Viruses And Their Implication

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Avian Influenza Viruses and their Implication for Human Health Donald Kaye1,2 and Craig R. Pringle2,3 1

Drexel University, College of Medicine, Philadelphia, Pennsylvania, and 2ProMED mail, International Society for Infectious Diseases, Boston, Massachusetts; and 3Biological Sciences Department, University of Warwick, United Kingdom

Widespread outbreaks of avian influenza in domestic fowl throughout eastern Asia have reawakened concern that avian influenza viruses may again cross species barriers to infect the human population and thereby initiate a new influenza pandemic. Simultaneous infection of humans (or swine) by avian influenza viruses in the presence of human influenza viruses could theoretically generate novel influenza viruses with pandemic potential as a result of reassortment of genome subunits between avian and mammalian influenza viruses. These hybrid viruses would have the potential to express surface antigens from avian viruses to which the human population has no preexisting immunity. This article reviews current knowledge of the routes of transmission of avian influenza A viruses to humans, places the risk of appearance of a new pandemic influenza virus in perspective, and describes the recently observed epidemiology and clinical syndromes of avian influenza in humans.

The current widespread outbreaks of avian influenza among domestic fowl throughout eastern Asia have reawakened concern that avian influenza viruses may again cross species barriers to infect the human population, either directly or via intermediate hosts, and thereby initiate a new influenza pandemic comparable to the great pandemics of 1918 (“Spanish flu”), 1957 (“Asian flu”), 1968 (“Hong Kong flu”), and 1977 (H1N1 virus). The influenza viruses are segmented genome RNA viruses classified in the family Orthomyxoviridae. They constitute 3 of the 5 genera of the family and are designated influenzavirus A, influenzavirus B, and influenzavirus C. Each is represented by single virus species: influenza A virus, influenza B virus, and influenza C virus [1]. The influenza A viruses exist as several Received 5 October 2004; accepted 4 November 2004; electronically published 7 December 2004. Reprints or correspondence: Dr. Donald Kaye, 1535 Sweet Briar Rd., Gladwyne, PA 19035 ([email protected]). Clinical Infectious Diseases 2005; 40:108–12
2004 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2005/4001-0016$15.00

distinct subtypes, defined by the hemagglutinin (H) and neuraminidase (N) surface antigens, which infect humans and a range of avian and mammalian species. The influenza B viruses do not exhibit subtype variation and appear to infect humans only, causing epidemics but not pandemics—presumably because there is no reservoir of novel antigenic variation in nonhuman hosts. Influenza C viruses infect humans and have also been isolated from pigs in China, but these viruses are not associated with either epidemic or pandemic disease in the human population. The influenza A viruses exist in greatest profusion in waterfowl. At present, 15 distinct H and 9 distinct N antigenic types are recognized (table 1), all of which occur in waterfowl in virtually all combinations. It is generally accepted that feral aquatic birds are the reservoir for influenza A viruses and that influenza in aquatic birds has achieved “evolutionary stasis” [2], meaning that the internal genes of the viruses show little genetic variation even over many decades, unlike those of the

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influenza viruses present in other species. A recent survey of influenza A viruses isolated from feral Canadian ducks over a period of 17 years confirmed the stability of the gene pool and, at the same time, revealed that extensive reassortment of genes was occurring more or less at random, so that all combinations of H and N antigen subtypes were present [3]. In contrast, the combinations of H and N subtype genes in mammalian influenza viruses and avian influenza viruses present in domestic fowl are strictly limited. The avian influenza viruses causing disease in domestic poultry are predominantly viruses of H5 and H7 subtypes. Strains of low- (LPAI) and high- (HPAI) pathogenicity avian influenza virus of each subtype exist. Pathogenicity is determined in part by the presence of multiple basic amino acids (arginine and lysine) at the cleavage site of the H protein [4]. Cleavage of the H molecule is necessary for infectivity of the virus, and the susceptibility of the H molecule to specific cellular proteases determines the tissue tropism and virulence of the virus. Conversely, the re-

Table 1. Hemagglutinin (H) and neuraminidase (N) influenza A virus subtypes in different species. Subtype H subtype H1

Waterfowl

Humans

Swine

Equines

Other mammals

Yes

Yes

Yes

No

No

H2 H3 H4

Yes Yes Yes

Yes Yes No

No Yes No

No Yes No

No No Yes (seal)

H5 H6 H7 H8

Yes Yes Yes Yes

Yes No Yes No

No No No No

No No Yes No

No No Yes (seal) No

H9 H10 H11

Yes Yes Yes

Yes No No

No No No

No No No

No Yes (mink) No

H12 H13 H14

Yes Yes Yes

No No No

No No No

No No No

No Yes (whale) No

Yes

No

No

No

No

Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes Yes No No No No Yes No No

