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Herz 2018 · 43:423–430 B. Maisch1 ·P.Alter2 https://doi.org/10.1007/s00059-018-4719-x 1 Fachbereich Medizin, Philipps-Universität Marburg und Herz- und Gefäßzentrum (HGZ) Marburg, Published online: 15 June 2018 Marburg, Germany © The Author(s) 2018 2 Klinik für Innere Medizin-Pneumologie und Intensivmedizin, UKGM und Philipps-Universität Marburg, Marburg, Germany Treatment options in and inflammatory Focus on i. v. immunoglobulins

In 2012 we reviewed the treatment op- proBNP) and high-sensitivity (hs) tro- curtain of diabetic cardiomyopathy, viral tions in (peri)myocarditis and inflamma- ponin T or I as cardiac biomarkers of heart disease with or without inflamma- tory cardiomyopathy in a special issue of and necrosis, respectively. tion can be hidden. But which of the this journal devoted to heart failure and Of note, cardiac MRI is an important factors is then the major etiological de- [1]. Now, 5 years later, method for clarifying the presence of terminant? itistimelyandappropriatetotakestock inflammation or fibrosis in addition to This issue also holds true for alcoholic of old and new data on this topic. function and pericardial effusion, but it cardiomyopathy [8]. In these patients, al- cannot substitute endomyocardial biopsy cohol consumption of more than 40 g/day Evolution of diagnoses for establishing an etiologically based di- in men and more than 20g/day in women agnosis [1–5]. For the diagnosis of viral formorethan5yearsisthesomewhat In 2013, experts of the European Soci- vs. autoreactive (nonviral) myocarditis arbitrary diagnostic determinant for the ety of Cardiology (ESC) working group and for the diagnosis of eosinophilic or label of . In en- on myocardial and pericardial diseases myocarditis, endomyocardial domyocardial biopsy, some infiltrating published a position statement on “The biopsyremainsessential, whilethebiopsy leukocytes may even suggest myocardi- current state of knowledge on aetiol- work-up includes histology, immunohis- tis in immunocompetent alcohol-depen- ogy, diagnosis, management and therapy tology, and polymerase chain reaction dent individuals as a likely differential of myocarditis” [2]. Specifically named (PCR) for RNA or DNA viruses [1–6]. diagnosis. causes of myocarditis were either infec- tive or immune-mediated or toxic [2, 3]. Special considerations for Clinical syndromes associated . Table 1 sums up the long list of pos- complex diagnoses with inflammatory cardio- sible causative pathogens and compares myopathy and myocarditis them with the real-world data of the Mar- Whether diabetic cardiomyopathy is a di- burg Myocarditis Registry (MMR) com- agnosisofitsownisstillunderdiscussion. Depending on the etiology, genetic pre- prising records of 1098 biopsied patients In endomyocardial biopsies of patients disposition, and comorbidities of the in- with suspected inflammatory dilated car- with heart failure and , histology dividual patient, at least four clinical syn- diomyopathy and/or myocarditis [1, 4]. can show microangiopathy, some infil- dromes can be identified after coronary The comments add important clues on trating and leukocytes, and artery disease is excluded by angiography how the diagnosis was made in the MMR. also a positive PCR of viral genomes such (. Fig. 1): Not mentioned but self-evident are a full as parvovirus B19. Diabetic cardiomy- 1. Life-threatening heart failure or clinical work-up of the patient includ- opathy can be part of a syndrome com- rhythm disturbance ing a detailed history, electrocardiogram prising and microangiopa- 2. Acute chest wall syndrome with (ECG) at rest and at exercise, imaging thy due to hypertensive heart disease and pectoris-like symptoms, often by Doppler or cardiac diabetes and viral persistence [7]. For di- after an infection magnetic resonance imaging (MRI), as agnosisoftheunderlyingetiology, acom- 3. Acute onset of heart failure well as a complete laboratory examina- posite view of the clinical evidence and 4. Chronic heart failure tion with C-reactive protein (CRP) as exclusion of other causes of cardiomy- a marker of inflammation and N-termi- opathy by endomyocardial biopsy can be . Table 2 connects these clinical syn- nal pro-B-type natriuretic peptide (NT- an important clue. However, behind the dromes with classic textbook diagnoses

