What was one of the major challenges for the response to the 2015 hpai outbreak in the United States?

Highly Pathogenic Avian Influenza (HPAI) Viruses

HPAI viruses are large (300 nm diameter), negative sense RNA viruses having a segmented genome and belonging to the Orthomyxoviridae family. Domestic and wild birds are the major reservoir for these viruses. There are virtually hundreds of HPAI strains, however, only four have been shown to cause infection in humans; H5N1, H7N3, H7N7, and H9N2. Disease in humans is typically mild, except for the H5N1 virus, which has been responsible for a number of human deaths following outbreaks. The potential for spread of this virus through the food chain has been of concern because the virus appears to survive on imported meat. There is also concern for the risk of fecal contamination of water that is subsequently used in production agriculture or even for food preparation. However, it has been documented that HPAI is susceptible to thermal processes, meaning that the consumption of properly cooked food poses little risk for HPAI infection.

2.4 Highly Pathogenic Avian Influenza H5N1 and H5NX Virus in Wild Birds

Compared to all other HPAI virus outbreaks, the current epizootic of HPAI H5N1 virus is highly unusual in many regards. The HPAI H5N1 virus is considered endemic in many countries throughout Asia, the Middle East, and Africa, which results in regular poultry outbreaks and occasional zoonotic transmission to humans and other mammals, continuously changing genotypes and spill-back of the virus into wild birds, leading to outbreaks and circulation of the virus in those birds.

The ancestral HPAI H5N1 virus is believed to have originated from a virus circulating in domestic geese in Guandong province, China, in 1996 and introduced in Hong Kong poultry markets in 1997.57 Previously deemed unlikely, the direct transmission of a purely avian virus into humans during the 1997 Hong Kong outbreak signified a paradigm shift.58 After the local containment of the HPAI H5N1 virus outbreak, the virus reappeared in 2002 to cause an outbreak in waterfowl and various other bird species in two parks in Hong Kong.59–61 In 2003, the HPAI H5N1 virus was again transmitted to humans, leading to at least one fatal case. There is little information on the circulation of HPAI H5N1 virus during 1997–2002, although it is believed to have continuously circulated in China during that period.62 HPAI H5N1 virus resurfaced again in 2003–2004 to spread across a large part of Southeast Asia, including Cambodia, China, Hong Kong, Indonesia, Japan, Laos, Malaysia, South Korea, Thailand, and Vietnam.

Before 2005, HPAI H5N1 viruses had only been isolated sporadically from wild birds, but in April–June 2005, the first reported outbreak in wild migratory birds occurred, in Lake Qinghai, China. This HPAI H5N1 virus outbreak affected large numbers of wild birds, such as bar-headed geese (Anser indicus), brown-headed gulls (Larus brunnicephallus), great black-headed gulls (Larus ichthyaetus), and great cormorants (Phalacrocorax carbo).63,64 After the HPAI H5N1 virus outbreak in wild birds in 2005, the virus rapidly spread westward across Asia, Europe, the Middle East, and Africa, due to the movement of poultry and poultry products or via wild migratory birds.60,65,66 The role of wild migratory birds in the spread of HPAI H5N1 is contentious as infected birds may be too severely affected to continue migration.67 However, it has been shown that the pathogenesis of the HPAI H5N1 virus infection and the susceptibility of wild bird species to this infection varies considerably, depending on the bird species and previous exposure to influenza viruses. Experimental infections suggest that preexposure to LPAI viruses of homologous or heterologous subtypes may result in partial immunity to HPAI H5N1 virus infection.39 Such preexisting immunity might not prevent viral replication but could protect birds from developing severe disease, thereby enabling them to continue to migrate and potentially spread the virus to other birds across large geographical areas. Upon experimental HPAI H5N1 virus infection, some duck species were found to develop either minor or no disease signs while still excreting the virus, predominantly from the respiratory tract, whereas other species developed a largely fatal infection that would not allow them to spread the virus efficiently over a considerable distance.68–71 The outcome of HPAI H5N1 virus infections in wild bird species ranges from high morbidity and mortality (geese, swan, and certain duck species) to minimal morbidity without mortality (dabbling duck species). Therefore, although the spread of HPAI H5N1 into several parts of Asia was likely due to movement of poultry and poultry products,60,65,66 the introductions into Europe were probably caused by migratory birds,72,73 particularly as the affected regions had not reported outbreaks in poultry.74,75 Although swan deaths have been the first indicator for the presence of the HPAI H5N1 virus in several European outbreaks, this does not necessarily implicate this species as primary vectors, but instead they could have been sentinel birds infected by other migrating bird species.

Although HPAI H5N1 viruses have gradually spread throughout regions of Asia, Europe, the Middle East, and Africa during the 2000s, the most dramatic and rapid emergence of HPAI viruses has been observed in early 2010s, when reassortant HPAI H5N8 viruses spread from Asia, into Europe and North America in less than 12 months. The H5N8 reassortant influenza viruses contained an HA that was highly similar to that of HPAI H5N1 viruses (from subclade 2.3.4.4), and began causing outbreaks in poultry in South Korea in early 2014.76 The virus was thought to have been introduced into the summer breeding grounds of Beringia, a site that represents the convergence of a number of wild bird migratory flight paths. Coinciding with the autumn bird migration from Russia, the virus then spread west into Europe, resulting in poultry outbreaks in the Netherlands, Germany, the United Kingdom, and Italy, and east into North America.77 The latter presented the first HPAI outbreak in North American poultry due to a Eurasian influenza virus.

Within North America, the HPAI H5N8 virus further reassorted with local LPAI viruses resulting in a novel HPAI H5N2 reassortant that contained five RNA segments from the H5N8 and three from North American LPAI viruses.78 The H5N2 virus subsequently caused a substantial number of poultry outbreaks throughout the midwestern region of the United States in 2015. In addition, H5N1 viruses containing four RNA segments from the H5N8 virus and four from North American LPAI viruses were also detected in an apparently healthy duck in the United States during 2015.79 The reasons why the reassortant HPAI H5NX viruses have emerged and spread so rapidly compared to H5N1 is unclear, but may relate to a difference in the pathogenicity caused by the viruses in key migratory bird species.80 Besides the H5N6 virus in China, none of the other novel clade 2.3.4.4 H5NX viruses has caused human infections.

Current Highly Pathogenic Avian Influenza H5N1 Virus Epizootic

In 1996, an HPAI virus of the H5N1 subtype was isolated from an outbreak affecting domestic geese in Guangdong Province, China. A year later, a related virus emerged in Hong Kong that affected poultry, and led to the first human clinical respiratory cases, with hospitalization of 18 patients, of whom 6 died. Subsequent isolates in neighboring territories from 1998 to 2002 suggested that the virus continued to circulate in China, undergoing a number of genetic reassortments.23 In late 2003 and early 2004, eight countries in East and Southeast Asia reported outbreaks for the first time,1 with the virus establishing itself in some areas, particularly those integrating rice cultivation with free grazing of domestic ducks.13 By 2005, multiple sublineages of HPAI H5N1 virus had become established among domestic poultry in geographic subregions of Asia, indicating long-term endemicity and spatial isolation.7 Phylogenetic classification of these viruses, using a unified nomenclature based on H5N1 hemagglutination (HA) sequences from the goose Guangdong lineage, identified 10 major clades (designated 0 to 9) and numerous subclades.28 In spring 2005, an outbreak affecting wild migratory waterfowl in Qinghai Province, China,6 marked the onset of a range expansion that saw outbreaks in wild and domestic birds recorded over an area extending progressively westward through Central Asia to Europe to the Middle East and Africa.

By the end of 2009, 62 countries or territories had recorded outbreaks of HPAI H5N1,26 with 468 human cases and 282 deaths reported across 15 countries.29 Cases have also been recorded in a number of mammalian species, including canids, felids, viverids, mustelids, lagomorphs, suids, and primates. Globally, the number of outbreaks or cases in poultry and humans peaked annually in the January through March period each year, but the size of these peaks has declined annually.9 Although variation in the intensity of national surveillance and frequency of reporting inhibit firm conclusions, effective control measures appear to have led to a steady reduction in the numbers of countries affected, with the virus now largely confined to endemic regions in Northeast Africa and South and Southeast Asia.

The ongoing HPAI H5N1 epizootic has been unusual in the extent to which wild birds have been affected. Prior to this, the only records of HPAI in wild birds were the isolation of HPAI H5N3 virus following the death of 1300 common terns (Sterna hirundo) in South Africa in 1961 and a case of H7 infection in a saker falcon (Falco cherrug) in Italy at the time of an HPAI H7N1 virus outbreak affecting poultry. The first wild bird cases of HPAI caused by the H5N1 subtype were detected in Hong Kong in December 2002 in wild and ornamental birds at four sites. Initially, further (sporadic) cases in wild birds occurred in the vicinity of infected poultry and were likely the result of local spillover from poultry. The possibility that wild birds might be capable of long-distance transmission of virus arose with the mortality of over 6000 wild birds during the outbreak at Qinghai Lake in April 2005.6 Although the 2005 mortalities at Qinghai remain the largest reported in wild birds, further outbreaks involving tens or hundreds of birds of more than 60 species occurred at sites in Europe and Central Asia in 2006 and 2007. The regularity of wild bird outbreaks of Qinghai-like HPAI H5N1virus (clade 2.2) has declined since 2007. However, evidence is emerging that another strain of HPAI H5N1 virus, clade 2.3.2, may have established itself in wild birds, with isolates from Hong Kong in 2007 and 2008, Japan in 2008, Russia in 2009 and Mongolia in 2009 and 2010.

Avian Influenza in Humans

Before 1997 it was assumed that HPAI viruses could not infect and cause severe disease in humans. This concept dramatically changed after the diagnosis of several cases of severe human H5N1 influenza virus infections, many of which were associated with a lethal outcome in Hong Kong. After an initial period of containment, the reemergence of this virus in different areas of the world has been associated with more than 300 cases of severe influenza virus infection in humans, and more than 200 human deaths. Concerns about the human pandemic potential of this virus has prompted global efforts on the development of influenza pandemic preparedness plans, including stockpiling programs of antivirals and H5 vaccines in many countries. Fortunately, despite continuous circulation of H5N1 viruses in poultry, associated with antigenic changes and the appearance of numerous H5N1 clades, only very limited number of infections in humans have been recorded and even less cases of transmission of this virus between humans, only associated with a few infection clusters within members of the same family. Severe infection with H5N1 viruses in humans is likely associated with high levels of exposure to the virus, although it is also possible that predisposing genetic factors in the few individuals who have been infected and developed severe disease exist. Severe infection in humans is associated with high levels of viral replication, viral pneumonia, acute respiratory distress syndrome, and multiorgan dysfunction. Diarrhea episodes are also common during human H5N1 infections, and the virus has been isolated in some cases from feces, indicative of a more extended tissue tropism than regular human influenza virus infections. Viral RNA has also been detected in blood and in CNS in several human cases. However, most of the viral replication in humans appears to be associated with the respiratory tract, and this is also the case in H5N1 experimental inoculations of macaques. In contrast to most avian influenza viruses, H5N1 viruses appear to be highly promiscuous for different mammalian species, and they are known to cause lethal and disseminated disease in mice, cats, ferrets, and tigers.

