CIDRAP Avian Influenza Bird Flu - Implications for Human Disease

Avian Influenza (Bird Flu): Implications for Human Disease

Agent
Avian Influenza in Humans
The 2003-2005 Outbreak of H5N1 in Asia
Clinical and Treatment Considerations
Vaccine Development
WHO and CDC Travel Recommendations
Use of Seasonal Influenza Vaccine in Humans
Surveillance Considerations
Influenza Pandemic Considerations
Infection Control
References

Agent

Avian influenza is caused by influenza A virus. More information about avian influenza in bird populations can be found in the overview titled Avian Influenza (Bird Flu): Agricultural and Wildlife Considerations.

Family: Orthomyxoviridae
Genus: Influenza

Virions are 80 to 120 nm in diameter and may be filaments.
Eight different segments of negative-stranded RNA are present; this allows for genetic reassortments in single cells infected with more than one virus and may result in multiple strains that are different from the initial ones (see References: Voyles 2002).
Type designation is based on the antigenic character of the M protein located in the virus envelope and the nucleoprotein within the virus particle. There are three types of influenza viruses (A, B, and C).
The virus envelope glycoproteins have hemagglutinin (HA) and neuraminidase (NA) activity; these characteristics are used to subtype the A, B, and C viruses.

Type: Influenza A

Influenza A viruses are the cause of avian influenza and also are a major cause of influenza in humans.
All past influenza pandemics in humans have been caused by influenza A viruses.
Influenza A also occurs in pigs, horses, and certain marine mammals (whales and seals); recently H5N1 has been recognised in tigers and cats. The H5N1 avian influenza virus circulating in Asia has expanded its host range to include cats, tigers, and leopards, which generally have not been considered susceptible to influenza A (see References: Keawcharoen 2004, Kuiken 2004).
There are 16 different HA antigens (H1 to H16) and nine different NA antigens (N1 to N9) for influenza A. Until recently, 15 HA types had been recognised, but a new type (H16) was isolated from black-headed gulls caught in Sweden and the Netherlands in 1999 and reported in the literature in 2005 (see References: Fouchier 2005).
Human disease historically has been caused by three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2).
All known subtypes of influenza A can be found in birds, but only subtypes H5 and H7 have caused severe outbreaks of disease in bird populations (known as highly pathogenic avian influenza [HPAI]).

Avian Influenza in Humans

In the past several years, it has become clear that avian influenza viruses can infect humans. Situations where avian influenza viruses have been recognised in humans include the following:

Human Cases of Avian Influenza
Year	Subtype	No. of Cases	Location	Comments
1997	H5N1	18 (6 deaths)	Hong Kong	Cases were linked to an outbreak of H5N1 in poultry. Sustained person-to-person transmission did not occur and the outbreak stopped when all birds in the Hong Kong commercial poultry industry (about 1.4 million) were slaughtered
1999	H9N2	2 (children ages 4 yr, 13 mo)	Hong Kong	Both case-patients had been hospitalised with influenza-like illness and both recovered uneventfully (see References: Peiris 1999, Uyeki 2002). No additional cases of person-to-person transmission occurred. Further investigation demonstrated that H9N2 strains were circulating in poultry in Hong Kong and China, although the viruses were not highly pathogenic for birds.
2002	H7N2	1	United States (Virginia)	Evidence of infection was found in one person in Virginia following a poultry outbreak.
2003	H5N1	2 (1 death)	Hong Kong	The 2 case-patients were family members who had recently travelled to China (see References: CDC: Basic information about avian influenza). A third family member died while in China of an undiagnosed respiratory illness). No direct link between these cases and H5N1infection in poultry was identified.
2003	H7N7	89 (1 death)	The Netherlands	During an outbreak of H7N7 avian influenza in poultry, infection spread to poultry workers and their families in the area (see References: Fouchier 2004; Koopmans 2004). Most patients had conjunctivitis and several complained of influenza-like illness. The death occurred in a 57-year-old veterinarian. Subsequent serologic testing demonstrated that additional case-patients had symptomatic infection.
2003	H7N2	1	New York	The source of exposure was not determined (see References: NIAID: Significant dates in influenza history).
2003-2005 (ongoing)	H5N1	114 (59 deaths), according to official WHO numbers	Vietnam, Thailand, Cambodia, Indonesia	Human cases are associated with an ongoing extensive outbreak of avian influenza in poultry (see References: WHO: Cumulative number of confirmed human cases of avian influenza A (H5N1) since 28 January 2004; WHO: Avian influenza: situation in Viet Nam, Mar 7, 2005). To date, human-to-human transmission has been limited. More information on this situation can be found in the section below.
2004	H7N3	2	Canada (British Columbia)	Poultry workers became ill during an outbreak of H7N3 avian influenza in poultry (see References: Health Canada 2004).
2004	H9N2	1 (child)	Hong Kong	The source of infection remains unknown (see References: National Institute of Allergy and Infectious Diseases: Focus on the Flu).
2004	H10N7	2 (infants)	Egypt	One childs father was a poultry merchant (see References: NIAID: Significant dates in influenza history).