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Life-threatening heart failure or rhythm disturbance • Shock, heart failure NYHA III-IV, elevated Troponin I/T, elevated Nt- proBNP, variable ECG altera ns, CAD ruled out, life-threa ng •Prototype: giantcellmyocardi , eosinophilic myocardi s, toxic myocardi

Acute chest wall syndrome Biopsy Posi ve samples controls • Angina- like symptoms, CAD ruled out, variable ST/T altera in ECG, variable arrhythmias, intermi ent Troponin I/T- and NT- proBNP eleva ns •Prototype: Parvovirus B19 or other cardiotropic virus infec +/- pericardi

Acute heart failure(AHF) • Dyspnea, , reduced EF, but also diastolic AHF, variable ECG, non ischemic cardiomyopathy, intermi ent Troponin I/T- and NT- proBNP eleva ns •Prototype: viral ornon-viral myocardi s or inflammatory cardiomyopathy (DCMi) Fig. 1 9 Clinical and his- tological phenotypes of myocarditis and in- Chronic heart failure(CHF) flammatory cardiomy- opathy. CAD coronary • All CHF symptoms for longer span, CAD ruled out, ECG with artery disease, ECG elec- LBBB, RBBB, AV-Block variable ST-/T-alteraons, intermient Troponin I/T-and NT-proBNP elevaons trocardiogram, EF ejection • Prototype: every viral or non-viral(autoreac ve) focal myocardi s fraction, LBBB left bundle or DCMi branch block, NYHA New York Heart Association, RBBB right

such as fulminant, acute, chronic, or as the CONSENSUS trial with enalapril, glycosides were tested in the DIG trial, persistent chronic myocarditis. the SOLVD trial with captopril, the AT- which demonstrated a reduction of all- LAS trial with lisinopril, or the HOPE cause and heart failure-related hospital- Treatment trial with ramipril. In the CHARM and ization with no change in mortality rate. ELITE II trials, angiotensin receptor Their use in patients with tachyarrhyth- Restriction of physical activity blockers demonstrated a similar ben- mia reduces heart rate and improves the efit. Today, beta-blockade is part of quality of life. In suspected or histologically validated the therapeutic armamentarium in the Antiphlogistic treatment with non- myocarditis, restriction of physical activ- treatment of any form of heart failure steroidal anti-inflammatory drugs ity for at least 6 months is part of the inter- as demonstrated in the MERIT-HF trial (NSAIDs) such as ibuprofen or in- national guidelines. This is highly rec- for metoprolol, the CIBIS trial for biso- domethacin should be reserved for pa- ommended until the inflammation has prolol, and the COPERNICUS trial for tients with pericardial involvement, since disappeared—evidenced by cardiac MRI carvedilol. In acute cardiac decompen- in murine coxsackie B3 myocarditis this or endomyocardial biopsy—and cardiac sation, loop diuretics are effective and treatment was shown to be detrimental function has normalized. aldosterone receptor blockers should be [12]. For treatment of peri(myo)carditis, givenontopoftheotherheartfailure we prefer colchicine instead, not only Heart failure therapy for drugs as demonstrated by the RALES inrecurrentformsbutalsoforthefirst inflammatory cardiomyopathy trials for spironolactone in heart failure attack [13]. and by the EPHESUS trial for eplerenone Heart failure therapy is part of the treat- in heart failure patients after myocardial Antiarrhythmic treatment ment of inflammatory cardiomyopathy. infarction. According to the findings of It was successfully demonstrated in many the SHIFT trial, ivabradine can be given Apart from beta-blockers, antiarrhyth- heart failure trials on angiotensin-con- to treat sinus and to reduce mic treatments for heart failure and for verting enzyme (ACE) inhibition such heart rate to below 70 bpm. Cardiac cardiomyopathy patients have been dis-

