Influenza Virus Infection of Avian or Other Animal Origin

Flu, Bird Flu, Swine Flu

Clinical Description

Identification

Occasionally, a new subtype of influenza A emerges that is infectious for humans (a process termed shift). If such a virus is able to transmit from person to person efficiently enough to cause community outbreaks, then such a virus has the potential to cause a pandemic. Although most human infections with novel influenza A viruses probably result in sporadic cases or very limited human-to-human transmission, all human cases of novel influenza A infection must be considered a potential pandemic infection and should be investigated to assess the risk of human-to-human transmission. The first laboratory clue of a novel influenza A infection is the inability of available tests to subtype influenza A viruses. Suspicion is heightened if illness has occurred after exposure to birds, pigs or other animals that may be infected with influenza or exposure to their environments. Animal influenza A virus subtypes that have infected humans include H5N1, H7N2, H7N3, H7N7, H9N2, H10N7 and swine and avian H1 viruses, which are antigenically distinct from human H1 viruses. The current situation of widespread outbreaks of highly pathogenic avian influenza (HPAI) A(H5N1) virus infection among poultry is of a great concern because H5N1 virus is now endemic in poultry in some countries, causes high rates of death among infected poultry, and has resulted in a 60% case-fatality ratio among infected humans. Although human-to-human transmission of this H5N1 virus is currently limited and unsustained, continued vigilance is needed to detect changes in H5N1 viruses that might signal a pandemic. H5N1 viruses are dealt with in a separate section on influenza virus infection of avian and other animal origin, below.

New subtypes of influenza A can emerge among humans through direct transmission of an animal influenza virus to humans, or through reassortment of genes derived from an animal influenza virus and a human influenza virus. Such genetic reassortment can create a new virus that combines human and animal influenza properties. The 1918 pandemic virus is hypothesized to have developed from an avian influenza virus that adapted to humans. The 1957 and 1968 pandemic viruses were the result of genetic reasssortment between avian and human influenza viruses. Pandemic viruses in the past have spread globally within 4 months of detection; modern air travel may further hasten the spread of a new pandemic virus, leaving little time for vaccine development, manufacturing or administration to the world's population. Planning for responses to pandemics ahead of actual pandemics is therefore critical for preparedness.

Human infections with avian H7 influenza virus have been reported, resulting in subclinical infections, conjunctivitis, and respiratory tract symptoms. In 2003, there were 89 human cases of avian influenza A (H7N7) virus infection, including 1 death and limited human-to-human transmission in the Netherlands. In 2007, there were 4 cases of human infection with avian influenza A (H7N2) virus in the United Kingdom. In addition, four cases of avian influenza A (H9N2) illness in children in Hong Kong, SAR, China, were reported from 1999–2007. Swine influenza viruses have also caused illness in humans. Earlier, in 1976, the A/New Jersey/76 (Hsw1N1) influenza virus of swine origin caused severe respiratory illness in 13 soldiers, including one death, at Fort Dix, New Jersey, but did not spread beyond Fort Dix. Other human infections with swine influenza viruses have been sporadically identified, including 5 cases of human infection with a swine influenza A (H1N1) virus containing swine, avian, and human influenza virus genes (i.e. a triple reassortant) during 2007 in the United States. In most non-H5N1 cases, including swine influenza, symptoms associated with animal influenza virus infections have been similar to those for seasonal influenza infections. Conjunctivitis has been prominent in many cases of H7N7 and H7N2 infection. Of the animal influenza virus infections of humans, H5N1 has been the most studied and has the most advanced prevention guidance developed; thus this chapter will focus mostly on H5N1.

