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Eosinophilic myocarditis: characteristics, treatment and outcome based on a systematic revision of histologically proven reportsBrief title: Eosinophilic myocarditisMichela Brambatti, a* MD, Maria Vittoria Matassini,b* MD, Eric D. Adler,a MD, Karin Klingel,c MD, Paolo G. Camici,d,e MD, and Enrico Ammirati, e, f MD, PhDa) Department of Cardiology, University of California San Diego, San Diego, California, USAb) Arrhythmology and Cardiology Clinic, Ospedali Riuniti Ancona, Ancona, Italyc) Cardiopathology, Institute for Pathology, University Hospital Tuebingen, Tuebingen, Germanyd) San Raffaele Hospital, Milan, Italye) San Raffaele Vita-Salute University, Milan, Italyf) Transplant Center and “De Gasperis” Cardio Center, Niguarda Hospital, Milan, ItalySUPPLEMENTAL MATERIALSSUPPLEMENTAL METHODSData extraction and managementData were collected on patient demographics (age, gender, ethnicity, geographical origin), cardiovascular history and comorbidities, clinical presentation (symptoms, and laboratory findings), diagnostic tools (electrocardiogram, echocardiography, cardiac magnetic resonance [CMR] imaging, and coronary artery angiography), treatments, follow up and outcome. We classified cases as pediatric when patients were 16-year-old or younger. Echocardiographic data assessing left ventricular (LV) ejection fraction (EF) was available in 107 (73.3%) patients. When LVEF is described as a category, normal, mildly reduced, or severely reduced, it was arbitrarily reported as 60%, 45% and 25% respectively. Since 2001, CMR scans, including late gadolinium enhancement (LGE), were performed during hospitalization in 37 (20.7%) patients. Length of hospital stay and follow-up duration were reported in 55 (30.7%) and 88 (49.2%) patients respectively, and are reported as days.Identification of associated systemic disordersThe systemic condition associated with eosinophilic myocarditis (EM) has been reported on the basis of the systemic disorder that has been identified by the Authors in their articles. As the term hypereosinophilic syndrome (HES) has been generally used in a nonspecific manner by the Authors, we have revised all the diagnosis of HES, in accordance with the current expert consensus (11). We have classified as HES only those patients who experienced an EM in the setting of a persistent (>6 months) eosinophilia (eosinophils ≥1.5x109/L) with evidence of damage/dysfunction (directly attributable to the eosinophilia) of multiple organs with exclusion of secondary causes of eosinophilia (i.e helminth infections, non-hematologic malignancies, primary allergic disorders). This group of HES has been previously identified as idiopathic HES (10), and more recently has been called undefined complex HES (11). No cases of myeloproliferative variant of HES (i.e. platelet-derived growth factor receptor-A [PDGFRA]-associated HES or chronic eosinophilic leukemia) in accordance with the current classification (11) have been found among the histologically proven EM associated with HES. Diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA, formerly termed Churg-Strauss syndrome) was based on the diagnosis of Authors that in all cases were in accordance with Chapel Hill Consensus Conference nomenclature of vasculitides (8) or previous and more frequently used, American College of Rheumatology 1990 criteria (6). We have used the term idiopathic/undefined EM when the Authors had not performed or reported a diagnostic workup to identify a potentially associated systemic disorders or when EGPA or HES criteria were not fulfilled. We have classified in the same group those patients with hypereosinophila and isolated infiltration of the myocardium without evidence of history of persistent hypereosinophilia. Hypersensitivity forms were reported when the Authors identified a drug or substance with a temporal relation with the onset of the EM, including the cases associated with the drug rash and eosinophilia and systemic symptoms (DRESS)(5). Finally, we have reported a heterogeneous group called as “others” that collects other known conditions associated with EM that includes helminth infections and non-hematologic malignancies.Statistical analysisData were presented as mean and standard deviations (SD) or median and Q1-Q3 as appropriate (Shapiro-Wilk test of normality was performed). Group differences were tested using unpaired t-test, Mann-Whitney U test or ANOVA. Categorical variables were summarized as absolute frequency (percentage). Associations between categorical variables were tested using Fisher's exact or chi-square tests. Kaplan–Meier (KM) curves were generated and compared with use of the log-rank statistic. Patient events included death, heart transplantation (HTx), total artificial heart (TAH) or long-term left VAD (LVAD). Missing data (n=25) concerning the duration of the hospitalization in patients discharged alive have been replaced with the average duration of overall hospitalizations (i.e. 14 days). In case that an event took place during the hospitalization, but the Authors had not reported when it occurred (n=3), we have replaced the missing data with the average time from admission to the event (i.e. 3 days). A p value <0.05 was considered significant. If statistically significant, chi square, ANOVA and log-rank tests were Bonferroni-corrected for multiple comparisons. When omnibus test was significant, but Bonferroni-corrected comparisons were not significant, a post-hoc analysis of the extreme group versus all others was used. All Statistical analyses were performed using GraphPad Prism 5 (GraphPad Software Inc., La Jolla, USA).FULL LIST OF RECORDS OF NON-HISTOLOGICALLY PROVEN EOSINOPHILIC MYOCARDITISRizkallah J, Desautels A, Malik A et al. Eosinophilic myocarditis: two case reports and review of the literature.BMC Res Notes 2013;6:538.Eicher JC, Bonnotte B, L'Huillier I et al. [Cardiovascular manifestations of eosinophilia: clinical and echocardiographic presentation]. 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