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A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the literature
Diagnostic Microbiology and Infectious Disease xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio
Note
A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the literature Ruben Mylvaganam a,⁎, Allison Glaser b, Noah Moss c, Meenakshi Rana b a b c
Division of Internal Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place 1090, New York, NY 10029 Division of Cardiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place 1030, New York, NY 10029
a r t i c l e
i n f o
Article history: Received 8 June 2017 Received in revised form 19 January 2018 Accepted 22 January 2018 Available online xxxx
a b s t r a c t We describe a male patient who presents 2 years posttransplant with cough and dyspnea. A negative pulmonary workup led to an endomyocardial biopsy and the diagnosis of cytomegalovirus (CMV) myocarditis. The patient was treated with ganciclovir and intravenous immunoglobulin. This illustrates a very late presentation of posttransplant CMV myocarditis and the usefulness of myocardial biopsy in diagnosis of CMV carditis. © 2018 Elsevier Inc. All rights reserved.
Keywords: Late onset Cytomegalovirus myocarditis Orthotopic heart transplant recipient Case report Endomyocardial biopsy
We describe a male patient who presents 2 years posttransplant with cough and dyspnea. A negative pulmonary workup led to an endomyocardial biopsy and the diagnosis of cytomegalovirus (CMV) myocarditis. The patient was treated with ganciclovir and intravenous immunoglobulin (IVIG). This illustrates a very late presentation of posttransplant CMV myocarditis and the usefulness of myocardial biopsy in diagnosis of CMV carditis.
1. Case report A 74-year-old man with ischemic cardiomyopathy underwent orthotopic heart transplantation. The patient was seronegative for cytomegalovirus (CMV) (R−) and received a heart from a CMV-seropositive donor (D+). He developed squamous cell cancer of the skin and was thereby maintained on tacrolimus alone for chronic immunosuppression. Despite this, he developed no episodes of allograft rejection. According to our center’s protocol, he was maintained on valganciclovir prophylaxis which was discontinued after 1 year, and subsequent CMV viral polymerase chain reactions (PCRs) remained negative. Two years posttransplant, the patient presented to clinic with 2 days of fatigue, shortness of breath, and a dry cough. He was febrile to 102 °F, ⁎ Corresponding author. Tel.: +1-4138470014. E-mail address: [email protected] (R. Mylvaganam).
tachycardic to 150 beats per minute, and saturating 94% on room air, and he was subsequently admitted. The examination revealed a tachypneic elderly male with distended neck veins and bilateral wheezes. Laboratory data were significant for a brain natriuretic peptide level of 2463 pg/mL and CMV PCR of 3458 IU/ mL. Electrocardiogram revealed sinus tachycardia. Chest x-ray showed a small left pleural effusion. The patient was started on intravenous ganciclovir because of concern for severe disease. He subsequently defervesced but became hypoxic. A chest computed tomographic scan demonstrated small bilateral pleural effusions. A transthoracic echocardiogram (TTE) showed an ejection fraction (EF) of 50% (decreased from 67% on a prior TTE) and new moderate concentric left ventricular hypertrophy (LVH). To help differentiate between rejection and CMV myocarditis, a right catheterization with an endomyocardial biopsy (EMBx) was done and demonstrated normal filling pressures and extremely low cardiac output. The biopsy pathology revealed a lymphocytic myocarditis with viral inclusions confirmed by immunohistochemical stains, consistent with CMV myocarditis (Fig. 1). There was no evidence of rejection. Cardiac tissue CMV PCR resulted as positive. He was initiated on IVIG (100 mg/kg) every other day for six doses. Subsequent weekly CMV PCRs declined and became undetectable. The patient improved and was discharged on valganciclovir treatment dosing. Repeat CMV IgG was now positive. A TTE 2 months later revealed an improvement in EF to 56% and persistent LVH. The patient was
https://doi.org/10.1016/j.diagmicrobio.2018.01.016 0732-8893/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Mylvaganam R, et al, A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the litera..., Diagn Microbiol Infect Dis (2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.016
2
R. Mylvaganam et al. / Diagnostic Microbiology and Infectious Disease xxx (2018) xxx–xxx
Figure 1. Cardiac pathology with CMV inclusion bodies (arrows).
continued on indefinite valganciclovir for secondary prophylaxis, given severe disease, and to prevent relapse.
