Eye on ID

Is avian flu coming for you?

There is considerable concern about the risk for international spread that pathogenic avian influenza viruses pose for humans. Influenza A(H5N1) and A(H7N9) are the two most likely potential threats.

Thomas M. Yuill
Donald Kaye

Influenza A(H5N1)

Influenza A(H5N1), a highly pathogenic virus for poultry, first attracted attention in China in 1996, when an outbreak with high mortality occurred in domestic poultry. A year later, it caused an outbreak in poultry and infected 18 people, six of whom died. Beginning in 2003, the virus rapidly spread to other Southeast Asian countries with outbreaks in chickens and ducks that spilled over to humans. In 2005, there was an outbreak in wild, migratory bar-headed geese (Anser indicus) at Qinghai Lake. Migratory waterfowl and the movement of poultry and poultry products were reported to be responsible for spreading the virus to other Asian countries, the Middle East, Europe and Africa. The virus has become endemic in poultry in China, Vietnam, Indonesia, Bangladesh and Egypt, where cases occur sporadically in humans. As of Oct. 30, 2017, a total of 860 laboratory-confirmed cases of human infection with avian influenza A(H5N1) virus, including 454 deaths (53% case-fatality rate), have been reported to WHO from 16 countries. Infection has occurred mainly in children and young healthy adults. Backyard poultry exposure has been the major source of human infection. Mortality in poultry related to A(H5N1) and the culling of infected poultry populations to halt the outbreak resulted in significant economic losses.

Influenza A(H7N9)

A novel A(H7N9) influenza virus infection in three humans was first diagnosed in China in March 2013, followed shortly by additional cases. The severity of respiratory infections in humans caused by the virus rapidly became apparent, with fatalities in about one-third of hospitalized cases. Influenza virus drug resistance was soon demonstrated in A(H7N9) virus recovered from some hospitalized patients. Human cases have been associated with direct contact with poultry, birds and their contaminated environments, especially in live bird markets. This virus had low pathogenicity for poultry, and there was no illness recognized in the birds.

Exposure to poultry in live bird markets in China has been identified as a source of human infection with influenza A(H7N9).

Source: Shutterstock

By June 2013, 133 human cases and 43 deaths had been reported. The outbreak affected 10 provinces, with 106 of the cases being concentrated in the eastern coastal provinces of Zhejiang, Shanghai and Jiangsu. There was statistically significant spatial clustering of human cases. Again, most patients visited live poultry markets or had close contact with live poultry 7 to 10 days before illness onset, rather than having had contact with infected people. However, there was one instance of suspected human-to-human transmission when two almost genetically identical virus isolates were recovered, first from a father and then shortly after from his daughter.

During this time, health officials made progress identifying the origin of the virus subtype. The new A(H7N9) viruses were determined to have emerged through a two-step process of reassortment of RNA segments between other virus subtypes. The first took place in wild birds, in which genetic material from A(H9N2) viruses and unspecified H7 and N9 viruses was mixed to create precursor A(H7N9) viruses. The second step occurred in domestic birds in eastern China early in 2012, with the exchange of genetic material between the precursor A(H7N9) viruses and other A(H9N2) viruses to create new, genetically diverse A(H7N9) viruses that began to infect people.

Not all human infections with this subtype resulted in serious disease or death. There was evidence of the occurrence of asymptomatic infections in Zhejiang province, where 6.3% of healthy poultry workers had hemagglutination (HA)-inhibition antibodies to the virus.

Concern about the risk for epidemic spread in the human population led to studies in animal models. Researchers studied the transmissibility of the virus in mice, ferrets and nonhuman primates. Although studies demonstrated that the virus can be transmitted in these animals, the researchers also found that virus replication was more efficient at higher temperatures of the lower respiratory tract than at lower temperatures found in the upper respiratory tract, perhaps explaining in part why very little human-to-human transmission had been reported.

In October 2013, there was concern that the number of cases of A(H7N9) would increase seasonally during the colder months (October through March). A decision was made to close live bird markets to reduce the risk for human infection. These closures reduced the average daily number of human infections by 99% in Shanghai, 99% in Hangzhou, 97% in Huzhou and 97% in Nanjing. However, some people objected to the closures, arguing that they infringe upon Chinese traditions of buying live poultry and negatively impact the economy. In early February 2014, the economic consequences of live market closures, along with popular media reports, made closures an issue. The national association of poultry farmers and their provincial counterparts in Guangxi and Guangdong asked local authorities to stop reporting individual cases of A(H7N9) infections. An influential group, the National Animal Husbandry Association, claimed that identifying the virus as avian influenza had brought financial disaster to the poultry industry, resulting in losses of more than 100 billion yuan (currently around $15 billion). The letter was signed by 1,012 poultry industry executives who said some industry participants were facing heavy losses and even bankruptcy because of stigma associated with the disease, along with inaccurate information reported in the media regarding how the virus is spread via birds. However, a 2015 study found that the closures effectively reduced cases. When markets were reopened during the summer months, there were no A(H7N9) outbreaks, thus preserving the live bird market tradition.

In late 2013 and into 2014, cases increased with a second wave of the outbreak. At this time, the virus was isolated from an apparently healthy wild tree sparrow in Shanghai, raising the question if the virus might be transmitted among poultry and tree sparrows. Fortunately, no additional virus isolates were recovered from wild birds. Had this case been indicative of the presence of the virus in wild birds as healthy carriers, the epidemiological picture would have changed, and control of the disease in poultry and surveillance in general would have become much more difficult.

In the first four waves of the outbreak (2013-2016), there was no illness recognized in poultry. There is evidence that the fifth epidemic wave (2016-2017) was the most severe yet. A June 2017 review of the 5 years of outbreaks in China since 2013 compared their epidemiological characteristics and clinical severity. This study found that the 2016-2017 epidemic began earlier, occurred in a wider geographical area with more districts and counties in affected provinces, and resulted in more confirmed cases than the previous epidemic waves. Unlike A(H5N1), which primarily affected a young and healthy population, the A(H7N9) virus has caused disease in an older, mainly male population, often with underlying diseases. The proportion of cases in middle-aged adults increased steadily from 41% in the first wave to 57% in the fifth. The occurrence of cases in semi-urban and rural residents in the two most recent waves was higher than in the first three waves. However, the clinical severity of disease in hospitalized patients was similar in all epidemics waves. The CDC reported that in the fifth wave, there were 759 cases, nearly as many as were reported in all four previous epidemics combined. The total since the outbreak started in 2013 has been 1,564 cases and at least 612 deaths (case-fatality rate, 39%). However, because of the existence of asymptomatic disease, this mortality rate is undoubtedly overstated.

A(H7N9) has caused almost twice as many infections in about 4 1/2 years as A(H5N1) did in 15 years. In fact, A(H7N9) has caused almost as much disease in the fifth epidemic wave as A(H5N1) did in all 15 years. It should be noted that the sixth epidemic wave has just started. All A(H7N9) infections across all five waves were acquired in China, Hong Kong and Macao.

There have been recent changes in virus pathogenesis in poultry, with some A(H7N9) isolates causing morbidity and mortality in poultry, whereas in previous outbreaks, infections in birds were classified as having low pathogenicity. The virus is evolving. An analysis of HA gene sequences from 166 isolates collected during the fifth wave indicated that there are now two different lineages of the virus — the Pearl River lineage and the Yangtze River Delta lineage. All 166 viruses had the S31N mutation in the M2 protein, indicating resistance to amantadine and rimantadine. According to researchers, 160 were from human cases in mainland China, five were from Hong Kong and one was from Taiwan. The 2017 isolates were antigenically different from the 2013 isolates, raising questions about the efficacy of vaccines based on the 2013 virus.

Pandemic potential

Currently, neither A(H5N1) nor A(H7N9) are transmitted efficiently between humans because they do not infect the upper respiratory tract effectively. There have been no instances of sustained human-to-human transmission of these virus subtypes. However, future mutations, better adapted to humans or genomic reassortment, with more transmissible influenza virus strains, may facilitate upper respiratory infection with aerosol transmission between people and increase the risk for pandemic spread.

A(H5N1) has been causing disease in humans for about 15 years without any evidence of sustained human-to-human transmission. Although there is always the possibility of a mutation or recombination with another influenza virus that could change transmissibility, such an event seems less likely than with the A(H7N9) virus.

Should these mutants or reassortants result in subtypes that maintain their virulence for humans, a severe influenza pandemic with a high incidence of morbidity and mortality is possible. The 1918 pandemic resulted in the deaths of 30 to 50 million people, and the disease spread in the absence of commercial air travel. The H7N9 virus is rated by the CDC’s Influenza Risk Assessment Tool as having the greatest potential to cause a pandemic and severely impact public health, although that risk is considered low. However, should a mutant or reassorted virus appear and begin to spread, would production of vaccines for humans be rapid enough to halt human-to-human spread? Adequate surveillance of A(H7N9) and A(H5N1) infections in people and birds with timely laboratory support is essential to detect any such threat early.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

There is considerable concern about the risk for international spread that pathogenic avian influenza viruses pose for humans. Influenza A(H5N1) and A(H7N9) are the two most likely potential threats.

