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Fulminant Myocarditis Associated With Pandemic H1N1 Influenza A Virus in Children
<nobr>Andr?s Bratincs?k, MD, PhD<sup><sub>*</sub></sup></nobr>, <nobr>Howaida G. El-Said, MD, PhD</nobr>, <nobr>John S. Bradley, MD</nobr>, <nobr>Katayoon Shayan, MD</nobr>, <nobr>Paul D. Grossfeld, MD</nobr> and <nobr>Christopher R. Cannavino, MD</nobr> <sup><sub>*</sub></sup> Rady Children's HospitalSan Diego, University of California San Diego, School of Medicine, 3020 Children's Way, MC5004, San Diego, California 92123 (Email: bratiandris@yahoo.com<script type="text/javascript"><!-- var u = "bratiandris", d = "yahoo.com"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>).
<hr width="75%" noshade="noshade" size="2">To the Editor: Acute myocarditis is a well-recognized, albeit<sup> </sup>rare, manifestation of numerous viral infections (1) with a<sup> </sup>broad spectrum of symptoms and clinical features (2). Fulminant<sup> </sup>myocarditis may present with fatal arrhythmias, atrioventricular<sup> </sup>block, and/or varying degrees of cardiogenic shock (3). The<sup> </sup>prevalence of myocardial involvement in influenza infection<sup> </sup>ranges from 0 to 11% depending on the diagnostic criteria used<sup> </sup>to define myocarditis (4). Fulminant myocarditis is an uncommon<sup> </sup>complication, typically diagnosed in association with circulatory<sup> </sup>collapse or at autopsy in patients with influenza-associated<sup> </sup>fatal outcomes (5). A few case reports and series (68)<sup> </sup>represent the incidental diagnoses of influenza-associated acute<sup> </sup>fulminant myocarditis, but the true prevalence remains unknown.<sup> </sup> Here we present the first known report of acute myocarditis<sup> </sup>in pediatric population associated with the present pandemic<sup> </sup>H1N1 influenza A virus infection. Four cases occurred within<sup> </sup>a 30-day period, and 3 of them were diagnosed as fulminant myocarditis<sup> </sup>with fatal or near-fatal outcomes.<sup> </sup>
A retrospective chart review was conducted on all patients admitted<sup> </sup>to Rady Children's HospitalSan Diego with the diagnosis<sup> </sup>of H1N1 influenza A infection during October 2009. Criteria<sup> </sup>for fulminant myocarditis included echocardiographic and clinical<sup> </sup>evidence of severely decreased left ventricular systolic function<sup> </sup>and/or lymphocytic infiltration of the myocardium documented<sup> </sup>at autopsy.<sup> </sup>
Within a 30-day period, 80 children were admitted with H1N1<sup> </sup>influenza A infection to Rady Children's HospitalSan<sup> </sup>Diego. Serum troponin I and creatine phosphokinase myocardial<sup> </sup>band levels were obtained in 11 children, and echocardiography<sup> </sup>was performed in 8 children. We included 4 H1N1 influenzaassociated<sup> </sup>myocarditis cases based on elevated cardiac enzymes (n = 2),<sup> </sup>significant acute decrease in left ventricular systolic function<sup> </sup>demonstrated by the echocardiogram (n = 3), or histologic evidence<sup> </sup>of severe myocarditis (n = 1) (Fig. 1A). Three children presented<sup> </sup>with fulminant myocarditis, 1 with a fatal outcome and 2 requiring<sup> </sup>extracorporeal membrane oxygenation support. None of the children<sup> </sup>with fulminant myocarditis had evidence of sepsis or bacterial<sup> </sup>infection (negative blood, urine, and tracheal aspirate cultures).<sup> </sup>Two of the 3 children with decreased systolic function experienced<sup> </sup>recovery in 5 to 7 days (Figs. 1E and 1F). All 4 children had<sup> </sup>a positive rapid influenza enzyme immunoassay test result from<sup> </sup>a nasopharyngeal swab sample that was subsequently confirmed<sup> </sup>as H1N1 by reverse-transcriptase polymerase chain reaction performed<sup> </sup>at the San Diego County Department of Health (Fig. 1A).<sup> </sup>
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<center><table cellpadding="0" cellspacing="0" width="95%"><tbody><tr bgcolor="#e1e1e1"><td><table cellpadding="2" cellspacing="2"> <tbody><tr bgcolor="#e1e1e1"><td align="center" bgcolor="#ffffff" valign="top">
View larger version (131K):
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[Download PPT slide]
</nobr> </td><td align="left" valign="top"> Figure 1 Acute Myocarditis Associated With H1N1 Influenza A Infection (A) Demographics, symptoms, tests, and complications of 4 children with influenza-associated acute myocarditis. (B) Severe myocardial damage demonstrated in the interventricular septum with mononuclear cellular infiltration. (C) Enlarged area from B shows a large number of lymphocytes and macrophages infiltrating the myocardium (arrow) with surrounding cardiomyocyte necrosis. (D) Lymphocytic infiltration in the area of the atrioventricular (AV) node (*). (E) Severe dilation and poor systolic function of the left ventricle (LV) on a 2-dimensional and M-mode echocardiogram with an ejection fraction (EF) of 12%. (F) Resolution of left ventricular (LV) systolic function after 5 days of extracorporeal membrane oxygenation (ECMO) support demonstrated on 2-dimensional and M-mode echocardiogram with an improved EF of 68%. BP = blood pressure; bpm = beats/min; EIA = enzyme immunoassay; HR = heart rate; IVS = interventricular septum; LA = left atrium; RA = right atrium; rtPCR = reverse-transcripase polymerase chain reaction; RV = right ventricle.
