AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Avian influenza is a slightly misleading term, as influenza is among the natural infections found in birds. The term avian influenza used in this context refers to zoonotic human infection with an influenza strain that usually affects only birds.

Influenza virus is an orthomyxovirus—an enveloped, segmented, negative-sense RNA virus. Influenza virus has 3 strains—A, B, and C. (For additional information on influenza, see Medscape's Influenza Resource Center.) Avian influenza is caused by influenza A virus, which has 8 RNA segments. Avian influenza is a potential and unpredictable threat to humans because of the segmented nature of the genome.

The serotypes of influenza A virus are identified based on the hemagglutinin (H) and neuraminidase (N) proteins; 16 H serotypes and 9 N serotypes have been identified. For example, one currently circulating strain is designated as H3N2. The strain currently considered the greatest threat is H5N1, mostly because of the high associated mortality rate (up to 60%) in infected humans. These serotypic differences result in much of the species specificity due to differences in the receptor usage (specifically sialic acid, which binds to hemagglutinin and which is cleaved by neuraminidase when the virus exits the cell).

The immune response to these antigens is responsible for most host protection. The viral RNA polymerase lacks error-checking mechanisms and, as such, the antigenic drift from year to year is sufficient to ensure a significant susceptible host population. However, the segmented genome also has the potential to allow re-assortment of genome segments from different strains of influenza in a co-infected host.

Although all strains of influenza A virus naturally infect birds, certain strains can infect mammalian hosts such as pigs and humans. The re-assortment of an avian strain with a mammalian strain may produce a chimeric virus that is transmissible between mammals; such mutation products may contain hemagglutinin and/or neuraminidase proteins that are unrecognizable to the immune systems of mammals. This antigenic shift results in a much greater population of susceptible individuals in whom more severe disease is possible.

Such an antigenic shift can cause a pandemic, 3 of which have occurred in recorded history. The most striking pandemic occurred in 1918, when the Spanish influenza (H1N1) resulted in approximately 50 million deaths worldwide. Others included the pandemics of 1957 (H2N2) and 1968 (H3N2); smaller outbreaks occurred in 1947, 1976, and 1977. The fact that H3N2 is still circulating without causing an ongoing pandemic highlights the importance of herd immunity.

Avian influenza has low-pathogenic (LPAI) and highly pathogenic (HPAI) strains. H5N1 is typically a highly pathogenic virus in birds, resulting in severe disease and death. This strain has drawn more attention than other HPAI strains because of ongoing reports of bird-to-human transmissions that result in severe disease in the human host. Recently, some evidence has indicated that H5N1 may cause fewer symptoms in ducks, making them a potential reservoir for infection and spread by migratory flocks.¹

In theory, other highly pathogenic serotypes could become a threat if they started to spread from human to human. Several confirmed cases of human infection with LPAI strains (H7N2 in the United Kingdom and the US states of Virginia and New York; H7N7 in the Netherlands, H9N2 in China and Hong Kong) have been reported. In 2004, one outbreak of an HPAI H7N3 in Canada resulted in mild human disease.²

H5N1 was first reported to cause severe human disease in 1997 in an outbreak among infected chickens on Hong Kong Island. The outbreak was successfully contained with the slaughter of the entire local chicken population (around 1.5 million birds). However, 18 human cases were reported, of which 6 resulted in death.² Since then, H5N1 has been found in chickens, ducks, and migratory fowl throughout Asia and is now spreading west through Europe and North Africa. Human cases are following the route of the avian spread, but H5N1 has also been found in dead birds in several countries without any reported human cases (eg, the United Kingdom, Germany; see Image 2).