antiviral therapy (Brown et al., 1982; D'Alessandro et al., 1989; George et al., 1993). However, there are several case reports and reviews in patients with non-CMV viral myocarditis where IVIG has been shown to result in rapid improvement and restoration of left ventricular EF (McNamara et al., 1997). The addition of IVIG or CMV immune globulin to antiviral treatment remains unclear, but some guidelines suggest that it can be considered in the treatment of CMV pneumonitis and in other patients with severe or life-threatening disease (Razonable and Humar, 2013). In our case, given ongoing shortness of breath with hypoxia despite antiviral treatment, IVIG was administered after confirmation of the diagnosis of CMV myocarditis. The optimal duration of treatment for CMV disease should be individualized but should not be shorter than 2 weeks, continuing until resolution of clinical symptoms and until virological clearance based on PCR testing (Razonable and Humar, 2013). This strategy minimizes the risk of recurrence of CMV disease and development of resistance (Kotton et al., 2010). In our case of CMV myocarditis, treatment was continued until resolution of clinical symptoms, virological clearance, and echocardiogram showed further improvement. Transplant patients with CMV infection often present with nonspecific symptoms and comorbidities that may obscure the clinical picture. Therefore, CMV-induced myocarditis is an important diagnosis to include on the differential, even in the late posttransplant period and despite extended antiviral prophylaxis. EMBx is often done to rule out rejection but also provides a tool for comprehensive pathological evaluation to evaluate for viral infections.
2. Discussion Patients who are D+/R− are at highest risk of CMV disease (7.5% vs. 25% in low- vs. high-risk groups, respectively) (Mendez-Eirin et al., 2012). CMV, while known to cause pneumonitis, gastrointestinal disease, and retinitis among others, is less well known for its ability to cause clinically significant myocarditis (Ljungman et al., 2002). CMV myocarditis has been previously described in the literature in case reports, primarily occurring early posttransplant before the use of routine antiviral prophylaxis with valganciclovir. In a recent review of 33 cases of CMV disease in solid organ transplant (SOT) recipients, three cases of myocarditis were described. These cases occurred in the early posttransplant period, usually within the first 100 days and in patients who received limited antiviral prophylaxis with IV ganciclovir (Partanen et al., 1991; Ando et al., 1992; Fica et al., 2007). Gonwa et al. described a presumed case of late CMV myocarditis, diagnosed clinically and without the support of EMBx. This case occurred 21 months after heart transplantation in a patient who did not receive antiviral prophylaxis (Gonwa et al., 1989). In the case described above, our patient received 1 year of posttransplant antiviral prophylaxis with valganciclovir, per our center’s protocol. Subsequent CMV surveillance PCRs done at cardiac follow-up visits were negative. Despite minimal immunosuppression, our patient developed late-onset CMV disease more than 2 years after transplant. There were many challenges in the management of our case. Initially, the presenting symptoms were concerning for CMV pneumonia, but imaging did not demonstrate the typical reticulonodular pattern to support this diagnosis (Kang et al., 1996). A cardiac workup was pursued because the initial differential included both rejection and CMV myocarditis. Ultimately, the EMBx provided a definitive diagnosis of CMV myocarditis, which helped guide management in this case. Although this is a rare complication, cardiac biopsy was crucial and helped avoid a delay in diagnosis. Oftentimes, cardiac biopsy is done to rule out rejection, and clinicians should consider pathological evaluation for viral inclusions when there is clinical suspicion for a viral process. Our patient was administered IVIG despite normal levels of immunoglobulins. Evidence supporting the use of either IVIG or CMV immune globulin in SOT recipients with severe CMV disease remains limited, with a few retrospective case series published prior to the use of current
Acknowledgment We are indebted to Mary B. Beasley, MD, for her guidance, preparation, and interpretation of our pathological biopsy specimens. Funding No grant funding was received to support the interpretation and completion of this case report. Disclosure statement None of the authors have conflicts of interest to disclose or a financial relationship with a commercial entity that has interest in the subject of the manuscript. References Ando H, Shiramizu T, Hisanou R. Dilated cardiomyopathy caused by cytomegalovirus infection in a renal transplant recipient. Jpn Heart J 1992;33:409–12. Brown C, Nicholls A, Edward N, Cuthbertson B, Yap P, McClelland D. Hyperimmune immunoglobulin therapy for cytomegalovirus infections in renal transplant patients. Proc Eur Dial Transplant Assoc 1982;20:271–9. D'Alessandro A, Pirsch J, Stratta R, Sollinger H, Kalayoglu M, Belzer F. Successful treatment of severe cytomegalovirus infections with ganciclovir and CMV hyperimmune globulin in liver transplant recipients. Transplant Proc 1989:3560–1. Fica A, Cervera C, Perez N, et al. Immunohistochemically proven cytomegalovirus endorgan disease in solid organ transplant patients: clinical features and usefulness of conventional diagnostic tests. Transpl Infect Dis 2007;9:203–10. George M, Snydman D, Werner B, et al. Use of ganciclovir plus cytomegalovirus immune globulin to treat CMV pneumonia in orthotopic liver transplant recipients. The Boston Center for Liver Transplantation CMVIG-Study Group. Transplant Proc 1993:22–4. Gonwa TA, Capehart JE, Pilcher JW, Alivizatos PA. Cytomegalovirus myocarditis as a cause of cardiac dysfunction in a heart transplant recipient. Transplantation 1989;47: 197–8. Kang E-Y, Patz Jr EF, Müller NL. Cytomegalovirus pneumonia in transplant patients: CT findings. J Comput Assist Tomogr 1996;20:295–9. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010;89: 779–95. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002;34:1094–7. McNamara DM, Rosenblum WD, Janosko KM, et al. Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy. Circulation 1997;95:2476–8.