</td></tr></tbody></table> </td></tr></tbody></table></center>
Fulminant myocarditis due to viral infection is an uncommon<sup> </sup>form of acute myocarditis (2,3). Influenza A virusassociated<sup> </sup>fulminant myocarditis is exceedingly rare, with only a few cases<sup> </sup>reported in the literature (4,5). We report the first 4 cases<sup> </sup>of acute myocarditis in children associated with the pandemic<sup> </sup>H1N1 influenza A virus, all occurring within a 30-day period.<sup> </sup> Our tertiary care hospital serves a geographic region that includes<sup> </sup>approximately 800,000 children. During the past 3 years, there<sup> </sup>was an annual average of 2 cases of acute myocarditis due to<sup> </sup>suspected viral etiology, none of which had evidence of influenza<sup> </sup>infection. Within a 30-day period in October 2009, there were<sup> </sup>3 cases of acute fulminant myocarditis and 1 case of acute perimyocarditis<sup> </sup>at Rady Children's HospitalSan Diego, all associated<sup> </sup>with confirmed H1N1 influenza A infection. There was serologic,<sup> </sup>echocardiographic, and/or histologic evidence of myocardial<sup> </sup>involvement in all cases (Fig. 1A). Three children had echocardiographic<sup> </sup>evidence of an acutely decreased myocardial function. One child<sup> </sup>died likely due to acute atrioventricular block, as suggested<sup> </sup>by severe lymphocytic infiltration of the conduction system<sup> </sup>(Figs. 1B to 1D). Two children required extracorporeal membrane<sup> </sup>oxygenation support with gradual improvement of the ventricular<sup> </sup>systolic function over a 1-week period (Figs. 1E and 1F), which<sup> </sup>is typically observed in patients with fulminant myocarditis<sup> </sup>(2).<sup> </sup>
The prevalence of influenza-associated fulminant myocarditis<sup> </sup>is not known because of the lack of comprehensive screening,<sup> </sup>with only a handful of clinical cases and autopsy findings reported<sup> </sup>in the literature (58). Our documented 4 cases within<sup> </sup>a 30-day period, compared with our previous experience, raise<sup> </sup>the possibility that the novel H1N1 influenza A virus is more<sup> </sup>commonly associated with a severe form of myocarditis than previously<sup> </sup>encountered influenza strains.<sup> </sup>
Our observations warrant a high index of suspicion for myocarditis<sup> </sup>in children with H1N1 influenza A infection. Early detection<sup> </sup>and aggressive management are paramount. Timely intervention<sup> </sup>with circulatory support may decrease morbidity and mortality,<sup> </sup>with the potential for a favorable cardiac prognosis.<sup> </sup>
<sup> </sup>
<sup> </sup>
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<table bgcolor="#e1e1e1" cellpadding="0" cellspacing="0" width="100%"> <tbody><tr><td align="left" bgcolor="#ffffff" width="5%" valign="middle"></td> <th align="left" width="95%" valign="middle"> Footnotes </th></tr></tbody></table>
<!-- null --> Please note: Leslie Cooper, MD, served as Guest Editor for this<sup> </sup>paper. Drs. Bratincs?k, El-Said, Grossfeld, and Cannavino<sup> </sup>contributed equally to this report.<sup> </sup>
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<table bgcolor="#e1e1e1" cellpadding="0" cellspacing="0" width="100%"> <tbody><tr><td align="left" bgcolor="#ffffff" width="5%" valign="middle"></td> <th align="left" width="95%" valign="middle"> References </th></tr></tbody></table> <table align="right" border="1" cellpadding="5"><tbody><tr><th align="left"> Top
References
</th></tr></tbody></table>
