Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis

ORIGINAL RESEARCH ARTICLE ORIGINAL RESEARCH ARTICLE Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis Editorial, see p 546 Enrico Ammirati, MD, PhD et al BACKGROUND: Previous reports have suggested that despite their dramatic presentation, patients with fulminant myocarditis (FM) might have better outcome than those with acute nonfulminant myocarditis (NFM). In this retrospective study, we report outcome and changes in left ventricular ejection fraction (LVEF) in a large cohort of patients with FM compared with patients with NFM. Downloaded from http://ahajournals.org by on June 19, 2020 METHODS: The study population consists of 187 consecutive patients admitted between May 2001 and November 2016 with a diagnosis of acute myocarditis (onset of symptoms <1 month) of whom 55 required inotropes and/or mechanical circulatory support (FM) and the remaining 132 were hemodynamically stable (NFM). We also performed a subanalysis in 130 adult patients with acute viral myocarditis and viral prodrome within 2 weeks from the onset, which includes 34 with FM and 96 with NFM. Patients with giant-cell myocarditis, eosinophilic myocarditis, or cardiac sarcoidosis and those <15 years of age were excluded from the subanalysis. RESULTS: In the whole population (n=187), the rate of in-hospital death or heart transplantation was 25.5% versus 0% in FM versus NFM, respectively (P<0.0001). Long-term heart transplantation–free survival at 9 years was lower in FM than NFM (64.5% versus 100%, log-rank P<0.0001). Despite greater improvement in LVEF during hospitalization in FM versus NFM forms (median, 32% [interquartile range, 20%–40%] versus 3% [0%–10%], respectively; P<0.0001), the proportion of patients with LVEF <55% at last follow-up was higher in FM versus NFM (29% versus 9%; relative risk, 3.32; 95% confidence interval, 1.45–7.64, P=0.003). Similar results for survival and changes in LVEF in FM versus NFM were observed in the subgroup (n=130) with viral myocarditis. None of the patients with NFM and LVEF ≥55% at discharge had a significant decrease in LVEF at follow-up. CONCLUSIONS: Patients with FM have an increased mortality and need for heart transplantation compared with those with NFM. From a functional viewpoint, patients with FM have a more severely impaired LVEF at admission that, despite steep improvement during hospitalization, remains lower than that in patients with NFM at long-term follow-up. These findings also hold true when only the viral forms are considered and are different from previous studies showing better prognosis in FM. Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 The full author list is available on page 543. *Drs Camici and Frigerio contributed equally (see page 543). Correspondence to: Enrico Ammirati, MD, PhD, De Gasperis Cardio Center and Transplant Center, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy, or Paolo G. Camici, MD, Vita Salute University and San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy. E-mail enrico. ammirati@ospedaleniguarda.it or camici.paolo@hsr.it Sources of Funding, see page 544 Key Words: extracorporeal membrane oxygenation ◼ immunosuppression ◼ magnetic resonance imaging ◼ myocarditis ◼ treatment outcome © 2017 American Heart Association, Inc. August 8, 2017 529 Ammirati et al Clinical Perspective What Is New? • Patients with acute viral myocarditis with fulminant presentation have a worse outcome compared with those with nonfulminant presentation. • From a functional viewpoint, patients with fulminant myocarditis have a more severely impaired left ventricular ejection fraction at admission that, despite steep improvement during hospitalization, remains lower than that in patients with nonfulminant myocarditis at long-term follow-up. • These findings are in contrast with previous studies in which patients with fulminant myocarditis were reported to have a better prognosis compared with those with nonfulminant acute myocarditis. • Long-term left ventricular ejection fraction was stable or improved in most patients after discharge. What Are the Clinical Implications? Downloaded from http://ahajournals.org by on June 19, 2020 • Hemodynamically unstable myocarditis, that is, fulminant myocarditis, has poor in-hospital outcome that requires proper monitoring and treatment with inotropes and mechanical support. • To reduce mortality rates, patients with suspected fulminant myocarditis should be referred early to tertiary centers with the ability to perform endomyocardial biopsy and to institute both shortand long-term mechanical support and heart transplantation. • Although most patients with myocarditis have a good long-term prognosis, those with fulminant presentation are more likely to have worse left ventricular function at follow-up. • Functional recovery takes place mostly in the first few weeks of the disease, which underlies the need for rapid therapeutic interventions. • These data could lead to trials designed to assess the efficacy of immunosuppressive agents in the specific setting of fulminant lymphocytic myocarditis with the objective of improving the in-hospital outcome and reducing myocardial injury. A mong patients admitted to hospital with clinically suspected acute myocarditis, symptoms may vary in type and severity, and it is unclear whether the clinical presentation can be used to predict patient outcome.1–3 In current clinical practice, the diagnosis of acute myocarditis in low-risk patients is based on clinical presentation, elevated biomarkers of cardiac necrosis, electrocardiographic changes, and evidence of myocardial dysfunction, edema, and fibrosis on cardiac magnetic resonance (CMR).2,4 Histology remains the gold standard for diagnosis, although endomyocardial biopsy (EMB) is generally pursued only in high-risk patients.5,6 530 August 8, 2017 Soon after hospital admission,7 it is important to recognize patients at higher risk of fatal complications to institute immediate aggressive pharmacological and device-based treatment. Definite clinical criteria for predicting outcome are not clear and may differ according to diagnostic workup and the timing of diagnosis.8,9 Previous studies, in relatively small cohorts of patients with biopsy-proven myocarditis, have asserted the rather counterintuitive finding that patients presenting with fulminant myocarditis (FM10; ie, distinct heart failure [HF] symptoms and hemodynamic compromise requiring inotropes and/or mechanical circulatory support [MCS]) may have a better prognosis than patients with the nonfulminant (NFM) form (ie, mild cardiac symptoms and no hemodynamic compromise).11,12 In the majority of these previous studies, patients were enrolled retrospectively, after the presumed acute phase, on the basis of evidence of chronic left ventricular (LV) dysfunction.11,12 Even after the acute phase, the course of patients with myocarditis remains poorly defined, and it is believed that those with lymphocytic FM generally have complete recovery of LV function, whereas some of those with NFM may progress to chronic LV dysfunction.12,13 However, long-term studies assessing changes in LV ejection fraction (LVEF) after a fulminant or a nonfulminant presentation are still lacking. The above-mentioned reports enrolled limited numbers of FM patients (the largest included 15 patients with FM) and had inadequate statistical power, and the main entry criterion was evidence of myocarditis at EMB. On the one hand, this approach allowed