Please cite this article as: Mylvaganam R, et al, A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the litera..., Diagn Microbiol Infect Dis (2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.016
R. Mylvaganam et al. / Diagnostic Microbiology and Infectious Disease xxx (2018) xxx–xxx Mendez-Eirin E, Paniagua-Martín M, Marzoa-Rivas R, et al. Cumulative incidence of cytomegalovirus infection and disease after heart transplantation in the last decade: effect of preemptive therapy. Transplant Proc 2012:2660–2. [Elsevier].
3
Partanen J, Nieminen M, Krogerus L, et al. Cytomegalovirus myocarditis in transplanted heart verified by endomyocardial biopsy. Clin Cardiol 1991;14:847–9. Razonable RR, Humar AAST. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013;13(s4):93–106.
Please cite this article as: Mylvaganam R, et al, A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the litera..., Diagn Microbiol Infect Dis (2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.016
Contents lists available at ScienceDirect
Diagnostic Microbiology and Infectious Disease journal homepage: www.elsevier.com/locate/diagmicrobio
Note
A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the literature Ruben Mylvaganam a,⁎, Allison Glaser b, Noah Moss c, Meenakshi Rana b a b c
Division of Internal Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place 1090, New York, NY 10029 Division of Cardiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place 1030, New York, NY 10029
a r t i c l e
i n f o
Article history: Received 8 June 2017 Received in revised form 19 January 2018 Accepted 22 January 2018 Available online xxxx
a b s t r a c t We describe a male patient who presents 2 years posttransplant with cough and dyspnea. A negative pulmonary workup led to an endomyocardial biopsy and the diagnosis of cytomegalovirus (CMV) myocarditis. The patient was treated with ganciclovir and intravenous immunoglobulin. This illustrates a very late presentation of posttransplant CMV myocarditis and the usefulness of myocardial biopsy in diagnosis of CMV carditis. © 2018 Elsevier Inc. All rights reserved.
Keywords: Late onset Cytomegalovirus myocarditis Orthotopic heart transplant recipient Case report Endomyocardial biopsy
We describe a male patient who presents 2 years posttransplant with cough and dyspnea. A negative pulmonary workup led to an endomyocardial biopsy and the diagnosis of cytomegalovirus (CMV) myocarditis. The patient was treated with ganciclovir and intravenous immunoglobulin (IVIG). This illustrates a very late presentation of posttransplant CMV myocarditis and the usefulness of myocardial biopsy in diagnosis of CMV carditis.
1. Case report A 74-year-old man with ischemic cardiomyopathy underwent orthotopic heart transplantation. The patient was seronegative for cytomegalovirus (CMV) (R−) and received a heart from a CMV-seropositive donor (D+). He developed squamous cell cancer of the skin and was thereby maintained on tacrolimus alone for chronic immunosuppression. Despite this, he developed no episodes of allograft rejection. According to our center’s protocol, he was maintained on valganciclovir prophylaxis which was discontinued after 1 year, and subsequent CMV viral polymerase chain reactions (PCRs) remained negative. Two years posttransplant, the patient presented to clinic with 2 days of fatigue, shortness of breath, and a dry cough. He was febrile to 102 °F, ⁎ Corresponding author. Tel.: +1-4138470014. E-mail address: [email protected] (R. Mylvaganam).