<!-- null -->1. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003;42:466-472.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:1" --><nobr>[Abstract/Free Full Text]</nobr><!-- /HIGHWIRE -->
<!-- null -->2. Lieberman EB, Hutchins GM, Herskowitz A, Rose NR, Baughman KL. Clinicopathologic description of myocarditis J Am Coll Cardiol 1991;18:1617-1626.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:2" -->[Abstract]<!-- /HIGHWIRE -->
<!-- null -->3. Cooper Jr LT. Myocarditis N Engl J Med 2009;360:1526-1538.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:3" --><nobr>[Free Full Text]</nobr><!-- /HIGHWIRE -->
<!-- null -->4. Mamas MA, Fraser D, Neyses L. Cardiovascular manifestations associated with influenza virus infection Int J Cardiol 2008;130:304-309.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:4" -->[CrossRef][Web of Science][Medline]<!-- /HIGHWIRE -->
<!-- null -->5. Guarner J, Paddock CD, Shieh WJ, et al. Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 20032004 season Clin Infect Dis 2006;43:132-140.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:5" -->[CrossRef][Web of Science][Medline]<!-- /HIGHWIRE -->
<!-- null -->6. Walker OJ. Pathology of influenza-pneumonia J Lab Clin Med 1919;5:22.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:6" --><!-- /HIGHWIRE -->
<!-- null -->7. Adams CW. Postviral myopericarditis associated with the influenza virus: report of eight cases Am J Cardiol 1959;4:56-67.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:7" -->[CrossRef][Web of Science][Medline]<!-- /HIGHWIRE -->
<!-- null -->8. Onitsuka H, Imamura T, Miyamoto N, et al. Clinical manifestations of influenza a myocarditis during the influenza epidemic of winter 19981999 J Cardiol 2001;37:315-323.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:8" -->[Medline]
http://content.onlinejacc.org/cgi/co....2010.01.004v1
Fulminant Myocarditis Associated With Pandemic H1N1 Influenza A Virus in Children
<nobr>Andr?s Bratincs?k, MD, PhD<sup><sub>*</sub></sup></nobr>, <nobr>Howaida G. El-Said, MD, PhD</nobr>, <nobr>John S. Bradley, MD</nobr>, <nobr>Katayoon Shayan, MD</nobr>, <nobr>Paul D. Grossfeld, MD</nobr> and <nobr>Christopher R. Cannavino, MD</nobr> <sup><sub>*</sub></sup> Rady Children's HospitalSan Diego, University of California San Diego, School of Medicine, 3020 Children's Way, MC5004, San Diego, California 92123 (Email: bratiandris@yahoo.com<script type="text/javascript"><!-- var u = "bratiandris", d = "yahoo.com"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>).
<hr width="75%" noshade="noshade" size="2">To the Editor: Acute myocarditis is a well-recognized, albeit<sup> </sup>rare, manifestation of numerous viral infections (1) with a<sup> </sup>broad spectrum of symptoms and clinical features (2). Fulminant<sup> </sup>myocarditis may present with fatal arrhythmias, atrioventricular<sup> </sup>block, and/or varying degrees of cardiogenic shock (3). The<sup> </sup>prevalence of myocardial involvement in influenza infection<sup> </sup>ranges from 0 to 11% depending on the diagnostic criteria used<sup> </sup>to define myocarditis (4). Fulminant myocarditis is an uncommon<sup> </sup>complication, typically diagnosed in association with circulatory<sup> </sup>collapse or at autopsy in patients with influenza-associated<sup> </sup>fatal outcomes (5). A few case reports and series (68)<sup> </sup>represent the incidental diagnoses of influenza-associated acute<sup> </sup>fulminant myocarditis, but the true prevalence remains unknown.<sup> </sup> Here we present the first known report of acute myocarditis<sup> </sup>in pediatric population associated with the present pandemic<sup> </sup>H1N1 influenza A virus infection. Four cases occurred within<sup> </sup>a 30-day period, and 3 of them were diagnosed as fulminant myocarditis<sup> </sup>with fatal or near-fatal outcomes.<sup> </sup>