the collection of patients with histologically proven myocarditis, but on the other, it might have led to the exclusion of patients with clinically suspected myocarditis who did not undergo EMB or died before it. The main objective of this retrospective study was to ascertain whether comprehensive clinical characterization of patients admitted to hospital with a diagnosis of myocarditis, supported by histology or by the combination of elevated necrosis biomarkers and CMR imaging, might be used to guide treatment and to predict longterm outcome. METHODS Study Population All patients admitted to Niguarda Hospital, Milan, and San Matteo Hospital, Pavia, both in Italy, with a diagnosis of acute myocarditis between May 2001 and November 2016 were retrospectively included in the analysis. Patients were identified through the International Classification of Diseases, Ninth Revision diagnostic codes (422.0, 422.91, 422.92, 422.93, 422.99, 429.89) recorded in hospital discharge forms and confirmed by revision of clinical records. Only patients with onset of cardiovascular symptoms within 30 days before admission were considered. Patients with prior or current diagnosis of Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis Diagnosis of Myocarditis Clinically, myocarditis was suspected on the basis of medical history, presenting symptoms and signs, ECG, echocardiography, and biomarkers of myocardial necrosis, and inflammation and after the exclusion of coronary artery disease. On the basis of risk-benefit considerations, CMR was the noninvasive technique of choice for confirming the diagnosis, whereas EMB was pursued in patients with hemodynamic compromise or anamnestic, clinical, or laboratory features indicating possible autoimmune, infective, or systemic disorders.5,14 FM was diagnosed in 55 patients (29%) on the basis of documented LV dysfunction and low cardiac output syndrome requiring inotropes or MCS,15,16 whereas the remaining 132 patients (71%) were classified as NFM. The subanalysis on viral acute myocarditis included 34 patients (26%) with fulminant presentation (called viral [v]-FM) and 96 (74%) patients with viral nonfulminant presentation (v-NFM). Downloaded from http://ahajournals.org by on June 19, 2020 Cardiac Magnetic Resonance CMR scans were performed on a 1.5-T clinical scanner (Siemens Avanto, Erlangen, Germany) with a 4-element phased-array receiver coil at Niguarda Hospital (Milan) and on a 1.5-T clinical scanner (Siemens Symphony, Erlangen, Germany) with a 4-element phased-array receiver coil at San Matteo Hospital (Pavia). Similar CMR imaging protocols were used in both hospitals, as previously described.17 Edema and late gadolinium enhancement (LGE) were used for diagnosis of acute myocarditis according to Lake Louise criteria.4 Edema was evaluated with the dark-blood T2-weighted short tau inversion recovery (STIR) sequence.18 LGE images were acquired starting 10 minutes after intravenous injection of gadolinium-based contrast agent (gadobutrol, Bayer Schering Pharma, Berlin, Germany; 0.15 mmol/kg) and using a segmented inversion-recovery gradient echo sequence. Image analysis was performed offline by experienced cardiologists in both centers (P.P. and A.R. in Milan and C.R. and S.G. in Pavia), who independently determined the dichotomous presence or absence of myocardial LGE and edema by reviewing all CMR images. Discordant interpretations were resolved by consensus. Two patterns of LGE were identified: focal, with typical nonischemic pattern (subepicardial or intramyocardial, often with a patchy distribution), and diffuse LGE, globally affecting LV myocardium.4 Pathology EMB was performed via the right internal jugular vein with standard technique. Hematoxylin and eosin–stained myocardial specimens were examined by an experienced pathologist (E.B.). Histological diagnosis of myocarditis was established in accordance with the revised Dallas criteria.6,19 Hearts made available after heart transplantation (HTx) or death also were analyzed. The presence and extent of inflammatory cells were assessed with immunohistochemical labeling for lymphocytes (CD3 or CD8), macrophages (CD68), and HLA-DR+ cells. Presence of virus in the myocardium was assessed in selected cases on the basis of a suspicion of specific viral infections suggested by histological or clinical and laboratory findings. An independent examination was performed by a second pathologist (D.P. in Milan) blinded to the clinical data and the previous pathology results to provide histopathological scores based on the extent of immune cell infiltration and necrosis. In the absence of largely validated grading systems in the setting of acute myocarditis, we borrowed the International Society for Heart Transplantation heart rejection grading system, adopting both the 1990 (grade 0–4, from no infiltrates/ sparse lymphoid infiltrates to diffuse and polymorphous infiltrate with or without edema, hemorrhage, and vasculitis) and the 2004 (0R–3R, from negative to diffuse infiltrate with multifocal myocyte damage±edema±hemorrhage±vasculitis) criteria working formulations.20 Patient Management Figure 1. Flow diagram describing the selection of 130 adult patients with acute viral (v-) myocarditis from the overall population with acute myocarditis. FM indicates fulminant myocarditis; and NFM, nonfulminant myocarditis. Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Clinically stable patients with LV dysfunction received recommended HF treatment.21 Patients with severe/worsening HF and low cardiac output syndrome (FM) received intravenous diuretics, oxygen supplementation, and ventilation plus inotropes.15 Patients with impending or overt cardiogenic shock were treated with MCS.15,16 An intra-aortic balloon pump alone or in combination with venous-arterial extracorporeal membrane oxygenation (va-ECMO; Levitronix CentriMag centrifugal pump, Levitronix LLC, Waltham, MA) was added in case of persistence of low cardiac output syndrome, generally with the femoral approach.22 In the pediatric population, central va-ECMO was the first choice. Before introduction of vaECMO in this clinical setting (2004), we used paracorporeal biventricular ventricular assist devices (MEDOS Medizintechnik GmbH, Stolberg, Germany). August 8, 2017 531 ORIGINAL RESEARCH ARTICLE ischemic heart disease or alternative diagnosis at discharge were excluded. Thus, the study cohort included 187 patients with acute myocarditis, 173 adults (93%) and 14 of pediatric age (<15 years). The primary subanalysis focused on adults with acute myocarditis presenting with viral prodromal symptoms (called viral acute myocarditis; n=130) and excluded patients with nonlymphocytic myocarditis at EMB, those with a clinical history or systemic findings suggestive of a different pathogenesis (ie, peripheral eosinophilia), and patients with symptoms for >2 weeks before hospital admission (Figure 1). The local ethics committees approved the study. Ammirati et al Immunosuppressive therapy was given on the basis of individual patient characteristics,6 with intravenous steroids being most frequently used. In children and young adults, intravenous immunoglobulins were also frequently administered.23 In accordance with recent evidence,24,25 rabbit antithymocyte globulin (ATG-Fresenius, Bad Homburg, Germany; or thymoglobulin, Genzyme, Cambridge, MA) 1 mg/kg (single dose) was given to treat acute giant-cell myocarditis (GCM), in association with cyclosporine (5 mg/kg daily) and intravenous