Thomas M. Yuill
Donald Kaye

Influenza A(H5N1)

Influenza A(H5N1), a highly pathogenic virus for poultry, first attracted attention in China in 1996, when an outbreak with high mortality occurred in domestic poultry. A year later, it caused an outbreak in poultry and infected 18 people, six of whom died. Beginning in 2003, the virus rapidly spread to other Southeast Asian countries with outbreaks in chickens and ducks that spilled over to humans. In 2005, there was an outbreak in wild, migratory bar-headed geese (Anser indicus) at Qinghai Lake. Migratory waterfowl and the movement of poultry and poultry products were reported to be responsible for spreading the virus to other Asian countries, the Middle East, Europe and Africa. The virus has become endemic in poultry in China, Vietnam, Indonesia, Bangladesh and Egypt, where cases occur sporadically in humans. As of Oct. 30, 2017, a total of 860 laboratory-confirmed cases of human infection with avian influenza A(H5N1) virus, including 454 deaths (53% case-fatality rate), have been reported to WHO from 16 countries. Infection has occurred mainly in children and young healthy adults. Backyard poultry exposure has been the major source of human infection. Mortality in poultry related to A(H5N1) and the culling of infected poultry populations to halt the outbreak resulted in significant economic losses.

Influenza A(H7N9)

A novel A(H7N9) influenza virus infection in three humans was first diagnosed in China in March 2013, followed shortly by additional cases. The severity of respiratory infections in humans caused by the virus rapidly became apparent, with fatalities in about one-third of hospitalized cases. Influenza virus drug resistance was soon demonstrated in A(H7N9) virus recovered from some hospitalized patients. Human cases have been associated with direct contact with poultry, birds and their contaminated environments, especially in live bird markets. This virus had low pathogenicity for poultry, and there was no illness recognized in the birds.

Exposure to poultry in live bird markets in China has been identified as a source of human infection with influenza A(H7N9).

Source: Shutterstock

By June 2013, 133 human cases and 43 deaths had been reported. The outbreak affected 10 provinces, with 106 of the cases being concentrated in the eastern coastal provinces of Zhejiang, Shanghai and Jiangsu. There was statistically significant spatial clustering of human cases. Again, most patients visited live poultry markets or had close contact with live poultry 7 to 10 days before illness onset, rather than having had contact with infected people. However, there was one instance of suspected human-to-human transmission when two almost genetically identical virus isolates were recovered, first from a father and then shortly after from his daughter.

PAGE BREAK

During this time, health officials made progress identifying the origin of the virus subtype. The new A(H7N9) viruses were determined to have emerged through a two-step process of reassortment of RNA segments between other virus subtypes. The first took place in wild birds, in which genetic material from A(H9N2) viruses and unspecified H7 and N9 viruses was mixed to create precursor A(H7N9) viruses. The second step occurred in domestic birds in eastern China early in 2012, with the exchange of genetic material between the precursor A(H7N9) viruses and other A(H9N2) viruses to create new, genetically diverse A(H7N9) viruses that began to infect people.

Not all human infections with this subtype resulted in serious disease or death. There was evidence of the occurrence of asymptomatic infections in Zhejiang province, where 6.3% of healthy poultry workers had hemagglutination (HA)-inhibition antibodies to the virus.

Concern about the risk for epidemic spread in the human population led to studies in animal models. Researchers studied the transmissibility of the virus in mice, ferrets and nonhuman primates. Although studies demonstrated that the virus can be transmitted in these animals, the researchers also found that virus replication was more efficient at higher temperatures of the lower respiratory tract than at lower temperatures found in the upper respiratory tract, perhaps explaining in part why very little human-to-human transmission had been reported.

In October 2013, there was concern that the number of cases of A(H7N9) would increase seasonally during the colder months (October through March). A decision was made to close live bird markets to reduce the risk for human infection. These closures reduced the average daily number of human infections by 99% in Shanghai, 99% in Hangzhou, 97% in Huzhou and 97% in Nanjing. However, some people objected to the closures, arguing that they infringe upon Chinese traditions of buying live poultry and negatively impact the economy. In early February 2014, the economic consequences of live market closures, along with popular media reports, made closures an issue. The national association of poultry farmers and their provincial counterparts in Guangxi and Guangdong asked local authorities to stop reporting individual cases of A(H7N9) infections. An influential group, the National Animal Husbandry Association, claimed that identifying the virus as avian influenza had brought financial disaster to the poultry industry, resulting in losses of more than 100 billion yuan (currently around $15 billion). The letter was signed by 1,012 poultry industry executives who said some industry participants were facing heavy losses and even bankruptcy because of stigma associated with the disease, along with inaccurate information reported in the media regarding how the virus is spread via birds. However, a 2015 study found that the closures effectively reduced cases. When markets were reopened during the summer months, there were no A(H7N9) outbreaks, thus preserving the live bird market tradition.

