Diagnostic Microbiology and Infectious Disease 78 (2014) 98–100

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Case Report

Disseminated coxsackievirus B fulminant myocarditis in an immunocompetent adult: A case report Case of disseminated coxsackievirus myocarditis Uma Nahar Saikia a,⁎, Baijayantimala Mishra b, Mirnalini Sharma b, Ritambhra Nada a, BD Radotra a a b

Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India Department of Virology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

a r t i c l e

i n f o

Article history: Received 19 June 2013 Received in revised form 24 July 2013 Accepted 31 July 2013 Available online 29 October 2013

a b s t r a c t Coxsackieviral myocarditis is associated with systemic involvement in neonates; however, fulminant coxsackieviral myocarditis is rare in adults, and its dissemination with fatal myocarditis involving kidneys, liver, and adrenal is further rarely reported. We report a case of fulminant myocarditis along with dissemination of coxsackievirus, which was clinically unrecognized. © 2014 Elsevier Inc. All rights reserved.

Keywords: Coxsackievirus Fulminant Myocarditis Dissemination

1. Case report A 34-year-old male presented with history of fever with chills for 20 days later in the month of August. There was associated history of vomiting and abdominal pain for 7 days and shortness of breath for last 4 days. No history of chest pain, palpitation, or any other cardiac symptoms were present. The general examination showed increased pulse rate (96/min) and blood pressure (100/60). The cardiovascular and respiratory system examination did not reveal any basal creps, wheeze, or any other specific abnormality. The patient was conscious and febrile. A clinical diagnosis of leptospirosis versus dengue was suspected. On investigations, patient had anemia, 10.7 gm% (normal 140–160 g/L) and thrombocytopenia, 20,000/L (normal: 150–400 × 109/L) with lymphocytosis in the differential count (50%). The liver enzymes serum glutamic oxaloacetic transaminase and serum glutamic-pyruvic transaminase were 238.97 (normal: 2–41 U/L) and 106.03, respectively (normal: 2–40 U/L), and serum bilirubin was high 8.89 mg% (normal: 0–1 mg%). The D-dimer was positive, but the serology for dengue and leptospira was negative. Ultrasound of abdomen showed mild hepatosplenomegaly. The patient was treated symptomatically for dengue, and Septran was given for leptospirosis; however, he succumbed to his illness on the third day of admission. A partial autopsy was performed. Grossly, the heart was overweighed (420 g) globular, flabby, and soft to feel (Fig. 1A). There was ⁎ Corresponding author. Tel.: +172-2755142; fax: +91-172-744401. E-mail address: [email protected] (U.N. Saikia). 0732-8893/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.diagmicrobio.2013.07.011

dilatation of all the chambers with presence of mural thrombi. Microscopically moderate interstitial lymphocytic infiltrate and edema were seen with myocytolysis and myonecrosis of both ventricles (Fig. 1B). These infiltrating cells were predominantly CD3 positive along with few scattered CD68-positive cells and no CD20 positivity indicating active myocarditis. Polymerase chain reaction (PCR) was performed for both parvovirusB19 (PVB19) and adenovirus (AdV) using specific primers, as described in the literature (Hierholzer et al., 1993; Mishra et al., 2012). Immunohistochemistry (IHC) was done using monoclonal antibodies specific for PVB19 VP1 (Novocastra, Richmond, VA, USA) and hexon protein of AdV (Milipore, MA, USA) using standard protocol. For Epstein-Barr virus (EBV), only IHC was performed against latent membrane protein and Zebra antigens (Dako, Carpinteria, CA, USA) using standard protocol. Both PCR and IHC for PVB 19 and AdV and IHC for EBV were negative. The reverse transcriptase PCR (RT-PCR) for coxsackievirus B (CVB) using specific primers for 5′ non-coding region of CVB, as described previously, showed a positive band at 314 bp in myocardium (Sharma et al., 2012). The myocardial tissue section was subjected to IHC using monoclonal antibody specific for enterovirus VP1 protein (Novocastra, Newcastle, UK), which showed brown color indicating CVB antigen positivity. Thus, a diagnosis of coxsackieviral myocarditis was confirmed. The liver was enlarged (1700 g), bile stained, and soft to firm. It showed moderate lymphohistiocytic inflammation within the portal tracts with interphase hepatitis and hemophagocytosis within the histiocytes (Fig. 2A). The kidneys and adrenals also revealed interstitial inflammation. There was hemophagocytosis in bone marrow and spleen.

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Fig. 1. (A) Gross photograph showing dilated heart with discolored soft myocardium and mural thrombi (arrow). (B) Microphotographs showing dense interstitial infiltrate and marked oedema in the myocardium (haematoxylin & eosin [H&E] × 10×) and lymphohistiocytic infiltrate with myocyte necrosis (H&E × 20×).