Yes Yes No No No No No No No

No No No No No No Yes Yes No

No Yes (whale) No Yes (mink) Yes (seal) No Yes (seal) No Yes (whale)

H15 N subtype N1 N2 N3 N4 N5 N6 N7 N8 N9

sistance or susceptibility of different varieties of domestic fowl may be determined by the specificity of their cellular proteases. The diversity of influenza A virus in feral aquatic fowl contrasts with the limited range of antigenic subtypes associated with epidemic disease in domestic fowl. It is clear that the simple crossinfection between avian hosts is not sufficient by itself to generate a new pathogenic virus; additional genetic changes are required. Feral aquatic birds generally do not become ill from influenza viruses, whereas HPAI virus causes devastation in domestic flocks of poultry. As a useful concept, domestic poultry may be considered to be an intermediate host between feral aquatic birds and humans. Domestic ducks have recently been shown to become infected with no apparent illness and to shed large

amounts of H5N1 virus for long periods of time [5]. Swine have been considered by some to be prime candidates for the role of intermediate host in the potential transmission of avian influenza viruses to humans by virtue of the fact that the respiratory tract epithelial cells of pigs contain the sialic acid receptors preferred by both avian (a2,3-N-acetylneuraminic acid-galactose) and human (a2,6-acetylneuramnic acidgalactose) influenza viruses [6]. For this reason, pigs have been hypothesized as filling the role of “mixing vessels” [7, 8], facilitating genetic interaction between viruses previously restricted to avian or mammalian hosts. Recent reports of detection of avian-like influenza viruses in swine in China [9] have heightened concerns that such interactions may result in the evolution of a new pandemic influenza

virus. However, there is no evidence for pigs ever having served as “mixing vessels.” None of the 4 major human influenza pandemics of 1918 (H1N1), 1957 (H2N2), 1968 (H3N2), and 1977 (H1N1) appear to have originated by this route. The 1957 and 1968 pandemics are thought to have originated by reassortment of genome subunits from avian and human influenza viruses. The origin of the 1918 pandemic virus is less certain [10], and the enigmatic reappearance of the H1N1 subtype virus in 1977 is similarly unresolved. These mechanisms of evolution of influenza virus pathogens are not specific to birds and humans. In 1989 and 1990, there were severe outbreaks of equine H3N8 virus influenza in northeast China that were caused by an influenza virus in which 6 of the 8 genes were of recent avian origin [11]. Subsequent cases of an avian-like H3N8 virus involved other species, including humans [12]. A new phenomenon has been the appearance of severe sporadic cases of avian H5N1 subtype viruses in humans, occurring first in the Hong Kong Special Administrative Region of China and later in Thailand and Vietnam [13–15]. Molecular analysis has established that these viruses are almost certainly avian influenza viruses transmitted directly to humans from domestic poultry that, in turn, were infected by aquatic birds. These viruses were unaltered by passage through an intermediate mammalian host. The H5N1 subtype viruses have been associated with severe illness and death, as discussed below, but so far have been associated with very limited person-to-person transmission of clinical infection. Influenza in swine caused by a virus of subtype H1N1 was first described in the United States around the time of the 1918 pandemic in humans [16]. Subsequently, viruses of subtypes H1N1 and H3N2 appeared in Europe and elsewhere in domestic pigs. The isolation of subtype H1N1 swine influenza viruses from military recruits at Fort Dix, New Jersey, in

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1976 caused considerable concern, despite the absence of an epidemic, and sparked a massive precautionary immunization campaign. Influenza (predominantly due to H1N1 virus) is now a common and economically important cause of respiratory disease in pigs. Infection of farmers and abattoir workers is relatively common, but illness is mild and person-to-person transmission very limited. The total number of zoonotic infections that have been described is exceedingly small in relation to the huge number of individuals exposed to infection worldwide [17]. The H1N1 virus responsible for the human pandemic in 1977 was not closely related to the H1N1 virus present in swine, but was very similar to the H1N1 virus present in humans during the interpandemic period prior to the 1957 pandemic, before it was replaced in the human population by the H2N2 virus. Other factors equally relevant to the emergence of pandemic influenza are the increasing size and mobility of the human population and the vast expansion of the poultry industry worldwide (and in eastern Asia, in particular). The avian influenza A (i.e., H5N1) virus cases in eastern Asia were preceded in 2003 by a devastating outbreak of avian influenza in poultry in The Netherlands that was caused by an H7N7 virus [18]. This virus was responsible for the death of a veterinarian and extensive conjunctivitis among those employed in disposal of diseased birds. Recent serological surveys suggest that the infection spread wider than was originally supposed. Approximately 500 people were infected either directly from their relatives or from colleagues, but no one who had indirect contact with diseased birds showed symptoms of infection [19]. A smaller outbreak of H7 virus (N subtype unconfirmed) occurred in British Columbia early in 2004 with little impact on the human population [20]. In 1997, H5N1 HPAI viruses were circulating in poultry farms and markets in the Hong Kong Special Administrative Region of China, and 18 cases of human