PAGE BREAK

In late 2013 and into 2014, cases increased with a second wave of the outbreak. At this time, the virus was isolated from an apparently healthy wild tree sparrow in Shanghai, raising the question if the virus might be transmitted among poultry and tree sparrows. Fortunately, no additional virus isolates were recovered from wild birds. Had this case been indicative of the presence of the virus in wild birds as healthy carriers, the epidemiological picture would have changed, and control of the disease in poultry and surveillance in general would have become much more difficult.

In the first four waves of the outbreak (2013-2016), there was no illness recognized in poultry. There is evidence that the fifth epidemic wave (2016-2017) was the most severe yet. A June 2017 review of the 5 years of outbreaks in China since 2013 compared their epidemiological characteristics and clinical severity. This study found that the 2016-2017 epidemic began earlier, occurred in a wider geographical area with more districts and counties in affected provinces, and resulted in more confirmed cases than the previous epidemic waves. Unlike A(H5N1), which primarily affected a young and healthy population, the A(H7N9) virus has caused disease in an older, mainly male population, often with underlying diseases. The proportion of cases in middle-aged adults increased steadily from 41% in the first wave to 57% in the fifth. The occurrence of cases in semi-urban and rural residents in the two most recent waves was higher than in the first three waves. However, the clinical severity of disease in hospitalized patients was similar in all epidemics waves. The CDC reported that in the fifth wave, there were 759 cases, nearly as many as were reported in all four previous epidemics combined. The total since the outbreak started in 2013 has been 1,564 cases and at least 612 deaths (case-fatality rate, 39%). However, because of the existence of asymptomatic disease, this mortality rate is undoubtedly overstated.

A(H7N9) has caused almost twice as many infections in about 4 1/2 years as A(H5N1) did in 15 years. In fact, A(H7N9) has caused almost as much disease in the fifth epidemic wave as A(H5N1) did in all 15 years. It should be noted that the sixth epidemic wave has just started. All A(H7N9) infections across all five waves were acquired in China, Hong Kong and Macao.

There have been recent changes in virus pathogenesis in poultry, with some A(H7N9) isolates causing morbidity and mortality in poultry, whereas in previous outbreaks, infections in birds were classified as having low pathogenicity. The virus is evolving. An analysis of HA gene sequences from 166 isolates collected during the fifth wave indicated that there are now two different lineages of the virus — the Pearl River lineage and the Yangtze River Delta lineage. All 166 viruses had the S31N mutation in the M2 protein, indicating resistance to amantadine and rimantadine. According to researchers, 160 were from human cases in mainland China, five were from Hong Kong and one was from Taiwan. The 2017 isolates were antigenically different from the 2013 isolates, raising questions about the efficacy of vaccines based on the 2013 virus.

PAGE BREAK

Pandemic potential

Currently, neither A(H5N1) nor A(H7N9) are transmitted efficiently between humans because they do not infect the upper respiratory tract effectively. There have been no instances of sustained human-to-human transmission of these virus subtypes. However, future mutations, better adapted to humans or genomic reassortment, with more transmissible influenza virus strains, may facilitate upper respiratory infection with aerosol transmission between people and increase the risk for pandemic spread.

A(H5N1) has been causing disease in humans for about 15 years without any evidence of sustained human-to-human transmission. Although there is always the possibility of a mutation or recombination with another influenza virus that could change transmissibility, such an event seems less likely than with the A(H7N9) virus.

Should these mutants or reassortants result in subtypes that maintain their virulence for humans, a severe influenza pandemic with a high incidence of morbidity and mortality is possible. The 1918 pandemic resulted in the deaths of 30 to 50 million people, and the disease spread in the absence of commercial air travel. The H7N9 virus is rated by the CDC’s Influenza Risk Assessment Tool as having the greatest potential to cause a pandemic and severely impact public health, although that risk is considered low. However, should a mutant or reassorted virus appear and begin to spread, would production of vaccines for humans be rapid enough to halt human-to-human spread? Adequate surveillance of A(H7N9) and A(H5N1) infections in people and birds with timely laboratory support is essential to detect any such threat early.

Disclosures: Kaye and Yuill report no relevant financial disclosures.