The lungs showed features of diffused alveolar damage and alveolar hemorrhages. A final diagnosis of disseminated fulminant coxsackievirus infection resulting in acute viral myocarditis with inflammatory cardiomyopathy and viral spread to kidneys, liver, and adrenals was made. The kidney tissue was also positive for coxsackievirus RNA by RTPCR, as described earlier (Sharma et al., 2012). The meninges also revealed mild lymphohistiocytic infiltrate, but there was no encephalitis (Fig. 2B). 2. Discussion Myocarditis is defined as inflammation of the myocardium and is a major cause of sudden cardiac death in children and young adults (Blauwet and Cooper, 2010; Bowles et al., 2003; Feldman and McNamara, 2000). The most common viruses implicated in viral myocarditis include CVB, adenovirus, parvovirus B-19, and human herpesvirus type 6 (Friman et al., 1995; Pankuweit et al., 2003; Pauschinger et al., 1999; Rohayem et al., 2001). However, myocarditis from the coxsackievirus is only occasionally fatal in adults, and the dissemination of coxsackieviral infection with fatal myocarditis is further rarely reported in adults. The association of viral infections and myocarditis was first described by Grist and Bell (1974) with serologic confirmation of enteroviral infection. Group B coxsackieviruses belonging to genus Enterovirus were initially identified as the primary cause of viral myocarditis (Friman et al., 1995; Grist and Bell, 1974). More recently, other viruses including adenovirus and parvovirus B19 have also been implicated in myocarditis (Pankuweit et al., 2003; Pauschinger et al., 1999; Rohayem et al., 2001; Towbin et al., 1994). Myocarditis has varying clinical manifestation, i.e., non-specific constitutional symptoms to cardiogenic shock, and hence, its exact

history is still not well understood (Grist and Bell, 1974; Paleev, 2006). Fulminant myocarditis can also present as sudden onset of heart failure after a recent viral illness. This makes fulminant or nonfulminant myocarditis a diagnostic challenge. Myocarditis caused by coxsackievirus is occasionally fatal commonly in young infants and usually presents as ventricular arrhythmias (Grist and Bell, 1974; Nathan et al., 2008; Sun et al., 1993). The patient described in the study also had non-specific symptoms, i.e., history of fever with breathlessness. There was no chest pain or any signs of congestive cardiac failure to suggest a probable clinical diagnosis of myocarditis. History of any arrhythmias was also absent in our patient to further consider the diagnosis of myocarditis. Myocarditis through different mechanisms can stimulate immune system, which eliminates the viral particles with destruction of infected myocytes, thereby limiting viral dissemination (Esfandiarei and McManus, 2008; Holm et al., 2010). This occurs due to the balance of CD4+ T-lymphocytes (T-helpers types 1 and 2), which determines the character of the immune response in myocarditis, and is important at the initial stages of immunization. The cytotoxic CD8+ lymphocytes are responsible for direct myocardial injury (Paleev, 2006). In our patient too, there was predominance of CD8 cells over CD4 cells indicating increased cytotoxic cells and few activated macrophages suggesting a diagnosis of active myocarditis further leading to inflammatory cardiomyopathy (i-CMP) due to viral persistence. This relationship of viral myocarditis and i-CMP has been discussed for several years, as there is impairment in elimination of activated lymphocytes versus cytotoxic lymphocytes causing an imbalance in the immune system releasing more cytokines with further activation of autoreactive T-lymphocytes and thus development of i-CMP. Viral invasion and its persistence into the myocardium are one of the reasons for i-CMP development in viral myocarditis.

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with fever and having raised liver enzymes and bilirubin suggesting liver involvement. There was evidence of active florid myocarditis with hepatitis and mild meningitis at autopsy in the patient. The final diagnosis of disseminated coxsackieviral infection causing fulminant myocarditis, hepatitis, mild meningitis, and acute renal failure was made by histopathologic findings with detection of coxsackieviral RNA in tissues. To conclude, CVB can affect virtually any organ system and can have a variety of clinical presentations. It should be considered in the differential diagnosis of febrile illness with multisystem involvement even in adults. References

Fig. 2. Microphotographs showing (A) lymphohistiocytic infiltrate in the portal tracts and macrovesicular steatosis (H&E × 20×) (B) mild oedema and minimal inflammation in the meninges (H&E × 10×).

Another component, i.e., Proteinase A, an ingredient of enteroviruses, induces dystrophin proteolysis, thereby impeding cardiac function. Hence, a viral infection may cause viral (infective and immune) myocarditis and i-CMP (Magnani and Dec, 2006; Paleev, 2006). The virus may be present longer in children and in those whose immune system is weak (Chia et al., 2010; Jartti et al., 2004). Enterovirus infection has been recognized as one of the most common viral infections in the perinatal and neonatal periods and is frequently the cause of mortality (Nathan et al., 2008; Sun et al., 1993). The illness begins with a mild febrile prodrome followed by severe systemic involvement, with meningitis, myocarditis, hepatosplenomegaly, and disseminated intravascular coagulation (DIC) (Sun et al., 1993). Another case of neonatal enteroviral myocarditis with multisystem organ failure presenting with hepatitis, meningo-encephalitis, and DIC causing ischemic cardiomyopathy is described in literature (Dec, 2003; Nathan et al., 2008). However, fulminant coxsackieviral myocarditis is rare in adults, and CVB dissemination with fatal myocarditis involving kidneys, liver, and adrenal is further rare. The present case possibly is the first of its kind with disseminated coxsackieviral infection with involvement of liver to the best of our knowledge. He had prodromal symptom of viral infection presenting

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