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Disseminated Intravascular Coagulation Complicating Epstein-Barr Virus Infection in a Cardiac Transplant Recipient: A Case Report
CARDIAC
Disseminated Intravascular Coagulation Complicating Epstein-Barr Virus Infection in a Cardiac Transplant Recipient: A Case Report D.S. O’Connor, S. Elmariah, L.M. Aledort, and S.P. Pinney ABSTRACT Viral infections are particularly common after cardiac transplantation. Herein we have presented a case of Epstein-Barr infection that presented as a viral syndrome with respiratory symptoms, but was complicated by multiorgan failure and disseminated intravascular coagulation. Transplant physicians should be aware of this unique complication of an otherwise self-limited infection. PSTEIN-BARR virus (EBV) infections are usually self-limited and rarely life threatening. In solid organ transplant recipients, EBV has been implicated in lymphoproliferative disorders and infrequently with hemophagocytic syndrome. Herein we have reported a novel case of disseminated intravascular coagulation (DIC) and multiorgan failure complicating an EBV infection in a cardiac transplant recipient.
E
CASE DESCRIPTION A 59-year-old man was admitted to hospital with a 4-day history of dyspnea and malaise. He had received a heart transplant 3 years before admission for treatment of an ischemic cardiomyopathy. He had no history of significant rejection or opportunistic infection before this presentation. He had serologic evidence of cytomegalovirus (CMV), EBV, and herpes simplex virus (HSV) infection before cardiac transplantation. His immunosuppressive medicines included cyclosporine, mycophenolate mofetil, and prednisone. On the day of admission, he complained of nonproductive cough and fever. On examination he was tachypneic and ill appearing. He was afebrile with a blood pressure 104/82 mmHg and pulse 114 beats per minute. The arterial saturation was 82%, but improved to 92% breathing 2 L/min supplemental oxygen. The jugular veins were not distended. Crackles were present at both bases. The heart was tachycardic with an S3 gallop. There was no hepatosplenomeg-
aly, and the lower extremities were without edema. A chest radiograph showed bibasilar atelectasis with small effusions, but no infiltrates. Pertinent laboratory findings included a white cell count of 10.1 (103/L), sodium 126 (mEq/L), creatinine 2.0 (mg/dL), estimated glomerular filtration rate (GFR) 37 (mL/min). Cardiac troponin was not elevated, and the cyclosporine level was therapeutic. Ceftriaxone was administered in the emergency department for treatment of community acquired pneumonia, and azithromycin was added for coverage against legionella. The next day he was endotracheally intubated and placed on mechanical ventilation. Echocardiography revealed a nondilated left ventricle with global severe dysfunction and an ejection fraction of 15%. The right ventricle was mildly dilated with moderately decreased function. There was no pericardial effusion. Endomyocardial biopsy was performed. His resting hemodynamics were right atrium 30 mm Hg, pulmonary artery 62/42 mm Hg mean 49 mm Hg, pulmonary capillary wedge 38 mm Hg, and cardiac output 6.3 L/min. Methylprednisolone and thymoglobulin were administered daily for treatment of suspected allograft rejection. ValganFrom The Mount Sinai School of Medicine, New York, New York. Address reprint requests to Sean Pinney, MD, One Gustave Levy Place, Box 1030, New York, NY 10029. E-mail: sean.pinney@ mssm.edu
© 2010 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2009.11.044
Transplantation Proceedings, 42, 1973–1975 (2010)
1973
1974
O’CONNOR, ELMARIAH, ALEDORT ET AL Table 1. Hematologic Parameters Consistent With DIC
Hgb Platelets AST/ALT Cr Fibrinogen FDP D-Dimer INR
HD 1
HD 2
HD 3
HD 4
HD 7
HD 10
HD 12
HD 14
15.4 215 30/53 2 — — — 1.1
13.7 121 6479/6859 2.3 211 — — 2.7
12.5 94 2727/6190 4.3 167 ⬎20 22.1 3
12.3 73 270/2036 4.7 147 ⬎20 15.86 2.5
12 54 114/1941 1.9 187 ⬎20 7.42 1.1
12.4 77 77/1208 1.6 191 19.9 2.99 1.1
12.4 116 80/740 1.5 265 NEG ⬍5 1.53 0.9
11.6 232 44/198 1.4 400 NEG ⬍5 1.55 0.9
ALT, alanine aminotransferase (units/L); AST, aspartate aminotransferase (units/L); Cr, creatinine (mg/dL); FDP, fibrin degredation products (mg/L); HD, hospital day, Hgb, hemoglobin concentration (g/dL); INR, International Normalized Ratio; D-Dimer in g/dL; fibrinogen in mg%, platelets in ⫻10 sup⬎3/L.