steroids. Maintenance immunosuppression was given to survivors with a diagnosis of GCM or within the framework of a multisystem autoimmune disorder. HTx was pursued in eligible patients who did not recover to an extent allowing weaning from MCS or pharmacological support. LV assist device (LVAD) was used in 1 patient with persistent LV dysfunction causing refractory HF. The 2 centers had similar facilities for MCS and HTx and applied comparable protocols for managing cases of acute myocarditis. Echocardiography Because of the long recruitment period, various echocardiographic machines were used over the years. For the purposes of this study, the records of echocardiographic clips obtained at admission, before discharge, and at last follow-up were centrally reviewed by an expert cardiologist (A.M. in Milan), and LVEF was calculated with the biplane Simpson rule from apical 4- and 2-chamber views. An LVEF <55% was considered abnormal. A similar approach was used in Pavia, where the images were centrally reviewed (by C.R.). Downloaded from http://ahajournals.org by on June 19, 2020 Comparison Between FM and NFM Patients diagnosed with FM and NFM were compared with respect to demographics, baseline clinical data, echocardiographic parameters, CMR, and pathology findings. The following end points were considered: overall survival and HTx-free survival (in-hospital and at the last follow-up) and echocardiographic LVEF changes between discharge and last follow-up. Median follow-up after discharge was 59 months (first to third interquartile [Q1–Q3], 29–83 months). The same analyses were applied to the subgroup of adult patients with viral myocarditis (v-FM versus v-NFM) with the aim of reducing potential confounding factors resulting from the inclusion of multiple histological forms of myocarditis and children. Overall survival and HTx-free survival were ascertained by a review of medical reports of follow-up visits at the outpatient clinic; through phone contact with the patient, his or her family, or the family physician; or, when all of these were unavailable, by electronic vital statistics. Follow-up was completed in all patients except 3 (1.6%) with NFM and preserved LVEF who were lost after discharge (1 non-European citizen and 2 Italian citizens not resident in Lombardy where both hospitals are located). Statistical Analysis Continuous variables are reported as mean±SD or as median and Q1 to Q3, according to normal or nonnormal distribution as per the Shapiro-Wilk normality test. Groups were compared by use of the unpaired Student t test when normally distributed, whereas the Mann-Whitney U test was 532 August 8, 2017 applied to those with nonnormal distribution. The Wilcoxon matched-paired signed-rank test was used to analyze paired data at different time points. Categorical variables were compared via the Fisher exact test. The relative risk (RR) was estimated and the 95% confidential interval (CI) was calculated with the method of Katz et al.26 Survival curves were generated according to the Kaplan-Meier (KM) method and were compared with the use of the log-rank statistic. All analyses were 2 tailed. Differences with values of P<0.05 were considered statistically significant. Analyses were performed with IBM SPSS Statistics software version 20 and GraphPad Prism software version 6. The adequacy of the sample size for demonstrating significant differences in survival in v-FM versus v-NFM was verified with R (version 3.2.3 with the powerSurvEpi package), considering a superiority study with an estimated HTx-free 1-year survival of 95%8 in 1 group (v-NFM) versus 70%13 in the other (v-FM). For a statistical power of 0.80, with a relative proportion of 3:1 between v-NFM and v-FM and a 2-sided significance level of 0.05, the minimum sample size needed was 57 in the NFM group and 19 in the v-FM group. RESULTS The main characteristics of the 2 patient groups (FM versus NFM) are reported in Table 1. None of the patients had a previous history of cardiac disease. Coronary angiography or computed tomography angiography was performed in 56% in the FM group versus 41% in the NFM group (P=0.08) on the basis of age, risk factors, or clinical presentation, and all were normal. At baseline, LVEF was significantly lower in FM than in NFM, and pericardial effusion was more frequently observed in patients with FM. The main characteristics of the adult patients with viral myocarditis presenting with fulminant versus nonfulminant form are reported in Table I in the online-only Data Supplement. Similar differences between FM and NFM were observed both in the whole population and in the subgroup of adults with viral forms. The proportion of female patients was larger, and dyspnea, prodromal gastrointestinal manifestations, left bundlebranch block,7 and arrhythmias at presentation were more frequent in FM than in NFM in both the whole patient population and the subgroup of adults with the viral form. A comparison of the data at clinical presentation based on sex is presented in Table II in the online-only Data Supplement. Women were significantly older than men (median age, 38 versus 31 years; P=0.01). As expected, because of the significantly larger prevalence of women with the fulminant form (P<0.0001), they more frequently had dyspnea (P<0.0001), prodromal gastrointestinal disorders (P=0.0007), associated autoimmune disorders (P=0.01), reduced LVEF (median, 35% versus 55%; P=0.0002), and need for MCS (P<0.0001). Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis ORIGINAL RESEARCH ARTICLE Table 1. Clinical Presentations of 187 Patients With Acute Myocarditis FM Patients With Available Data, n n NFM Value Patients With Available Data, n 55 Value P Value 132 Age (Q1–Q3), y 55 33 (17–42) 132 33 (23–40) Female, n (%) 55 28 (51) 132 16 (12) <0.0001 0.78 White, n (%) 55 49 (89) 132 119 (90) 0.80 Age <15 y, n (%) 55 8 (15) 132 6 (5) 0.03 Clinical presentation, n (%) 54 131 Dyspnea 54 49 (91) 131 14 (11) <0.0001 Chest pain 53 21 (40) 130 122 (94) <0.0001 Syncope 54 8 (15) 131 4 (3) 0.009 Duration of presenting symptoms <1 month, n (%) 55 55 (100) 132 132 (100) … Fever, n (%) 52 38 (73) 131 95 (73) Prodromal symptoms, n (%) 53 45 (85) 131 102 (78) 0.32 Sore throat, n (%) 53 31 (58) 131 51 (39) 0.02 Respiratory tract infection, n (%) 53 6 (11) 131 2 (2) 0.008 Gastrointestinal disorders, n (%) 52 27 (51) 131 33 (25) 0.0008 Associated autoimmune disorders, n (%)* 47 10 (21) 132 8 (6) 0.008 ECG at admission, n (%) 46 Normal 1 130 Downloaded from http://ahajournals.org by on June 19, 2020 3 (7) 19 (15) ST-segment elevation 17 (37) 82 (63) Other abnormal ST-T segment 15 (33) 24 (18) Bundle-branch block 8 (17) 1 (1) Arrhythmia 3 (7) 4 (3) <0.0001 Laboratory findings, n (%) Increased CRP at admission, n (%) 46 42 (91) 124 106 (85) Increased troponin T/CK-MB at admission, n (%) 50 50 (100) 132 131† (99) 50 50 (91) 130 130 (98) LVEF (Q1–Q3), % 50 22 (18–30) 130 55 (50–60) <0.0001 LVEDD (only adults) (Q1–Q3), mm 36 48 (43–50) 86 49 (46–51) 0.39 Presence of pericardial effusion, n (%) 46 27 (59) 110 14 (13) <0.0001 54 30 (56) 130 53 (41) 0.08 Echocardiography at admission, n (%) Coronary angiography or CT angiography performed, n (%) No evidence of CAD, n (%) Arrhythmia during the acute phase, n (%) 0.44 1 0.59 30 30 (100) 53 53 (100) … 55 18 (33) 132 16 (12) 0.002 Supraventricular tachycardia 7 (13) 3 (2) 0.008 Nonsustained VT 2 (4) 8 (6) 0.73 VT/VF 9 (16) 3 (2) 0.001 2 (2) … Episodes of complete AV block during myocarditis, n (%) Undefined 55 7 (13) 