Transmission of highly pathogenic avian influenza A (H5N1) associated with possible human pandemic: A review of the current literature
Ashley Marie Jackson
Introduction
Highly pathogenic avian influenza (HPAI) has emerged in humans as the strain H5N1, with over 200 infections having been confirmed. The dates of these cases coincided with outbreaks of H5N1 in poultry, elevating fears of a new human pandemic virus (Maines et al., 2006). Before 1997, H5N1 had never been detected in a human being; after a young boy died from the virus, panic erupted concerning a possible worldwide pandemic of ‘bird flu’ (Class et al., 1998). While the pandemics of 1957 and 1968 were the result of mixtures of avian and human influenza genes in a new virus, H5N1 is a purely avian strain, toward which humans harbor no immunity (Claas et al., 1998, Smith et al. 2006). In both previous pandemics, hundreds of thousands of people were killed around the world. Since the last influenza pandemic in 1968, the increased mobility of the human population coupled with the expansion of the poultry industry have escalated the probability of an occurrence of another global avian influenza pandemic. Waterfowl naturally carry the H5N1 strain of HPAI which infects domestic poultry, resulting in a high proportion of severe illness and death. This virus, if transmitted to humans could have the same outcome as previous pandemics. The three criteria for a pandemic virus are the ability to replicate in humans, an absence of antibodies in the majority of the human population, and rapid spread from human to human (Claas et al., 1998). H5N1 currently meets the first two criteria. On a large scale, humans lack antibodies for the H5 glycoprotein in H5N1 (Bridges et al., 2000). If the virus evolves the ability to transmit efficiently within the human species, a pandemic could emerge, infecting and killing people across the globe. According to the study by Bridges et al. (2000) on human infections in Hong Kong, “low levels of human transmission may lead to adaptation of the virus to humans through the accumulation of point mutations or through reassortment with a human influenza virus (p.1005).” Either mode of adaptation by the virus could lead to a hybrid virus with high potential for a human pandemic (Ito et al., 1998). A resulting hybrid virus could easily be transmitted from one infected host to a susceptible organism if it lacks immunity to that virus. Without knowing exactly how these viruses arise, predicting the probability of a pandemic is difficult at best. An understanding of the modes of transmission of avian influenza within and among species is crucial for predicting and controlling a possible HPAI pandemic. This paper evaluates the current research on transmission of avian influenza between poultry and humans, as well as the likelihood of another global pandemic. Because avian influenza transmission is a relatively new issue and research has only recently begun to address the probability of another pandemic, suggestions for future research are also mentioned. Modes of AI virus transmission Transmission to humans via reassortment vs. direct transfer Reassortment of genes between two different viral strains has shown itself to produce pandemic viruses. Both the pandemics of 1957 and 1968 were human influenza strains containing several avian virus glycoproteins, which is proof of reassortment and a possible explanation for production of pandemic viruses (Claas et al., 1998). The longer the two strains remain together in 10 an organism, the greater the probability of reassortment occurring. Menach et al. (2006) suggest the best method for preventing a pandemic is to control outbreaks in poultry before the virus is given the opportunity to reassort. The pandemic of 1957 was the result of reassortment of avian influenza strain H2N2 with human H1N1. The new hybrid virus led to pandemic effects due to a lack of general immunity in humans. However, the species in which this recombination took place is unknown (Day et al., 2006). A popular hypothesis is that the pig is a mixing vessel for novel influenza viruses. Pigs contain receptors in their trachea for both avian and human influenza, which allow for reassortment to occur when a pig is co-infected with both types (Ito et al., 1998). In addition, humans have been suggested as possible vessels for reassortment (Claas et al., 1998). If a human influenza outbreak coincides with an avian influenza outbreak, reassortment could occur in the same manner as with pigs, though no concrete evidence has been found (Claas et al., 1998). More research needs to be conducted to determine specific mammal species that could act as mixing vessels in order to predict pandemic virus emergence. Reassortment is but one possible mode of producing pandemic viruses in humans. HPAI could be transferred from an infected bird into a human. Direct transmission of avian influenza from poultry to humans has been documented. Claas et al. (1998) found a young boy infected with an H5N1 virus containing identical genes as an H5N1 outbreak in a nearby chicken flock. This case has been dismissed by other studies as merely a rare event of direct transfer from infected poultry to a human (Yuen et al., 1998, Vong et al., 2006). Future research should address reassortment efficiency between existing H5N1 and circulating human influenza viruses to determine if direct transfer without reassortment is possible. Poultry-to-human mode of transmission Avian influenza has been speculated to directly transmit from infected poultry to humans. Infections of HPAI in poultry tend to correlate with those in humans. In Hong Kong, 18 human cases of H5N1 coincided with outbreaks in the local poultry market at the end of 1997, suggesting numerous, independent poultry-to-human transmissions of H5N1 viruses (Bridges et al., 2002). After the slaughter of 1.5 million chickens in Hong Kong, no more human cases were detected. When the workers involved in the slaughter were tested for the presence of H5N1 in their blood, poultry farm employees contained a greater percentage of antibodies than did government workers only involved for the one-day slaughter. This suggests that prolonged contact with infected chickens in poultry markets is a greater risk factor for becoming exposed and possibly infected with the virus (Bridges et al., 2002). Halvorson’s and Hueston’s (2006) exposure risk index also supports this finding. Their model states that the likelihood of disease exposure is related to the virus stock as well as proximity to vulnerable animals. In addition, infection in poultry tends to follow live poultry movement, shifting of workers and equipment, and depopulation routes. Both studies show a high correlation between poultry