424 Herz 5 · 2018 Abstract · Zusammenfassung appointing. A meta-analysis of all trials Herz 2018 · 43:423–430 https://doi.org/10.1007/s00059-018-4719-x with amiodarone demonstrated a reduc- © The Author(s) 2018 tion in total mortality of 13% [14], but the SCD-HeFT trial, in which patients B.Maisch·P.Alter with a single-chamber implantable car- Treatment options in myocarditis and inflammatory dioverter-defibrillator (ICD) were ran- cardiomyopathy. Focus on i.v. immunoglobulins domized to amiodarone or to placebo, showed a decrease in mortality for the Abstract treatment group only [15]. The discus- For myocarditis and inflammatory cardiomy- disease can resolve spontaneously, often opathy, an etiologically driven treatment is specific treatment directed against the sion of whether rate or rhythm control today the best option beyond heart failure causative agent is required. For fulminant, is more beneficial in the treatment of therapy. Prerequisites for this are nonin- acute, and chronic autoreactive myocarditis, atrial fibrillation is still ongoing. Suffi- vasive and invasive biomarkers including immunosuppressive treatment has proven to cient anticoagulation is important under endomyocardial biopsy and polymerase be beneficial in the TIMIC and ESETCID trials; all circumstances. chainreactiononcardiotropicagents. for viral cardiomyopathy and myocarditis, Imaging by Doppler echocardiography and intravenous immunoglobulin IgG subtype cardiac magnetic resonance imaging as well and polyvalent intravenous immunoglobulins Device therapy as cardiac biomarkers such as C-reactive IgG, IgA, and IgM can frequently resolve protein, N-terminal pro-B-type natriuretic inflammation. However, despite the In patients with peptide , and troponins can contribute to elimination of inflammation, the eradication withorwithoutinflammation, antibrady- the clinical work-up of the syndrome but of parvovirus B19 and human herpesvirus-6 is not toward elucidating the underlying still a challenge, for which ivIg treatment can cardia pacing in second- and third-de- cause or pathogenetic process. This review become a future key player. gree or in brady- summarizes the phases and clinical features is well established. If the of myocarditis and gives an up-to-date short Keywords ejection fraction (EF) is below 35% and overview of the current treatment options Carditis · Inflammation · Cardiomyopathies · acute myocarditis is diagnosed, cause- starting with heart failure and antiarrhythmic Treatment · Intravenous immunoglobulins therapy. Although inflammation in myocardial specific treatment should be carried out with a LifeVest wearable defibrillator. If inflammation has disappeared and car- Behandlungsoptionen bei Myokarditis und inflammatorischer diac function remains low (EF < 35%), Kardiomyopathie. Immunglobuline i.v. im Fokus the implantation of an ICD is warranted according to current guidelines [16]. Zusammenfassung Bei Myokarditis und inflammatorischer Die spontane Rückbildung der Entzündung ist Immunosuppressive treatment Kardomyopathie ist heute neben der zwar möglich, oft wird aber eine spezifische bewährten Behandlung der Herzinsuffizienz Therapie erforderlich. Bei fulminanter, akuter eine ätiologisch begründete Therapie die und chronischer autoreaktiver Myokarditis Idiopathic giant cell myocarditis beste Option. Voraussetzungen dafür sind hat sich gemäß der TIMIC- und ESETCID- die Bestimmung nichtinvasiver und invasiver Studie eine immunsuppressive Behandlung If untreated, the natural course of gi- Biomarker inklusive Endomyokardbiopsie als nützlich erwiesen. Bei viraler inflammato- ant cell myocarditis is fatal in almost all und Polymerasekettenreaktion (PCR) auf kar- rischer Kardiomyopathie und Myokarditis sind i.v.-Immunglobuline (IgG bzw. IgGAM, also cases [17]. The few patients in the MMR diotrope Substanzen. Bildgebende Verfahren wie Echodoppler- und kardiale MRT-Unter- polyvalente IgG, IgA und IgM) in der Lage, die were treated with a combination of pred- suchung sowie kardiale Biomarker wie CRP, Entzündung fast immer, die virale Ursache nisone and azathioprine (see autoreactive NT-proBNP, Troponin können die Diagnostik (Parvovirus B19 und humanes Herpesvirus 6, myocarditis). The maintenance doses in Bezug auf das Syndrom ergänzen, zielen HHV6) bei der überwiegenden Zahl der of prednisone (7.5mg/day) and azathio- aber nicht auf den verursachenden Erreger betroffenen Patienten zu eliminieren. prine (50mg/day) were given as a life- oder den zugrunde liegenden autoreaktiven Pathomechanismus. Neben den Phasen Schlüsselwörter long therapy. All patients received an und dem klinischen Bild der Myokarditis Karditis · Inflammation · Kardiomyopathie · ICD and have survived 5 years without werden kurz die aktuelle Herzinsuffizienz- Therapie · Intravenöse Immunglobuline heart transplantation. und antiarrhythmische Therapie dargestellt.

