Recent H5N1 Developments
By Eric Toner, M.D., October 15, 2007
Several articles published in recent weeks help shed light on the virulence of H5N1 virus, the pathogenesis of severe H5N1 disease in people, and a possible new approach to treatment. A brief summary of the articles follows.
Finkelstein and colleagues1 from St. Jude’s Children’s Research Hospital have identified markers in influenza viruses that might be used to monitor viruses of pandemic potential. They compared the amino acid sequences of more than 9,000 avian and 13,000 human influenza viruses, including the viruses of all three pandemics of the 20th century and H5N1 viruses recovered from both birds and humans. Through this comparison, they found 32 specific amino acid markers that distinguish avian and human viruses as well as a subset of 13 markers that were common to all pandemic viruses. In H5N1 viruses obtained from infected humans, they also found a small number of viruses that had acquired 2 of the 32 human host markers, indicating some small degree of adaptation to the human host. Most of these amino acid markers (26 of 32) were found in 3 of the 4 proteins that make up the viral RNA replication complex (NP, PA and PB2). One of these markers, a substitution of lysine for glutamine at amino acid position 627 (E627K) of the polymerase basic protein-2 (PB2) has been previously associated with increased viral replication in mammals. It is hoped that by monitoring these markers in future viral specimens, viruses with pandemic potential can be identified in advance.
Hatta and Colleagues2, working with H5N1 infected mice, found that this E627K substitution of PB2 confers on the virus the ability to replicate efficiently at lower temperatures. Birds have core body temperatures of 41° C, whereas humans have core body temperatures of 37° C and the temperature of the human nasal mucosa is 33° C. Thus, this mutation, which has been found in most H5N1 specimens in Europe and Africa, allows the virus to replicate in the respiratory tract of humans.
The degree to which extrapulmonary infection with H5N1 exists in humans has been an issue of some interest. In humans, infection with seasonal influenza is limited to the respiratory tract. In birds, low pathogenic avian influenza infection is limited to the respiratory and gastrointestinal tract. However, highly pathogenic H5N1 and other highly pathogenic avian influenza viruses cause severe disease in birds by causing systemic infections. Until now, the evidence for systemic H5N1 infection in humans has been inconclusive.
In a post-mortem study of 2 adults and 1 fetus infected with H5N1, Jiang Gu3 and colleagues found evidence of extrapulmonary infection with the virus. In this study, Gu and colleagues found viral genetic sequences and antigens in the lymph nodes, brain, placenta, and fetus as well as in the lung and trachea. Viral genetic sequences were also found in the intestine. This study supports the notion that H5N1 is a systemic infection in people; however, it does not revolve the question of the relative contribution of systemic infection and systemic cytokine storm in the clinical manifestations of the disease.
In a letter to the editor in the NEJM, Zhou and colleagues describe the treatment of a patient infected with H5N1 virus with convalescent plasma. Initially, the patient was treated with high dose oseltamivir (150 mg bid), which was followed with serial determinations of viral load. The viral load was high and rising after initiation of oseltamivir therapy, so treatment with convalescent plasma was tried. After one infusion of 200 ml of plasma, the viral load dropped by a factor of 12 (from 1.68x105 copies per ml to 1.42x104 copies per ml) over 8 hours. Following 2 more infusions, the virus was undetectable and the patient recovered. This report suggests that passive immunotherapy may be a treatment approach worthy of further investigation.
Finkelstein DB, Mukatira S, Mehta PK, et al. Persistent Host Markers in Pandemic and H5N1 Influenza Viruses. J Virol 2007;81:10292-9 http://jvi.asm.org/cgi/content/full/81/19/10292?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&author1= finkelstein&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT
Hatta M, Hatta Y, Kim JH, Watanabe S, Shinya K, et al. (2007) Growth of H5N1 Influenza A Viruses in the Upper Respiratory Tracts of Mice. PLoS Pathog 3(10): e133 doi:10.1371/journal.ppat.0030133
Gu J, Xie Z, Gao Z, Jinhua Liu et al. H5N1 infection of the respiratory tract and beyond: a molecular pathology study. Lancet 2007;370:1137-1145
Zhou B, Zhong N, Guan Y. Treatment with Convalescent Plasma for Influenza A (H5N1) Infection. NEJM 2007;357:1450-1451