disease were confirmed, 6 of which resulted in death. Genome sequencing of the H5N1 virus established later that this virus possessed an H gene from an avian influenza virus present in geese and an N gene from waterfowl (teal). The remaining 6 internal genes originated either from the virus present in teal or from the virus present in quail. Because quail appeared to support the replication of most subtypes of avian influenza virus, it was suggested that quail might also function as a “mixing vessel” for generation of hybrid avian influenza virus [21]. In February 2003, a similar H5N1 strain again infected humans, causing illness in a family group of 3 individuals who were visiting southern China from Hong Kong, 2 of whom died. Later in 2003, an HPAI subtype virus (H5N1 virus) reappeared and spread rapidly through 8 countries in eastern Asia from Indonesia to China, resulting in the slaughter of some 100 million birds in largely unavailing efforts to contain the spread of infection. As of 28 September 2004, the World Health Organization (WHO) had confirmed, by laboratory testing, a total of 42 human cases of infection resulting in 30 deaths in Thailand and Vietnam (the cumulative number of avian A virus cases and deaths can be accessed at the WHO Web site [22]). No human cases have been confirmed from other east Asian countries up to the present, suggesting that social and lifestyle considerations, history of exposure to human influenza viruses (i.e., original antigenic sin), or perhaps genetic differences may play a role in susceptibility to infection. Alternatively, differences in the intensity of surveillance may play a role. Genome sequencing of viruses isolated from humans have so far not revealed systematic differences from circulating avian (H5N1) subtype viruses. Avian influenza A (i.e., H5N1) virus appears now to be enzootic in eastern Asia, and the risk of emergence of a human pandemic virus remains high. There is opportunity for a new pandemic virus to arise, either by progressive mutation and

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selection for a virus transmissible from person-to-person or by a human host assuming the role of “mixing vessel” and facilitating genetic interaction of avian and mammalian influenza viruses. Despite the widespread outbreaks of highly pathogenic avian influenza in birds in recent years, mainly in Asia, there have been relatively few reports of transmission to humans. Transmission from human to human has been even less frequent. Although human infection with H9N2 virus (a low pathogenic avian strain), H7N7 virus (a highly pathogenic avian strain), and H7 virus (N subtype unconfirmed) has been reported in people with close contact with infected poultry (in Hong Kong, The Netherlands, and Canada [specifically, in the Fraser Valley region of British Columbia], respectively), these cases have generally been mild. In contrast, human infection with H5N1 virus has been very severe, with a recent reported mortality rate of ∼70%. Serological test results positive for H9N2 avian strains with isolation from the throats of some patients with mild influenza-like illnesses were reported from China in 1999 [23, 24]. In an outbreak of H7N7 virus in poultry in The Netherlands in 2003, the virus was demonstrated in 78 poultry workers with conjunctivitis and 7 with influenza-like illnesses, as well as in 4 with other symptoms [25]. Three of 83 contacts were found to have evidence of infection, 1 of whom developed an influenza-like illness [18]. All illness was mild, except in the case of 1 of the patients with an influenza-like illness who developed evidence of primary viral pneumonia and acute respiratory distress syndrome and died [25]. In past years, H7N7 virus has caused isolated cases of infection in humans, including laboratory acquired infections. All infections were mild and were isolated to the eyes [26–31]. There has been a single probable case of human-to-human transmission of clinical disease with H5N1 virus, from a child to a mother who cared for her during her illness. Both individuals died [32].