Cardiac sarcoidosis

In cardiac sarcoidosis the infiltration of other immunosuppressive drugs, e.g., rare diseases. Its common pathogenetic cells including giant cells is confined to azathioprine or cyclosporine [18]. denominator is the overproduction of cy- thenoncaseousgranuloma. IntheMMR, totoxic eosinophils [19]. cardiac sarcoidosis was six times more Eosinophilic heart disease Our experience with long-term pred- frequent than giant cell myocarditis. The nisone and azathioprine documents treatment algorithm is either corticoid Eosinophilic heart disease (EHD) and a survival rate of 9 out 10 cases over therapy alone or in combination with the resulting endomyocardial fibrosis are a mean period of 8.4 years [20].

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Table 1 Causes of myocarditis and inflammatory cardiomyopathy in the MMRa mation. Following this pathogenetic hy- Infectious agent %pos. Comments pothesis, immunosuppressive treatment in MMR Diagnosis made via: either by prednisone alone or in combi- 1. Infectious myocarditis nation with azathioprine or cyclosporine Bacteria Chlamydia pneumoniae 0.03 Serodiagnosis was examined in five trials, the results of . Mycobacterium tuberculosis 0.02 IGRA (Quantiferon) or mi- which are summarized in Table 3. croscopy from sputum, peri- The first randomized, placebo-con- cardial fluid, in Africa more trolled trial on prednisone in myocarditis frequent was conducted by Parillo et al. [21], who Haemophilus influenzae 0.002 Serodiagnosis treated 60 patients with inflammation Staphylococci 0.03 Blood culture, in sepsis or and 62 without inflammation out of a dilated cardiomyopathy cohort of 122 Streptococci 0.02 In rheumatic , in cooper- patients with prednisone: 67% of the pa- ation with Chandigarh tients with inflammation who received Spirochete Syphilis 0.001 Serodiagnosis prednisone and 28% of inflammation Borrelia burgdorferi 0.7 ELISA and Western blot or PCR controls experienced an improvement in from EMB leftventricularEFof>5%(p= 0.004). The Rickettsia Coxiella burnetiid 0.005 Serodiagnosis, predominant Myocarditis Treatment Trial (MTT) by Mason et al. in 1995 [22] showed neither Fungi Candida 0.002 In immunocompromised a benefit nor an increased mortality after patients, diagnosed by culture a 6-month treatment with cyclosporine A Protozoa Plasmodium falciparum (malaria) 0.002 Microscopy (thick blood film) or azathioprine and prednisone when Toxoplasma gondii 0.002 Serodiagnosis compared with placebo. However, the Helminthic infec- – 0 None in MMR study was underpowered and did not tions distinguish viral from nonviral disease, Viruses (RNA subtype) as pointed out in a letter to the editor [23]. Picornaviruses Coxsackie A + B 0.019 All by PCR, epidemiologic In the first 6 months of the immuno- shift in late 1990s, none since suppressive therapy, the MTT showed 2002 a trend for the benefit of immunosup- Echo 0.005 PCR pression with respect to transplant-free Hepatitis B and C 0.002 Serodiagnosis or PCR survival, but it missed statistical signifi- Orthomyxoviruses Influenza A or B 0.002 Serodiagnosis cance by one patient. In the later follow- H1N1 0.001 Serodiagnosis up, the results remained neutral. Paramyxoviruses 0.001 Serodiagnosis Wojnicz et al. randomized 84 patients 0.002 Serodiagnosis with dilated heart muscle disease and in- creased human leukocyte antigen (HLA) Toga-/Rubivirus 0.001 Serodiagnosis expressionforatreatmentofazathioprine Flavi-/Arbovirus Dengue 0.001 Serodiagnosis and prednisone or placebo for 3 months. Viruses (DNA subtype) In the treatment group, EF improved and Adenoviruses A1,2,3,5 0.011 PCR survival remained comparable between Erythroviruses Parvovirus B19 types 1–3 28 PCR the placebo and verum group [24]. Herpesviruses: human herpes 0.03 PCR; sometimes together with In the TIMIC study, Frustaci et al. re- 6virus PVB 19 virus ported that the EF of 43 patients in the Cytomegalovirus 0.02 PCR or ISH treatment group improved from 26.5% at Epstein–Barr virus 0.012 PCR baseline to 45.6% at 6 months (p< 0.001). Varicella zoster 0.001 Serodiagnosis Similarly, left ventricular end-diastolic Retrovirus: HIV 0.005 PCR or by serodiagnosis volume, left ventricular diameter, and Rhabdovirus 0.001 – New York Heart Association class im- proved significantly [25]. TheESETCID(EuropeanStudy on the Treatment in autoreactive, with respect to immunosuppressive ther- Epidemiology and Treatment of Cardiac lymphocytic myocarditis apy in myocarditis. Inflammatory Disease) is a double- Viral infection, according to common blind, randomized, placebo-controlled Immunosuppression belief, may trigger an autoreactive cellu- three-armed trial with prednisolone and No randomized or blinded treatment tri- lar and humoral immune response that azathioprine for autoreactive (virus neg- als have been published in the past 6 years leads to myocardial damage with inflam- ative) inflammatory dilated cardiomy-