Nevertheless, HPAI H5N1 viruses are not unique in their ability to cause sporadic severe human disease. In 2003, an outbreak of HPAI H7N7 viruses in chicken in the Netherlands resulted in several human cases of conjunctivitis associated with contact with this virus, and in one human case of fatal severe respiratory infection. Low pathogenic avian H9N2 viruses, widely distributed in poultry in different countries, are also known to infect humans, although not associated with disease. However, any process resulting in selection of viruses of non-H1 and non-H3 subtypes with the ability to infect humans and transmit from human to human will result in a new pandemic, and, therefore, avian influenza viruses need to be closely monitored for any possible changes that might increase their tropism for humans.

While severe infections in birds and mammals with H5N1 HPAI are mainly associated with the multibasic cleavage site of its HA, other viral determinants are known to contribute to increased virulence in mammals. HAs from avian and human influenza viruses recognize sialic acid-containing receptors. However, HAs from human influenza viruses have a preference for binding to sialic acids linked to sugars through alpha2,6 linkages, and HAs from avian influenza viruses have a preference for binding to sialic acids linked to sugars through alpha2,3 linkages. This correlates with the relative abundance of these linkages in the tissues where these viruses replicate: the upper respiratory tract in humans and the intestinal tract in birds. Intriguingly, alpha2,3-linked sialic acids are more abundant in the lower respiratory tract of humans, and this may facilitate replication of H5N1 viruses in the lungs, resulting in severe disease, while restricting replication in the upper respiratory tract, limiting transmission. Also interestingly, changes in receptor specificity of the human 1918 virus from alpha2,6- to alpha2,3-linked sialic acids did not prevent severe disease, but prevented sneezing and aerosol/droplet-mediated transmission in ferrets, suggesting that avian influenza viruses will need to change receptor specificity of their HAs from alpha2,3- to alpha2,6-linked sialic acids as one of the requirements to be transmissible in humans. Polymorphisms in the polymerase genes of HPAI H5 and H7, and especially in the PB2 gene, have also been associated with increased virulence in mammals. A few amino acid changes in the C-terminal PB2 appear to be selected during mammalian or human adaptation of these viruses, resulting in more efficient replication especially at the relative lower temperature of human cells as compared with avian cells. Possible interactions of PB2 with specific host factors have also been postulated and some PB2 adaptive mutations from avian to mammalian hosts have been associated with enhanced recognition of this viral protein by the mammalian nuclear import machinery, required for proper transport of PB2 in mammalian cells. The NS1 gene from H5N1 viruses and from some other avian influenza viruses have also been associated with increased virulence in some mammalian species. The presence of a glutamate at position 92, typical of several H5N1 strains, appears to increase virulence by increasing the ability of the NS1 to mediate resistance to the host interferon-mediated antiviral response. A robust PDZ ligand motif at the C-terminal domain of NS1, typical of most avian influenza viruses, appears to enhance virulence in mice through mechanisms that still are not well understood. Finally, infections of mammals with HPAI H5N1 viruses have been associated with disregulated cytokine responses in macrophages and with lymphocytic depletion, and these factors are also likely to contribute to enhanced disease.

Clinical Features and Epidemiology

The disease caused in chickens and turkeys by HPAI viruses has historically been called “fowl plague.” Today, the term should be avoided, except where it is part of the name of well-characterized strains [eg, A/fowl plague virus/Rostock/1934 (H7N1)]. The HPAI viruses cause sudden death without prodromal symptoms. If birds survive for more than 48 hours (which is more likely in older birds), there is a cessation of egg laying, respiratory distress, lacrimation, sinusitis, diarrhea, edema of the head, face and neck, and cyanosis of unfeathered skin, particularly the comb and wattles. Birds may show nervous signs such as tremors of the head and neck, inability to stand, torticollis, and other unusual postures if surviving more 3–5 days after exposure.

