Histologic, viral, and molecular correlates of dengue fever infection of the liver using highly sensitive immunohistochemistry.
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.
de Macedo
Fabiane Carvalho
FC
Department of Pathology-Antônio Pedro University Hospital (Federal Fluminense university), Niterói, Rio de Janeiro, Brazil.
Nicol
Alcina F
AF
Cooper
Lynn D
LD
Yearsley
Martha
M
Pires
Andrea Rodrigues Cordovil
AR
Nuovo
Gerard J
GJ
D003716:Dengue Virus / Q000235:genetics / Q000302:isolation & purification*; D006525:Hepatitis, Viral, Human / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000473:pathology* / Q000821:virology; D009336:Necrosis; D012367:RNA, Viral / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019595:Severe Dengue / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014764:Viral Proteins / Q000032:analysis
D007376:Interleukin-2; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins