July 2006

Literature Review

Avian influenza virus infection in humans
Go to full text in PubMed: Wong SS, Yuen KY Chest 2006;129;156

The authors from the University of Hong Kong provide a review of avian influenza virus infections in people.

Microbiology: The major antigenic determinants of influenza A viruses are the hemagglutinin and neuraminidase with 16 hemagglutinin types and 9 neuraminidase types. Attachments and entry of the virus in two host cells is determined by hemagglutinin by binding to sialic acid receptors on cell surfaces; hemagglutinin is also the main viral target of humoral immunity for protection. The binding affinity accounts for host specificity; for human viruses the pair is preferential finding to sialic acid linked to galactose by alpha-2, 6 linkages found in the human respiratory tract, and in avian viruses the preferential binding is to alpha-2, 3 linkages found in duck intestinal epithelium. The pig tracheal epithelium has both receptors which is the reason it serves as a “mixing vessel”.  Chickens may have a similar role. It is noted that the change of one amino acid of the H5 protein is sufficient to change receptor binding specificity of H5N1 [Gambaryan A Virology-in press]. 

Epidemiology:  Waterfowl are the natural reservoir of all influenza A virus subtypes. These periodically spread directly from birds to humans to cause either conjunctivitis or “influenza-like illness” (ILI). The recent history of these infections is summarized in the following table:

Abbreviations:  ILI – Influenza-like illness, Conjunct = conjunctivitis
*Avian flu (H5N1) = Updated data through 6/20/06; syndromes include ILI, pneumonia, encephalitis and diarrhea

The recent epidemic of H5N1 is unique in two ways:  first is the geographic extent of the epidemic, which is unprecedented.  Second, this virus shows increased virulence in mammals as shown in mouse and ferret studies [Li Z, Chen H, Jiao P, et al. J Virol 2005;79:12058; Maines TR, Lu XH, Erb SM, et al. J Virol 2005;79:11788; Kuiken T, Rimmelzwaan G, van Riel D, et al. Science 2004;306:241]. The experience to date is that human-human transmission of H5N1 has been sporadic. The outbreak in 1997 in Hong Kong indicated one of 18 patients had no history of poultry exposure and 3.7% of health care workers were found to be seropositive [Buxton Bridges C, Katz JM, Seto WH, et al. J Infect Dis 2000;181:344]. The more recent experience in Southeast Asia has shown evidence of sporadic human-human transmission, serologic studies of health care workers failed to show any evidence of transmission [Liem NT, Lim W Emerg Infect Dis 2005;11:210; Le QM, Kiso M, Someya K, et al. Nature 2005;437:1108]. For other avian influenza viruses, there was evidence of human-human transmission of H7N7 in the 2003 outbreak in the Netherlands, a total of three cases in household contacts [Koopmans M, Wilbrink B, Conyn M, et al. Lancet 2004;363:587].  

Clinical Features: The most striking findings for H5N1 infections in people are: 1) the relatively young age, with median ages of 10-20 years in most series; 2) an incubation period of 3-4 days after exposure, with a range of 2-8 days; 3) the universal presence of pneumonia and fever at presentation; 4) a high frequency of diarrhea, generally reported in 40-70% of patients; 5) laboratory studies showing lymphopenia and thrombocytopenia, both being prognostic for bad outcome; 6) rapid progression in many to ARDS; and 7) a fatality rate of 50-80% [Tran TH, Nguyen TL, Nguyen TD, et al. N Engl J Med 2004;350:1179; Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, et al. Emerg Infect Dis 2005;11:201; WHO N Engl J Med 2005;353:1374].

Autopsy Findings: There are relatively few reports, but the findings in two patients showed DIC, diffuse alveolar damage, and evidence of virus in the intestine and spleen [To KF, Chan PK, Chan KF, et al. J Med Virol 2001;63:242; Uiprasertkul M, Puthavathana P, Sangsiriwut K, et al. Emerg Infect Dis 2005;11:1036].

Treatment: 
Therapy:

1. Adamantines (Amantadine and Rimantidine)

• Resistance:  M2 is an ion channel crucial for maturation of hemagglutinin, and is the target of this class. Mutations in M2 at codon 31 causes resistance.  This may occur as early as two days after treatment [Hayden FG, Hay AJ Curr Top Microbiol Immunol 1992;176:119]
• Adamantines remain attractive if the prevalent virus is sensitive since it has low cost and a shelf life of over 25 years. 

2. Neuraminidase inhibitors (Oseltamivir and Zanamivir)

• Resistance:  These drugs target neuraminidase which facilitates spread of the virus in the host by cleaving the glycosidic linkages to sialic acid on host cells and viral surface particles.  The main mutation is that codon 274 of neuraminidase and this mutation has been noted with avian influenza strains [Le QM, Kiso M, Someya K, et al. Nature 2005;437:1108]. The frequency of resistance in human influenza strains and in avian influenza strains in humans has been low.
• Efficacy decreases with time after onset of symptoms, but the length of this window of opportunity for human avian influenza infection is unknown.
• Avian flu strains that are more virulent appear to have reduced response to neuraminidase inhibitors, but may respond better to higher doses and longer duration of treatment [Yen HL, Monto AS, Webster RG, , et al. J Infect Dis 2005;192:665].
• The combination of oseltamivir and rimantadine is synergistic with H9N2 both in vitro and in animal studies [Leneva IA, Roberts N, Govorkova EA, et al. Antiviral Res 2000;48:101; Govorkova EA, Fang HB, Tan M, et al. Antimicrob Ag Chemother 2004;48:4855]. One method to increase the exposure to oseltamivir is concurrent use with Probencid, which doubles the AUC [Hill G, Cihlar T, Oo C, et al. Drug Metab Dispos 2002;30:13].
• Most authorities recommended oseltamivir over zanamivir due to the lack of treatment data for H5N1 infections with zanamivir and because the distribution of zanamivir is largely limited to the upper airways and is sometimes difficult to administer.  Nevertheless, zanamivir is active against oseltamivir-resistant strains and should be considered for prophylaxis specifically for health care workers taking care of patients being treated with oseltamivir.
• Zanamivir has been given in doses up to 1.2 gm/day IV and was well tolerated [Cass LM, Efthymiopoulos C, Bye A Clin Pharmacokinet 1999;36 Supplement 1:11; Calfee DP, Peng AW, Cass LM, et al. Antimicrob Agents Chemother 1999;43:1616].
• Peramivir is another intravenous neuraminidase inhibitor which is not currently available, but under development.

3. Ribavirin: This is not considered to be a preferred drug for influenza, but could be used for synergistic activity

with a neuraminidase inhibitor [Sidwell RW, Bailey KW, Wong MH, et al. Antiviral Res 2005;68:7]. Ribavirin is highly effective in an animal model of influenza B and viramidine is also highly active although neither drug has been FDA approve for this indication nor are the studies extensive.

4. Immunomodulation: Studies of corticosteroids and IVIG have limited studies, but no evidence to support their use in Avian influenza [Beigel JH, Farrar J, Han AM, et al. N Engl J Med 2005;353:1374].  

Infection Control: 

The authors note that WHO has recommended contact and droplet precautions “as key measures”.  They point out that there is good evidence of GI involvement with high rates of diarrhea and high counts of the virus in stool in some patients.  For disinfection, the WHO recommendation is for 1% sodium hypochloride or 70% alcohol. 

Literature Review by John G. Barlett, M.D. Professor, Division of Infectious Diseases

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