Influenza, Avian

Paul G. Auwaerter, M.D.

PATHOGENS

  • Categorized according to the ability to kill chickens in a laboratory setting:
    • Highly pathogenic avian influenza (HPAI):
      • Influenza (H5N1), avian first detected in Chinese geese in 1996
      • Occasional human pathogen since 1997
        • Since 2003, the WHO has reported 888 H5N1 human avian influenza cases in 23 countries (mostly SE Asia), with a mortality rate of ~50%.
        • H5 avian influenza infection in man from Colorado (CDC, April 2022) with direct poultry exposure; extensive avian influenza among poultry flocks and wild birds in N. America in 2021-2022.
        • Since 2020, H5 clade 2.3.4.4b variants have caused considerable deaths among wild birds and poultry, striking countries in Africa, Asia and Europe. By 2021, it had spread to North America and then, in 2022, to Central and South America.
          • Sixty-seven countries reported infection with HPAI 2022 in either poultry or wild birds.
          • Also afflicts a wide variety of mammals, land- and sea-based.
        • U.S. (2022-2025): 66 human cases (as of 1/6/25) among workers related to dairy cows or poultry exposure. California and Colorado are leading in case numbers.
          • Mild disease typically, contrary to experience in SE Asia.
            • One fatality due to H5N1 in an older person with multiple comorbidities in December 2024 in Louisiana
              • Genetic analysis suggests the virus mutated within the patient, leading to a more severe illness.
            • Some cases are described without a known link to exposure (animal or infected person).
          • Considered to be low risk for human-to-human spread.
          • CDC webpage with the most up-to-date information.
    • Low pathogenic avian influenza (LPAI):
      • Occasional human infections are rarely fatal.
    • WHO has regularly updated reports from the Western Pacific region regarding HPAI and LPAI.

CLINICAL

  • The influenza pandemic 1918 virus had unusual virulence in mice and sequences similar to the current avian strain, H5N1. The concern is that the 1918 pandemic ("Spanish flu") killed 50 million with an average age of 30 yrs.
  • Epidemiology:
    • The latest updates are available at CDC Avian Influenza. Human avian influenza risk from H5 or H7 is considered low, and they are considered poorly adapted for human transmission.
      • Human cases typically occur only after considerable contact with infected birds (saliva, mucous or feces/respiratory acquisition/contact) or dairy cows.
      • Workers at risk (per CDC)
        • Broiler breeder farms, hatcheries, grow-out farms, and processing plant workers
        • Layer farm workers
        • Turkey farm workers
        • Disease control and eradication workers (federal, contract, and company workers)
        • Live-bird market workers
        • Wildlife biologists who handle birds
        • Animal control, welfare, and rescue workers who handle infected animals
      • WHO has updated reports on all avian influenza from the Western Pacific region
    • H5N1 is endemic in poultry in SE Asia and has recently been spread by waterfowl to many countries. Human cases are mainly in Asia and Africa. 75% of human cases have poultry contact.
      • H5N1 avian influenza has genetic and biological similarities to the Spanish flu virus, and it threatens a pandemic, but efficient human-human transmission has not succeeded.
        • Significant infections among domesticated poultry and wild birds in SE Asia, North America and Europe (2022-2024).
        • Control is achieved through culling.
        • Recent spread among dairy cows in multiple state outbreaks in the U.S. (2024).
      • Human disease: >1000 cases since 2013 in 21 countries; mortality rate of 40-61%. Mean age 16 yrs; rare deaths in people >40 yrs. Transmission risk to humans from birds is very, very low.
        • Sporadic human infections continue but not with an apparent increase with the 2022-2024 avian influenza epidemic among poultry.
      • The first H5N1 case in North America was reported (Jan 2014), imported.
        • The risk from wild birds is thought to be minimal for human acquisition.
        • Since 2022, 11 human cases have been reported in the U.S. following exposure to poultry or dairy cows.
    • The H7N9 outbreak was first seen in China from the spring of 2013 through the winter of 2014.
      • The local epidemic in China from 2016 to 2018 was primarily due to poultry exposure; a national poultry immunization program is underway.
        • Although the age distribution and case sources have changed since 2013, there are more middle-aged and urban patients than rural patients. The severity remains similar.
      • Human-to-human transmission appears to be very rare to date.
      • In more than 1,000 cases described since 2013, it appears to cause severe infection with an estimated mortality of 40-61%.
      • Travelers should avoid poultry exposure in China, especially live birds in markets.
    • Sites of infection:
      • Lungs: hemorrhagic pneumonia
      • GI: enteric symptoms are common, including nausea, vomiting, diarrhea
      • Pharyngitis: only about half of the patients have URI symptoms
      • Ocular: conjunctivitis

DIAGNOSIS

  • For suspected cases, contact the local public health department ASAP; see Interim Guidance on Testing from CDC.
    • H5- or H7-specific RT-PCR (can be performed on refrigerated or frozen specimens).
    • Viral culture (if suspected, suggest BSL-3 lab): call the local health department and transfer to CDC for confirmatory testing.
    • Paired serology: acute/convalescent for H5N1 specific antibody. The test should only be performed at CDC.

TREATMENT

Antivirals

  • In the U.S., the most current guideline for the treatment of avian influenza can be reviewed in the CDC Interim Guidance document for people exposed to birds with avian influenza A virus associated with the potential to cause severe human infection.
  • Preferred: neuraminidase inhibitors are generally active against avian strains, although some Asian H5N1 and H7N9 strains may display resistance.
    • Oseltamivir 75mg PO twice daily; active in vitro vs. nearly all H5N1 strains tested.
      • Duration: The duration is uncertain, but the current recommendation is 10 days for those severely ill (as opposed to 5 days for seasonal influenza).
      • Early treatment appears critical; don’t delay confirming the diagnosis.
      • Administer even if > 48h after the onset of symptoms, given the severity of many human avian influenza infections.
        • The ability to impact illness when used 48-72h after symptoms onset is uncertain, though.
  • Alternatives:
    • Peramivir
      • IV agent is usually given as a one-time dosing.
      • Little experience regarding use in non-seasonal influenza, but would dose daily for at least 5d initially with severe infection.
    • Zanamivir 10mg inhaled twice daily x 5d; more active in vitro than oseltamivir, but experience with H5N1 limited.
  • Others:
  • Antibacterials (secondary bacterial pneumonia): anticipated pathogens - S. pneumoniae, group A strep and S. aureus. Empiric treatment with ceftriaxone (1gm q 12h IV) or cefotaxime (1gm q 8h IV) +/- vancomycin or linezolid for MRSA.
  • MRSA superinfection (Gram stain or culture): vancomycin target trough level of 15-20 mcg/ml +/- rifampin 300mg IV/PO q 12h, or linezolid 600mg IV/PO q 12h +/- rifampin 300mg IV/PO q 12h.
  • Steroids: anecdotal experience shows no evidence of efficacy.

Prevention: General Measures

  • Avoid exposure to potential avian influenza A when possible (sick/dead infected poultry or birds, contaminated surfaces, bird feces, infected humans).
    • Monitoring of exposed persons: 10d period suggested looking for fever and respiratory symptoms.
    • May consider chemoprophylaxis for all exposed.
    • Depending on current local epidemics, travelers should avoid poultry markets (China and perhaps elsewhere in SE Asia).
  • Three strategies: vaccines, antivirals and community mitigation.
    • Vaccines: In development (subunit vaccine), and some are stockpiled.
    • Antivirals: oseltamivir 75mg PO twice daily x 4 weeks, or zanamivir 10mg inhalation twice daily x 4 weeks.
    • "Community mitigation"
      • "Social distancing:" close schools, businesses, subways, malls.
      • Epidemiologic control: cases are treated (to reduce viral shedding) and isolated. Contacts are treated with antiviral prophylaxis +/—vaccine (if available). Potential contacts are vaccinated.
  • Stockpiles:
    • Antivirals - WHO recommends countries purchase oseltamivir for 25% of the population.
    • H5N1 vaccine: stockpiled in the U.S.
  • Hospital infection control: N95 mask, negative-pressure room, limit visitors, and oseltamivir treatment.
  • Healthcare workers with exposure: monitor temperatures; if febrile or aerosol exposure, give oseltamivir (75-150mg PO twice-daily x 10d); remove from patient care.
  • Household contact: Monitor temperatures; if fever or aerosol exposure is present, give oseltamivir.

