Oct 2, 2007 (CIDRAP News) – Researchers from Beijing and New York who conducted pathology studies on tissue samples of a man and a pregnant woman who died of H5N1 avian flu infection found that the virus spread beyond the lungs to other organ systems—even to the fetus.
The authors published their findings in the Sep 29 issue of The Lancet. The patients were both from China. The 24-year-old woman whose samples were studied died in November 2005 and was 4 months pregnant; she appears to be China's second H5N1 case-patient, according to World Health Organization (WHO) reports. The other patient—a 35-year-old man—died in January 2006 and appears to be China's sixth H5N1 case-patient, according to past WHO statements.
Tissues from the patients were collected during autopsies. The researchers' investigations included in-situ hybridization and immunohistochemistry studies to detect and identify antibodies to hemagglutinin and nucleoprotein, as well as several assays to detect viral RNA in organ tissue samples.
In the two adults, the investigators found viral genomic sequences and antigens in type 2 epithelial cells of the lungs, ciliated and nonciliated epithelial cells of the trachea, T cells of the lymph node, and neurons of the brain. In the placenta, the researchers found evidence of the virus in Hofbauer cells and cytotrophoblasts. Viral sequences, but not antigens, were detected in the intestinal mucosa.
In fetal samples, the researchers detected viral evidence and antigens in the lungs, circulating mononuclear cells, and macrophages of the liver.
The authors concluded that the virus's apparent spread beyond the respiratory system has several public health implications, one being that a mother has been shown to transmit the H5N1 virus to her fetus through the placenta.
The authors wrote that few epithelial cells in the lungs harbored the virus, which contrasts with the severe histopathological damage they observed.
"Direct viral injury to the epithelial cells of the respiratory tract is, in our view, unlikely to cause such severe pathological changes," they reported, adding that their findings could lend support to the role of cytokine storm, a destructive immune-system overreaction that many researchers believe causes much of the lethal damage in H5N1 infections.
Also, the researchers said the study suggests the virus can reach the brain by penetrating the blood-brain barrier or invading certain afferent nerve fibers. However, they reported that a lack of histologic changes in the patients' brains suggests that viral replication may not be specifically pathogenic.
In an editorial accompanying the study, two Chinese researchers—Wai Fu Ng and Ka Fai To—wrote that the virus has been known to affect many organ systems in birds but has been thought mainly to affect the lower respiratory tract in humans. The study adds to accumulating data that support H5N1 transmission to many body sites in humans, they added.
The finding that the virus infects epithelial cells in the trachea is a concern, Ng and To wrote. It may suggest that other viral mediators may exist or that the virus might develop mechanisms to overcome respiratory tract defenses. "The clinical significance of such findings needs further assessment," they wrote.
Evidence of the virus in the patients' intestines could have important implications for infection control, the authors noted.
Frederick Hayden, MD, an antiviral expert with the WHO, said the report is the first to contain autopsy data for a pregnant woman or her fetus, according to a Sep 28 Canadian Press (CP) report. "WHO is trying to work with clinicians in affected countries to collect data on H5N1 illness in pregnancy," he said.
Menno de Jong, MD, PhD, a virologist at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam, said he's not surprised that the researchers found the virus in the placenta, because evidence already shows that the virus can circulate in the blood and cause diffuse effects, the CP reported.
Gu J, Xie Z, Gao Z, et al. H5N1 infection of the respiratory tract and beyond: a molecular pathology study. Lancet 2007;370(9593):1137-45 [Abstract]
Ng W, To K. Pathology of human H5N1 infection: new findings. Lancet 2007;377(9593):1106-8