The 2003-2005 Outbreak of H5N1 in Asia

An outbreak of HPAI caused by a strain of H5N1 avian influenza started in Asia in the fall of 2003 and spread in domestic poultry farms at an historically unprecedented rate. The outbreak tapered off in spring 2004 but in summer re-emerged in several areas and is still of great concern. The strain causing the outbreak is genetically distinct from the one isolated from humans in Hong Kong in 2003.

Areas affected by H5N1 avian influenza in poultry include:

Cambodia
China
Hong Kong
Indonesia
Japan
Laos
Malaysia
South Korea
Thailand
Vietnam
Russia
Kazakhstan
Mongolia

WHO has officially recognised 114 human cases of H5N1 influenza, 59 of them fatal, as of September 19, 2005; cases have been reported from Vietnam, Thailand, Cambodia, and Indonesia (see References: WHO: Cumulative number of confirmed human cases of avian influenza A [H5N1]; WHO: Situation updates). Media reports put the number higher . A recent report suggests that low perceived risk and high population exposures to live chickens are factors that may contribute to the spread of H5N1 in Asia (see References: Fielding 2005). One case of encephalitis has been confirmed as H5N1 (see References: de Jong 2005).

Guidelines have been issued from WHO and CDC regarding reporting (see References: WHO: Cumulative number of confirmed human cases of avian influenza A (H5N1) since 28 January 2004; CDC: Outbreaks of avian influenza A (H5N1) in Asia and interim recommendations for evaluation and reporting of suspected cases United States, 2004).

Sustained person-to-person transmission has not occurred to date, although a suspected person-to-person transmission in a family cluster, thought to be an isolated event, occurred in Thailand in fall 2004 (see References: Ungchusak 2005). In that situation, an ill child apparently spread the virus to her mother and aunt. Genetic analysis of the strain circulating indicates that no reassortment with human genes has occurred.

The virus has, however, shown an ability to jump species, infecting cats, pigs, tigers, and leopards in recent years. A summer 2004 study showed that the virus was causing increasingly severe disease when injected into laboratory mice (see References: Chen 2004). In August 2005, H5N1 was confirmed in civets in Vietnam

Clinical and Treatment Considerations

A recent report of avian influenza A (H5N1) in 10 patients in Vietnam (see References: Hien 2004) demonstrated the following clinical features of the illness:

For eight of nine patients in whom a history of exposure to infected birds could be ascertained, the median time of exposure to onset of illness was 3 days (range, 2 to 4 days).
All patients presented with fever, shortness of breath, and cough; median time from onset of illness to hospitalisation was 5.9 days (range, 3 to 8 days).
Five patients (50%) reported sputum production and in three of these patients, the sputum was blood-tinged.
Seven patients (70%) reported diarrhoea.
None of the patients complained of sore throat, conjunctivitis, rash, or a runny nose.
All patients had abnormal chest radiographs at the time of admission (including extensive bilateral infiltration, lobar collapse, focal consolidation, and air bronchograms).
All of the patients had lymphopenia at the time of presentation; the median lymphocyte count was 700 per cubic millimetre (range, 250 to 1,100 with the lower limit of normal being 1500).
Nine of the patients also had thrombocytopenia; the median platelet count was 75,500 per cubic millimetre (range, 45,000 to 174,000 with the lower limit of normal being 150,000).
Eight patients (80%) died.
All patients received broad-spectrum antibiotics and five were treated with oseltamivir (four of whom died).

The 2004 H5N1 strain is resistant to amantadine and rimantadine, complicating treatment and prophylaxis for human infections. The neuraminidase inhibitors are generally effective against influenza A and may be useful in treatment of and prophylaxis against H5N1 influenza, although the clinical utility of neuraminidase inhibitors in treating patients with H5N1 influenza is not yet known.