The LPAI viruses may also cause considerable losses, particularly in turkeys, because of anorexia, lethargy, decreased egg production, respiratory disease, and sinusitis. Clinical signs in chickens and turkeys may be exacerbated markedly by concurrent infections (eg, various viral, bacterial, and mycoplasma infections), the use of live-attenuated virus vaccines, or environmental stress (eg, poor ventilation and overcrowding). Low-pathogenicity (LPAI) H9N2 viruses are ubiquitous in terrestrial poultry throughout Asia, and parts of North Africa and the Middle East. H9N2 have been identified as a source of poultry-adapted genes for reassortment with new hemagglutinin subtypes from aquatic birds, eg, H10Nx and H7N9, enabling circulation of new viruses in poultry flocks.

Avian influenza virus is shed in high concentrations in the feces of wild birds, and can survive for long periods in cold water. The virus is often introduced into susceptible flocks periodically by interspecies transmission—that is, from wild aquatic birds, especially wild ducks, to premises with mixed poultry species; thus facilities where wild birds have access facilitate this type of transmission. It is unclear how the many subtypes of avian influenza A viruses are maintained in wild birds from year to year; it is hypothesized that the viruses are maintained by circulation at low levels in large wild bird populations, even during migration and overwintering. Studies of wild ducks in Canada have shown that up to 60% of juvenile birds are already infected silently as they congregate before their southern migration. Avian influenza viruses have also frequently been isolated in many countries from imported caged birds, although such passerine and psittacine birds are not natural reservoirs of LPAI viruses and they probably only become infected after exposure to infected village poultry, especially domestic and captive ducks.

Live markets also may be critical to the epidemiology of influenza virus infections. The Eurasian H5N1 epizootic clearly confirms the risk associated with the continuous influx of susceptible animals and mixing of multiple avian species (including terrestrial and aquatic birds), leading to viral amplification, reassortment and rapid evolution through serial transmission in birds at these markets. The first indication of a potentially new epizootic of avian influenza virus was the isolation of an HPAI virus from a goose in Guangdong, China, in 1996, with subsequent spread and outbreaks among poultry in Hong Kong in 1997, 2001, and 2002. In addition, this unique virus caused 18 human infections, with 6 deaths; the first document human fatal infections by an HPAI virus. Efforts to control the outbreak by depopulation and some vaccination with an H5N2 vaccine eliminated the disease and infection in Hong Kong, but by 2003 this H5N1 HPAI virus had spread to Korea, Japan, Indonesia, Thailand, and Vietnam. Wild water fowl experimentally infected with HPAI viruses isolated before 1997 did not show clinical signs. However, in 2002, waterfowl in two parks in Hong Kong developed neurological disease after infection with this Goose/Guangdong-(Gs/GD)-lineage H5N1 virus. Furthermore, captive tigers and lions in Thailand died after being fed infected poultry, which confirmed its unusual properties. The H5N1 HPAI virus that circulated in 2002 showed multiple gene reassortments and mutations as compared with the 1997 virus. In early 2005, H5N1 HPAI virus was isolated from dead wild birds in Qinghai Lake of central China and the virus then was detected in Mongolia, Siberia, Kazakhstan, and Eastern Europe later that year. This Eurasian H5N1 HPAI virus was detected in most countries of Asia, Europe, and parts of Africa in 2006, although the “virus” has undergone many changes since the initial isolate from the goose in 1996 (Fig. 21.7). The Eurasian lineage H5N1 virus has become enzootic in poultry populations from China, Vietnam, Cambodia, Bangladesh, India, Indonesia, Egypt, and other countries in these regions. In addition, sporadic outbreaks were detected in the Korean Peninsula, Japan, Laos, and Nepal. Eurasian-lineage H5N8 viruses were also detected in poultry in Germany, the Netherlands, Italy, and the United Kingdom. The first outbreak was detected on November 5, 2014 at a turkey farm in Mecklenburg-Vorpommern, Germany.