Prevention: Travelers to Endemic Area

  • Immunize with seasonal influenza vaccine (to avoid confusion).
    • Offers NO protection from H5N1 avian influenza.
  • CDC recommendations for travel to countries with outbreaks of avian influenza A:
    • Avoid poultry contact, visiting live poultry markets or visiting poultry farms or infected dairy herds.
    • Avoid eggs and undercooked/raw poultry.
    • Liberal use of alcohol-based hand wipes.
    • Do not consume raw milk or undercooked beef.
      • Pasteurized dairy products only; uncertain if raw milk poses a threat, but virus found in dairy herds.
      • Cook all beef meat and products.
    • Medical consultation if a febrile illness with respiratory symptoms develops within 10 days of returning from an endemic region.

Selected Drug Comments

Drug

Recommendation

Amantadine

Has no activity against avian influenza.

Baloxavir

Approved in December 2019 for influenza. In vitro studies suggest activity against avian and swine strains of influenza. There is no human experience yet with using this agent.

Rimantadine

Has no activity against avian influenza.

Oseltamivir

The FDA approved it in 1999 as the first available neuraminidase inhibitor for influenza, which, like zanamivir, is active vs. influenza A & B. The Main side effect is GI intolerance. Approved for treatment and prophylaxis (age > 1 year). In vitro activity against avian influenza, but actual clinical experience in SE Asia has not shown efficacy, possibly due to the late use of the drug > 48 hours after symptom onset.

Peramivir

Approved by the FDA in 2014 for treatment of uncomplicated influenza with < 48 h symptom onset, but is used off-label for seasonal influenza in severely ill, hospitalized patients. No significant experience with the use of this drug for avian influenza strains.

Zanamivir

FDA approved in 1999 for treating seasonal influenza (A and B). It must be inhaled with a tricky gadget. A major side effect is bronchospasm, primarily in asthmatics. FDA-approved only for treatment, but it works for prophylaxis. Receiving some renewed interest due to concerns of avian influenza with an observation of very high drug levels in the lung that can inhibit viral replication within minutes of application. IV formulation has shown activity against Asian avian influenza strains, including oseltamivir-resistant virus and may be available for compassionate use from GSK IND.

OTHER INFORMATION

  • Public health risk in the U.S. from avian influenza was judged low from outbreaks in wild birds or poultry.
  • Concerns for H5N1:
    • Spread in poultry, dairy cows, and other mammals
    • Highly lethal in humans despite good care and oseltamivir (40-61%)
      • Most U.S. human cases have been mild.
    • Similar virulence to the 1918-19 influenza strain
    • Ability to "jump species" (birds to cats, tigers, leopards, humans, etc.).
  • The current limitation of H5N1 is that there is no sustained human-to-human transmission. The reason is receptors in the upper respiratory tract.
  • The average age of lethal cases from annual influenza in the U.S. is 80; in 1918 influenza, age was 30; H5N1 is 16.
  • Oseltamivir is active in vitro vs. H5N1 but must be given within 2 days of sx for efficacy with seasonal influenza A or B strains.
  • The vaccine is developed from the Vietnam strain and is now stockpiled; the initial study shows safety and good antigenic response but limited supply (2% of the population and concern for subsequent clade shift).
  • Mortality with avian flu appears to be viral pneumonia progressing to ARDS and death, not bacterial superinfection.