In humans, infection with H5N1 virus has been deadly. In 1997 and then again starting in December of 2003 and continuing to the present, there have been severe cases of H5N1 infection in humans in Asia, with devastating outcomes. In 1997, in Hong Kong, there were 18 documented cases involving 6 deaths in people exposed to live poultry [15, 33, 34]. Eleven of the 18 patients developed viral pneumonia, and 6 of them died of acute respiratory distress syndrome and/or multiorgan failure. Although there were no clinical cases in a survey of poultry workers, 10% had serological evidence of infection [15]. More-intensive poultry exposure was related to higher rates of positive serological test results in the poultry workers. There was evidence of human-to-human transmission, but with low efficiency, because 3.7% of exposed health care workers had positive serological test results, compared with 0.7% of nonexposed heath care workers [35]. Similarly, there was 1 household contact of an H5N1-infected patient who had positive serological test results with no history of poultry contact [36]. Most of the 42 reported cases and 30 deaths among patients with H5N1 disease (from December 2003 through 28 September 2004) have been in children and young adults; however, the mortality rate has been higher in older adults [33, 37]. Most of the individuals who died had no obvious underlying disease. There was 1 reported case of Reye syndrome in a 3year-old child who was receiving aspirin and died of severe pulmonary disease [38]. The incubation period in the reported cases seemed to be 2–4 days (similar to that in cases of human influenza), followed in most patients by fever, cough, and dyspnea. Diarrhea was variably reported, and sore throat and runny nose were noted in some of the patients. A striking feature was marked lymphopenia in those patients that were severely ill. One of the cases probably resulted from close exposure to an infected child, as described above, and, if so, this represents trans-

mission of clinical infection from one human to another [32]. In those individuals with severe disease, there was rapid progression with increasing dyspnea; this is very much like what is seen in cases of primary influenza virus pneumonia caused by human viruses. However, unlike in cases of human influenza (in which primary viral pneumonia has been rare since the 1957–1958 epidemic, and in which secondary bacterial pneumonia has been a much more common complication), in the H5N1 avian virus cases, primary viral pneumonia was common, whereas secondary bacterial pneumonia has not been reported. The marked lymphopenia—together with the observation in a limited number of autopsies of a reactive hemophagocytic syndrome in bone marrow, lymph nodes, spleen, lungs, and liver—suggested to some investigators that a cytokine-driven condition might explain multiorgan failure in some patients [33, 39, 40]. It is unclear why so few of those individuals who are apparently exposed become infected and why the mortality rate is so high among those who become clinically infected. A genetic predisposition to infection, as well as to severe infection, must be considered, as well as the possibility that a strain that is more virulent for humans is found in a subset of the poultry. There was no obvious beneficial effect of treatment with corticosteroids, amantadine, ribavirin, or oseltamivir. However, patients were treated late in the course of illness, and earlier treatment might have been more effective. It can be concluded that clinically apparent H5N1 influenza infection in humans is a severe infection with a high mortality rate. Fortunately, avian-to-human and human-to-human transmission is inefficient and almost always seems to be a dead end, with no further onward transmission of the virus. At present, there is no good evidence for effective therapy or prophylaxis. However, trials with oseltamavir seem reasonable and should be further evaluated. Should the virus somehow

become more easily transmitted among humans, the result could be catastrophic.

Acknowledgments Potential conflicts of interest. All authors: no conflicts.

References 1. Van Regenmortel M. Virus taxonomy: 7th report of the International Committee on Taxonomy of Viruses. San Diego and London: Academic Press, 2000. 2. Gorman OT, Bean WJ, Webster RG. Evolutionary processes in influenza viruses: divergence, rapid evolution, and stasis. Curr Top Microbiol Immunol 1992; 176:75–97. 3. Hatchette TF, Walker D, Johnson C, Baker A, Pryor SP, Webster RG. Influenza A viruses in feral Canadian ducks: extensive reassortment in nature. J Gen Virol 2004; 85:2327–37. 4. Klenk HD, Rott R. The molecular biology of influenza virus pathogenicity. Adv Virus Res 1988; 34:247–81. 5. Li KS, Guan Y, Wang J, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 2004; 430:209–13. 6. Ito T, Couceiro JN, Kelm S, et al. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 1998; 72:7367–73. 7. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992; 56:152–79. 8. Scholtissek C, Burger H, Kistner O, Shortridge KF. The nucleoprotein as a possible major factor in determining host specificity of influenza H3N2 viruses. Virology 1985; 147:287–94. 9. ProMED-mail. Avian influenza porcine, H5N1–China: susp. ProMED-mail archive 20040820.2311. 20 August 2004. Available at: http://www.promedmail.org. Accessed 2 December 2004. 10. Reid AH, Taubenberger JK. The origin of the 1918 pandemic influenza virus: a continuing enigma. J Gen Virol 2003; 84:2285–92. 11. Guo Y, Wang M, Kawaoka Y, et al. Characterization of a new avian-like influenza A virus from horses in China. Virology 1992; 188: 245–55. 12. Guo Y, Wang M, Zheng GS, Li WK, Kawaoka Y, Webster RG. Seroepidemiological and molecular evidence for the presence of two H3N8 equine influenza viruses in China in 1993–94. J Gen Virol 1995; 76:2009–14. 13. ProMED-mail. Avian influenza, human—East Asia (44): Vietnam. ProMED-mail archive 20040912.2537. 12 September 2004. Available at: http://www.promedmail.org. Accessed 2 December 2004. 14. ProMED-mail. Avian influenza, human—

Avian Influenza and Human Health • CID 2005:40 (1 January) • 111

15.