To date, avian influenza remains a zoonosis, with no sustained human-to-human transmission. Family clusters have been reported but appear to be almost always related to common exposures; however, limited human-to-human spread through close proximity could not be officially ruled out. In September 2004, one case in Thailand probably involved daughter-to-mother transmission; the mother died.³

A 1996 case of suspected severe acute respiratory syndrome (SARS) was shown to be due to H5N1 influenza.²

Pathophysiology

The pathophysiology of avian influenza differs from that of normal influenza. Avian influenza is still primarily a respiratory infection but involves more of the lower airways than human influenza typically does. This is likely due to differences in the hemagglutinin protein and the types of sialic acid residues to which the protein binds. Avian viruses tend to prefer sialic acid alpha(2-3)  galactose, which, in humans, is found in the terminal bronchi and alveoli. Conversely, human viruses prefer sialic acid alpha(2-6) galactose, which is found on epithelial cells in the upper respiratory tract. One group has reported that ex vivo cultures of human tonsillar, adenoidal, and nasopharyngeal tissues can support replication of H5N1 avian influenza.⁴

Although this results in a more severe respiratory infection, it probably explains why few, if any, definite human-to-human transmissions of avian influenza have been reported; infection of the upper airways is probably required for efficient spread via coughing and sneezing. Many are concerned that subtle mutation of the hemagglutinin protein through antigenic drift will result in a virus capable of binding to upper and lower respiratory epithelium. The 1918 pandemic strain was so lethal partially because the receptor utilization of the hemagglutinin differed from that of other strains, and H5N1 has that potential to acquire that same biology through mutation.

Differences in the PA, NP, M1, NS1, and PB2 genes tend to correlate with human strains of influenza, including human infections with avian influenza.⁵ The functional role of these genetic markers has yet to be determined but likely involves replication enhancement and immune suppression.

Unlike with human influenza, most deaths associated with avian influenza have been due to primary viral pneumonia, with no evidence of secondary bacterial infection.

Frequency

United States

Normal influenza results in approximately 200,000 hospitalizations and 36,000 deaths annually in the United States, with the peak season in the winter months.⁶ However, no cases of avian influenza have been reported in the United States.

International

As of October 17, 2007, 331 cases had been reported worldwide, with 203 deaths.⁷ Most cases have been in eastern Asia; some cases have been reported in Eastern Europe and North Africa. Underreporting has been a concern, particularly in China, but the prevailing attitude about the need to suspect, test, and report cases of avian influenza is growing.

Although the risk remains largely theoretical, the ease of global travel emphasizes the possibility of international spread.

Global map of countries where avian influenza (bird and human infections) has been reported. Image courtesy of PandemicFlu.gov.

Mortality/Morbidity

The extraordinarily high mortality rate of avian influenza (>60%) is worrying and reasonably accurate. In most instances, the policy is to test exposed individuals around an outbreak (human and avian). Therefore, a large population of exposed but untested people is unlikely.

Race

Race appears to be a factor only to the extent that geographic differences in the rate of HPAI among birds and the degree of bird-to-human contact are significant.

Sex

Avian influenza appears to have no sex predilection.

Age

Avian influenza has the highest case-fatality rate among persons aged 10-39 years. Unlike seasonal influenza, which disproportionately affects very young and very old individuals, young adults make up a large proportion of the avian influenza cases.

Fifty percent of reported cases have been in people younger than 20 years. Forty percent of cases involve persons aged 20-40 years.

CLINICAL

Section 3 of 11  

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History

The key history component that should prompt consideration of avian influenza as a possible diagnosis is exposure to sick, dead, or dying poultry. Many cases involve close contact, such as plucking or gutting of dead birds, removing infected carcasses, or ingesting incompletely cooked bird meat or blood.

• Fever (temperature >38°C)
• Diarrhea (watery, nonbloody)
• Vomiting
• Chest and/or abdominal pain
• Encephalitis (Two persons in Vietnam presented with encephalitis only.⁸)

Physical

• Tachypnea and crackles are common.
• Wheeze is occasionally apparent.
• Case reports have described other occasional signs, including hepatomegaly and bleeding gums, always in the presence of respiratory signs.⁸

DIFFERENTIALS

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WORKUP

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Lab Studies

If avian influenza is suspected, the laboratory should be called ahead of time and forewarned before specimens for identification of viral infection (eg, nasal washes) are obtained. Pneumatic tubing is not recommended for transport; hand transport using a leak-proof specimen bag is preferred. The specimen should be clearly labeled as "suspected AI," and the person who transports the specimen should use appropriate protective equipment.

