing focus of the laboratory. Eosinophils express several inhibitory receptors, including Siglec-7, Siglec-8 and CD300a. Whereas Siglec-8 and CD300a have been implicated in the downregulation of allergic inflammatory responses, little is known about Siglec-7 expression and function on human eosinophils. Using whole blood flow cytometry, we have demonstrated that Siglec-7 and Siglec-8 are expressed on human eosinophils from normal and eosinophilic donors and, unlike IL-5 receptor alpha, do not appear to be down-modulated in vivo in individuals with HES (Legrand et al. J Allergy Clin Immunol 2016;137:AB549). Whereas antibodies to Siglec-8 cause eosinophil apoptosis, the consequences of targeting Siglec-7 on eosinophils are unknown and currently under study. Helminth infections can be associated with dramatic eosinophilia and complications that are indistinguishable from HES. This is particularly true in loiasis where symptoms are associated with increased eosinophil granule protein levels (indicative of eosinophil activation and degranulation) as well as elevated levels of eosinophil-associated cytokines (Herrick et al. Clin Inf Dis 2015;60:55-63). In some infections, eosinophilia and eosinophil-related symptoms can be exacerbated by effective treatment. In the past year, we completed a double-blind, placebo-controlled study of the anti-IL-5 antibody, reslizumab, to prevent post-treatment side effects of DEC in patients with Loa loa infection. The results have recently been unblinded, and analysis is ongoing. Finally, in the past year, we have continued to look for biomarkers of eosinophil activity for use in monitoring responses to therapy and helping to dissect out the mechanisms of eosinophil pathogenesis. In collaboration with Dr. Mejia-Henao, we examined the role of a long non-coding RNA, MORRBID, in the regulation of eosinophilia (Kotzin et al. Nature 2016 Epub ahead of print). Complementing their studies in mouse models, we demonstrated that MORRBID expression is elevated in eosinophils from human patients with hypereosinophilic disorders and is correlated with serum levels of the IL-5. Together, our results indicate that locus-specific regulation of gene expression by lncRNAs is a powerful mechanism by which environmental cues are integrated to achieve optimal immune cell homeostasis. Moreover, MORRBID may represent a potential therapeutic target for eosinophilic disorders.

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Kuang, Fei Li; Fay, Michael P; Ware, JeanAnne et al. (2018) Long-Term Clinical Outcomes of High-Dose Mepolizumab Treatment for Hypereosinophilic Syndrome. J Allergy Clin Immunol Pract 6:1518-1527.e5
Panch, Sandhya R; Bozik, Michael E; Brown, Thomas et al. (2018) Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes. Blood 132:501-509
Khoury, P; Stokes, K; Gadkari, M et al. (2018) Glucocorticoid-induced eosinopenia in humans can be linked to early transcriptional events. Allergy 73:2076-2079
Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83
Groves, Daniel W; Klion, Amy D; Chen, Marcus Y et al. (2018) Swiss cheese heart. Eur Heart J 39:255-256
Herrick, Jesica A; Legrand, Fanny; Gounoue, Raceline et al. (2017) Posttreatment Reactions After Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa Infection. Clin Infect Dis 64:1017-1025
Ma, Chi A; Xi, Liqiang; Cauff, Brian et al. (2017) Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood 129:650-653
Wechsler, Michael E; Akuthota, Praveen; Jayne, David et al. (2017) Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med 376:1921-1932
Khoury, Paneez; Makiya, Michelle; Klion, Amy D (2017) Clinical and Biological Markers in Hypereosinophilic Syndromes. Front Med (Lausanne) 4:240
Kuang, Fei Li; Klion, Amy D (2017) Biologic Agents for the Treatment of Hypereosinophilic Syndromes. J Allergy Clin Immunol Pract 5:1502-1509

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