Avian influenza A(H5N1) virus infection in humans: In 1997, the first avian influenza A(H5N1) outbreak among humans occurred in Hong Kong, SAR, China; since 2003, there has been a resurgence of H5N1 outbreaks, first among poultry in southeast Asia, with subsequent rapid spread to other parts of the world. In association with this panzootic in poultry, sporadic cases and clusters of human infection have been reported. Human H5N1 illness typically manifests as severe pneumonia, and the case fatality has been high (60%). Common initial symptoms are fever (usually higher than 38°C) and cough, plus signs and symptoms of lower respiratory tract involvement including dyspnea. Upper respiratory tract symptoms such as sore throat and coryza are present only sometimes. Gastrointestinal symptoms were frequently reported in cases in Thailand and Vietnam in 2004, but less frequently since 2005, suggesting that clinical presentations may differ depending on the virus (see II.2 for different virus clades). Severe lower respiratory tract manifestations often develop early in the course of illness, and clinically apparent pneumonia with radiological changes has usually been found at presentation. The disease progresses rapidly, and often progresses to an acute respiratory distress syndrome. Median times of 4 days from the onset of illness to presentation at a health care facility and 9 to 10 days until death in fatal cases has been reported. Atypical presentations have included fever and diarrhea without pneumonia, and fever with diarrhea and seizures progressing to coma. Common laboratory findings include leukopenia, lymphopenia, mild-to-moderate thrombocytopenia, and elevated levels of aminotransferases. Lymphopenia and increased levels of lactate dehydrogenase at presentation have been associated with a poor prognosis. Other reported abnormalities include elevated levels of creatine phosphokinase, hypoalbuminemia, and increased D-dimer levels and changes indicative of disseminated intravascular coagulopathy. Of six infected pregnant women, four have died, and the two survivors had spontaneous abortion. Mild illnesses such as upper respiratory illnesses without clinical or radiological signs of pneumonia have been reported more frequently recently in children. Limited seroepidemiologic studies conducted since 2004 suggest that subclinical infection appears uncommon.

Infectious Agents

The first outbreak of highly pathogenic avian influenza (HPAI) A(H5N1) virus infections in humans—in Hong Kong, SAR, China, in 1997—was coincident with local outbreaks in poultry. In the intervening years, reports of limited H5N1 infections among birds in southeast Asia were reported, but starting in 2003, H5N1 infections led to large and recurring outbreaks in poultry. The viruses have spread, and are now entrenched among poultry populations in parts of Eurasia, Africa and the Middle East. In the summer of 2005, outbreaks in migratory birds in China preceded rapid spread of H5N1 through Mongolia and Russia to many European, Middle Eastern and African countries. A(H5N1) virus infections have been associated with high levels of mortality among poultry and substantial economic losses. Based on evolution of the hemagglutinin gene, H5N1 viruses can now be divided into 10 phylogenetically distinct clades that are antigenically distinguishable, and additional subclades; however, only 3 clades have caused human illness since 1997. The influenza A(H5N1) viruses that have infected humans so far have contained only avian influenza virus genes, and generally have been similar to strains circulating among poultry and wild birds in the same general location. Although migratory birds may sometimes spread A(H5N1) viruses to new geographic regions, their importance as a vector for spread is uncertain. Gene sequencing of some viruses isolated from infected humans showed mutations that may reflect some adaptation in humans.


Diagnosis

Diagnosis of animal influenza viruses often requires specialized laboratories, since these viruses cannot be typed by reagents used for seasonal influenza viruses. Detection of viral RNA in respiratory and other clinical specimens by means of conventional or real-time reverse-transcriptase polymerase chain reaction remains the best method for the initial diagnosis. Infection can be also confirmed by documenting seroconversion based upon a rise in antibody titer between an acute and a convalescent serum specimen. Otherwise, point-of-care rapid testing (also sometimes called “rapid tests”) used for human influenza viruses have been insensitive for animal influenza viruses, and generally not useful. If an animal influenza virus infection is suspected, a negative test result by a point-of-care test does not exclude the presence of the virus infection.