Basis for recommendation

  1. Adisasmito W, Chan PK, Lee N, et al. Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. 2010;202(8):1154-60.  [PMID:20831384]

    Comment: H5N1 Global Registry tabulated information on 308 cases of influenza A (H5N1). Overall survival was 44% among patients who received at least one dose of oseltamivir vs. 24% who did not (p=< 0.001). The benefit was noted when the drug was started up to 6-8 days after symptoms.

  2. CDC. Information on Avian Influenza: https://www.cdc.gov/flu/avianflu/index.htm (accessed 1/13/2025, last updated 5/22/22)

    Comment: Helpful site updates the information on bird flu, H5N1 most famously, but others such as H7N9, with the fifth epidemic, described onset in early 2017 in China. Current diagnosis, treatment, and prophylaxis recommendations are taken from here—also low pathogenic avian influenza A infections listed (H6, H9 and H10).

  3. CDC. Prevention and Antiviral Treatment of Avian Influenza A Viruses in People. https://www.cdc.gov/bird-flu/prevention/index.html (last updated 7/19/24, accessed 1/13/2025)

    Comment: Prevention is advocated and includes links for special protection measures for animal workers. Other measures include dealing with poultry, beef and milk. Avoidance of raw, unpasteurized milk. Treatment is similar to seasonal influenza. Seasonal influenza vaccination does not offer protection against H5N1 avian influenza.

References

  1. Shi J, Zeng X, Cui P, et al. Alarming situation of emerging H5 and H7 avian influenza and effective control strategies. Emerg Microbes Infect. 2023;12(1):2155072.  [PMID:36458831]

    Comment: Recent outbreaks have resulted in significant culling of flocks in Europe and North America. While H5 gets more attention, H7 has also been a concern, with H7N9 emerging in 2013.

  2. Xu H, Zhu S, Govinden R, et al. Multiple Vaccines and Strategies for Pandemic Preparedness of Avian Influenza Virus. Viruses. 2023;15(8).  [PMID:37632036]

    Comment: Vaccines remain controversial in controlling avian outbreaks because they may foster the drive of viruses that escape.

  3. Govorkova EA, Takashita E, Daniels RS, et al. Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018-2020. Antiviral Res. 2022;200:105281.  [PMID:35292289]

    Comment: To date, there has not been sufficient evidence of significant antiviral resistance to drugs used for treatment, including Influenza A subtypes. Baloxivir resistance is highest in Japan, where use is most.

  4. Liu WJ, Wu Y, Bi Y, et al. Emerging HxNy Influenza A Viruses. Cold Spring Harb Perspect Med. 2022;12(2).  [PMID:32928891]

    Comment: Review focus on the influenza A variants and potential for human infection.

  5. Lewis NS, Banyard AC, Whittard E, et al. Emergence and spread of novel H5N8, H5N5 and H5N1 clade 2.3.4.4 highly pathogenic avian influenza in 2020. Emerg Microbes Infect. 2021;10(1):148-151.  [PMID:33400615]

    Comment: One of the regular updates on the status of concerning influenza strains infecting birds.

  6. Taniguchi K, Ando Y, Nobori H, et al. Inhibition of avian-origin influenza A(H7N9) virus by the novel cap-dependent endonuclease inhibitor baloxavir marboxil. Sci Rep. 2019;9(1):3466.  [PMID:30837531]

    Comment: This study includes murine data that suggests an effect on replication with this cap-dependent endonuclease inhibitor that works at an earlier stage than neuraminidase inhibitors in the influenza viral life cycle.

  7. Li YT, Linster M, Mendenhall IH, et al. Avian influenza viruses in humans: lessons from past outbreaks. Br Med Bull. 2019;132(1):81-95.  [PMID:31848585]

    Comment: Many papers argue that only by close surveillance of avian strains among birds will there be an early warning of disease jumps to humans.