Oseltamivir is approved for treatment of influenza in persons aged 1 year and older and approved for prophylaxis of influenza in persons aged 13 years and older.
Zanamivir is approved for treatment of influenza in persons 7 years and older but is not an approved form prophylaxis.

Another report involving 12 confirmed H5N1 influenza cases from Thailand showed similar findings (see References: Chotpitayasunondh 2005). Laboratory tests on admission demonstrated leukopenia in seven (58%), lymphopenia in seven (58%), and thrombocytopenia in four (33%). Eight (67%) patients died. Acute respiratory distress syndrome (ARDS) was associated with a fatal outcome, and leukopenia and thrombocytopenia at time of admission were associated with development of ARDS. All 12 patients had abnormal chest radiographs by 7 days after onset of fever; two patients had interstitial infiltrates and 10 had patchy lobar infiltrates in a variety of patterns.

A recent case report of a 4-year-old Vietnamese child with H5N1 avian influenza who presented in 2004 with encephalitis demonstrated the following features (see References: de Jong 2005):

The child presented with a 2-day history of fever, headache, vomiting, and severe diarrhoea. (approximately 10 episodes per day). The stools were watery without blood or mucus.
Laboratory tests on admission were unremarkable and chest x-ray was normal.
On the third day following initial presentation, the child had a generalised convulsion and became comatose. He developed respiratory failure and died on the fifth day after initial presentation. Acute encephalitis of unknown origin was reported as the cause of death; no autopsy was performed.
H5N1 influenza A virus was isolated from cerebrospinal fluid, fecal, throat, and serum specimens.
The patient’s 9-year-old sister had died 2 weeks earlier from a similar clinical syndrome.

Vaccine Development

Because of concerns about the pandemic potential of H5N1, WHO has been working with laboratories in the WHO influenza network to develop vaccines against this subtype (see References: WHO: Development of a vaccine effective against avian influenza H5N1).

Candidate vaccines were developed during 2003 by network laboratories in London and in Memphis, Tennessee, for protection against the strain that was isolated from humans in Hong Kong in February of that year. However, the 2004 strain is different from that strain.
In April 2004, WHO made the prototype seed strain for an H5N1 vaccine available to manufacturers (see References: WHO: Avian flu: situation in Thailand; status of pandemic vaccine development).
The National Institute of Allergy and Infectious Diseases (NIAID) awarded two contracts to support the production and clinical testing of an investigation vaccine based on the prototype seed strain made available by WHO (see References: NIAID: Press release, May 2004).
The contracts were awarded to Aventis Pasteur (now Sanofi Pasteur) of Swiftwater, Pennsylvania, and to Chiron Corporation of Emeryville, California. Each manufacturer is using established techniques in which the virus is grown in eggs and then inactivated and further purified before being formulated into vaccines.
Clinical trials of candidate H5N1 vaccines are currently under way (see References: WHO: Avian flu: situation in Thailand; status of pandemic vaccine development; Mar 23, 2005. On August 6, 2005, NIAID announced that the Sanofi Pasteur vaccine was meeting with positive results in the first wave of testing in healthy adults. However, the amount of antigen needed was 180 mcg versus the 15 mcg given in annual flu shots, which makes the problem of adequate production far more acute. Further testing is ongoing, including trials to determine effectiveness and safety in children and the elderly (see August 8, 2005.

At this point, it is not clear if prototype H5 vaccines will offer protection against an emergent pandemic strain. Research in this area is a high priority because stockpiling prototype vaccines may be worthwhile if protection against emergent strains can be demonstrated (see References: Schwartz 2005).

One recent study demonstrated good cross-protection against H5N1 in mice following vaccination with an H5 influenza vaccine created through reverse genetics (see References: Lipotov 2005). Protection was achieved despite antigenic differences and incomplete matching between the vaccine strain and the challenge virus. Although these findings are promising, it is not clear if similar protection would occur for humans.
A second study suggested that use of adjuvanted prototype vaccines may induce antibody capable of neutralising a pandemic strain until a well-matched vaccine can be made available. In the study, 14 human subjects vaccinated with an adjuvanted influenza A/duck/Singapore 97 (H5N3) vaccine demonstrated higher seroconversion rates to four strains of H5N1 compared with 11 subjects who were vaccinated with a nonadjuvanted vaccine (see References: Stephenson 2005). For those who received the MF59-adjuvanted vaccine, 100% seroconverted to A/HongKong/156/97 and A/HongKong/213/03, 71% to A/Thailand/16/04, and 43% to A/Vietnam/1203/04.