Intercontinental wild bird migrations introduced a related H5N8 virus from Asia into North America during late 2014. A wild bird surveillance program identified in early December 2014 a wholly Eurasian 2.3.4.4 H5N8 from a gyrafalcon (Falco rusticolus) in the state of Washington. Reassortment between the Eurasian H5N8 and North American aquatic bird low pathogenic viruses resulted in the emergence of new subtypes; eg, H5N1 and H5N2 and new genotypes with three to four additional genes of North American origin; PB1, PA, NA, and NS (H5N1) and PB1, NP, NA (H5N2). These viruses are designated Eurasian–American (EA–AM) H5Nx. In March 2015, a highly pathogenic H5N2 virus (HPAI) was detected in commercial poultry facilities in Minnesota, Missouri, Arkansas, and Kansas. The outbreak pattern supported the introduction of the virus into the Midwest by migrating waterfowl in the Mississippi flyway. By the end of the outbreak, over 200 commercial facilities in 16 states were depopulated with a loss of over 48 million turkeys and chickens with a direct loss of 1.6 billion dollars, clearly the most expensive “foreign” animal disease outbreak in US history. The HPAI H5N2 appears to now be endemic in the waterfowl using the North American flyways. While rapid depopulation of infected premises is still considered the preferred control strategy, limited use of vaccines may be used as a temporary measure to contain an outbreak.

The role of wild birds in the transmission of the Eurasian H5Nx virus is intimately linked to its differential pathogenicity for at least some species of wild aquatic birds. Legal and illegal trade in poultry and wild birds must also be carefully monitored, as H5Nx infection has been detected in imported birds at international borders. Intense surveillance for the Eurasian H5Nx (x=1, 2, 3, 6 or 8) viruses has been reinitiated in Europe, North America, and elsewhere since late 2014. In North America, initial efforts targeted Alaska, western Canada, and the west coast of the United States, because of the overlapping migration routes of Asian and North American wild birds, but now the program has expanded into the Mississippi and Atlantic flyways.

AVIAN INFLUENZA ASSOCIATED WITH HUMAN CASES

Human infections and outbreaks following interspecies transmission of highly pathogenic avian influenza viruses have rarely been reported before 1997.121 Reports are increasing of human infections associated with direct or indirect contact with infected birds. In 1997, the infection of 18 humans, of whom 6 died, with an avian H5N1 virus raised the level of global concern of a possible human influenza pandemic. In 1999, H9N2 avian influenza infected two children in Hong Kong and there were other cases in mainland China. In 2003, H5N1 and H9N2 infections were confirmed in Hong Kong, while in the Netherlands, a large avian influenza outbreak involved an H7N7 virus. Up to 1000 cases among farmers and poultry workers occurred. Since late 2003, outbreaks of avian H5N1 have been reported among poultry in Southeast Asia.122 Human infections and deaths were initially reported in Vietnam and Thailand. This virus has become endemic in domestic poultry in Asia and has spread globally after infecting migratory waterfowl.123 Subsequently, there have been reports of human infections in an increasing number of countries. Clusters of human infection are small, suggesting that if human-to-human transmission is occurring, it is very inefficient.

As this H5N1 virus continues to circulate in and be spread by domestic and migratory avian species, there is an ongoing risk of human infection and a threat of the emergence of a human pandemic virus. Whether the H5N1 virus or one of the other potential pandemic subtypes (H2, H5, H7, or H9 viruses) will adapt to efficient human-to-human transmission remains unknown. Currently, no mechanism of prediction of the emergence of novel influenza A viruses exists, highlighting the importance of the ongoing global surveillance of animal and human influenza viruses by the WHO.

Antigenic Fingerprinting via SPR

SPR binding analysis was performed to characterize infections with H7 highly pathogenic avian influenza (HPAI) viruses. Results show strong correlation between HA1 binding antibodies (HA1 binding mostly contributed by IgA antibodies) and H7N7 HI titres. Antibodies against NA7 are less frequent but have binding sites close to the sialic acid binding site. Strong antibody response was also found against PA-X, a putative virulence factor in H7N7 exposed individuals, thus indicating immune recognition of the virus during infection. This was unknown so far in human. This will pave the way for effective prophylactic and therapeutic strategies against the influenza virus (Khurana et al., 2016a,b).