426 Herz 5 · 2018 Table 1 (Continued) opathy in patients with an EF below Infectious agent %pos. Comments 45% at baseline. Interferon alpha is in MMR Diagnosis made via: giveninenteroviralmyocarditis,and 2. Noninfectious Autoreactive myocarditis 53 Exclusion of microbial agents intravenous immunoglobulins (ivIg) are myocarditis given in cytomegalovirus, adenovirus, Systemic Giant cell myocarditis 0.03 Histology and parvovirus B19 myocarditis, vs. autoimmune Wegner’s granulomatosis 0.01 Histology a placebo drug. The intermediate analy- diseases Sarcoid heart disease 0.015 Histology sis of the immunosuppressive treatment arm showed a positive trend for EF Rheumatoid arthritis 0.03 Histology and serology and major adverse cardiac events after Sjögren syndrome 0.02 Serology 6 months of treatment and significant Systemic lupus 0.05 Serodiagnosis benefit after 1 year of follow-up for both Crohn’s disease 0.02 Serodiagnosis groups [26]. Remarkably, the control Dermatomyositis 0.02 Serodiagnosis group also showed also some sponta- Kawasaki syndrome 0.015 – neous resolution. Rejection After heart transplantation 1 In cooperation with Hannover Medical School Intravenous immunoglobulins After stem cell transplantation 0.002 – ivIg have demonstrated benefit in various Hypereosinophilic Löffler’s endomyocarditis 0.01 Biopsy and histology inflammatory settings, clinically and ex- syndrome (HES) Churg–Strauss syndrome 0.01 Biopsy and histology perimentally. Treatment with ivIg relies 3. Toxicity on a polypragmatic therapy approach: Alcohol Alcoholic cardiomyopathy 0.2 History, negative PCR on IvIg interact widely with the immune microorganisms system. In addition to immunoglobu- Drug toxicity Aminophylline, amphetamine, 0.02 Only anthracycline induced lin G (ivIgG), the IgGAM Pentaglobin®, anthracycline, chloramphenicol, CMP in the MMR in even lower concentrations than ivIgG, cocaine, cyclophosphamide, exerts proinflammatory and anti-inflam- d5-fluorouracil, mesylate, matory effects. This has been shown in methyl sergide, phenytoin, sepsis and also in viral heart disease both trastuzumab, zidovudine, ipili- mumab and nivolumab antibod- clinicallyandexperimentally. Proinflam- ies matory effects are the activation of im- Hypersensitivity Azithromycin, benzodiazepine, 0.001 Only one patient with lithium mune cells and of the complement sys- reaction (drugs) clozapine, cephalosporin, intoxication in MMR tem and the opsonization of infective dobutamine, lithium, diuret- agents [27]. Anti-inflammatory effects ics, methyldopa, mexiletine, comprise the neutralization of bacterial streptomycin, sulfonamides, and other toxins, of degradation prod- NSAIDs, tetracycline, tricyclic antidepressants ucts, and of an excess of complement Hypersensitivity Bees,wasps,scorpions,snakes, 0 – factors and . This can stimu- reactions (ven- spider late immune cells to set anti-inflamma- oms) tory cytokines such as interleukin (IL)- Radiation injury – 0.015 History + biopsy + imaging 1RA and IL-8 free and inhibit the lib- Metabolic disor- Diabetic cardiomyopathy 0.02 History + biopsy + imaging in eration of proinflammatory cytokines, der diabetes patients e.g., IL-6 and IL-1 [1]. Anthony et al. 4. Other DCM – 16.62 – [28] have shown that the anti-inflamma- patients tory activity of monomeric IgG is com- aThe MMR included 1098 patients with the diagnosis of suspected myocarditis or inflammatory pletely dependent on the sialylation of cardiomyopathy who were examined during 1990–2010 (modified from1 [ , 2, 4]). Diagnoses were the N-linked glycan of the IgG Fc frag- made in most cases via left or right ventricular EMB with PCR, histology, and immunohistology or ment. The IgM fraction in ivIgGAM can conclusive serodiagnosis including cardiac autoantibodies play a distinct role in controlling inflam- CMP cardiomyopathy, DCM dilated cardiomyopathy, Echo enteric cytopathic human orphan virus, EMB endomyocardial biopsy, ELISA enzyme-linked immunosorbent assay, IGRA interfer- matory and autoimmune disease. Fur- on-gamma-release assay, ISH in situ hybridisation, NSAIDs nonsteroidal anti-inflammatory drugs, thermore, IvIgGAM can reduce oxidative PCR polymerase chain reaction, pos. positive stress [29].Itseffecthasbeenshownin heart failure[30–34], in peripartum car- diomyopathy [35], in fulminant [36–38], acute [30, 39–46], and chronic myocardi- tis [38], in dilated cardiomyopathy [46], as well as in enteroviral [47]andinpar-