Epidemiology

Mode of Transmission

The first outbreak of highly pathogenic avian influenza (HPAI) A(H5N1) virus infections in humans—in Hong Kong, SAR, China, in 1997—was coincident with local outbreaks in poultry. In the intervening years, reports of limited H5N1 infections among birds in southeast Asia were reported, but starting in 2003, H5N1 infections led to large and recurring outbreaks in poultry. The viruses have spread, and are now entrenched among poultry populations in parts of Eurasia, Africa and the Middle East. In the summer of 2005, outbreaks in migratory birds in China preceded rapid spread of H5N1 through Mongolia and Russia to many European, Middle Eastern and African countries. A(H5N1) virus infections have been associated with high levels of mortality among poultry and substantial economic losses. Based on evolution of the hemagglutinin gene, H5N1 viruses can now be divided into 10 phylogenetically distinct clades that are antigenically distinguishable, and additional subclades; however, only 3 clades have caused human illness since 1997. The influenza A(H5N1) viruses that have infected humans so far have contained only avian influenza virus genes, and generally have been similar to strains circulating among poultry and wild birds in the same general location. Although migratory birds may sometimes spread A(H5N1) viruses to new geographic regions, their importance as a vector for spread is uncertain. Gene sequencing of some viruses isolated from infected humans showed mutations that may reflect some adaptation in humans.

Incubation Period

For H5N1 disease associated with poultry exposure, 7 days or less, and often 2–5 days. For swine influenza, 2–7 days has been reported.

Period of Communicability

For H5N1 disease, limited data suggest that patients may remain infectious as long as 3 weeks, and perhaps even longer in immunosuppressed patients (e.g. those using corticosteroids). The longest documented period has been 27 days after the onset of illness, based upon detection of virus antigen in a patient's respiratory specimens.

Reservoir

Aquatic birds are natural reservoirs of influenza A subtypes. For some avian influenza viruses, and particularly H5N1, the range of mammals that can be infected from aquatic birds (pigs, whales, seals, horses, ferrets, cats, dogs, tigers, etc.) has been wide. Domestic poultry are also infected, and are the main source of human infections. Swine influenza viruses are endemic in pigs. Influenza infections are also known to occur in other animals besides birds and pigs, including horses and dogs, but with the exception of pigs, influenza viruses have not been shown to transmit from these mammals to humans.

Susceptibility

H5N1 illness occurs in all age groups, and limited serological studies demonstrate negligible pre-existing immunity in the subjects. Duration of protection from immunity generated by previous infection or immunization by an H5N1 vaccine is unknown. The role of host factors other than acquired immunity is uncertain.

Occurrence

Epidemiology of Human infection with HPAI A(H5N1) virus: By the end of February 2008, over 360 cases of Human infection with HPAI A(H5N1) virus in humans had been reported from Azerbaijan, Cambodia, China, Djibouti, Egypt, Indonesia, Iraq, Lao People's Democratic Republic, Myanmar, Nigeria, Pakistan, Thailand, Turkey and Viet Nam, with an overall case fatality of 64%. Regular updates on case counts are available at: https://www.who.int/csr/disease/avian_influenza/country/en/index.html

Reasons for national differences in mortality are uncertain, but in all countries, mortality has been high. Potential differences could be differences in patient behaviors, types of viral exposure, time before case recognition, access to health care and/or clinical management, or differences in surveillance. The case fatality is highest among persons 10 to 19 years of age and lowest among persons 50 years of age or older. The median age of patients is approximately 18 years with 90% of patients 40 years of age or younger. In comparison to estimated numbers of poultry infections and human exposures to infected birds, human infections by an influenza A(H5N1) virus remain relatively rare. During situations in which there was close, prolonged and unprotected contact between a severely ill patient and a susceptible person, and most often a family member acting as a care giver, instances of non-sustained human-to-human transmission are thought to have occurred.