A retrospective chart review was conducted on all patients admitted<sup> </sup>to Rady Children's HospitalSan Diego with the diagnosis<sup> </sup>of H1N1 influenza A infection during October 2009. Criteria<sup> </sup>for fulminant myocarditis included echocardiographic and clinical<sup> </sup>evidence of severely decreased left ventricular systolic function<sup> </sup>and/or lymphocytic infiltration of the myocardium documented<sup> </sup>at autopsy.<sup> </sup>
Within a 30-day period, 80 children were admitted with H1N1<sup> </sup>influenza A infection to Rady Children's HospitalSan<sup> </sup>Diego. Serum troponin I and creatine phosphokinase myocardial<sup> </sup>band levels were obtained in 11 children, and echocardiography<sup> </sup>was performed in 8 children. We included 4 H1N1 influenzaassociated<sup> </sup>myocarditis cases based on elevated cardiac enzymes (n = 2),<sup> </sup>significant acute decrease in left ventricular systolic function<sup> </sup>demonstrated by the echocardiogram (n = 3), or histologic evidence<sup> </sup>of severe myocarditis (n = 1) (Fig. 1A). Three children presented<sup> </sup>with fulminant myocarditis, 1 with a fatal outcome and 2 requiring<sup> </sup>extracorporeal membrane oxygenation support. None of the children<sup> </sup>with fulminant myocarditis had evidence of sepsis or bacterial<sup> </sup>infection (negative blood, urine, and tracheal aspirate cultures).<sup> </sup>Two of the 3 children with decreased systolic function experienced<sup> </sup>recovery in 5 to 7 days (Figs. 1E and 1F). All 4 children had<sup> </sup>a positive rapid influenza enzyme immunoassay test result from<sup> </sup>a nasopharyngeal swab sample that was subsequently confirmed<sup> </sup>as H1N1 by reverse-transcriptase polymerase chain reaction performed<sup> </sup>at the San Diego County Department of Health (Fig. 1A).<sup> </sup>
<!-- null -->
<center><table cellpadding="0" cellspacing="0" width="95%"><tbody><tr bgcolor="#e1e1e1"><td><table cellpadding="2" cellspacing="2"> <tbody><tr bgcolor="#e1e1e1"><td align="center" bgcolor="#ffffff" valign="top">
View larger version (131K):
<nobr>[in this window]
[in a new window]
[Download PPT slide]
</nobr> </td><td align="left" valign="top"> Figure 1 Acute Myocarditis Associated With H1N1 Influenza A Infection (A) Demographics, symptoms, tests, and complications of 4 children with influenza-associated acute myocarditis. (B) Severe myocardial damage demonstrated in the interventricular septum with mononuclear cellular infiltration. (C) Enlarged area from B shows a large number of lymphocytes and macrophages infiltrating the myocardium (arrow) with surrounding cardiomyocyte necrosis. (D) Lymphocytic infiltration in the area of the atrioventricular (AV) node (*). (E) Severe dilation and poor systolic function of the left ventricle (LV) on a 2-dimensional and M-mode echocardiogram with an ejection fraction (EF) of 12%. (F) Resolution of left ventricular (LV) systolic function after 5 days of extracorporeal membrane oxygenation (ECMO) support demonstrated on 2-dimensional and M-mode echocardiogram with an improved EF of 68%. BP = blood pressure; bpm = beats/min; EIA = enzyme immunoassay; HR = heart rate; IVS = interventricular septum; LA = left atrium; RA = right atrium; rtPCR = reverse-transcripase polymerase chain reaction; RV = right ventricle.