Many laboratories are not equipped to deal with the isolation needed to safely contain avian influenza (category 3+ containment, higher than that used for HIV). If a sample is sent, the laboratory may need to be shut down for decontamination. Samples from patients with suspected avian influenza should be sent to a dedicated central reference laboratory such as at the Center for Disease Control and Prevention (CDC). The CDC laboratory can perform antiviral sensitivity testing, as well as subtyping of the virus.

Laboratory tests and findings include the following:

• Nasal wash specimens for detection of virus and viral subtyping are crucial.
• Leukopenia (usually a lymphopenia) may be present.
• Thrombocytopenia is common.
• Elevated levels of liver enzymes are common.
• Disseminated intravascular coagulation (DIC) may be evident.

Other tests, including blood cultures, lumbar punctures for CSF analysis (including polymerase chain reaction [PCR]), and sputum cultures, should be performed based on clinical suspicion for alternative or complicating diagnoses.

Imaging Studies

Chest radiography should be performed. The most common finding is multifocal consolidation; effusions and lymphadenopathy are also observed, as well as cystic changes.

The severity of radiologically apparent disease is a good predictor of mortality, including findings consistent with acute respiratory distress syndrome (ARDS), such as a diffuse, bilateral ground-glass appearance.

Chest radiograph of severe lung disease in a patient with avian influenza.

Procedures

• Intubation may be necessary for ventilatory support
• Lumbar punctures for CSF analysis may need to be performed based on clinical suspicion.

TREATMENT

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Medical Care

The mainstay of treatment is the administration of antiviral medication.

Supportive care such as oxygen therapy, intravenous fluids and parenteral nutrition may be needed.

Severe cases may require ventilatory support with intubation and low-volume (high-frequency) ventilation.

• Antiviral therapy should be tailored to the patient's age and the antiviral resistance profile of the virus from the area of exposure. Therapy should be initiated even when the presentation is late.
• Antibiotics may be needed to treat bacterial pneumonia but are not empirically necessary.
• Steroids have not been shown to be beneficial, except perhaps in the setting of sepsis with adrenal insufficiency.⁸  

An important consideration is that of infection control and prevention of transmission to other patients and health care workers. Droplet precautions should be used, including eye protection. No evidence shows that airborne spread is possible, but, if fine aerosols are expected because of specific procedures, a particulate respirator should be properly fitted and used.

Adults and children older than 12 years require one week of infection-control precautions, from the initial onset of symptoms. Children younger than 12 years may shed high titers of human influenza virus for up to 21 days after the illness onset, and the World Health Organization (WHO) recommends the same duration for avian influenza precautions.⁸

Consultations

• Consultation with an infectious disease expert is recommended.
• Intensive care specialists need to be involved to manage severe disease.
• Ultimately, the WHO and/or CDC should be contacted; the CDC can safely perform serotyping for suspected avian influenza strains.

MEDICATION

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Current WHO guidelines (2007) recommend therapy regimens with a neuraminidase inhibitor, preferably oseltamivir. Studies are ongoing as to the relative effectiveness of high-dose and/or prolonged courses of therapy with oseltamivir.⁸ If high-dose regimens prove to be more effective, the availability of antiviral medication in the event of a massive outbreak, as well as treatment considerations for mildly versus severely ill people, would be affected.