10.6 Highly Pathogenic Avian Influenza

Influenza A viruses of many different HA and NA subtypes circulate in wild bird populations, particularly waterfowl, where the disease is epizootic, meaning that it is epidemic in an animal population. Eighteen different HA subtypes (H1–H18) and eleven different NA subtypes (N1–N11) exist, but only three HA subtypes have circulated in humans: H1, H2, and H3. Therefore, the possibility remains that more human pandemics could occur through direct infection of humans with a mutated avian influenza, or through reassortment of an avian influenza with a human influenza in a host infected by both, such as swine. To infect humans, however, the avian HA protein needs to acquire the ability to infect human cells efficiently. The avian influenza, which normally is a gastrointestinal virus in birds, binds its HA protein to sialic acids linked to galactose with an alpha-2,3 linkage, meaning that the second carbon of sialic acid binds to the third carbon of the galactose sugar under it (see Fig. 10.5). In contrast, human influenzas bind to alpha-2,6-linked sialic acids. This slight change in receptor preference means that avian HA proteins do not efficiently bind to the human influenza virus receptor. For the H2 and H3 subtypes, the ability of the avian virus to bind human cells occurred through mutations in the HA protein’s receptor binding site so that the avian HA protein acquired the ability to bind 2,6-linked sialic acids. For the H1 subtype, however, the HA location that directly binds the human receptor remains the same as in the avian HA protein, but an overall change in the structure of the HA protein allows it to bind the human alpha-2,6 sialic acid receptor.

Only over the past 20 years have we directly observed that highly pathogenic avian influenza (HPAI) viruses could be directly transmissible from birds to humans and cause severe respiratory syndromes, pneumonia, and death. The first known case of this occurred in Hong Kong in 1997, when a 3-year-old boy died of influenza-like symptoms. The virus was isolated and confirmed to be of the H5N1 strain, a strain that had not previously been known to infect humans, with an HA gene derived from geese (Fig. 10.15A). The same H5N1 strain was killing poultry

Case Study: Cases of Influenza A (H5N1)—Thailand, 2004

Excerpted from Centers for Disease Control Morbidity and Mortality Weekly Report, February 13, 2004: 53(05), 100–103.

The human H5N1 viruses identified in Asia in 2004 are antigenically and genetically distinguishable from the 1997 and February 2003 viruses. To aid surveillance and clinical activities, this report provides a preliminary clinical description of the initial five confirmed cases in Thailand.

Of the five laboratory-confirmed cases in Thailand, four were in male children aged 6–7 years, and one was in a female aged 58 years; all patients were previously healthy (Table 10.4). Four patients reported deaths in poultry owned by the patient’s family, and two patients reported touching an infected chicken. One patient had infected chickens in his neighborhood and was reported to have played near a chicken cage. None of the confirmed cases occurred among persons involved in the mass culling of chickens.

Table 10.4. Clinical Features, Treatment, and Outcomes in Five Patients With Laboratory-Confirmed Influenza A (H5N1), by Sex and Age of Patient—Thailand, 2004

Patients reported to hospitals 2–6 days after onset of fever and cough (Table 10.4). Other early symptoms included sore throat (four), rhinorrhea (two), and myalgia (two). Shortness of breath was reported in all patients 1–5 days after symptom onset. On admission, clinically apparent pneumonia with chest radiograph changes was observed in all patients. Diarrhea and vomiting were not reported.

All patients had respiratory failure and required intubation a median of 7 days (range: 4–10 days) after onset of illness. Two patients had a collapsed lung (pneumothorax). Three patients required support for decreased cardiac function; two patients had renal (kidney) impairment as a later manifestation. None had documented evidence of secondary bacterial infection.

Late in the course of illness, three patients were treated with oseltamivir for 3–5 days. All received broad-spectrum antibiotics for community-acquired pneumonia while the cause of illness was under investigation. Four were treated with systemic steroids for increasing respiratory distress and clinically diagnosed acute respiratory distress syndrome with compatible chest radiograph changes.