Prevention and Control

1)    Preventive measures:

a)    Preventing human exposure to infected animals or contaminated environments and controlling spread of infection among domesticated animal populations are critical elements for protecting humans from animal influenza virus infections. Guidelines for controlling outbreaks in domesticated animals have been issued by relevant national and international agencies (e.g. the Food and Agriculture Organization of the United Nations and the World Organization for Animal Health).

b)    Rapid information sharing between animal and/or agricultural sectors and human health authorities is essential for timely implementation of public health actions. Social mobilization and risk communication targeting high-risk populations in affected areas are important measures for raising disease awareness and initiating protective behavioral changes.

c)    Use of appropriate personal protective equipment (PPEs) and proper training is recommended for groups considered to be at high risk of exposure to infected birds (e.g. poultry workers, persons involved in mass culling operations, outbreak investigators, etc.). Following a probable exposure, asymptomatic persons should be followed for signs of illness for at least one week, while symptomatic persons should be tested for infection, administered antiviral medicines, and monitored closely.

d)    Immunization: Inactivated H5N1 vaccines for human use have been developed based on WHO recommended strains and licensed in several countries, but are not yet generally available, although this situation is expected to change. Some countries are stockpiling these vaccines as part of pandemic preparedness measures. Although immunogenic, the effectiveness of these vaccines in preventing the H5N1 infection or reducing disease severity is unknown. Use of seasonal influenza vaccination in certain high-risk animal exposure occupational groups is recommended in some countries for reducing influenza-like illness caused by seasonal influenza viruses. Such vaccines will not provide direct protection against animal influenza virus infections, but may prevent seasonal and animal influenza co-infections.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Laboratory-confirmed human infection with a novel subtype of influenza A virus, or influenza A infection where the virus cannot be subtyped, should be reported immediately to the national authority and then to WHO. Reporting to WHO is mandatory under the International Health Regulations (2005).

b)    Isolation: When possible, suspected or confirmed cases with H5N1 and other non-human influenza virus infections should be treated using well-ventilated single isolation rooms with implementation of Standard and Droplet Precautions. Use of higher-level precautions such as airborne precautions may be considered when aerosol-generating procedures (e.g. sampling respiratory specimens, suction, use of nebulizers, intubation and mechanical ventilation) are to be performed.

c)    Concurrent disinfection: Regular surface cleaning and disinfection with a commonly used detergent or hospital disinfectant is desirable during hospitalization and after removal of a patient from the room. Environmental disinfection should follow guidelines published by relevant agencies (e.g. Food and Agriculture Organization of the United Nations, World Organization for Animal Health).

d)    Quarantine: Hospital isolation is recommended for symptomatic patients infected with novel influenza A viruses, including H5N1. In large-scale outbreak settings, voluntary home quarantine of contacts may be used. Symptomatic contacts with mild illness that do not require hospitalization should be placed in isolation and provided with antiviral treatment.

e)    Protection of contacts: A neuraminidase inhibitor drug (oseltamivir or zanamivir) should be administered as chemoprophylaxis for 7–10 days to close contacts (such as household or family members) after the last exposure to a person strongly suspected or confirmed to have a H5N1 infection. This includes pregnant women. Where neuraminidase inhibitors are not available, amantadine or rimantadine might be used for chemoprophylaxis of high-risk exposure groups if the virus is known or likely to be susceptible to these drugs. However, these drugs should not be used as chemoprophylaxis in pregnant women.

f)    Investigation of contacts and source of infection: When an influenza infection with H5N1 is suspected, clinical samples (e.g. throat swab and other respiratory specimens) should be collected and tested to confirm infection. Virus isolation or PCR testing will allow further genetic characterization of the virus. When concomitant animal outbreaks are ongoing, coordination with the animal and/or agricultural sectors is essential. Epidemiological field investigations should identify the source of infection, identify situation-specific control measures, and determine whether human-to-human transmission has occurred. If a novel influenza virus is associated with efficient spread among people, then rapid containment, using antivirals and vaccines, may be indicated to try and prevent pandemic spread. The WHO protocol for such operation is available, and can be found at: http://www.who.int/csr/disease/avian_influenza/guidelines/RapidContProtOct