One way of protecting against all types of influenza, including emerging pandemic strains, would be a universal flu vaccine that would not have to be re-engineered each year. The British company Acambis announced in early August 2005 that it is developing such a vaccine and has had successful results in animal testing (see References: Acambis 2005). The vaccine would focus on the M2 viral protein, which does not change, rather than the surface hemagglutinin and neuraminidase proteins targeted by traditional vaccines. The universal vaccine is made through bacterial fermentation technology, which would greatly speed up the rate of production over that possible with culture in chicken eggs, plus the vaccine could be produced continuously, since its formulation would not change. Still, such a vaccine is years away from full testing, approval, and use. Other researchers are also working on a universal agent.

WHO and CDC Travel Recommendations

As of Feb 11, 2004, WHO has released the following advice to international travellers regarding H5N1 influenza (see References: WHO: Advice to international travellers):

No restrictions on travel to areas affected by H5N1 are currently recommended.
Travellers to areas that are experiencing outbreaks of H5N1 in poultry should avoid contact with live animal markets and poultry farms.
Since influenza viruses are destroyed by heat, consumers in areas affected by H5N1 should ensure that all foods from poultry (including eggs) are thoroughly cooked. In addition, WHO has stressed the importance of good hygiene practices during handling of poultry products (eg, good handwashing, prevention of cross-contaminations, and adequate cooking).

CDC issued a similar advisory to travellers to Vietnam in March 2005 (last updated August 11 [see References: CDC: Update: Notice to travellers about avian influenza A]). The advisory is intended for travellers to Cambodia, China, Indonesia, Malaysia, and Thailand, as well as Vietnam. CDC recommends the following:

Before You Leave

Educate yourself and others who may be ravelling with you about avian influenza A (H5N1).
Be sure you are up-to-date with all your shots, and see your doctor or healthcare provider at least 4 to 6 weeks before travel to get any additional shots or information you may need.
Assemble a travel health kit containing basic first-aid and medical supplies. Be sure to include a thermometer and alcohol-based hand rub for hand hygiene. Additional information is available from CDC on putting together a kit (see References: CDC: Travellers’s Health Kit).
Identify in-country healthcare resources in advance of your trip.
Check your health insurance plan or get additional insurance that covers medical evacuation in case you become sick. Information about medical evacuation services is provided on the US Department of State website (see References: US Department of State).

During Travel

Avoid places such as poultry farms and bird markets where live poultry are raised or kept, and avoid contact with sick or dead poultry.
As with other infectious illnesses, one of the most important preventive practices is careful and frequent handwashing. Cleaning your hands often, using either soap and water or waterless alcohol-based hand rubs, removes potentially infectious materials from your skin and helps prevent disease transmission.
Influenza viruses are destroyed by heat; therefore, as a precaution, all foods from poultry, including eggs and poultry blood, should be thoroughly cooked.
If you become sick with symptoms such as a fever, difficulty breathing, cough, or any illness that requires prompt medical attention, a US consular officer can assist you in locating medical services and informing your family or friends (see References: Travellers’s Health: Illness Abroad).
It is advisable that you defer further travel until you are free of symptoms.

After Your Return

Monitor your health for 10 days.
If you become ill with fever, difficulty breathing, cough, or any illness during this period, consult a healthcare provider. Before you visit a healthcare setting, tell the provider about your symptoms and recent travel so that he or she can be aware you have travelled to an area reporting avian influenza.

Use of Seasonal Influenza Vaccine in Humans at Risk for H5N1 Infections

On January 30, 2004, WHO released guidelines for the use of seasonal influenza vaccine among persons at risk for H5N1 influenza (see References: WHO: Guidelines for the use of seasonal influenza vaccine in humans at risk of H5N1 infection). WHO is recommending targeted use of seasonal influenza vaccine to reduce the potential for humans to be infected with H5N1 at the same time that they are harbouring a human influenza strain. This will decrease the opportunity for genetic reassortment of the avian H5N1 strain with genes from a human (H1 or H3) strain and thereby reduce the likelihood that a novel pandemic strain will emerge from the current situation in Asia.