cyclovir and atovaquone were given as prophylaxis against CMV and pneumocystis, respectively. His condition continued to worsen with evidence of DIC and multiorgan failure (Table 1). Cultures of blood and urine remained without growth by the third hospital day. The endomyocardial biopsy was graded 1R,1 and was not believed to be responsible for the patient’s clinical deterioration. Thymoglobulin was discontinued. Computed tomography of the chest, abdomen, and pelvis revealed patchy, ground glass opacities and bilateral pleural effusions. There was no hepatosplenomegaly or significant lymphadenopathy. An infusion of heparin at 200 /hr was initiated to prevent further DIC. Although suspected, CMV infection was excluded by the results of a polymerase chain reaction (PCR) for viral DNA. By hospital day 5, the patient’s clinical condition had improved enough to allow removal of mechanical ventilation (Table 1). Two days later, PCR for EBV returned with 3,374 copies. He was discharged home after a 2-week hospitalization. One month after his initial presentation, repeat EBV viral load was reduced to 381 copies and was undetectable 3 months later. One year later, he continues to have severe left ventricular dysfunction and has been readmitted twice for treatment of allograft failure.
acute rejection and cardiac allograft vasculopathy through direct activation of inflammatory mediators (nuclear factor kappa B, Toll-like receptors, and nitric oxide synthase), and modulation of humoral immunity through induction of anti-endothelial cell antibodies.15,16 The etiology of persistent left ventricular dysfunction remains elusive, but was unlikely to be the result of either rejection or cardiac allograft vasculopathy. A direct EBV-related myocarditis also seems unlikely as the endomyocardial biopsy was negative because an EBV-encoded RNAER performed on the endomyocardial biopsy was negative for EBV. Additionally, a C4D stain of the endomyocardial biopsy was negative, making humoral rejection unlikely.17 Consequently, we postulate that the persistent left ventricular dysfunction resulted from profound microvascular disease secondary to severe DIC. As this case demonstrates, physicians should be mindful that DIC may occur as a complication of acute EBV infection, which is not always a self-limited infection in immunocompromised patients.
DISCUSSION
REFERENCES
EBV is a recognized pathogen in both immunocompetent and immunosuppressed hosts. Infection in adults typically causes a self-limited, acute mononucleosis with symptoms of pharyngitis, fever, and malaise.2 Some well-recognized complications of EBV infection include splenic rupture,3 autoimmune hemolysis,4 hemophagocytic syndrome,5,6 and, infrequently, acute myocarditis.7,8 DIC has been described previously in a few reports,9,10 but we believe this is the first description of its occurrence in a transplant recipient. Whether this case represented reactivation of EBV or primary reinfection is unclear. Classically, EBV infection is an acute, self-limiting disease most appropriately treated with supportive care. The addition of antiviral therapy seems to be of no additional benefit in immunocompetent hosts.11 In our patient, DIC led to multiorgan failure and hemodynamic compromise. We believe our patient benefited from aggressive supportive care rather than from antiviral therapy. Additionally, heparin infusion probably abrogated the DIC, although the efficacy of heparin in this setting has not been definitively established.12–14 CMV infection has an established role in
1. Billingham M, Kobashigawa JA: The revised ISHLT heart biopsy grading scale. J Heart Lung Transplant 24:1709, 2005 2. Peter J, Ray CG: Infectious mononucleosis. Pediatr Rev 19:276, 1998 3. Asgari MM, Begos DG: Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 70:175, 1997 4. Lee MH, Cho KS, Kahng KW, et al: A case of hemolytic uremic syndrome associated with Epstein-Barr virus infection. Korean J Intern Med 13:131, 1998 5. Kashiwagi Y, Kawashima H, Sato S, et al: Virological and immunological characteristics of fatal virus-associated haemophagocytic syndrome (VAHS). Microbiol Immunol 51:53, 2007 6. Yamamoto T, Shirakawa A, Kawaguchi M, et al: Lytic infection of Epstein-Barr virus (EBV) in hemophagocytic syndrome associated with EBV-induced lymphoproliferative disorder. Ann Hematol 83:127, 2004 7. Roubille F, Gahide G, Moore-Morris T, et al: Epstein Barr virus (EBV) and acute myopericarditis in an immunocompetent patient: first demonstrated case and discussion. Intern Med 47:627, 2008 8. Kuhl U, Pauschinger M, Noutsias M, et al: High prevalence of viral genomes and multiple viral infections in the myocardium of adults with ‘idiopathic’ left ventricular dysfunction. Circulation 111:887, 2005
