National Survey of Influenza Myocarditis in Japanese Children in Three

Acute myocarditis is a potentially lethal disease, and the etiological agents of viral myocarditis include Enteroviruses, Adenoviruses, Parvoviruses, Cytomegalovirus, Influenza virus and others [1-10]. Fulminant myocarditis causes severe hemodynamic dysfunction and requires high-dose catecholamine and mechanical circulatory support [1,6-8,11]. An Influenza pandemic occurred in 2009 [6,1214]. The causative organism, Influenza H1N1pdm, has been reported to cause fatal myocarditis as well as pneumonia [2-4,6-10]. Based on national surveillance in Japan, we previously reported that fifteen fulminant myocarditis patients (adults: 13, children: 2) with Influenza A H1N1pdm were seen in the 2009/2010 season, while only two (adults: 2, children: 0) were seen in the 2010/2011 season, and that electrocardiogram (ECG) was useful for screening for myocarditis [7].

of Japanese pediatricians concerning the diagnosis of Influenza myocarditis. The study protocol was approved by the Institutional Review Board of Osaka Medical College.

Results
Completed questionnaires were received from 285 hospitals that have pediatric departments in Japan. About 300,000 children were admitted per year in these hospitals. Fifteen Influenza myocarditis patients were reported, with 8 (H1N1pdm2009 Cardiac symptoms developed on the first to third day of illness in most patients. Mortality was 33.3% (5/15) among the myocarditis patients. Twelve patients (12/15, 80%) were diagnosed with fulminant myocarditis with fatal arrhythmias and/or cardiogenic shock. Myocardial circulatory support was emergently inserted in 4 patients, three of whom were rescued. Three of the 9 patients treated without myocardial circulatory support survived. Respirators were used in 9 patients. Myocardial biopsies were not performed, and autopsy showed myocarditis in two patients.
Ten patients had no baseline disease, and only two patients suffered from bronchial asthma. Three patients with myocarditis also developed pneumonia. RT-PCR or quick diagnostic testing yielded positive results in all patients. Most patients showed ECG abnormalities, such as ST segment elevation and/or T wave abnormality (ST-T abnormalities). Echocardiography revealed abnormalities of left ventricular wall motion in 10 patients. Cardiac dysfunction recovered almost completely in 9 patients, but partially remained in one patient. Eleven patients (73%) were treated with neuraminidase inhibitors.
Answers to the attitude survey concerning the diagnosis of Influenza myocarditis were received from 451 pediatricians ( Figure 1). Overall, 8.4% of Japanese pediatricians always assumed the presence of Influenza myocarditis in pediatric Influenza patients, 13.2% in hospitalized patients, and 71.3% in patients with serious illness; however, 7.1% of Japanese pediatricians never assumed that Influenza myocarditis was present in pediatric Influenza patients. In addition, 87.6% of Japanese pediatricians routinely examined the chest X-rays when their pediatric patients were admitted to hospital, and 3.3% of pediatricians routinely examined the ECG, which is useful for screening of myocarditis (Figure 1).

Discussion
The  [14]. The low casefatality rate in Japan may be a result of early diagnosis and aggressive early intervention with antiviral drugs [15,16]   pediatric myocarditis patients were reported in 2 seasons in our previous study [7]. Since the number of pediatric myocarditis patients seemed to be smaller than in adult patients, this study was performed. Myocarditis was proven by autopsy in only 2 fulminant myocarditis patients in this study, and the pathological findings were relatively mild. Many kinds of viruses have been implicated as a cause of myocarditis, with different viruses having different potentials to cause myocarditis [1][2][3][4][5][6][7][8]. The affinity of the Influenza virus for cardiac myocytes seemed to be low in previous studies [1][2][3]17,18]. The pathological mechanism of Influenza myocarditis appears to differ depending on the pathogen, and it may depend on host immunity. These results suggest that vaccination is able to suppress myocarditis associated with seasonal Influenza A virus in Japan.
The questions about the attitudes of Japanese pediatricians to the diagnosis of Influenza myocarditis showed that most of them did not usually assume that their patients had Influenza myocarditis. The ECG was found to be a sensitive and convenient tool for diagnosis of myocarditis in our previous study. ST elevation, T inversion, and conduction block are frequently observed. However, only 3.3% of Japanese pediatricians ordered routine ECGs on admission for Influenza. Thus, mild cases of myocarditis in children may be missed by pediatricians.

Conclusion
Increased awareness of Influenza myocarditis in children is very important during future Influenza pandemics.