Although most H5N1 influenza cases are resistant to amantadine or rimantadine (reflecting mutations in the M2 gene segment), combination therapy is recommended unless the patient was exposed in an area known to contain virus strains resistant to the other antiviral agents. Treatment failures due to resistance to single-drug oseltamivir regimens have been reported.⁸

Zanamivir has not yet been tested in people with H5N1 disease, but animal studies are promising and the resistance mutations to oseltamivir do not cause cross-resistance. Some researchers have recommended dual therapy with both existing neuraminidase inhibitors. One concern is that inhaled zanamivir is unlikely to reach distal airways in severe disease.⁸

Two experimental drugs exist; arbidol is available in China and Russia, and peramivir is still being studied. Neither is yet available in the United States.

Currently, the CDC is recommending against using the M2 ion-channel blockers amantadine and rimantadine for routine influenza treatment or prophylaxis because of increasing resistance rates (up to 14.5% in the first half of the 2007-2008 flu season). This advice is subject to change.⁹

Probenecid, a uricosuric, approximately doubles the effective dose of oseltamivir by disrupting renal excretion of the drug and may have a role in a pandemic or in severe infections.¹⁰ No studies have yet been performed to confirm the appropriate dosing regimen in this situation.

Drug Category: Antiviral Agent

Agents that inhibit neuraminidase activity may be of benefit.

Drug Category: Uricosuric agents

Agents that inhibit the tubular secretion of the active metabolite of the drug may be used as adjunctive therapy.

FOLLOW-UP

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Deterrence/Prevention

No vaccine is currently available to the public, although various products are in clinical trials and appear immunogenic. One complication is that the highly pathogenic viruses cannot be easily grown using the traditional embryonated chicken egg method, as the embryos often die during incubation. Alternative methods for producing immunogenic particles include tissue culture and reverse-genetic approaches using recombinant viruses. One option for increasing the immunogenicity (and hence potentially lowering the dose needed to vaccinate) is to use an adjuvant agent such as aluminum hydroxide. All of these methods are being evaluated for an avian influenza vaccine.

An H5N1 monovalent killed-virus vaccine produced by Sanofi-Pasteur has been approved by the US Food and Drug Administration (FDA) in the United States but is available only to government agencies and stockpiles. It is derived from the influenza A/Vietnam/1203/2004 strain isolated from humans, and is a formalin-inactivated/detergent-disrupted, purified virus grown in embryonated chicken eggs. The vaccine was approved based on a limited safety and immunogenicity study of 500 adults aged 18-64 years. Fewer than half of those receiving the highest dose of vaccine responded and achieved antibody titers expected to be fully effective (ie, hemagglutination inhibition antibody titers >1:40) based on experience with seasonal influenza. The vaccine contains thimerosal (unlike many other seasonal influenza vaccines) because of the need for multidose vials.¹¹

Prophylactic antivirals are not indicated for patients who plan to travel to areas where avian influenza has been reported. Travelers who plan to travel to areas of the world affected by avian influenza outbreaks in birds and/or humans are advised to avoid close contact with poultry, especially diseased or dead birds, and to consume only adequately cooked meat. If contact with birds in enclosed spaces is unavoidable, an N-95 respirator mask (or equivalent), gloves, and goggles should be used to minimize contact with droplets or particulates. PandemicFlu.gov details more specific travel recommendations.

Prognosis

The prognosis of confirmed human cases of avian influenza is grave. The cases to date have exhibited a 60% mortality rate, which is largely predicted based on the degree of respiratory disease.

Little evidence regarding the long-term effects of disease among survivors is available.

MISCELLANEOUS

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Medical/Legal Pitfalls

Not suspecting avian influenza in a patient with severe, acute, febrile respiratory disease is a medicolegal pitfall. Risk factors or features that should raise the index of suspicion include the following:

• Travel to (within the last 2 wk) or location in a country with known avian influenza cases in animals or humans
• Unusual comorbidities such as encephalopathy or diarrhea
• History of exposure to birds, especially living in close proximity to birds, contact with sick or dying birds, or consumption of incompletely cooked bird meat
• History of exposure to individuals with known avian influenza, especially family, or to sick people in a country with known human cases of avian influenza

The situation can be complicated during outbreaks of severe respiratory disease not due to avian influenza. The first case of laboratory-confirmed avian influenza infection was documented during the SARS outbreak and was mistakenly misdiagnosed as SARS.

