Limited pathologic studies of RVF infection, based on a few human cases, field animal samples, and experimental animal specimens, have been reported previously. Abdel-Wahab and others12
observed severe liver necrosis, interstitial pneumonia, and myocardial degeneration in postmortem tissues of two human cases. The RVFV was isolated from post-mortem samples of liver, cerebro-spinal fluid, pericardial and pleural fluid, and from a throat swab of these two cases. Arborio and Hall13
showed RVF viral antigen in fixed liver tissue of a human case by the immunoperoxidase method. The RVF viral antigen was present mainly in the cytoplasm of hepatocytes adjacent to areas of hepatocellular necrosis. They did not observe immunostaining in other cell types. Coetze reported massive diffuse necrosis of hepatocytes as the most characteristic histopathologic finding in new-born lambs infected with RVFV.14,15
Other less common findings included bile thrombi and intranuclear inclusions in hepatocytes. Lymphoid depletion in lymph nodes and spleen has been seen in many animal samples examined, and similar histopathologic findings have also been observed in cattle, calves, and aborted fetuses with RVFV infection.16
Autopsy samples from rhesus monkeys experimentally infected with RVFV displayed severe liver necrosis as the major microscopic finding.17,18
Van der Lugt and others19
studied the distribution of RVF viral antigens by immunoperoxidase in liver, spleen, lymph node, lung, and kidney of eight experimentally infected new-born lambs and four new-born lambs that died of RVF. Viral antigens were most prominent in the liver and were detected in the cytoplasm of hepatocytes at early stage of infection. Viral antigens were consistently present in the cytoplasm of large numbers of degenerated or necrotic hepatocytes and in acidophilic bodies at a later stage of infection. Immunostaining was rarely observed in the nucleus of hepatocytes and few cells stained positively in the spleen, lymph node, lung, and kidney. The authors concluded that hepatocytes constitute the primary site of RVFV replication in infected animals.
Our studies are consistent with other reports identifying extensive hepatocellular necrosis as the most prominent histopathologic change in animals and humans infected with RVFV and this histopathologic feature correlates well with the IHC test results. However, unlike some previous reports, we did not observe a particular zonal distribution or conspicuous inclusions. No prominent inflammatory reaction associated with necrosis was observed in the liver. Similar hepatic pathology can be seen in hemorrhagic fevers caused by other viruses, including yellow fever virus,20
Lassa fever virus,21
Crimean-Congo hemorrhagic fever virus,22
and Ebola virus.24
As with the geographic ranges of more common febrile illnesses, many of these exotic infections occur sympatrically with RVFV in Africa; thus, specific diagnostic tests are critical to identify the causative agent. As we observed, the IHC assay can detect viral antigens in tissues, and is a specific diagnostic method for samples obtained from patients and animals dying from clinically suspected RVF. Abundant immunostaining was present within necrotic and neighboring hepatocytes, and in scattered Kupffer cells. In our studies, immunostaining for RVF viral antigens was seen in focal renal tubular epithelial cells in one single human kidney sample. This observation suggests possible excretion of RVF viral antigens in urine; however, its validity and clinical importance warrants further investigation. Madani and others6
reported the epidemiological, clinical, and laboratory characteristics of the RVF epidemic that occurred in Saudi Arabia, 2001. In their cohort study, renal impairment or failure was found in almost one-third of the patients with RVF. Whether this clinical observation is related to the renal damage by RVFV infection or a consequence of systemic shock is unknown. The RVFV antigen in animal kidney was described in a few reports,19,25
but has never been described in human sample. Our observation of RVFV antigen in the kidney is a novel finding, although it was seen in only one human sample in this report.
Localization of viral antigens can also elucidate the pathogenetic mechanisms involved in certain viral hemorrhagic fevers.22,26,27
Despite similar clinical manifestations among various viral hemorrhagic fevers, there are clear differences in their pathogenesis and clinical progression.28,29
The lytic virus-cell interaction suggests that the major pathogenesis of RVFV infection involves direct, virus-induced cellular necrosis, particularly in the liver. Unlike some other hemorrhagic fever viruses, such as Lassa fever virus, Crimean-Congo hemorrhagic fever virus, Marburg virus, and Ebola virus, no prominent immunostaining is seen in endothelial cells or Kupffer cells in liver infected with RVFV. Unfortunately, more thorough histopathologic and immunopathologic studies were hampered by autolysis of many of the animal samples, and the limited tissue types available for evaluation.
In sub-Saharan Africa, many other severe febrile illnesses can have similar presentations. Pathological studies of postmortem tissue samples are helpful in differentiating RVF from other endemic infections, especially when clinical manifestations of those infections are similar to RVF yet the infection is potentially treatable. The detection of human herpes simplex virus and P. falciparum, in our studies, illustrates the usefulness of pathologic examination in patients who die of febrile illness that resembles RVF, but in fact are caused by pathogens other than RVFV. Because of this, pathologic studies can contribute valuable information to outbreak detection and response.
Future opportunities for more complete examination of autopsy and necropsy tissue obtained from humans and animals during outbreaks of RVF will lead to improved understanding of this disease.