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Table 2 Phenotypes of myocarditis and treatment options (modified from [1]) Clinical phenotype Fulminant myocarditis Acute myocarditis Chronic active or persistent myo- carditis Syndrome Life-threatening heart failure or rhythm Acute chest wall syndrome or acute on- Chronic heart failure, variable EF with disturbance set of heart failure; pericardial effusion LV dilatation, (up to 10%); angina in parvovirus B19 pericardial effusion (up to 10%); angina myocarditis in parvovirus B19 myocarditis Dallas criteria [9] Infiltrate (active myocarditis or giant Active, often focal lymphocytic myo- Borderline myocarditis, focal small cells), necrosis carditis infiltrates World Heart Federa- ≥50 infiltrating cells/mm²,necrosis, ≥14 infiltrating cells, mostly lympho- ≥14 infiltrating cells, lymphocytes and tion criteria [10, 11] possibly giant cells cytes, necrosis, necrosis likely macrophages, necrosis and apoptosis not obligatory Immunohistology Immunoglobulin binding mostly IgM Immunoglobulin (IgM, IgA and IgG) Immunoglobulin (IgG) binding to sar- to sarcolemma and fibrils and comple- binding to sarcolemma and fibrils colemma and fibrils ment fixation PCR of microbial Negative in giant cell or autoreactive Negative in autoreactive lymphocytic Negative in autoreactive lymphocytic pathogens myocarditis, positive in up to one third myocarditis, positive in up to one third myocarditis, positive in up to one third of cases of cases of cases Course Variable: from fatal outcome to sponta- Variable: from deterioration to defec- Chronic heart failure neous healing tive healing Treatment 1. Immunosuppression in PCR-negative 1. Immunosuppression in PCR-negative 1. Immunosuppression in PCR-negative cases, cases, cases, 2. In virus-positive biopsies; ivIg, 2. In virus-positive biopsies; ivIg, 2. In viral myocarditis ivIg or 3. In all patients: assist device and ICDs, 3. In all patients: assist device and ICDs, IFN in controlled trials if indicated; heart failure treatment if indicated; 3. In all patients: prophylactic ICDs, heart failure treatment when EF< 35%; heart failure treatment EF ejection fraction, ICDs implantable cardioverter-defibrillators, IFN interferon, ivIg intravenous immunoglobulin, LV left ventricular, PCR polymerase chain reaction

