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

Abstract

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 alpha, 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 alpha 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.

Fatal Fulminant Hepatic Failure in a Diabetic with Primary Dengue

“…Dengue characteristically causes zone 2 necrosis of the liver, and the changes are similar to those of the yellow fever [8]. Liver biopsy usually reveals massive infiltration by the virus, with minimal mononuclear cell infiltrate [9]. Other findings include Councilman bodies, kupffer cell hyperplasia, and steatosis [1].…”

Cells in Dengue Virus Infection In Vivo

“…Recently, the phagocytic phenomenon has been confirmed in dengue hemorrhagic nonhuman primate model [64]. Due to difficulties and inconsistencies in identifying the cell lineages responsible for dengue viremia at the acute stage, monocytes and/or macrophages are gradually being assumed as the main cells for dengue virus propagation for the following reasons: (i) like the cells that can propagate the virus, they can adhere to cell culture flasks [63, 65], (ii) they are capable of phagocytosis [23, 66], and (iii) infrequently observed dengue viral antigens in cells with a similar morphology in tissues obtained postmortem [20, 67, 68]. These observations then led to the postulated hypothesis of antibody-dependent enhancement (ADE) [69] in an attempt to explain the epidemiological observation in which secondary infection with subsequent heterologous dengue serotypes is a risk factor for DHF/DSS [70].…”

Extensive haemorrhagic necrosis of liver is an unpredictable fatal complication in dengue infection: a postmortem study

“…Over the years the pathophysiology of dengue virus infection had been extensively studied [5]. Studies suggest that three main systems play an important role in the pathogenesis of DHF/DSS: the immune system, the liver and endothelial cell linings of blood vessels [6]. Increased permeability of microvasculature and plasma leak is supposed to be the main dysfunction that leads to DHF and DSS [6].…”

“…Studies suggest that three main systems play an important role in the pathogenesis of DHF/DSS: the immune system, the liver and endothelial cell linings of blood vessels [6]. Increased permeability of microvasculature and plasma leak is supposed to be the main dysfunction that leads to DHF and DSS [6]. With this understanding many management guidelines have been developed totally based on fluid resuscitation, resulting in reduced mortality [7].…”