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Histologic, Viral, and Molecular Correlates of Dengue Fever Infection of the Liver Using Highly Sensitive Immunohistochemistry

Carvalho de Macedo, Fabiane MD*; Nicol, Alcina F. PhD; Cooper, Lynn D. MD; Yearsley, Martha MD§; Cordovil Pires, Andrea Rodrigues MA*; Nuovo, Gerard J. MD

Diagnostic Molecular Pathology: December 2006 - Volume 15 - Issue 4 - pp 223-228
doi: 10.1097/
Original Articles

The mechanism by which the virus associated with dengue fever can cause a fatal hepatitis is not well understood. The purpose of this study was to examine 9 cases of fatal dengue hemorrhagic fever-associated hepatitis, and to correlate the histologic findings with viral detection and cytokine response. The histologic changes were nonspecific and included massive hepatic necrosis and a pauci-cellular acute hepatitis. Viral cDNA detection by reverse transcriptase in situ polymerase chain reaction demonstrated that the fatal hepatitis was due to infection on average of >90% of hepatocytes and many Kupffer cells. Similar results were obtained using immunohistochemistry for viral protein using an automated highly sensitive system. Immunohistochemical analysis for tumor necrosis factor α, and interleukin-2, showed rare positive Kupffer cells. In comparison, fatal cases of hepatitis C associated liver failure demonstrated far fewer infected hepatocytes and a concomitant strong up-regulation of many cytokines, notably tumor necrosis factor α and interleukin-2. It is concluded that fatal dengue hemorrhagic fever is associated with acute, severe liver damage due primarily to massive direct infection of hepatocytes and Kupffer cells with minimal cytokine response. The infection can be readily detected in a few hours using an automated system that has a sensitivity equivalent to reverse transcriptase in situ polymerase chain reaction.

*Department of Pathology-Antônio Pedro University Hospital (Federal Fluminense university), Niterói, Rio de Janeiro

Immunopathology Laboratory, IOC, Department of Biochemistry and Molecular Biology, Fiocruz, Rio de Janeiro, Brazil

Department of Pathology, Ohio State University Medical Center, Columbus

§Department of Pathology. The Cleveland Clinic Medical Center, Cleveland, OH

Supported by a grant from the Lewis Foundation (G.J.N.) and National Cancer Institute, HL70574 (GJN).

Reprints: Gerard J. Nuovo, MD, Department Pathology, The Ohio State University Medical Center, 081 Davis Heart and Lung Research Institute; 473 W 12th Avenue, Columbus, OH (e-mail:

© 2006 Lippincott Williams & Wilkins, Inc.