Three children died 2–4 weeks after symptom onset, and one child and the adult died 8 days after symptom onset. All patients had laboratory evidence of influenza A (H5N1) by reverse transcriptase-polymerase chain reaction. In three cases, the virus was isolated in tissue culture, and in three cases, the viral antigens were identified by immunofluorescent assay.

Reported by T Chotpitayasunondh, S Lochindarat, P Srisan, Queen Sirikit National Institute of Child Health; K Chokepaibulkit, Faculty of Medicine, Siriraj Hospital, Mahidol Univ, Bangkok; J Weerakul, Buddhachinaraj Hospital, Phitsanulok; M Maneerattanaporn, 17th Somdejprasangkaraj Hospital, Suphanburi; P Sawanpanyalert, Dept of Medical Sciences, Ministry of Public Health, Thailand. World Health Organization, Thailand. CDC International Emerging Infections Program, Thailand.

in the live bird markets of Hong Kong, and 17 additional human cases of H5N1 influenza occurred, all through direct contact with chickens. The government ordered the culling of all poultry within the region, which was effective in controlling the local transmission of the virus to humans. The virus replicated very efficiently in humans, and of the 18 people infected, 6 of them died (33%). No human-to-human transmission was reported, although it was feared that reassortment of the H5N1 strain with a circulating seasonal influenza within an infected person could result in a highly pathogenic virus able to be transmitted between humans.

Part of the reason that the H5N1 subtype is so virulent in the human host was because of the tropism of the virus. Avian influenza viruses more readily bind alpha-2,3-linked sialic acids (Fig. 10.5). In the human lung, these can be found deeper in the lung on the nonciliated cuboidal epithelial cells at the junction between the bronchioles and the alveoli (Fig. 10.1A). Researchers have shown that the H5N1 subtype exhibits tropism for these cuboidal epithelial cells, as well as alveolar macrophages and type II pneumocytes, both found in the alveoli of the lungs. The tropism of the H5N1 virus for the deepest part of the lower respiratory tract is a contributing factor to why the virus is so pathogenic in humans.

There have been over 600 cases of H5N1 transmission to humans since the WHO began recording them in 2003. The majority of cases have occurred in children and young adults, and 60% of those infected have died. Most of the infections occurred through direct bird-to-human transmission, although a handful of cases suggest that human-to-human transmission occurred between the sick individual and a close family member who was caring for the infected person.

The H5N1 virus continues to circulate throughout the world in both wild birds and poultry populations, currently endemic in China, Bangladesh, Indonesia, Vietnam, India, and Egypt. In addition to birds, the HPAI H5N1 has also been shown to infect pigs, dogs, ferrets, housecats, and wild cat species, among others.

In 2013, human infections with a novel HPAI H7N9 virus were reported in China. The H7N9 strain was also found within bird populations as a new reassortant infecting domestic ducks, wild birds, and domestic poultry (Fig. 10.15B and C). Like HPAI H5N1, the virus was transmitted to humans through direct contact with birds and caused severe respiratory infection. Of 163 human cases reported in China in 2013, 50 people (31%) died. H7N9 strains were identified that were able to efficiently bind both avian and human cell surface receptors. Interestingly, there have been no reports of H7N9 infection in swine populations.

Bird ’flu

Influenza type A subtype H5N1 can cause an illness known as ‘avian influenza’ or ‘bird ’flu’ in birds, humans and many other animal species. HPAI A(H5N1) – ‘highly pathogenic avian influenza virus of type A of subtype H5N1’ – is the causative agent and is enzootic in many bird populations, especially in South-East Asia. It has spread globally and resulted in the deaths of over 100 people and the slaughter of millions of chickens. A vaccine that could provide protection (Prepandrix) has been cleared for use in the European Union. H5N7 is a more recent emergent infection, similar in many respects.