Table 3 Trials on immunosuppressive treatment Author Treatment Endpoint Patients/controls (n) Result Comment Parillo et al. [21] P Function+ mortality after 60/62 Improved 67% No viral PCR 3months Mason et al. (MTT) P+A/CyA Function, mortality 64/47 No benefit, no harm Underpowered, no viral [22] PCR Wojnicz et al. [24] P+A EF+ function, mortality 41/43 EF improved No viral PCR Frustaci et al. (TIMIC) P+A EF+ mortality after 43/42 88.3% improved Treatment in virus-neg- [25] 6months ative pts. only Maisch et al. (ESET- P+A EF+ function, MACE 54/47 EF+ function im- Treatment in virus-neg- CID) [26] proved after 2 years ative pts. only A azathioprine, CyA cyclosporine, EF ejection fraction, MACE major adverse cardiac events, P prednisone, PCR polymerase chain reaction

vovirus B19-associated heart disease [48, The MMR data support a positive ef- High-dose ivIG in cytomegalovirus 49]. IgM-enriched immunoglobulins ap- fect of 20g i.v. pentaglobin in adeno- myocarditis pear to be effective in lower doses [34], virus-positivemyocarditisforclinicalim- Inbiopsy-provencytomegalovirus(CMV) which corresponds to our own observa- provement, with eradication of both the myocarditis, one controlled trial of 18 pa- tion with Pentaglobin®. . Table 4 gives inflammation and the virus [51]. In par- tients reported on the eradication of an overview of the ivIg studies. Not all vovirus B19 myocarditis, our data in- inflammation and elimination of the studies reported hemodynamic benefit dicate a clinical improvement; however, virus [52]. The patients had received or improvement, however: The IMAC, only inflammation is successfully elim- 2ml/kg i.v. cytomegalovirus hyperim- a randomized controlled trial, demon- inated, whereas parvovirus B19 persis- munoglobulin (CMVhIg) for 3 days strated improvement in both the treat- tenceremainsaprobleminmanypatients and 1 ml/kg for an additional 2 days, ment and placebo arm [42], so that in although the viral load is often decreased. alternately. a recent multi-institutional analysis [50] In parvovirus B19-associated inflam- the benefit in a pediatric population was matory dilated cardiomyopathy, dose- questioned. finding studies and randomized trials