DIC IN EBV INFECTION 9. van Steijn JH, van Tol KM, van Essen LH, et al: Disseminated intravascular coagulation as an unusual presentation of an EpsteinBarr virus infection. Neth J Med 57:169, 2000 10. Soma N, Akiyama M, Suzuki H, et al: [A case of acute hepatitis induced by Epstein-Barr virus complicated with disseminated intravascular coagulation]. Nippon Shokakibyo Gakkai Zasshi Jun 89:1386, 1992 11. Torre D, Tambini R: Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis 31:543, 1999 12. Hoyle CF, Swirsky DM, Freedman L, et al: Beneficial effect of heparin in the management of patients with APL. Br J Haematol 68:283, 1988 13. Riewald M, Riess H: Treatment options for clinically recognized disseminated intravascular coagulation. Semin Thromb Hemost 24:53, 1998
1975 14. Feinstein DI: Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood 60:284, 1982 15. Potena L, Valantine HA: Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis 20:425, 2007 16. Toyoda M, Petrosian A, Jordan SC: Immunological characterization of anti-endothelial cell antibodies induced by cytomegalovirus infection. Transplantation 68:1411, 1999 17. Crespo-Leiro MG, Veiga-Barreiro A, Domenech N, et al: Humoral heart rejection (severe allograft dysfunction with no signs of cellular rejection or ischemia): incidence, management and the value of C4d for diagnosis. Am J Transplant 5:2560, 2005
Disseminated Intravascular Coagulation Complicating Epstein-Barr Virus Infection in a Cardiac Transplant Recipient: A Case Report D.S. O’Connor, S. Elmariah, L.M. Aledort, and S.P. Pinney ABSTRACT Viral infections are particularly common after cardiac transplantation. Herein we have presented a case of Epstein-Barr infection that presented as a viral syndrome with respiratory symptoms, but was complicated by multiorgan failure and disseminated intravascular coagulation. Transplant physicians should be aware of this unique complication of an otherwise self-limited infection. PSTEIN-BARR virus (EBV) infections are usually self-limited and rarely life threatening. In solid organ transplant recipients, EBV has been implicated in lymphoproliferative disorders and infrequently with hemophagocytic syndrome. Herein we have reported a novel case of disseminated intravascular coagulation (DIC) and multiorgan failure complicating an EBV infection in a cardiac transplant recipient.
E
CASE DESCRIPTION A 59-year-old man was admitted to hospital with a 4-day history of dyspnea and malaise. He had received a heart transplant 3 years before admission for treatment of an ischemic cardiomyopathy. He had no history of significant rejection or opportunistic infection before this presentation. He had serologic evidence of cytomegalovirus (CMV), EBV, and herpes simplex virus (HSV) infection before cardiac transplantation. His immunosuppressive medicines included cyclosporine, mycophenolate mofetil, and prednisone. On the day of admission, he complained of nonproductive cough and fever. On examination he was tachypneic and ill appearing. He was afebrile with a blood pressure 104/82 mmHg and pulse 114 beats per minute. The arterial saturation was 82%, but improved to 92% breathing 2 L/min supplemental oxygen. The jugular veins were not distended. Crackles were present at both bases. The heart was tachycardic with an S3 gallop. There was no hepatosplenomeg-