infection and human infection. While these studies concluded that poultry infection is often followed by human exposure and possible infection, other studies found different results. The study by Vong et al. (2006) addressed farmers in Cambodia with H5N1 infected flocks. It was found that none of the 351 villagers tested had either been infected or had antibodies for H5N1, even though 73% of them had lost chickens to the virus within the past month. However, one farmer died from H5N1 in the area before the study was conducted, though it has been suggested that he might have been unique in susceptibility to the virus, resulting in a systemic inflammatory response that killed him. Due to such high contrast in conclusions in each of these studies, future research should focus on finding evidence on whether interspecies transmission of H5N1 is occurring and the exact modes of avian 11 influenza spread. Human-to-human transmission In order for a pandemic virus to emerge, human-to-human transmission must be shown to be efficient. The possibility of human-to-human transmission has been confirmed in Rimmelzwaan et al.’s study (2006). Their findings suggest that the H5N1 virus is expelled through the feces, urine, and lung excretion of infected cats, leading to intraspecies spread of H5N1and potentially creating a pandemic. Although this study used cats as a model, cats and humans have the same influenza receptors in their lungs, so these results are general to humans as well. A more conclusive study in Hong Kong found human-to-human transmission of H5N1. Bridges et al. (2000) found that after admission of infected patients to a hospital, 3.7% of healthcare workers with both indirect and direct exposure to the patients (and no poultry contact), tested positive for H5N1 antibodies after two weeks. Although this seems like a low percentage of transmission, the findings show that human-to-human transmission can and does occur, which increases the potential of pandemic avian influenza in humans. In contrast to these findings, a study performed using ferrets as a model for H5N1 intraspecies transmission found that the virus lacked the ability to transmit effectively between ferrets (Maines et al., 2006). The virus was recovered only in small quantities in nasal secretions in uninfected ferrets housed with H5N1 infected ferrets. This shows that the virus cannot effectively transfer itself between certain mammal hosts, as it does in poultry. The results of these studies show a relatively low frequency of avian influenza transmission within a species, suggesting that H5N1 has yet to meet the final characteristic of a pandemic virus. More research needs to be conducted to evaluate transmission efficiency of current H5N1 and potential recombinant strains to monitor pandemic potential. Virus replication Once an organism is infected with HPAI, the virus rapidly replicates in the host’s tissues and is transmitted out of the body before the host is killed. However, the replication of influenza viruses in mammals is poorly understood, especially within and between hosts. It has been suggested that the pathogenic nature of avian influenza in mammals is due to systemic infection beyond the respiratory tract (Rimmelzwaan et al., 2006). Virulent strains such as H5N1 infect, spread, and kill their hosts rapidly, with devastating results for at risk species. Yuen et al. (1998) state that “definitive evidence of virus replication in organs other than the respiratory tract is lacking (p.470).” However, in a breakthrough study by Rimmelzwaan et al. (2006) on H5N1 infection in cats, significant viral replication in the brain, heart, kidneys, and liver, in addition to the lungs was found. The systemic nature of H5N1 symptoms fuels fear of a deadly human pandemic; severe necrosis of tissue and inflammation throughout the body are difficult to treat, with death occurring only days after hospitalization (Rimmelzwaan et al., 2006). This study is the first to show evidence of viral replication in organs other than the respiratory tract. If H5N1 acquired ability to replicate more readily in humans, the second criterion of a human pandemic would be met. Future research should scrutinize replication efficiency in other mammalian species, including humans, as well as quantify such efficiency. Viral mutations Avian influenza viruses have the potential to bind effectively to human receptors without undergoing recombination with human influenza. Day et al.’s (2006) model predicts that mutation without reassortment can produce a pandemic virus that binds directly to human influenza receptors. Such 12 a shift in receptor specificity has not been thoroughly researched and the mechanism by which it occurs is unknown. In 2006, Maines et al. found that a shift in avian virus receptor SA alpha 2,3 to human virus receptor SA alpha 2,6 is necessary for efficient replication and spread of a new pandemic strain. This process of shifting receptor specificity is thought to happen during viral adaptation to a novel host species. Maines et al. (2006) also found that H5N1 tends to retain receptor preference for SA alpha 2,3 suggesting stability in receptor specificity and a decrease in probability of mutation. This shows that the virus prefers its natural avian hosts and thus is less of a threat as a human pandemic. In contrast, Smith et al. (2006) found that a single amino acid substitution in H5N1 was associated with increased replication in mammals, a mutation that could lead to a more virulent pandemic virus. Regardless of these differences in results, future research should focus on determining the structure of mutant genes in avian influenza to predict emergence of new pandemic viruses (Ito et al., 1998). Conclusion The current research on HPAI transmission seems to be in the beginning stages of forming definitive conclusions. All studies recognize the limitations of their research and suggest that more research must be conducted to determine the viability of a global human pandemic. Future research must clearly define efficient transmission, as the studies currently lack a universal definition of the term. Reassortment efficiency between H5N1 and human influenza needs to be investigated further to determine whether direct transfer does occur. Furthermore, the species that are suitable mixing vessels for recombination need to be established to monitor pandemic probability over time. Similarly, the structure of mutant genes in H5N1 needs to be determined in order to verify their origin. Interspecies and intraspecies transmission also require further analysis to demonstrate the modes of avian influenza spread and find out which species are at-risk for infection. Finally, viral replication...........continued in print edition.