Groups recommended for vaccination include:

All persons who expected to be in contact with poultry or poultry farms suspected or known to be affected with avian influenza (H5N1), especially:

Cullers involved in destruction of poultry
People living and working on poultry farms where H5N1 has been reported or is suspected or where culling takes place

Healthcare workers involved in the daily care of known or confirmed human cases of influenza H5N1
Healthcare workers in emergency care facilities in areas where there is confirmed occurrence of influenza H5N1 in birds (provided that sufficient supplies of vaccine are available)

Surveillance Considerations

According to current recommendations from CDC (see References: CDC: Outbreaks of avian influenza A (H5N1) in Asia and interim recommendations for evaluation and reporting of suspected cases, United States, 2004), testing for H5N1 of patients hospitalised in the United States is indicated for patients who have both of the following conditions:

Radiographically confirmed pneumonia, acute respiratory distress syndrome (ARDS), or other severe respiratory illness for which an alternative diagnosis has not been established
A history of travel within 10 days of symptom onset to a country with documented H5N1 avian influenza infection in poultry or humans

Testing for influenza A (H5N1) also should be considered for patients with all of the following:

Documented temperature of over 100.4:F (38:C)
Cough, sore throat, or shortness of breath
History of contact with poultry or domestic birds (eg, visited a poultry farm, a household raising poultry, or a bird market) or a known or suspected patient with influenza A (H5N1) in an H5N1-affected country within 10 days of symptom onset)

The Centre's for Disease Control and Prevention (CDC) recommends the following for laboratory testing of clinical specimens from patients with suspected H5N1 influenza A:

Virus isolation studies on respiratory specimens should not be performed unless all biosafety level (BSL)-3+ laboratory conditions are met.
Clinical specimens can be tested by polymerase chain reaction (PCR) assays by using standard BSL-2 work practices in a Class II biological safety cabinet.
Commercially available antigen-detection tests can be used under BSL-2 levels to test for influenza.
Specimens from suspected cases should be sent to CDC if they test positive for influenza A either by PCR or antigen-detection testing, or if PCR assays for influenza are not locally available.

Influenza Pandemic Considerations

Past influenza pandemics occurring during the 20th century apparently all arose from the Eurasian avian lineage of viruses. These strains underwent genetic reassortment, most likely in pigs, before spreading widely among humans. It is unclear whether reassortment in another animal host is necessary or whether an avian strain could directly cause a global pandemic in humans

Of the avian influenza subtypes, H5N1 is of concern for the following reasons (see References: WHO: Avian influenza: assessing the pandemic threat):

The subtype mutates rapidly.
It has shown a propensity to acquire genes from viruses infecting other animal species.
It causes severe disease in humans, with a high case-fatality rate.
The virus has spread rapidly throughout poultry flocks in Asia, increasing the likelihood of infecting humans or pigs, where genetic reassortment with human strains could occur, leading to a new pandemic strain.

The current H5N1 strain circulating in Asia appears to be highly pathogenic for humans, and immunity in the human population is generally lacking. However, the strain has not been shown to be easily transmitted between humans, and sustained person-to-person transmission has not yet occurred. If the virus continues to circulate widely among poultry, it has a greater potential to infect humans and other animals (such as pigs), where genetic reassortment could take place and create a new pandemic strain. A WHO consultation held May 6-7, 2005, in Manila suggested that the pandemic potential of H5N1 is continuing to evolve (see References: WHO: Inter-country consultation on influenza A/H5N1 in humans in Asia). However, WHO stated June 30, 2005, that a team of experts sent to Vietnam found no laboratory evidence that the virus had changed appreciably (see References: WHO: Situation updates: avian flu [click update 24]).

Infection Control

Recently, WHO developed guidelines on infection control for management of patients with H5N1 avian influenza (see References: WHO: Influenza A [H5N1]: WHO interim infection control guidelines for health care facilities). The WHO infection control guidelines recommend that the following precautions be implemented for patients with H5N1 influenza:

Standard precautions
Droplet precautions
Contact precautions
Airborne precautions (including use of high-efficiency masks and negative-pressure rooms if available)

For adults and children over 12 years of age, these precautions should be implemented at the time of admission and maintained until 7 days after resolution of fever. For children 12 and under, precautions should be continued until 21 days have lapsed from onset of illness.

The WHO guidelines also recommend that all healthcare workers who may come into contact with the H5N1 virus or with infected patients should be vaccinated with the current WHO-recommended vaccine. Although this will not protect against H5N1 influenza A, it will help avoid simultaneous infection with other influenza strains and may thereby decrease the risk of genetic reassortment.

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