g)    Specific treatment: The efficacy of antiviral drugs for treating non-seasonal influenza infections is uncertain, due to limited opportunities for documentation. For H5N1 disease, early treatment with oseltamivir is recommended, using the standard regimen indicated for treatment of seasonal influenza. Data from uncontrolled clinical studies suggest this improves survival, although the optimal dose and duration of therapy are uncertain and no data from controlled trials are available. Based on in vitro and animal studies suggesting improved outcomes, physicians may consider using higher doses of oseltamivir therapy, longer durations of treatment, or combination therapy (oseltamivir + amantadine). Clade 1 H5N1 viruses and most clade 2 subclade 1 H5N1 viruses from Indonesia are fully resistant to M2 inhibitors, whereas clade 2 subclade 2 H5N1 viruses from the lineages in other parts of Eurasia and Africa and clade 2 subclade 3 H5N1 viruses from China are usually susceptible. During oseltamivir therapy, the emergence of highly resistant H5N1 variants was observed in Vietnamese patients, with fatal outcomes. Infection by viruses partially resistant to oseltamivir, before treatment, was reported in two Egyptian patients who died. Treatment of H5N1-associated ARDS should follow published national guidelines. In principle, early intervention by intermittent positive pressure ventilation (IPPV) using low tidal volumes and low pressure ventilation may help, and is recommended. Corticosteroid therapy has not been shown to be effective in patients with influenza A(H5N1) virus infection, and it has not been determined whether other immunomodulators and serotherapy are useful.

3)    Epidemic measures:

a)    Clinicians and local public health officers should be aware that human infections may occur in countries with outbreaks of influenza A(H5N1) among poultry. The clinical presentation of influenza A(H5N1) disease is nonspecific, and has often resulted in an initial misdiagnosis, especially in circumstances in tropical countries where endemic acute febrile diseases are common. Influenza A(H5N1) virus infection should be considered in the differential diagnosis for patients who present with fever, rapidly progressing atypical pneumonia and epidemiologic risk factors.

b)    Develop or use a case definition and undertake active surveillance in the appropriate epidemiological setting for early detection of human cases. If an infection occurs or is strongly suspected, family members and household contacts should be placed under medical observation and provided with antiviral chemoprophylaxis or treatment according to national guidelines.

c)    Establish a mechanism for rapidly obtaining reliable laboratory testing results. Characterization of the virus and its susceptibility to antivirals are important factors for disease control.

d)    Provide information about the disease and preventive measures to at-risk population. Social mobilization including sensitization campaigns may be required for effective message penetration. Timely provision of information to the public is essential.

e)    Collect epidemiological, clinical and other information to assess the situation. If efficient human-to-human transmission is observed, a large-scale containment operation should be considered to stop further spread of the infection.

4)    Disaster implications:

The emergence of an animal virus with the capacity to transmit and spread easily among humans could result in a global pandemic.

5)    International measures:

Human influenza caused by a new subtype is subject to notification to WHO under IHR (2005), Class 1.

a)    Any specimen from a patient suspected of novel influenza A virus infection, including H5N1, should be immediately tested and forwarded to a national reference laboratory or WHO Collaborating Centre/Reference Laboratories for confirmatory testing. WHO Collaborating Centres provide support as required—more information on the Centres can be found at: http://www.who.int/collaboratingcentres/database/en/

b)    Under the 2005 International health regulations, human influenza caused by a new subtype is considered as an event that may constitute a public health emergency of international concern.

c)    Continued viral and disease surveillance is critical for identifying human infections caused by influenza viruses of animal origin, including H5N1, and determining their ability to transmit efficiently among humans.

Pandemic Influenza: The response to an influenza pandemic must be planned at the local, national and international levels; guidance is provided on the WHO website: http://www.who.int/csr/disease/avian_influenza/en/

Similar information is available on the websites of many governments, including that of the USA at: www.pandemicflu.gov
 

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.
 


Available Vaccines

WHO-Prequalified Influenza A H1N1 Vaccines