tachycardic to 150 beats per minute, and saturating 94% on room air, and he was subsequently admitted. The examination revealed a tachypneic elderly male with distended neck veins and bilateral wheezes. Laboratory data were significant for a brain natriuretic peptide level of 2463 pg/mL and CMV PCR of 3458 IU/ mL. Electrocardiogram revealed sinus tachycardia. Chest x-ray showed a small left pleural effusion. The patient was started on intravenous ganciclovir because of concern for severe disease. He subsequently defervesced but became hypoxic. A chest computed tomographic scan demonstrated small bilateral pleural effusions. A transthoracic echocardiogram (TTE) showed an ejection fraction (EF) of 50% (decreased from 67% on a prior TTE) and new moderate concentric left ventricular hypertrophy (LVH). To help differentiate between rejection and CMV myocarditis, a right catheterization with an endomyocardial biopsy (EMBx) was done and demonstrated normal filling pressures and extremely low cardiac output. The biopsy pathology revealed a lymphocytic myocarditis with viral inclusions confirmed by immunohistochemical stains, consistent with CMV myocarditis (Fig. 1). There was no evidence of rejection. Cardiac tissue CMV PCR resulted as positive. He was initiated on IVIG (100 mg/kg) every other day for six doses. Subsequent weekly CMV PCRs declined and became undetectable. The patient improved and was discharged on valganciclovir treatment dosing. Repeat CMV IgG was now positive. A TTE 2 months later revealed an improvement in EF to 56% and persistent LVH. The patient was
https://doi.org/10.1016/j.diagmicrobio.2018.01.016 0732-8893/© 2018 Elsevier Inc. All rights reserved.
Please cite this article as: Mylvaganam R, et al, A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the litera..., Diagn Microbiol Infect Dis (2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.016
2
R. Mylvaganam et al. / Diagnostic Microbiology and Infectious Disease xxx (2018) xxx–xxx
Figure 1. Cardiac pathology with CMV inclusion bodies (arrows).
continued on indefinite valganciclovir for secondary prophylaxis, given severe disease, and to prevent relapse.
antiviral therapy (Brown et al., 1982; D'Alessandro et al., 1989; George et al., 1993). However, there are several case reports and reviews in patients with non-CMV viral myocarditis where IVIG has been shown to result in rapid improvement and restoration of left ventricular EF (McNamara et al., 1997). The addition of IVIG or CMV immune globulin to antiviral treatment remains unclear, but some guidelines suggest that it can be considered in the treatment of CMV pneumonitis and in other patients with severe or life-threatening disease (Razonable and Humar, 2013). In our case, given ongoing shortness of breath with hypoxia despite antiviral treatment, IVIG was administered after confirmation of the diagnosis of CMV myocarditis. The optimal duration of treatment for CMV disease should be individualized but should not be shorter than 2 weeks, continuing until resolution of clinical symptoms and until virological clearance based on PCR testing (Razonable and Humar, 2013). This strategy minimizes the risk of recurrence of CMV disease and development of resistance (Kotton et al., 2010). In our case of CMV myocarditis, treatment was continued until resolution of clinical symptoms, virological clearance, and echocardiogram showed further improvement. Transplant patients with CMV infection often present with nonspecific symptoms and comorbidities that may obscure the clinical picture. Therefore, CMV-induced myocarditis is an important diagnosis to include on the differential, even in the late posttransplant period and despite extended antiviral prophylaxis. EMBx is often done to rule out rejection but also provides a tool for comprehensive pathological evaluation to evaluate for viral infections.