16.

17.

18.

19.

20.

21.

22.

Thailand (06). ProMED-mail archive 20040909.2513. 9 September 2004. Available at: http://www.promedmail.org. Accessed 2 December 2004. Bridges CB, Lim W, Hu-Primmer J, et al. Risk of influenza A (H5N1) infection among poultry workers, Hong Kong, 1997–1998. J Infect Dis 2002; 185:1005–10. Bachman P. Swine influenza virus. In: Pensaert M, ed. Virus infections of vertebrates. Vol. 2. Amsterdam: Elsevier, 1989:193–207. Olsen C, Brammer L, Easterday BC, et al. Serologic evidence of H1 swine influenza virus infection in swine farm residents and employees. Emerg Infect Dis 2002; 8:814–9. Koopmans M, Wilbrink B, Conyn M, et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 2004; 363:587–93. Dutch find greater threat to humans from avian influenza. 14 September 2004. Available at: http://www.reutershealth.com. Accessed 2 Decmber 2004. ProMED-mail. Avian influenza, H7, poultry—Canada (BC)(22). ProMED-mail archive 20040505.1233. 5 May 2004. Available at: http: //www.promedmail.org. Accessed 2 December 2004. Perez DR, Lim W, Seiler JP, et al. Role of quail in the interspecies transmission of H9 influenza A viruses: molecular changes on HA that correspond to adaptation from ducks to chickens. J Virol 2003; 77:3148–56. World Health Organization. Cumulative number of confirmed human case of avian influenza A (H5N1) since 28 January 2004. Available at: http://www.who.int/csr/disease/

23.

24.

25.

26.

27.

28.

29.

30.

31.

112 • CID 2005:40 (1 January) • Kaye and Pringle

avian_influenza/country/cases_table_2004_ 10_04/en/. Accessed 2 December 2004. Guo Y, Li J, Cheng X. Discovery of men infected by avian influenza A (H9N2) virus [in Chinese]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 1999; 13:105–8. Gou Y, Xie J, Wang M. A strain of influenza A H9N2 virus repeatedly isolated from human population in China [in Chinese]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2000; 14:209–12. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci U S A 2004; 101: 1356–61. DeLay PD, Casey HL, Tubiash HS. Comparative study of fowl plague virus and a virus isolated from man. Public Health Rep 1967; 82:615–20. Campbell CH, Webster RG, Breese SS, Jr. Fowl plague virus from man. J Infect Dis 1970; 122: 513–6. Taylor HR, Turner AJ. A case report of fowl plague keratoconjunctivitis. Br J Ophthalmol 1977; 61:86–8. Webster RG, Geraci J, Petursson G, Skirnisson K. Conjunctivitis in human beings caused by influenza A virus of seals. N Engl J Med 1981; 304:911. Kurtz J, Manvell RJ, Banks J. Avian influenza virus isolated from a woman with conjunctivitis. Lancet 1996; 348:901–2. Banks J, Speidel E, Alexander DJ. Characterisation of an avian influenza A virus isolated from a human—is an intermediate host necessary for the emergence of pandemic influenza viruses? Arch Virol 1998; 143:781–7.

32. ProMED-mail. Avian influenza, human—East Asia (48): Thailand. ProMED-mail archive 20040928.2680. 28 September 2004. Available at: http://www.promedmail.org. Accessed 2 December 2004. 33. Chan PK. Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis 2002; 34(Suppl 2): S58–64. 34. Yuen KY, Chan PK, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998; 351:467–71. 35. Buxton Bridges C, Katz JM, Seto WH, et al. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 2000; 181:344–8. 36. Katz JM, Lim W, Bridges CB, et al. Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts. J Infect Dis 1999; 180:1763–70. 37. Tran TH, Nguyen TL, Nguyen TD, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 2004; 350:1179–88. 38. Ku AS, Chan LT. The first case of H5N1 avian influenza infection in a human with complications of adult respiratory distress syndrome and Reye’s syndrome. J Paediatr Child Health 1999; 35:207–9. 39. To KF, Chan PK, Chan KF, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 2001; 63:242–6. 40. Peiris JS, Yu WC, Leung CW, et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 2004; 363:617–9.