Influenza A H5N1 Replication Sites in Humans
I think this is important. The full article can be found here:
http://www.cdc.gov/ncidod/EID/vol11no07/04-1313.htm
and is long and full of virology terminology. The really important part is in the discussion section which I will copy here.
xoxo
Discussion
Detailed autopsy data on patients with H5N1 disease are limited, and our data provide an insight into the pathogenesis of H5N1 virus in humans. We provide evidence that H5N1 viral replication is not confined to the respiratory tract but may also occur in the gastrointestinal tract. However, a fecal sample was not available for detection of virus. Although viral RNA was detected in the spleen, no evidence of viral replication was seen in this organ. The patient was treated with an antiviral agent for 2 days before death, which could have lowered the level of viral replication in the examined tissues. However, we still found viral mRNA in lungs and intestines, indicating that the viral replication was still ongoing. Viral replication in lungs and intestines was greater than in other sites. Our data agree with previous reports of human cases and cases in experimentally infected macaques, which also suggest that H5N1 influenza virus replication takes place predominantly in the lungs (10,11,21). We also show that type II pneumocytes, not columnar tracheal epithelial cells, are the major site of H5N1 viral replication in humans. Type II pneumocytes are surfactant-producing, alveolar epithelial cells and progenitor cells of both type I and type II cells. This cell type has been shown to contain sialic acid in newborn human lung (22). Whether the availability of the receptor alone determined the site of H5N1 infection needs further investigation.
Infection of the gastrointestinal tract by avian influenza virus, including H5N1, is common in avian species (23,24). However, involvement of the gastrointestinal tract in H1 and H3 influenza infection is rare in humans (25). A patient with H5N1 influenza virus infection was reported to have diarrhea as the initial symptom, which raises the question of whether the gastrointestinal tract may is another site of viral replication and shedding, similar to its function in avian species (26). In another recent report of a patient with a fatal H5N1 infection and severe diarrhea and encephalitis in Vietnam, the virus was found in a rectal swab (27). Our data confirm that H5N1 influenza virus replication can occur in the gastrointestinal tract even in the absence of diarrhea. However, we do not know the extent of viral shedding in stool in this patient. The absence of pathologic changes in the intestine, despite the viral replication, is intriguing.
The absence of viral antigen in the trachea indicated that the upper airway is probably not an active site of the viral replication. This finding is in marked contrast to the circumstances with human influenza, in which the upper respiratory tract and the tracheal and bronchial epithelium are primarily targeted (19). The predilection of H5N1 influenza virus for the lower airways may explain why detecting virus in upper airway specimens for diagnosis of H5N1 infection in humans is difficult (1). This finding also implies that specimens from the lower respiratory tract, such as sputum or bronchoalveolar lavage, would have a higher sensitivity for viral detection than an upper respiratory specimen, such as nasopharyngeal aspirates or throat swab specimens. Our data showing the absence of viral antigen in columnar epithelial cells contrast with a recently published report that H5N1 viral replication took place selectively in ciliated bronchial epithelial cells in an in vitro culture model (28). Whether this result was due to properties of specific viral strains or a difference attributable to the in vitro model needs further clarification.
In contrast to previous reports (10,11), we did not find prominent hemophagocytosis in any of the organs. The presence of hemophagocytosis in these reports supports the cytokine dysregulation model of pathogenesis. Whether the young age of our patient or prior treatment with immunosuppressive corticosteroids affected this manifestation in this patient is unclear.
TNF-α mRNA was detectable in the lungs but not in other tissues. This finding is in agreement with previous observations that H5N1 viruses isolated from human disease hyperinduce production of cytokines, most prominently TNF-α, in cultured human macrophages in vitro (20,29). The simultaneous presence of viral mRNA and cytokine mRNA in the same organ suggests a direct induction of cytokine in productively infected cells. In accordance with this finding, we also found that the viral isolate from this patient induced a high level of TNF-α production from primary human macrophages, which is comparable to the previously described strains (M. Peiris, unpub. data). However, we could not rule out the possibility that the superimposed fungal infection might have played a role in the induction of TNF-α in this patient. The hemagglutinin of the 1918 pandemic H1N1 influenza virus also appears to hyperinduce production of cytokines and chemokines in a mouse model of disease (30).
In conclusion, we have documented that H5N1 disease in humans is one in which viral replication is restricted to the respiratory and gastrointestinal tracts. The multiorgan dysfunction observed in human H5N1 disease, despite the apparent confinement of infection to the lungs, has remained an enigma. The hypothesis that cytokine dysregulation may contribute to the pathogenesis of severe H5N1 disease (20) remains a possibility. An understanding of the pathogenesis of human H5N1 disease is important in preparing for a pandemic.
