Using a cohort of more than 250 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to look for new markers that distinguish between variants of hypereosinophilic syndrome. Assessment of serum and surface IL-5 receptor levels in a large cohort of patients with eosinophilia and/or mastocytosis suggests that regulation of this receptor occurs in vivo. Serum levels of the receptor were correlated with eosinophilia, serum levels of IL-5 and IL-13 and markers of eosinophil activation. Interestingly, serum receptor levels were also elevated in patients with systemic mastocytosis without eosinophilia and correlated with both serum tryptase and surface markers of eosinophil activation. These findings may have important implications in the setting of recently developed therapeutic agents targeting IL-5 and its receptor. We have previously described a family with an autosomal dominant variant of hypereosinophilic syndrome that maps to chromosome 5q31-33. Exhaustive attempts to identify the gene responsible for this condition, including candidate gene sequencing, array CGHY, expression analysis, 454 sequencing of the region upstream of IL-5, in collaboration with John Rioux and Jan Cools, have been unsuccessful to date. Whole genome sequencing of DNA from two family members has been completed and analysis is underway. We continue to follow affected family members for development of clinical manifestations. To date, there has been no progression of disease and markers of eosinophil activation have remained stable. In the past year, we have identified and/or characterized several novel subgroups of patients with eosinophilia. We studied four patients with episodic eosinophilia and angioedema and demonstrated that multiple lineages, including neutrophils, eosinophils and platelets, cycle with a 25-30 day periodicity. Eosinophil cycling is preceded by elevations in eosinophil related cytokines, including IL-5, GM-CSF and eotaxin, and followed by rises in inflammatory markers. Unlike cyclic neutropenia, mutations in ELANE do not appear to be involved. We have also identified 7 subjects with marked eosinophilia (>1,500/mm3) of >5 years duration and no evidence of clinical manifestations despite not being treated. Comparison of these subjects to patients with hypereosinophilic syndrome reveals that they are a heterogeneous group, but have little evidence of eosinophil activation. A multicenter study is being organized to examine and compare subjects who are asymptomatic despite marked eosinophilia to those who present without symptoms but go on to develop clinical disease. We have continued to study the effects of novel therapies for the treatment of hypereosinophilic syndromes, including monoclonal antibodies to IL-5 and the tyrosine kinase inhibitor, imatinib. Long-term (5 year) followup of subjects enrolled on a placebo-controlled study of the anti-IL-5 antibody, mepolizumab has just been completed. The drug continued to show excellent efficacy in the majority of subjects and was not associated with toxicity or the development of neutralizing antibodies. We have also begun to explore new therapeutic approaches for the treatment of refractory L-HES in collaboration with Dr. Dunleavy (NCI). Additionally, we have expanded our studies of monoclonal antibodies targeting IL-5 to explore the role of eosinophilia in post-treatment reactions in the filarial infection, loiasis, since we have previously demonstrated an association between eosinophilia and side effects of DEC treatment in these patients. A clinical study is currently underway to examine the effects of the anti-IL-5 antibody, reslizumab, on post-treatment side effects of DEC in patients with Loa loa infection.
| 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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