0 (0) 132 3 (2) 0.008 Cardiac arrest during the acute phase, n (%) 55 9 (16) 132 0 (0) <0.0001 AV indicates atrioventricular; CAD, coronary artery disease; CK-MB, creatine kinase isoenzyme-MB; CRP, C-reactive protein; CT, computed tomography; FM, fulminant myocarditis; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; NFM, nonfulminant myocarditis; Q1–Q3, first–third quartiles; VF, ventricular fibrillation; and VT, ventricular tachycardia. *Associated autoimmune disorders were present in the FM group: 4 eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome; in 1 case, endomyocardial biopsy did not confirm eosinophilic myocarditis, but it was performed after administration of intravenous steroids and rituximab), 3 autoimmune thyroiditis, 1 multiple sclerosis, 1 connective-tissue disease, and 1 systemic lupus erythematosus. In the NFM group: 2 eosinophilic granulomatosis with polyangiitis, 2 ulcerative colitis, 1 systemic lupus erythematosus, 1 psoriasis, 1 hypothyroidism, and 1 undefined. †In the NFM group, 1 patient (1-year-old baby girl) had normal troponin T/CK-MB at admission, but clinical history and echocardiographic findings were highly suggestive of myocarditis. Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 August 8, 2017 533 Ammirati et al EMB and CMR Findings transplanted within the initial hospitalization; and only 1 patient recovered after 21 days on va-ECMO.27 Of the 5 patients with eosinophilic myocarditis, 2 died during the initial hospitalization, 1 died within 1 year of noncardiac cause,28 1 recovered after 13 days on va-ECMO,29 and 1 recovered after 4 days on an intra-aortic balloon pump, confirming the poor outcome of these 2 specific forms of myocarditis.6,30 The 4 nonlymphocytic cases in the group with NFM (2 cardiac sarcoidosis and 2 eosinophilic forms) presented with reduced LVEF (<55%) at admission that persisted at the last follow-up. Overall, 149 patients (80%) underwent CMR (Table 2). Because of their critical condition, CMR was less feasible and often delayed in patients with FM. CMR sequences suggestive of edema (STIR) and LGE were found in all patients. A diffuse LGE pattern was observed more frequently in patients with FM (Figure 2A–2D and Movies I–IV in the online-only Data Supplement). Among patients with viral myocarditis, 112 (86%) underwent CMR. Results are summarized in Table V in the online-only Data Supplement. EMB was performed in 50 patients (27%). Postmortem diagnosis of myocarditis was reached in 5 cases (in 1 case, EMB was negative, but lymphocytic myocarditis was identified at autopsy). In another case with negative EMB, the final diagnosis of GCM was obtained after HTx. EMB was performed more frequently in FM than in NFM (Table 2). Of 28 patients who underwent EMB without a CMR, 26 had FM. In the FM group, 4 patients died before EMB could be done, and 13 others did not undergo EMB (Table III in the online-only Data Supplement gives details). All 13 patients survived with an improvement of LVEF (from admission to discharge) from 20% to 48%. In 6 patients, neither CMR nor EMB was performed because of patient frailty, early recovery, or organizational problems (Table IV in the online-only Data Supplement gives details). Lymphocytic myocarditis was the most frequent form. Of the 26 adult patients with histologically proven lymphocytic FM, 18 required MCS, 4 died, 1 underwent implantation of an LVAD followed by HTx, and 1 was still on the HTx list at the end of follow-up. Of the 5 pediatric patients with histologically proven lymphocytic FM, 1 required MCS and 3 died. In addition, in the FM group, 6 cases of GCM and 5 of eosinophilic myocarditis were observed. One patient with GCM died; 4 patients were Patient Management Thirty-five patients (64%) in the FM group needed MCS (70% of adults, 25% of pediatric patients). An intra- Downloaded from http://ahajournals.org by on June 19, 2020 Table 2. Pathology and Magnetic Resonance Imaging Findings in 187 Patients With Acute Myocarditis FM Patients, n NFM Value Patients, n Value P Value 11/132 (8) <0.0001 0.30 Histology at EMB, Explant or Autopsy (Patients With Available Data) Endomyocardial biopsy performed, n (%) 39/55 (71) Active myocarditis, n (%) 36/39 (92) 9/11 (82) Borderline/negative for myocarditis, n (%) 3*/39 (8) 2/11 (18) Postmortem examination without EMB, n (%) 4/55 (7) 0 … Lymphocytic myocarditis 32/43 (72) 5/11 (45) 0.004 GCM 7/43 (14) 0/11 (0) 0.004 Specific forms of myocarditis, n (%) Cardiac sarcoidosis 0/43 (0) 2/11 (18) 0.004 Eosinophilic myocarditis 5/43 (12) 2/11 (18) 0.004 Borderline/negative 1/43 (2) 2/11 (18) CMR (Patients With Available Data) CMR performed, n (%) 55 25 (45) 132 124 (94) <0.0001 Time to CMR since admission (Q1–Q3), d 24 15 (6–22) 115 4 (3–7) <0.0001 LVEF (Q1–Q3), % 22 54 (43–62) 113 60 (55–66) 0.003 2 21 76 (63–82) 111 79 (70–90) 0.19 CMR-STIR+ suggestive for myocarditis, n (%) 22 22 (100) 123 123 (100) … Diffuse LGE, n (%) 25 20 (80) 127 61 (48) 0.004 LVEDV indexed (Q1–Q3), mL/m CMR indicates cardiac magnetic resonance; EMB, endomyocardial biopsy; FM, fulminant myocarditis; GCM, giant-cell myocarditis; LGE, late-gadolinium enhancement; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; NFM, nonfulminant myocarditis; Q1–Q3, first–third quartiles; and STIR, T2-weighted short tau inversion recovery. *One patient had negative endomyocardial biopsy but positive histology at post mortem analysis, and another patient had negative endomyocardial biopsy but positive histology on explanted heart. 534 August 8, 2017 Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis ORIGINAL RESEARCH ARTICLE Downloaded from http://ahajournals.org by on June 19, 2020 Figure 2. Illustrative cardiac magnetic resonance (CMR) images of patients with fulminant (FM) and nonfulminant myocarditis (NFM). A, A 41-year-old (y.o.) woman with diffuse myocardial hyperintense signal on short tau inversion recovery (STIR) T2-weighted images (signal intensity ratio between myocardium and skeletal muscle, 3.5; arrows) and diffuse late gadolinium enhancement (LGE; arrows), no left ventricular (LV) dilation (LV end-diastolic volume indexed [LVEDV-i], 43 mL/m2), and a significant increase in wall thickness and LV mass indexed (LVMass-i; 94 g/m2). Cine images (Movie I in the online-only Data Supplement) showed severe global hypokinesis. Cardiogenic shock occurred a few hours later, requiring mechanical circulatory support (MCS; patient 28 in Table 3). At the 3-year follow-up, echocardiography showed full recovery with normal LV volumes and ejection fraction (LVEF). B, A 28-year-old man who presented with cardiac arrest and underwent MCS for 11 days (patient 52 in Table 3). The first CMR scan performed 21 days after clinical presentation showed dilated LV with increased LVEDV-i (normal LVEDV had been demonstrated at first echocardiogram performed after resuscitation), diffuse edema (STIR) and LGE, and severely impaired LVEF (Movie II in the online-only Data Supplement). The patient was still on the heart transplant waiting list at the end of follow-up. C, A 33-year-old man with viral nonfulminant myocarditis (NFM) who presented with chest pain and significantly increased troponin levels after a recent episode of fever and gastrointestinal disorder. CMR images showed localized edema and LGE and preserved LVEF (Movie III in the online-only Data Supplement). Subsequent follow-up was uneventful with normal LVEF after 9 years. D, A 28-year-old man with NFM who was admitted for chest pain and increased troponin levels a few days after an episode of fever and sore throat who presented with a small area of edema and LGE and had preserved LVEF at CMR (Movie IV in the online-only Data Supplement). The patient remained asymptomatic up to the end of follow-up at 10 months. FM indicates fulminant myocarditis. Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 August 8, 2017 535 Ammirati et al aortic balloon pump was most commonly used (in 29 adult patients) alone or in combination with other MCS, in particular peripheral va-ECMO (in 14 cases). Details on mechanical support and other nonpharmacological treatments in adult and pediatric patients with FM are provided in Table 3 and Table VI in the online-only Data Supplement. Among adult patients with v-FM, MCS was used in 71% of cases. Table VII in the online-only Data Supplement shows details on the types of MCS in adults with v-FM. Data on medical therapy in the overall population and in adult patients with viral myocarditis are summarized in Table 4 and Table VIII in the onlineonly Data Supplement, respectively. Clinical Outcome Downloaded from http://ahajournals.org by on June 19, 2020 In-hospital mortality was 18.2% (10 deaths) in the FM group compared to 0% (P<0.0001) in the NFM group. The composite of mortality and HTx was 25.5% (10 deaths and 4 HTx) and 0% (P<0.0001), respectively. KM curves of HTx-free survival were significantly reduced in FM compared with NFM at 9 years of follow-up (64.5% versus 100% respectively; log-rank P<0.0001; Figure 3A). In the FM group, the majority of adverse events occurred during hospitalization: 10 deaths (all from cardiac causes), 4 HTxs, and 1 LVAD implantation in a patient who was transplanted within 1 year. Among the 10 in-hospital deaths, 1 patient had GCM, 2 patients had eosinophilic myocarditis, and 7 patients had lymphocytic myocarditis. Four transplanted patients had GCM, and 1 patient discharged on LVAD had lymphocytic myocarditis. We did not observe major events in the NFM group. After discharge, 3 noncardiac deaths occurred in the FM group (1 due to lung cancer, 1 due to brain cancer, and 1 due to suicide). When only verifiable cardiac deaths are considered, KM curves showed worse survival for FM compared with NFM at 9 years of follow-up (74.9% versus 100%; log-rank P<0.0001; figure not shown). Likewise, when children were excluded; HTx-free survival was significantly reduced in the FM compared with the NFM group (63.8% versus 100%; log-rank P<0.0001; figure not shown). In the 14 children (age <15 years), we had 3 in-hospital deaths among the 8 children with FM (all lymphocytic myocarditis) and no events among the 6 with NFM. In a comparison of the FM group with 48 NFM patients with hemodynamically stable presentation but with LV systolic dysfunction (ie, LVEF <55%, median LVEF, 45%; Q1–Q3, 40%–50%), FM was more frequently associated with death or HTx during hospitalization (P<0.0001). Clinical Outcome of Adults With Viral Myocarditis In the 130 adult patients with acute viral myocarditis, in-hospital mortality was 11.8% (4 deaths) in the v-FM 536 August 8, 2017 group compared with 0% (P<0.0001) in the v-NFM group. KM curves of HTx-free survival showed worse outcome in the v-FM compared with v-NFM group at 9 years of follow-up (80.7% versus 100%, respectively; log-rank P<0.0001; Figure 3B; 1 death during follow-up was due to brain cancer). Considering only verifiable cardiac deaths, KM survival curves showed a worse outcome for FM compared with NFM at 9 years of follow-up (83.8% versus 100%, respectively; logrank P=0.0001; figure not shown). In a comparison of the v-FM group with 35 v-NFM patients with hemodynamically stable presentation but with LV systolic dysfunction (median LVEF, 50%; Q1–Q3, 43%–50%), v-FM was more frequently associated with death during hospitalization (P=0.05). Adult patients with lymphocytic v-FM (n=25) generally had more inflammatory infiltrate at histology compared with patients with lymphocytic v-NFM (n=5; details on histology are presented in Table IX in the online-only Data Supplement, and illustrative cases of v-FM and v-NFM EMB shown in Figure 4). Median time from admission to EMB was 2 days (Q1–Q3, 1–5 days). Furthermore, adult patients (n=30) with lymphocytic myocarditis who received MCS or died during hospitalization had a greater degree of inflammatory infiltrate (defined as 3A–4 or 2R–3R, 55.6% [10 of 18]) compared with patients who survived without MCS (8.3% [1 of 12]; P=0.018). Evolution of LVEF During Hospitalization LVEF improved significantly (P<0.0001) in both groups during hospitalization (Figure 5A and 5B), although LVEF at discharge was significantly lower in the FM group (P=0.0006 not shown). LVEF improvement was larger in FM compared with NFM (P<0.0001; Figure 5C). This also holds true in the comparison of the improvement in LVEF in patients with FM and the 47 patients with NFM with LV systolic dysfunction (P<0.0001; Figure IA in the online-only Data Supplement). Similar results were obtained in the subanalysis including only adults with viral myocarditis (Figure 5D through 5F and Figure IB in the online-only Data Supplement). Last, the proportion of patients with LVEF <55% at discharge was larger in the FM (21 of 40, 53%) than in the NFM (24 of 128, 19%; P<0.0001) group, with an RR of being discharged with reduced LVEF of 2.80 (95% CI, 1.76–4.46; Figure IC in the online-only Data Supplement). Likewise, considering adults with viral myocarditis, the proportion of patients with LVEF <55% at discharge was larger in the v-FM (14 of 29, 48%) than in the v-NFM (14 of 93, 15%; P=0.0006) group, with an RR of being discharged with LVEF <55% of 3.21 (95% CI, 1.74–5.92; Figure ID in the online-only Data Supplement). Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis Year Age, Patient y Sex CVVH Outcome LVEF at Admission, % LVEF at FollowUp, % Downloaded from http://ahajournals.org by on June 19, 2020 MCS, n TI Diagnosis Immunosuppression Notes 2001 1 32 M BiVAD (MEDOS) (19) IABP (1) X (6) X Recovery 22 50 LM 0 HIV seroconversion; histology negative for HIV, CMV, EBV, toxoplasma 2001 2 38 F BiVAD (MEDOS) (10) IABP (1) X (11) X Death 10 NA LM Steroids 2002 3 30 M Impella (6) X 0 Recovery NA 62 LM NA 2002 4 3 M 0 X (0) 0 Death NA NA Autopsy: LM 0 2002 5 45 F BiVAD (MEDOS) X 0 HTx NA NA GCM NA 2003 6 11 F 0 X (0) 0 Death NA NA Autopsy: LM 0 2003 7 41 F BiVAD (MEDOS) (1) Impella (2) IABP (2) X (4) X Death 20 10 Autopsy: Eosinoph Steroids 2003 8 1 M 0 X (0) 0 Death NA NA Autopsy: LM 0 2003 9 46 F 0 0 0 Recovery 20 55 LM Oral steroids 2003 10 50 F IABP (15) X 0 HTx 30 20 GCM Steroids+AZA+ IVIG 2004 11 16 M LVAD (Novacor) IABP (1) X 0 HTx 15 22 LM 0 M pneumo IgM+ 2004 12 25 F IABP 0 0 Partial recovery 40 48 LM Steroids+AZA M pneumo IgM+ 2004 13 44 F 0 X 0 Recovery 15 57 LM 0 Pheo 2004 14 2 F 0 0 0 Recovery 40 58 LM Steroids Toxoplasma IgM+ 2005 15 60 M p-ECMO X 0 Death 35 NA GCM Steroids 2005 16 34 F p-ECMO (6) IABP (9) X (9) 0 Recovery 15 67 No EMB 0 2006 17 22 F IABP (8) X X Recovery 20 54 LM Steroids 2006 18 25 M IABP (6) 0 0 Recovery 20 60 No EMB 0 2007 19 2 F c-ECMO (28) X (28) 0 Recovery 12 60 No EMB Steroids+IVIG 2007 20 36 M 0 0 0 Recovery* 30 66 No EMB 0 2008 21 33 F IABP (5) X 0 Recovery 18 72 No EMB 0 2008 22 46 M 0 X 0 Death 47 NA LM 0 2008 23 17 F p-ECMO (1) IABP X 0 HTx 20 20 EMB: negative Histology of the heart: GCM 0 2008 24 23 M 0 0 0 Recovery 23 58 LM 0 2008 25 42 M 0 X (5) 0 Recovery 35 58 No EMB Steroids 2010 26 38 F p-ECMO (9) IABP (9) X 0 Recovery 21 53 LM 0 