aly, and the lower extremities were without edema. A chest radiograph showed bibasilar atelectasis with small effusions, but no infiltrates. Pertinent laboratory findings included a white cell count of 10.1 (103/L), sodium 126 (mEq/L), creatinine 2.0 (mg/dL), estimated glomerular filtration rate (GFR) 37 (mL/min). Cardiac troponin was not elevated, and the cyclosporine level was therapeutic. Ceftriaxone was administered in the emergency department for treatment of community acquired pneumonia, and azithromycin was added for coverage against legionella. The next day he was endotracheally intubated and placed on mechanical ventilation. Echocardiography revealed a nondilated left ventricle with global severe dysfunction and an ejection fraction of 15%. The right ventricle was mildly dilated with moderately decreased function. There was no pericardial effusion. Endomyocardial biopsy was performed. His resting hemodynamics were right atrium 30 mm Hg, pulmonary artery 62/42 mm Hg mean 49 mm Hg, pulmonary capillary wedge 38 mm Hg, and cardiac output 6.3 L/min. Methylprednisolone and thymoglobulin were administered daily for treatment of suspected allograft rejection. ValganFrom The Mount Sinai School of Medicine, New York, New York. Address reprint requests to Sean Pinney, MD, One Gustave Levy Place, Box 1030, New York, NY 10029. E-mail: sean.pinney@ mssm.edu
© 2010 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2009.11.044
Transplantation Proceedings, 42, 1973–1975 (2010)
1973
1974
O’CONNOR, ELMARIAH, ALEDORT ET AL Table 1. Hematologic Parameters Consistent With DIC
Hgb Platelets AST/ALT Cr Fibrinogen FDP D-Dimer INR
HD 1
HD 2
HD 3
HD 4
HD 7
HD 10
HD 12
HD 14
15.4 215 30/53 2 — — — 1.1
13.7 121 6479/6859 2.3 211 — — 2.7
12.5 94 2727/6190 4.3 167 ⬎20 22.1 3
12.3 73 270/2036 4.7 147 ⬎20 15.86 2.5
12 54 114/1941 1.9 187 ⬎20 7.42 1.1
12.4 77 77/1208 1.6 191 19.9 2.99 1.1
12.4 116 80/740 1.5 265 NEG ⬍5 1.53 0.9
11.6 232 44/198 1.4 400 NEG ⬍5 1.55 0.9
ALT, alanine aminotransferase (units/L); AST, aspartate aminotransferase (units/L); Cr, creatinine (mg/dL); FDP, fibrin degredation products (mg/L); HD, hospital day, Hgb, hemoglobin concentration (g/dL); INR, International Normalized Ratio; D-Dimer in g/dL; fibrinogen in mg%, platelets in ⫻10 sup⬎3/L.
cyclovir and atovaquone were given as prophylaxis against CMV and pneumocystis, respectively. His condition continued to worsen with evidence of DIC and multiorgan failure (Table 1). Cultures of blood and urine remained without growth by the third hospital day. The endomyocardial biopsy was graded 1R,1 and was not believed to be responsible for the patient’s clinical deterioration. Thymoglobulin was discontinued. Computed tomography of the chest, abdomen, and pelvis revealed patchy, ground glass opacities and bilateral pleural effusions. There was no hepatosplenomegaly or significant lymphadenopathy. An infusion of heparin at 200 /hr was initiated to prevent further DIC. Although suspected, CMV infection was excluded by the results of a polymerase chain reaction (PCR) for viral DNA. By hospital day 5, the patient’s clinical condition had improved enough to allow removal of mechanical ventilation (Table 1). Two days later, PCR for EBV returned with 3,374 copies. He was discharged home after a 2-week hospitalization. One month after his initial presentation, repeat EBV viral load was reduced to 381 copies and was undetectable 3 months later. One year later, he continues to have severe left ventricular dysfunction and has been readmitted twice for treatment of allograft failure.
acute rejection and cardiac allograft vasculopathy through direct activation of inflammatory mediators (nuclear factor kappa B, Toll-like receptors, and nitric oxide synthase), and modulation of humoral immunity through induction of anti-endothelial cell antibodies.15,16 The etiology of persistent left ventricular dysfunction remains elusive, but was unlikely to be the result of either rejection or cardiac allograft vasculopathy. A direct EBV-related myocarditis also seems unlikely as the endomyocardial biopsy was negative because an EBV-encoded RNAER performed on the endomyocardial biopsy was negative for EBV. Additionally, a C4D stain of the endomyocardial biopsy was negative, making humoral rejection unlikely.17 Consequently, we postulate that the persistent left ventricular dysfunction resulted from profound microvascular disease secondary to severe DIC. As this case demonstrates, physicians should be mindful that DIC may occur as a complication of acute EBV infection, which is not always a self-limited infection in immunocompromised patients.