Not suspecting avian influenza in persons with atypical disease who have risk factors is a medicolegal pitfall.

Although a small percentage overall, several cases in which respiratory disease was limited or not apparent (with even normal chest radiography findings) have been described.⁸ The primary presenting illness has been encephalitis and/or diarrhea.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Chest radiograph of severe lung disease in a patient with avian influenza.
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Media type:  X-RAY

Media file 2:  Global map of countries where avian influenza (bird and human infections) has been reported. Image courtesy of PandemicFlu.gov.
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Media type:  Image

REFERENCES

Section 11 of 11

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1. Hulse-Post DJ, Sturm-Ramirez KM, Humberd J, Seiler P, Govorkova EA, Krauss S, et al. Role of domestic ducks in the propagation and biological evolution of highly pathogenic H5N1 influenza viruses in Asia. Proc Natl Acad Sci U S A. Jul 26 2005;102(30):10682-7. [Medline]. [Full Text].
2. World Health Organization. H5N1 avian influenza: Timeline of major events. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/Timeline_2007_03_20.pdf. Accessed October 2007.
3. Ungchusak K, Auewarakul P, Dowell SF, Kitphati R, Auwanit W, Puthavathana P. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med. Jan 27 2005;352(4):333-40. [Medline].
4. Nicholls JM, Chan MC, Chan WY, Wong HK, Cheung CY, Kwong DL, et al. Tropism of avian influenza A (H5N1) in the upper and lower respiratory tract. Nat Med. Feb 2007;13(2):147-9. [Medline].
5. Chen GW, Chang SC, Mok CK, Lo YL, Kung YN, Huang JH. Genomic signatures of human versus avian influenza A viruses. Emerg Infect Dis. Sep 2006;12(9):1353-60. [Medline].
6. Centers for Disease Control and Prevention. Key Facts About Seasonal Influenza (Flu). Centers for Disease Control and Prevention. Available at http://www.cdc.gov/flu/keyfacts.htm. Accessed October 2007.
7. World Health Organization. Confirmed Human Cases of Avian Influenza A(H5N1). World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/country/en/. Accessed October 2007.
8. World Health Organization. Clinical management of human infection with avian influenzaA (H5N1) virus. World Health Organization. Available at http://www.who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf. Accessed October 2007.
9. Centers for Disease Control and Prevention. Recommended Antiviral Agents for Seasonal Influenza for 2007-2008. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/flu/professionals/antivirals/agents.htm. Accessed October 2007.
10. Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos. Jan 2002;30(1):13-9. [Medline].
11. US Food and Drug Administration. H5N1 Influenza Virus Vaccine. US Food and Drug Administration. Available at http://www.fda.gov/cber/products/h5n1san041707qa.htm. Accessed October 2007.
12. Auewarakul P, Suptawiwat O, Kongchanagul A, Sangma C, Suzuki Y, Ungchusak K, et al. An avian influenza H5N1 virus that binds to human-type receptor. J Virol. Sep 2007;81(18):9950-5 Epub 2007 Jul 11. [Medline].
13. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med. Sep 29 2005;353(13):1374-85. [Medline]. [Full Text].
14. Chen H, Smith GJ, Zhang SY, Qin K, Wang J, Li KS, et al. Avian flu: H5N1 virus outbreak in migratory waterfowl. Nature. Jul 14 2005;436(7048):191-2. [Medline].
15. Finkelstein DB, Mukatira S, Mehta PK, Obenauer JC, Su X, Webster RG, et al. Persistent host markers in pandemic and H5N1 influenza viruses. J Virol. Oct 2007;81(19):10292-9. [Medline].
16. Shi D, Yang J, Yang D, LeCluyse EL, Black C, You L. Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther. Dec 2006;319(3):1477-84. [Medline].

Article Last Updated: Jun 6, 2008