Temporary pacemaker Clozapine EBV IgM+ (Continued ) Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 August 8, 2017 537 ORIGINAL RESEARCH ARTICLE Table 3. Characteristics, Treatment, and Outcomes in Patients With Acute Fulminant Myocarditis Ammirati et al Table 3. Year 2010 Continued Age, Patient y Sex 27 15 MCS, n TI M 0 X (6) CVVH Outcome 0 Recovery LVEF at Admission, % LVEF at FollowUp, % Diagnosis Immunosuppression 35 67 No EMB 0 IVIG Notes Downloaded from http://ahajournals.org by on June 19, 2020 2010 28 41 F IABP (9) X (8) 0 Recovery 20 67 LM 2010 29 39 M 0 0 0 Recovery 18 52 No EMB 0 2011 30 34 F IABP (5) X 0 Recovery 35 63 No EMB Steroids+IVIG 2011 31 45 F 0 0 0 Partial recovery 20 40 No EMB 0 2012 32 2 F c-ECMO (9) X (15) 0 Recovery 20 60 LM Enterovirus+ Steroids+IVIG+ cyclosporine 2012 33 15 M p-ECMO (8) IABP (13) X (11) X Recovery 20 58 LM Steroids+IVIG+ cyclosporine 2012 34 32 M p-ECMO (21) IABP (23) X (2) 0 Recovery 12 63 GCM Steroids+RATGs+ cyclosporine 2012 35 3 M 0 0 0 Partial recovery 21 43 No EMB Steroids+IVIG+ cyclosporine 2013 36 38 F p-ECMO (7) IABP (7) X (7) 0 Death 20 20 EMB: negative Autopsy: LM 0 2013 37 42 M p-ECMO (12) IABP (12) X (12) 0 Death 30 30 LM Steroids 2013 38 15 M p-ECMO (5) IABP (11) X (5) 0 Recovery 15 65 LM Steroids+IVIG 2013 39 35 F p-ECMO (13) IABP (13) X (13) X Recovery 15 53 LM Steroids 2013 40 25 M p-ECMO (13) IABP (13) X (11) 0 Partial recovery 15 35 Eosinoph. Steroids+ methotrexate Churg-Strauss 2013 41 6 F 0 X (8) 0 Recovery 15 60 No EMB Steroids+IVIG+ AZA PV19, Coxsackie B IgM+ 2013 42 1 M 0 X 0 Recovery 20 67 No EMB Steroids+ cyclosporine 2014 43 55 F IABP (5) X (9) 0 Recovery* 25 59 Eosinoph. Steroids 2014 44 57 F p-ECMO (19) IABP (20) X (20) X HTx 22 22 GCM Steroids+RATGs+ cyclosporine 2014 45 23 M 0 X (17) 0 Recovery* 25 55 LM 2015 46 38 F p-ECMO (7) IABP (8) X (8) 0 Recovery 15 55 LM Steroids ANA 1:640 2015 47 68 M IABP (33) X (33) X Death 30 37 Eosinoph. Steroids+ cyclophosphamide Churg-Strauss 2015 48 53 F IABP X (46) X Recovery 25 50 EMB: negative (after rituximab) Steroids+ rituximab+ mycophenolate Churg-Strauss 2015 49 18 M p-ECMO (4) IABP (6) X (6) 0 Recovery 5 55 LM Steroids B burgdorferi IgG+ 2015 50 24 M 0 0 0 Recovery 25 59 LM/ histiocytic 0 Acute relapsing MS Enterovirus IgM+ SLE Toxoplasma IgM+ Lung cancer Brain cancer (Continued ) 538 August 8, 2017 Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis Year ORIGINAL RESEARCH ARTICLE Table 3. Continued Age, Patient y Sex CVVH Outcome LVEF at Admission, % LVEF at FollowUp, % MCS, n TI Diagnosis Immunosuppression 2015 51 32 M 0 0 0 Recovery 35 60 LM Steroids 2016 52 28 M p-ECMO (10) IABP (11) X (17) X No recovery 22 23 LM Oral steroids 2016 53 36 F p-ECMO (5) X 0 Recovery 15 52 LM Steroids 2016 54 35 M IABP (4) 0 0 Partial recovery 29 42 Eosinoph. Steroids+cyclophosphamide 2016 55 45 F 0 0 0 Recovery 40 51 LM Steroids Notes Churg-Strauss ANA indicates antinuclear antibodies; AZA, azathiprine; B burgdorferi, Borrelia burgdorferi; BiVAD, biventricular assist device; c-ECMO, central arteriovenous extracorporeal membrane oxygenation; CMV, cytomegalovirus; CVVH, continuous venovenous hemofiltration; EBV, Epstein-Barr virus; EMB, endomyocardial biopsy; Eosinoph., eosinophilic myocarditis; GCM, giant cell myocarditis; HTx, heart transplantation; IABP, intra-aortic balloon pump; IVIG, intravenous immunoglobulins; LM, lymphocytic myocarditis; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; M pneumo, Mycoplasma pneumoniae; MS, multiple sclerosis; NA, not available; p-ECMO, peripheral arteriovenous extracorporeal membrane oxygenation; Pheo, pheochromocytoma; PV19, parvovirus B19; RATGs, rabbit antithymocyte globulins (ATG-Fresenius; Bad Homburg, Germany); SLE, systemic lupus erythematosus; and TI tracheal intubation. In the table, the LVEF at admission is reported. This may not represent the lowest LVEF during the hospitalization. X and 0 mean that TI or CVVH was instituted or not, respectively. The numbers in parentheses indicate the number of days on MCS or of TI/CHHV. *Patients who recovered after fulminant myocarditis and died subsequently of a cause not directly related to the myocarditis (see text). Long-Term Changes in LVEF Downloaded from http://ahajournals.org by on June 19, 2020 Considering the last available LVEF after discharge with a median follow-up of 22 months (Q1–Q3, 11–52 months), the proportion of patients with LVEF <55% was still higher in patients with FM (9 of 31, 29%) than in patients with NFM (9 of 103, 9%; P=0.007). The RR of a reduced LVEF at follow-up was 3.32 in the FM group (95% CI, 1.45–7.64; Figure IIA in the online-only Data Supplement). Likewise, considering adults with viral myocarditis, the proportion of patients with LVEF <55% at the last echocardiographic assessment was higher in the v-FM (5 of 22, 23%) than in the v-NFM (2 of 71, 3%; P=0.008) group, with an RR of being discharged with LVEF <55% of 8.01 (95% CI, 1.68– 38.7; Figure IIB in the online-only Data Supplement). In patients with available echocardiographic data, a further modest improvement in LVEF was observed in the whole population of FM and NFM after discharge (Figure IIC and IID in the online-only Data Supplement), as well as in the subgroup with viral FM and NFM (Figure IIE and IIF in the online-only Data Supplement). None of the patients with NFM and LVEF ≥55% at discharge had a significant decrease in LVEF (a decrease >10% or to <50%) during follow-up, whereas in the FM group, only a 3-year-old child had a decrease of LVEF from 68% to 43%, although he remained asymptomatic. One patient with lymphocytic FM was on the waiting list for HTx at the end of follow-up (LVEF at discharge, 23%; last LVEF, 23% after 6 months). DISCUSSION The main finding of the present report is that overall patients with FM have an increased mortality and need Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 for HTx compared with those with NFM. From a functional viewpoint, patients with FM have more severely impaired LVEF at admission that, despite steep improvements during hospitalization, remains lower than in patients with NFM at long-term follow-up. All these findings also hold true if one confines the analysis to adults with viral myocarditis. The finding that patients with v-FM have a worse outcome compared with patients with v-NFM is at odds with the results of previous studies that led to the belief that the prognosis of lymphocytic FM was better than that of NFM.11,12 The discrepancies with previously published reports can be explained by a number of reasons: low number of FM cases (≤15) in prior studies7,8,11,13 that may have resulted in inadequate statistical power, a longer time frame between symptom onset and study entry that could have contributed to a selection bias (ie, exclusion of patients with the most aggressive acute course), and different entry criteria.11,12 The present report includes a larger cohort of consecutive patients admitted at 2 centers who were diagnosed with acute myocarditis on the basis of clinical, instrumental, laboratory, CMR, or pathology criteria. The key enrollment criterion was recent onset of symptoms (within 30 days from hospital admission or within 2 weeks in the subanalysis of adults with viral myocarditis), thus capturing acute inflammatory myocardial injury close to the time of its onset.3 This was integrated with long-term follow-up data (median follow-up after discharge, ≈5 years [59 months]). The high proportion of FM (29%) is due to transfer of the most