</td></tr></tbody></table> </td></tr></tbody></table></center>
Fulminant myocarditis due to viral infection is an uncommon<sup> </sup>form of acute myocarditis (2,3). Influenza A virusassociated<sup> </sup>fulminant myocarditis is exceedingly rare, with only a few cases<sup> </sup>reported in the literature (4,5). We report the first 4 cases<sup> </sup>of acute myocarditis in children associated with the pandemic<sup> </sup>H1N1 influenza A virus, all occurring within a 30-day period.<sup> </sup> Our tertiary care hospital serves a geographic region that includes<sup> </sup>approximately 800,000 children. During the past 3 years, there<sup> </sup>was an annual average of 2 cases of acute myocarditis due to<sup> </sup>suspected viral etiology, none of which had evidence of influenza<sup> </sup>infection. Within a 30-day period in October 2009, there were<sup> </sup>3 cases of acute fulminant myocarditis and 1 case of acute perimyocarditis<sup> </sup>at Rady Children's HospitalSan Diego, all associated<sup> </sup>with confirmed H1N1 influenza A infection. There was serologic,<sup> </sup>echocardiographic, and/or histologic evidence of myocardial<sup> </sup>involvement in all cases (Fig. 1A). Three children had echocardiographic<sup> </sup>evidence of an acutely decreased myocardial function. One child<sup> </sup>died likely due to acute atrioventricular block, as suggested<sup> </sup>by severe lymphocytic infiltration of the conduction system<sup> </sup>(Figs. 1B to 1D). Two children required extracorporeal membrane<sup> </sup>oxygenation support with gradual improvement of the ventricular<sup> </sup>systolic function over a 1-week period (Figs. 1E and 1F), which<sup> </sup>is typically observed in patients with fulminant myocarditis<sup> </sup>(2).<sup> </sup>
The prevalence of influenza-associated fulminant myocarditis<sup> </sup>is not known because of the lack of comprehensive screening,<sup> </sup>with only a handful of clinical cases and autopsy findings reported<sup> </sup>in the literature (58). Our documented 4 cases within<sup> </sup>a 30-day period, compared with our previous experience, raise<sup> </sup>the possibility that the novel H1N1 influenza A virus is more<sup> </sup>commonly associated with a severe form of myocarditis than previously<sup> </sup>encountered influenza strains.<sup> </sup>
Our observations warrant a high index of suspicion for myocarditis<sup> </sup>in children with H1N1 influenza A infection. Early detection<sup> </sup>and aggressive management are paramount. Timely intervention<sup> </sup>with circulatory support may decrease morbidity and mortality,<sup> </sup>with the potential for a favorable cardiac prognosis.<sup> </sup>
<sup> </sup>
<sup> </sup>
<!-- null -->
<table bgcolor="#e1e1e1" cellpadding="0" cellspacing="0" width="100%"> <tbody><tr><td align="left" bgcolor="#ffffff" width="5%" valign="middle"></td> <th align="left" width="95%" valign="middle"> Footnotes </th></tr></tbody></table>
<!-- null --> Please note: Leslie Cooper, MD, served as Guest Editor for this<sup> </sup>paper. Drs. Bratincs?k, El-Said, Grossfeld, and Cannavino<sup> </sup>contributed equally to this report.<sup> </sup>
<!-- null -->
<table bgcolor="#e1e1e1" cellpadding="0" cellspacing="0" width="100%"> <tbody><tr><td align="left" bgcolor="#ffffff" width="5%" valign="middle"></td> <th align="left" width="95%" valign="middle"> References </th></tr></tbody></table> <table align="right" border="1" cellpadding="5"><tbody><tr><th align="left"> Top
References
</th></tr></tbody></table>
<!-- null -->1. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. Evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003;42:466-472.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:1" --><nobr>[Abstract/Free Full Text]</nobr><!-- /HIGHWIRE -->
<!-- null -->2. Lieberman EB, Hutchins GM, Herskowitz A, Rose NR, Baughman KL. Clinicopathologic description of myocarditis J Am Coll Cardiol 1991;18:1617-1626.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:2" -->[Abstract]<!-- /HIGHWIRE -->
<!-- null -->3. Cooper Jr LT. Myocarditis N Engl J Med 2009;360:1526-1538.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:3" --><nobr>[Free Full Text]</nobr><!-- /HIGHWIRE -->
<!-- null -->4. Mamas MA, Fraser D, Neyses L. Cardiovascular manifestations associated with influenza virus infection Int J Cardiol 2008;130:304-309.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:4" -->[CrossRef][Web of Science][Medline]<!-- /HIGHWIRE -->
<!-- null -->5. Guarner J, Paddock CD, Shieh WJ, et al. Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 20032004 season Clin Infect Dis 2006;43:132-140.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:5" -->[CrossRef][Web of Science][Medline]<!-- /HIGHWIRE -->
<!-- null -->6. Walker OJ. Pathology of influenza-pneumonia J Lab Clin Med 1919;5:22.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:6" --><!-- /HIGHWIRE -->
<!-- null -->7. Adams CW. Postviral myopericarditis associated with the influenza virus: report of eight cases Am J Cardiol 1959;4:56-67.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:7" -->[CrossRef][Web of Science][Medline]<!-- /HIGHWIRE -->
<!-- null -->8. Onitsuka H, Imamura T, Miyamoto N, et al. Clinical manifestations of influenza a myocarditis during the influenza epidemic of winter 19981999 J Cardiol 2001;37:315-323.<!-- HIGHWIRE ID="0:2010:j.jacc.2010.01.004v1:8" -->[Medline]
http://content.onlinejacc.org/cgi/co....2010.01.004v1
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