2. Discussion Patients who are D+/R− are at highest risk of CMV disease (7.5% vs. 25% in low- vs. high-risk groups, respectively) (Mendez-Eirin et al., 2012). CMV, while known to cause pneumonitis, gastrointestinal disease, and retinitis among others, is less well known for its ability to cause clinically significant myocarditis (Ljungman et al., 2002). CMV myocarditis has been previously described in the literature in case reports, primarily occurring early posttransplant before the use of routine antiviral prophylaxis with valganciclovir. In a recent review of 33 cases of CMV disease in solid organ transplant (SOT) recipients, three cases of myocarditis were described. These cases occurred in the early posttransplant period, usually within the first 100 days and in patients who received limited antiviral prophylaxis with IV ganciclovir (Partanen et al., 1991; Ando et al., 1992; Fica et al., 2007). Gonwa et al. described a presumed case of late CMV myocarditis, diagnosed clinically and without the support of EMBx. This case occurred 21 months after heart transplantation in a patient who did not receive antiviral prophylaxis (Gonwa et al., 1989). In the case described above, our patient received 1 year of posttransplant antiviral prophylaxis with valganciclovir, per our center’s protocol. Subsequent CMV surveillance PCRs done at cardiac follow-up visits were negative. Despite minimal immunosuppression, our patient developed late-onset CMV disease more than 2 years after transplant. There were many challenges in the management of our case. Initially, the presenting symptoms were concerning for CMV pneumonia, but imaging did not demonstrate the typical reticulonodular pattern to support this diagnosis (Kang et al., 1996). A cardiac workup was pursued because the initial differential included both rejection and CMV myocarditis. Ultimately, the EMBx provided a definitive diagnosis of CMV myocarditis, which helped guide management in this case. Although this is a rare complication, cardiac biopsy was crucial and helped avoid a delay in diagnosis. Oftentimes, cardiac biopsy is done to rule out rejection, and clinicians should consider pathological evaluation for viral inclusions when there is clinical suspicion for a viral process. Our patient was administered IVIG despite normal levels of immunoglobulins. Evidence supporting the use of either IVIG or CMV immune globulin in SOT recipients with severe CMV disease remains limited, with a few retrospective case series published prior to the use of current
Acknowledgment We are indebted to Mary B. Beasley, MD, for her guidance, preparation, and interpretation of our pathological biopsy specimens. Funding No grant funding was received to support the interpretation and completion of this case report. Disclosure statement None of the authors have conflicts of interest to disclose or a financial relationship with a commercial entity that has interest in the subject of the manuscript. References Ando H, Shiramizu T, Hisanou R. Dilated cardiomyopathy caused by cytomegalovirus infection in a renal transplant recipient. Jpn Heart J 1992;33:409–12. Brown C, Nicholls A, Edward N, Cuthbertson B, Yap P, McClelland D. Hyperimmune immunoglobulin therapy for cytomegalovirus infections in renal transplant patients. Proc Eur Dial Transplant Assoc 1982;20:271–9. D'Alessandro A, Pirsch J, Stratta R, Sollinger H, Kalayoglu M, Belzer F. Successful treatment of severe cytomegalovirus infections with ganciclovir and CMV hyperimmune globulin in liver transplant recipients. Transplant Proc 1989:3560–1. Fica A, Cervera C, Perez N, et al. Immunohistochemically proven cytomegalovirus endorgan disease in solid organ transplant patients: clinical features and usefulness of conventional diagnostic tests. Transpl Infect Dis 2007;9:203–10. George M, Snydman D, Werner B, et al. Use of ganciclovir plus cytomegalovirus immune globulin to treat CMV pneumonia in orthotopic liver transplant recipients. The Boston Center for Liver Transplantation CMVIG-Study Group. Transplant Proc 1993:22–4. Gonwa TA, Capehart JE, Pilcher JW, Alivizatos PA. Cytomegalovirus myocarditis as a cause of cardiac dysfunction in a heart transplant recipient. Transplantation 1989;47: 197–8. Kang E-Y, Patz Jr EF, Müller NL. Cytomegalovirus pneumonia in transplant patients: CT findings. J Comput Assist Tomogr 1996;20:295–9. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010;89: 779–95. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002;34:1094–7. McNamara DM, Rosenblum WD, Janosko KM, et al. Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy. Circulation 1997;95:2476–8.
Please cite this article as: Mylvaganam R, et al, A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the litera..., Diagn Microbiol Infect Dis (2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.016
R. Mylvaganam et al. / Diagnostic Microbiology and Infectious Disease xxx (2018) xxx–xxx Mendez-Eirin E, Paniagua-Martín M, Marzoa-Rivas R, et al. Cumulative incidence of cytomegalovirus infection and disease after heart transplantation in the last decade: effect of preemptive therapy. Transplant Proc 2012:2660–2. [Elsevier].
3
Partanen J, Nieminen M, Krogerus L, et al. Cytomegalovirus myocarditis in transplanted heart verified by endomyocardial biopsy. Clin Cardiol 1991;14:847–9. Razonable RR, Humar AAST. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013;13(s4):93–106.
Please cite this article as: Mylvaganam R, et al, A case of late-onset cytomegalovirus myocarditis in an orthotopic heart transplant recipient; case report and review of the litera..., Diagn Microbiol Infect Dis (2018), https://doi.org/10.1016/j.diagmicrobio.2018.01.016