Redefinition of Hypereosinophilic Disorders Based on an Analysis of 28 Cases of FIP1 L1-PDGFRA Negative Persistent Unexplained Eosinophilia (PUE) with Eosinophil End-Organ Damage (EEOD).
Authors: Brito-Babapulle Finella , Cross Nicholas C.P. 
Published: October 2019

In 1997 the term eosinophil end-organ damage(EEOD) was introduced to facilitate management of patients with high eosinophil counts in whom damage to organs such as heart, lungs, and skin by eosinophils was associated with persistent unexplained eosinophilia (no obvious cause for eosinophilia was identified). In 2003 Cools et al identified the presence of the FIP1L1-PDGFRA gene as the causation of eosinophilia in 50% of cases of hypereosinophilic syndromes with end organ damage. Cases which are negative for this gene and a Tcell clone appear to form a distinctive group whose aetiopathogenesis and clinical significance are different. In order to identify the extent of end organ damage in FIP1L1-PDGFRA negative cases and/or identify rarer causes of unexplained eosinophilia in all cases of eosinophilia presenting from 14.06.2002 to 14.06.2006, we looked at all patients who had persistent eosinophilia present on two separate blood tests done I month apart with eosinophil counts greater than 1–1.5 x 10 9/l. All cases of unexplained eosinophilia (Eosinophil count greater than 1– 1.5 x 10 9/L) seen at our institution in a 4 year period in whom no obvious cause of eosinophilia was found were evaluated for the presence of the FIP1L1-PDGFRA gene, TEL-PDGFRB and variant BCR-ABL gene. Of 40 cases seen 2 men were FIP1L1-PDGFRA positive, 3 others (2 men and 1 woman) had myeloproliferative diseases, I man had clozapine induced eosinophilia, one woman Kimura Weils disease and 1 man had cutaneous mastocytosis . There were 28 cases (14 women, 2 children,12 men) who were FIP1L1 -PDGFRA negative and had persistent unexplained eosinophilia without clonal T cells. These cases were followed up over a 4 year period and tested serially for damage to end organs by eosinophils. FIP1L1-PDGFRA was tested and found negative on two separate occasions. Ig E levels had to be less then 500 iu/l to exclude allergy and a therapeutic trial of mebendazole 100mg daily for three days was given in all cases even if parasite testing did not identify a parasitic infestation. There were 28 cases (14 women, 2 children,12 men) who were FIP1L1-PDGFRA negative which contrasts with the Male Female ratio seen in FIP1 L1-PDGFRA positive cases in which males predominate. The age ranged from 9–80. Four year follow up identified a chronic illness in these cases with no damage to vital organs. Clinical symptoms complained of included fatigue(28), joint and muscle pains(28), skin rashes(10), blackouts(1), thrombotic events(2), diarrhoea(2), fasciitis(2), gastroenteritis(2), cough(2), and breathlessness(2). No organomegaly was seen. In one clonal T cells were identified on serial testing after 1 year of follow up. We conclude that cases of FIP1L1-PDGFRA negative hypereosinophilia are a distinct group with a chronic illness mainly affecting skin and joints who respond well to symptomatic treatment, oral steroids, or hydroxyurea. We believe that hypereosinophilic diorders need to be redined as PUEand EEOD. When both PUE and EEOD are present the diagnosis is HES.