Authors: Messroghli DR, Pickardt T, Fischer M, Opgen-Rhein B, Papakostas K, Böcker D, Jakob A, Khalil M, Mueller GC, Schmidt F, Kaestner M, Udink Ten Cate FEA, Wagner R, Ruf B, Kiski D, Wiegand G, Degener F, Bauer UMM, Friede T, Schubert S; MYKKE Consortium
Am Heart J. 2017 May; 187: 133-144. doi: 10.1016/j.ahj.2017.02.027. Epub 2017 Feb 24.
Commented by: Sabine Pankuweit, Klinik für Innere Medizin, Kardiologie - Angiologie und Internistische Intensivmedizin, Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg, Baldingerstraße, D - 35043 Marburg
With the following I would like to introduce to you a multicenter registry and study platform for children and adolescents with myocarditis. The aim of the so called MYKKE is to generate prospective multi-center data on epidemiology, diagnostics, and therapy of pediatric patients with myocarditis in order to enable evidence-based diagnostic and therapeutic approaches for this myocardial disease.
The authors stated within the recently published paper that the aim of the project is to overcome the lack of prospectively collected multicenter data on epidemiology, clinical presentation, and diagnostic value of currently available diagnostic tools in children and adolescents with myocarditis to define age-specific properties and to establish clinically meaningful criteria for the diagnosis of myocarditis. To this end, MYKKE is designed to include patients with suspected myocarditis rather than patients with definitive myocarditis only, as the latter would introduce a preselection of cases and thus make an open evaluation of diagnostic criteria impossible. If successful, the infrastructure and results established in this project might serve as a platform for diagnostic and interventional substudies in myocarditis in the future.
Interestingly, the platform will consist of two stages and will have the aim first to derive evidence-based diagnostic criteria for the diagnosis of myocarditis in children and adolescents. To reach this aim, patient with suspected myocarditis as the leading diagnosis for referral/diagnostic workup and hospital admission and an age < 18 years will be included and the dataset of the first 150 MYKKE patients will be enriched with results from clinical tests by revising all available clinical records.
This database of the first 150 individuals will then be used to assess the diagnostic accuracy of those diagnostic criteria for myocarditis in adults, published in 2013 by the WG of myocardial and pericardial diseases within the European Heart Journal. Parameters assessed are more or less the same including 1) levels of C-reactive protein, troponin, and BNP/N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on laboratory testing, 2) arrhythmia and alterations of ST-segments on electrocardiogram (ECG); arrhythmia on 24-h Holter ECG; 3) LV and right ventricular (RV) size and function on echocardiography and 4) LV and RV function and size; presence of pericardial effusion, myocardial T1, and extracellular volume on MRI. As the authors postulate, that the trigger mechanism in most cases of myocarditis especially in children is believed to be acute viral infection the copy number of viral DNA by PCR on EMB will be included as 5th parameter. In a second step, the group will perform logistic regression analysis to test which combinations of symptoms and diagnostic parameters yields the highest diagnostic accuracy to identify patients with the diagnosis of myocarditis with the aim to establish diagnostic score derived from this data.
In stage 2 of the study, all clinical data of the next 100 patients included will be used to apply the diagnostic score derived from the first 150 patients to the second cohort. The aim is to calculate the diagnostic accuracy (sensitivity, specificity, and positive and negative predictive values) of the score for identifying a patient with myocarditis at admission. Last but not least the score will be compared once again with the conventional criteria published by the ESC WG21 and, most important, with the immunohistochemical and histopathological results of EMB alone which was taken from around 46% of the patients included so far. As a cardiac MRI was performed in 54% of included patients so far, this will be the second criterion to possibly identify patients with ‘true’ myocarditis.
As the study is planned as an observational registry with enrolment of a total 1500 patients with a target follow-up of 10 years MYKKE will serve as a study platform for interventional substudies by providing an established multicenter infrastructure with continuous access to patients with acute myocarditis. Authors are completely right when stating that based on this infrastructure, MYKKE patients will be invited to take part in prospective trials testing, for example, the use of angiotensin-converting enzyme inhibitors and immunoglobulins in symptomatic patients with normal LV ejection fraction (LVEF) at presentation or the effects of anti-inflammatory therapy in patients with persistent inflammatory response and impaired ventricular function.
The first results described in the paper derived from 149 patients show, that a high proportion of patients (57 patients = 38%) met strong endpoint criteria as death, survived sudden death, assist device, decompensated heart failure, catecholamine therapy or malignant arrhythmia. Taken this combined endpoint as marker of severity of disease younger patients (0-2 years) had a higher frequency of adverse advents and the highest frequency of severe reduced ejection fraction without significant gender differences.
Taking together, the MYKKE registry for children and adolescents is a very important registry designed to collect evidence on epidemiology, diagnosis and therapy in a large number of patients with myocarditis, which is because of a relatively low incidence not seen in single centers in high numbers. In addition, because of the wide range of clinical presentations, single centers may only see a fraction of the clinical picture, which will be overcome by this registry. The study group is planning further analyses and studies to test the performance of invasive and not invasing diagnostic tests in addition to the outcome of patients undergoing different therapeutic strategies.
As the possibly viral component of the disease and the heterogeneous epidemic distribution of these viruses might cause differences in the clinical presentation of patients in different regions in Germany or Europe, the extension of the registry to international centers is planned and exactly the right way, to get more valid data across Europe.
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