DISCUSSION
REFERENCES
EBV is a recognized pathogen in both immunocompetent and immunosuppressed hosts. Infection in adults typically causes a self-limited, acute mononucleosis with symptoms of pharyngitis, fever, and malaise.2 Some well-recognized complications of EBV infection include splenic rupture,3 autoimmune hemolysis,4 hemophagocytic syndrome,5,6 and, infrequently, acute myocarditis.7,8 DIC has been described previously in a few reports,9,10 but we believe this is the first description of its occurrence in a transplant recipient. Whether this case represented reactivation of EBV or primary reinfection is unclear. Classically, EBV infection is an acute, self-limiting disease most appropriately treated with supportive care. The addition of antiviral therapy seems to be of no additional benefit in immunocompetent hosts.11 In our patient, DIC led to multiorgan failure and hemodynamic compromise. We believe our patient benefited from aggressive supportive care rather than from antiviral therapy. Additionally, heparin infusion probably abrogated the DIC, although the efficacy of heparin in this setting has not been definitively established.12–14 CMV infection has an established role in
1. Billingham M, Kobashigawa JA: The revised ISHLT heart biopsy grading scale. J Heart Lung Transplant 24:1709, 2005 2. Peter J, Ray CG: Infectious mononucleosis. Pediatr Rev 19:276, 1998 3. Asgari MM, Begos DG: Spontaneous splenic rupture in infectious mononucleosis: a review. Yale J Biol Med 70:175, 1997 4. Lee MH, Cho KS, Kahng KW, et al: A case of hemolytic uremic syndrome associated with Epstein-Barr virus infection. Korean J Intern Med 13:131, 1998 5. Kashiwagi Y, Kawashima H, Sato S, et al: Virological and immunological characteristics of fatal virus-associated haemophagocytic syndrome (VAHS). Microbiol Immunol 51:53, 2007 6. Yamamoto T, Shirakawa A, Kawaguchi M, et al: Lytic infection of Epstein-Barr virus (EBV) in hemophagocytic syndrome associated with EBV-induced lymphoproliferative disorder. Ann Hematol 83:127, 2004 7. Roubille F, Gahide G, Moore-Morris T, et al: Epstein Barr virus (EBV) and acute myopericarditis in an immunocompetent patient: first demonstrated case and discussion. Intern Med 47:627, 2008 8. Kuhl U, Pauschinger M, Noutsias M, et al: High prevalence of viral genomes and multiple viral infections in the myocardium of adults with ‘idiopathic’ left ventricular dysfunction. Circulation 111:887, 2005
DIC IN EBV INFECTION 9. van Steijn JH, van Tol KM, van Essen LH, et al: Disseminated intravascular coagulation as an unusual presentation of an EpsteinBarr virus infection. Neth J Med 57:169, 2000 10. Soma N, Akiyama M, Suzuki H, et al: [A case of acute hepatitis induced by Epstein-Barr virus complicated with disseminated intravascular coagulation]. Nippon Shokakibyo Gakkai Zasshi Jun 89:1386, 1992 11. Torre D, Tambini R: Acyclovir for treatment of infectious mononucleosis: a meta-analysis. Scand J Infect Dis 31:543, 1999 12. Hoyle CF, Swirsky DM, Freedman L, et al: Beneficial effect of heparin in the management of patients with APL. Br J Haematol 68:283, 1988 13. Riewald M, Riess H: Treatment options for clinically recognized disseminated intravascular coagulation. Semin Thromb Hemost 24:53, 1998
1975 14. Feinstein DI: Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood 60:284, 1982 15. Potena L, Valantine HA: Cytomegalovirus-associated allograft rejection in heart transplant patients. Curr Opin Infect Dis 20:425, 2007 16. Toyoda M, Petrosian A, Jordan SC: Immunological characterization of anti-endothelial cell antibodies induced by cytomegalovirus infection. Transplantation 68:1411, 1999 17. Crespo-Leiro MG, Veiga-Barreiro A, Domenech N, et al: Humoral heart rejection (severe allograft dysfunction with no signs of cellular rejection or ischemia): incidence, management and the value of C4d for diagnosis. Am J Transplant 5:2560, 2005