428 Herz 5 · 2018 Table 4 Registries and trials with ivIg in inflammatory cardiomyopathy or myocarditis Authors Study design Patients (n) Histology ivIg dose Outcome /PCR Drucker et al. [40] Retrospective 46 children Partly, no PCR 2g/kgsingledose Reduced LVEDD McNamara et al. Uncontrolled 10 adults Partly, no PCR 2g/kgsingledose Improved EF [41] McNamara et al. RCT IMAC 62 DCM, only No PCR 2g/kgsingledose Both groups improved [42] 13 myocarditis Kishimoto et al. [30, Case series Total 9, No PCR 1–2g/kg single Improved NYHA and EF 46] 4 myocarditis dose Dennert et al. [49] Uncontrolled 25 PVB19 positive 2g/kgsingledose Decreased viral load, improved EF Maisch et al. [51] Uncontrolled 90 PVB19 PCR-positive for 20g per person at Improved EF in 90%, eradication of ADV 36 ADV PVB19 and ADV day 1 and 3 in 90%, of inflammation in 100%; PVB19 eradication in 40%, of inflammation in 70% Maisch et al. [52] Controlled 18/17 CMV by PCR 14 days, multiple Improved EF, complete CMV eradication doses ADV adenovirus, CMV cytomegalovirus, DCM dilated cardiomyopathy, EF ejection fraction, ivIg intravenous immunoglobulins, LVEDD left ventricular end-diastolic diameter, NYHA New York Heart Association, PCR polymerase chain reaction, PVB19 parvovirus B 19 are still lacking and should be planned 4 If no virus but autoreactive myo- References in the future. cardial inflammation is identified, immunosuppressive treatment is the 1. Maisch B, Pankuweit S (2012) Current treatment options in (peri)myocarditis and inflammatory Antiviral treatment with treatment of choice. cardiomyopathy. Herz37:644–656 interferon beta 2. Caforio AL, Pankuweit S, Arbustini E et al (2013) In the BICC trial, patients with en- Currentstateofknowledgeonaetiology,diagnosis, Corresponding address management, and therapy of myocarditis: terovirus-, adenovirus-, and parvo- a position statement of the European Society of virus B19-positive genomes received ei- Prof. Dr. B. Maisch Cardiology Working Group on Myocardial and ther 4× 106 or 8 × 106 IU interferon beta- Fachbereich Medizin, Philipps-Universität PericardialDiseases. EurHeartJ34(33):2636–2648 Marburg und Herz- und Gefäßzentrum (HGZ) 3. Pankuweit S, Maisch B (2013) Etiology, diagnosis, 1bvs. placebo[53]. Inthe smallenterovi- Marburg management, and treatment of myocarditis. ral and adenoviral myocarditis strata, Feldbergstr. 45, 35043 Marburg, Germany Position paper from the ESC Working Group interferon-beta tended to eliminate the [email protected] on Myocardial and Pericardial Diseases. Herz 38:855–861. https://doi.org/10.1007/s00059- viral genome, to decrease inflammation, 013-3988-7 and to improve hemodynamics, whereas Acknowledgements. This work was supported 4. Maisch B, Pankuweit S (2013) Standard and in parvovirus B19 and human her- by a grant from the Bundesministerium für Wis- etiology-directed evendence-based therapies in senschaft und Forschung (BMBF) in the German myocarditis: statoftheartandfutureperspectives. pesvirus 6 myocarditis, the response was Competence Net of Heart Failure (KNHI), by the Heart Fail Rev 18:761–795. https://doi.org/10. disappointing. For all three viruses, viral Prof. Dr. Reinfried Pohl Stiftung, by the Verein zur 1007/s10741-012-9362-7 elimination or viral load reduction was Förderung der Kardiologie (VFDK) Marburg, and the 5.AlterP,FigielJH,RuppTP,BachmannGF,MaischB, UKGM Foundation. Rominger MB (2013) MR, CT, and PET imaging in higher in the interferon beta-1b treat- pericardialdisease. HeartFailRev306:18–289 ment group than in the placebo group, 6. Maisch B, Ristic AD, Pankuweit S (2017) Inflamma- but least effective in the parvovirus B 19 torische Kardiomyopathie und Myokarditis. Herz Compliance with ethical 42:425–438. https://doi.org/10.1007/s00059- treatment arm. guidelines 017-4569-y 7. Maisch B, Alter P,Pankuweit S (2011) Diabetic car- diomyopathy—factorfiction? Herz36:102–115 Practical conclusion Conflict of interest. B. Maisch receives honoraria for 8. Maisch B (2016) Alcoholic cardiomyopathy: the lectures from Biotest Co. P.Alter declares that he has result of dosage and individual predisposition. 4 In inflammatory dilated cardiomy- no competing interests. Herz 41:484–493. https://doi.org/10.1007/ opathy and myocarditis, apart from s00059-016-4469-6 This article does not contain any studies with human 9. Aretz HT, Billingham M, Olsen E et al (1987) heart failure and antiarrhythmic participants or animals performed by any of the au- Myocarditis: the Dallas criteria. Hum Pathol therapies, there is no real alternative thors. 18:619–624 to an etiologically driven specific 10. Maisch B, Bültman B, Factor S et al (1999) Open AccessThisarticleisdistributedundertheterms World Heart Federation consensus conference’s treatment. of the Creative Commons Attribution 4.0 International definition of inflammatory cardiomyopathy 4 Diagnosis of the underlying micro- License (http://creativecommons.org/licenses/by/ (myocarditis): report from two expert committees bial agent is a prerequisite for the 4.0/), which permits unrestricted use, distribution, on histology and viral cardiomyopathy. Heartbeat and reproduction in any medium, provided you give 4:3–4 initiation of treatment with antiviral appropriate credit to the original author(s) and the 11. Maisch B, Portig I, Ristic A et al (2000) Definition of agents or ivIg, which is the focus of source, providealinktotheCreativeCommonslicense, inflammatory cardiomyopathy (myocarditis): on this review. and indicate if changes were made. thewaytoconsensus. Herz25:200–209

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