severe cases to our tertiary referral centers, that is, 41 of 55 cases (75%) of FM compared with 21 of 132 cases (16%) of NFM (P<0.0001). August 8, 2017 539 Ammirati et al Table 4. Immunosuppressive Regimens and Heart Failure Medications in Patients With Fulminant and Nonfulminant Myocarditis FM Patients, n n Available data, n (%) NFM Value Patients, n 55 132 53 (96) 132 (100) Value P Value Immunosuppressive therapy, n (%) 53 34 (64) 132 16 (12) <0.0001 Regimen including use of intravenous steroids, n (%) 53 23 (43) 132 10 (8) <0.0001 +IVIG 3 (6) 0 … +cyA 1 (2) 2 (2) … +IVIG+azathioprine 2 (4) 0 … +Thymoglobulin+cyA 2 (4) 0 … +Rituximab+mycophenolate 1 (2) 0 … +IVIG+cyA 3 (6) 0 … +Methotrexate 1 (2) 0 … +Azathioprine 2 (4) 0 … +Cyclophosphamide 2 (4) 1 (1) … Only intravenous steroids, n (%) 14 (26) 7 (5) 0.0001 Only oral steroids, n (%) 2 (4) 5 (4) … Only IVIG, n (%) 1 (2) Oral cyA, n (%) 0 0 … 1 (1) … Downloaded from http://ahajournals.org by on June 19, 2020 NSAID, n (%) 53 14 (26) 132 98 (74) <0.0001 ACEi/ARB, n (%) 46 34 (74) 132 55 (42) 0.0003 β-Blocker, n (%) 46 21 (46) 89 63 (48) 0.86 MRA, n (%) 46 11 (24) 89 9 (7) 0.005 ACEi indicates angiotensin-converting enzyme inhibitor; ARBs, angiotensin II receptor blockers; cyA; cyclosporine; FM, fulminant myocarditis; IVIG, intravenous immunoglobulins; MRA, mineralocorticoid receptor antagonist; NFM, nonfulminant myocarditis; and NSAID, nonsteroidal anti-inflammatory drug. McCarthy et al11 retrospectively included patients with cardiomyopathy who had symptoms of HF for <12 months or unexplained ventricular arrhythmia and LVEF ≤40% who underwent EMB. Therefore, even if they described a nested population of patients with biopsy-proven myocarditis and reduced LVEF, there was a selection bias. In fact, patients with FM could be underrepresented as a result of their rapid unfavorable course because in the study period (1984–1997) temporary MCS was less frequently used. Patients with histology known to be associated with unfavorable prognosis such as GCM and necrotizing eosinophilic myocarditis6,31 were excluded from the FM group in the study by McCarthy et al,11 thus introducing another potential bias because clinically lymphocytic FM is indistinguishable from a nonlymphocytic FM. The heterogeneous nature of our population, which also includes individuals with nonlymphocytic forms and children, might have led to different conclusions compared with prior studies. Comparison of this population with pure populations of adult patients with lymphocytic myocarditis may not be valid. For this reason, we have carried out a subanalysis in a homogeneous 540 August 8, 2017 adult population with characteristics comparable to previous studies in which we considered only patients who became acutely ill after a distinct viral prodrome and onset of symptoms within 2 weeks, in accordance with Lieberman et al.10 Moreover, in this subanalysis, we excluded individuals with GCM, eosinophilic myocarditis, and cardiac sarcoidosis at EMB and patients with a clinical history or systemic findings suggestive of a different pathogenesis (ie, peripheral eosinophilia). In this more homogeneous population of myocarditis, we confirmed that v-FM has worse outcome than v-NFM and that patients with v-FM have a higher probability of residual LV dysfunction compared with patients with v-NFM. It must be noted that, because we have not performed EMB in all patients, we prefer to use the term viral myocarditis (based on the presence of distinct prodromal symptoms) instead of lymphocytic myocarditis, which implies a histological examination. All patients with available EMB identified as viral myocarditis had histologically proven lymphocytic myocarditis in this analysis. It must be noted that some crucial differences exist between the McCarthy et al11 study and the present Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis ORIGINAL RESEARCH ARTICLE A B Figure 3. Long-term transplantation-free survival in fulminant myocarditis (FM) vs nonfulminant myocarditis (NFM). A, Kaplan-Meier curves of transplantation-free survival in FM vs NFM in the entire population (n=187) and (B) in the adult patients with viral myocarditis (n=130). Events that occurred in the first 30 days after hospitalization are shown in the inset. It is clearly shown that most adverse events in patients with FM occurred during this initial period, whereas no adverse events occurred in patients with NFM. Downloaded from http://ahajournals.org by on June 19, 2020 study in terms of the characteristics of patients with NFM. These might explain, at least in part, the different long-term outcome in the NFM group (100% survival rate at 9 years in our series compared with 45% at 11 years of follow-up in the McCarthy et al study). First, in the study of McCarthy et al, all NFM was histologically proven myocarditis according to the Dallas criteria6 (both borderline and active), whereas in the present study, only a minority of patients with NFM (8%) had a histologically proven diagnosis. This partly reflects the prominent role that CMR and necrosis biomarkers have reached in the diagnosis of myocarditis in more recent times.4 Second, in the McCarthy et al study, baseline LVEF was ≤40% in all patients, and this was an inclusion criterion. In contrast, we included consecutive patients with NFM independently of their LVEF. Indeed, most patients (64%) had preserved systolic function. Last, in the McCarthy et al study, patients with up to a 12-month history of HF were included, thus leading to the potential selection bias of including, in the NFM group, only patients who did not have a functional recovery during the acute phase of myocarditis. In our series, the latter group accounted for only 3% of all v-NFM. Future studies will need to address the issue of whether the subset of patients with acute NFM presenting with histologically proven lymphocytic infiltration and persisting LVEF ≤40% still have a better longterm prognosis compared with patients with FM. We also observed that the proportion of men and women with FM is close to 50% both in the overall population and in adults with viral myocarditis. In contrast, in the group with NFM, there was a male predominance, which is in line with previous epidemiological studies reCirculation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 viewed by Fairweather et al.32 More studies are needed to untangle the causes of this sex-related difference in the incidence and morbidity of myocarditis. Last, we confirm that in patients with lymphocytic FM the larger extent of inflammatory infiltrate present in the myocardium is associated with a worse in-hospital outcome,10 as demonstrated by the increased need for MCS. Long-Term Follow-Up No cardiac deaths occurred in our patients with FM and NFM after the acute phase. Long-term LVEF was stable or improved in most patients after discharge. Functional recovery took place mostly in the first few weeks of the disease, which underlies the need for rapid therapeutic interventions. This also holds true when we considered the subanalysis on viral myocarditis. The lack of consistent results in the MTT (Myocarditis Treatment Trial), assessing the efficacy of immunosuppressive agents in the setting of acute lymphocytic myocarditis with LVEF <45%, could be ascribed to a delay in the initiation of this potentially effective treatment.33 Fewer than 45% of patients started immunosuppressive therapy within 1 month of the onset of myocarditis, when the LV was already dilated (mean end-diastolic diameter, 64 compared to 46 mm in our v-FM group). Immunosuppressive Treatment Immunosuppressive treatment was not standardized, reflecting the substantial lack of data on the treatment of lymphocytic/viral myocarditis (Tables 3 and 4 and August 8, 2017 541 Ammirati et al Downloaded from http://ahajournals.org by on June 19, 2020 Figure 4. Histological images of 2 patients with fulminant (FM; A through C) and nonfulminant myocarditis (NFM; D through F). A, Hematoxylin and eosin (H&E) section (×20 magnification) of an endomyocardial biopsy (EMB) of a 41-year-old (y.o.) woman with FM complicated by cardiogenic shock (left ventricular ejection fraction [LVEF], 20%) requiring mechanical circulatory support (MCS; patient 28 in Table 3). There is evidence of diffuse lymphoid infiltrates (arrows) and neutrophilic infiltrates with edema and multifocal cardiomyocyte necrosis that can be equated to grade 3R or 4 acute rejection on the basis of the 1994 or 2004 International Society for Heart Transplantation heart rejection grading systems, respectively. B, H&E with ×40 magnification. C, A section is positive for CD3 staining (brown), which identifies T cells. The section was also diffusely positive for CD68 and HLA-DR (not shown). D, H&E section (×20 magnification) of an EMB of a 17-year-old man with NFM presenting with severe systolic dysfunction (LVEF, 28%) but who recovered spontaneously without the need for inotropes or MCS. There is evidence of foci of lymphoid infiltrates (arrows) and rare eosinophils with associated cardiomyocyte damage that can be equated to a 1R or 2 acute rejection. E, H&E with ×40 magnification. F, A section was positive for CD3 staining (red). The section was also diffusely positive for CD68 and HLA-DR (not shown). IABP indicates intra-aortic balloon pump. Table VIII in the online-only Data Supplement). Only 1 patient with GCM had evidence of functional recovery after treatment with thymoglobulin, intravenous steroids, and cyclosporine.27 On the other hand, full functional recovery was observed in some patients with lymphocytic FM who did not receive immunosuppressive treatment. Pediatric patients with FM who were treated with temporary MCS and immunosuppressive drugs had a favorable outcome. Generally, treatment included intravenous immunoglobulins and steroids, in line with previous studies.23 All pediatric patients recovered, although there was evidence of parvovirus B19 in the myocardium in 1 patient with FM and of systemic infection sustained by the parvovirus B19 in another patient with FM (both treated with immunosuppressive drugs). Study Limitations EMB was not performed in all patients. However, our approach is in line with the 2007 American Heart Association/American College of Cardiology/European Society of Cardiology consensus statement, which suggests performing EMB in patients with severe presentation or 542 August 8, 2017 LV dysfunction not improving early in the course of the disease.5 It must be noted that in recent reports using MCS for the treatment of FM, the proportion of EMB was low compared with current recommendations: EMB was performed in 26% of a multicenter Italian series of 57 patients with FM treated with va-ECMO34; EMB was not performed in a Japanese single-center series of 22 patients35; and EMB was not reported in the registry of the Extracorporeal Life Support Organization database on 147 patients with presumed FM treated with va-ECMO.36 We did not perform molecular analysis to search for viral genome systematically because of financial constraints and a lack of strong evidence supporting viral search in endomyocardial samples to guide therapy, even if some studies report a potential benefit from this strategy.37 Thus, the relation between the degree of recovery and the presence of a specific virus could not be investigated. Nonetheless, it must be observed that even without this piece of information, the longterm survival was good, thus challenging the idea that a molecular search for viruses should be performed in all patients in the acute phase. Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Fulminant Versus Nonfulminant Myocarditis ORIGINAL RESEARCH ARTICLE Downloaded from http://ahajournals.org by on June 19, 2020 Figure 5. Changes in left ventricular ejection fraction (LVEF) during hospitalization in patients with acute myocarditis. A, Echocardiographic data of LVEF at admission and discharge in the entire population of fulminant myocarditis (FM; available data, n=40 of 55) (B) and nonfulminant myocarditis (NFM; available data, n=128 of 132). Wilcoxon matched-pair signed-rank test was used for comparisons. C, Delta of LVEF improvement in FM vs NFM (Mann-Whitney U test was used for comparison). D through F, Similar analyses in the subgroup of adults with viral FM (available data, n=29 of 34) vs NFM (available data, n=93 of 96) after exclusion of pediatric age and those with giant-cell and eosinophilic forms. Conclusions and Clinical Implications Our data suggest that hemodynamically unstable myocarditis, that is, FM, has poor in-hospital outcome and requires proper monitoring in the intensive care unit and prolonged treatment with inotropes and temporary MCS, whereas HTx or a long-term LVAD might be necessary in case of no functional improvement. Recovery seems to occur up to 4 weeks after MCS has been instituted, at least in our series. Death or need for HTx can occur in fulminant cases both in relatively rare forms with high mortality (ie, GCM) and in less lethal forms such as lymphocytic myocarditis. Furthermore, although most patients with myocarditis have a good long-term prognosis, those with fulminant presentation are more likely to have worse LV function at follow-up. Circulation. 2017;136:529–545. DOI: 10.1161/CIRCULATIONAHA.117.026386 Last, because of the diagnostic accuracy of CMR and in agreement with the current consensus,5 we believe that EMB is indicated in patients with NFM only if LV systolic dysfunction persists despite medical therapy or when a systemic disorder is suspected. AUTHORS Enrico Ammirati, MD, PhD; Manlio Cipriani, MD; Marzia Lilliu, MD; Paola Sormani, MD; Marisa Varrenti, MD; Claudia Raineri, MD; Duccio Petrella, MD; Andrea Garascia, MD; Patrizia Pedrotti, MD; Alberto Roghi, MD; Edgardo Bonacina, MD; Antonella Moreo, MD; Maurizio Bottiroli, MD; Maria P. Gagliardone, MD; Michele Mondino, MD; Stefano Ghio, MD; Rossana Totaro, MD; Fabio M. Turazza, MD; Claudio F. Russo, MD; Fabrizio Oliva, MD; Paolo G. Camici, MD*; Maria Frigerio, MD* August 8, 2017 543 Ammirati et al SOURCES OF FUNDING The Fondazione Centro Cardiologia e Cardiochirurgia A. De Gasperis, Niguarda Hospital, Milan, Italy, contributed to the support of this research. DISCLOSURES None. AFFILIATIONS From Transplant Center and De Gasperis Cardio Center, Niguarda Hospital, Milan, Italy (E.A., M.C., M.L., M.V., A.G., F.M.T., M.F.); Cardiovascular Magnetic Resonance Unit (P.S., P.P., A.R.), Cardiovascular Imaging Service (A.M.), Cardiothoracic Anesthesiology Unit (M.B., M.P.G., M.M.), Cardiac Surgery Unit (C.F.R.), and Coronary Care Unit (F.O.), De Gasperis Cardio Center, and Pathology Laboratories (D.P., E.B.), Niguarda Hospital, Milan, Italy; Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (C.R., S.G.); Cardiac Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo and the University of Pavia, Italy (R.T.); and Vita Salute University and San Raffaele Hospital, Milan, Italy (P.G.C.). 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