  8. Kiso M, Yamayoshi S, Furusawa Y, et al. Treatment of Highly Pathogenic H7N9 Virus-Infected Mice with Baloxavir Marboxil. Viruses. 2019;11(11).  [PMID:31731678]

    Comment: Baloxivir may well have good activity in avian influenza settings, such as the case in this animal model using H7N9.

  9. Mishin VP, Patel MC, Chesnokov A, et al. Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir1. Emerg Infect Dis. 2019;25(10):1969-1972.  [PMID:31287050]

    Comment: This end-cap endonuclease inhibitor displays activity against both avian and swine influenza A viruses.

  10. Sutton TC. The Pandemic Threat of Emerging H5 and H7 Avian Influenza Viruses. Viruses. 2018;10(9).  [PMID:30154345]

    Comment: Circulating H5 and Asian H7N9 viruses display molecular changes that may have the ability to transmit to animals from existing avian sources, e.g., ferrets. The author points out that the hemagglutinin of these viruses is unstable, which may help prevent the emergence of these viruses, causing significant human-human airborne transmission.

  11. Shen Y, Lu H. Global concern regarding the fifth epidemic of human infection with avian influenza A (H7N9) virus in China. Biosci Trends. 2017;11(1):120-121.  [PMID:28250340]

    Comment: H7N9 continues to cause local epidemics in China. It, therefore, has garnered more concern especially given the severity of illness with high mortality, although, to date, human-to-human spread appears quite uncommon.

  12. Leung YH, To MK, Lam TS, et al. Epidemiology of human influenza A(H7N9) infection in Hong Kong. J Microbiol Immunol Infect. 2017;50(2):183-188.  [PMID:26220305]

    Comment: Of 10 cases described, all were imported from mainland China, and those who received delayed anti-virals faired worse. No secondary cases of transmission were identified. All infected patients had co-morbid conditions such as diabetes, CAD, or a history of CVA. Three patients received ECMO. Most received oseltamivir, although three received zanamivir as well.

  13. Wang X, Jiang H, Wu P, et al. Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis. 2017;17(8):822-832.  [PMID:28583578]

    Comment: Since the onset of H7M9 in mainland China, there has been some shift from rural/semi-suburban populations to more urban and middle-aged afflicted since 2013 when examining 2016-2017 patients (fifth epidemic). Most cases recently have been seen in Zhejiang, Jiangsu and Guangdong provinces.

  14. Ke C, Mok CKP, Zhu W, et al. Human Infection with Highly Pathogenic Avian Influenza A(H7N9) Virus, China. Emerg Infect Dis. 2017;23(8):1332-1340.  [PMID:28580899]

    Comment: The human case had a sequence in hemagglutinin cleavage site similar to the highly pathogenic strain of H7N9 killing birds. The authors wonder if this sequence may have contributed to the patient’s demise. The individual had close and frequent contact with sick poultry.

  15. Peiris JS, Cowling BJ, Wu JT, et al. Interventions to reduce zoonotic and pandemic risks from avian influenza in Asia. Lancet Infect Dis. 2016;16(2):252-8.  [PMID:26654122]

    Comment: Authors review the experience in China where the closure of live poultry markets appeared to staunch the outbreak of H7N9. Efforts to separate ducks & geese from chickens may assist in limiting such emergence of new strains, among other measures.

  16. Liem NT, Tung CV, Hien ND, et al. Clinical features of human influenza A (H5N1) infection in Vietnam: 2004-2006. Clin Infect Dis. 2009;48(12):1639-46.  [PMID:19435433]

    Comment: Observations in 67 cases in Vietnam. Findings included bilateral infiltrates on chest x-ray (72%), leukopenia (73%) and elevated transaminases (69%). The mortality rate was 39% and was higher for young persons (< 16 years) compared to older persons (0.001). Oseltamivir showed a survival benefit.
    Rating: Important

  17. Swaminathan A, Martin R, Gamon S, et al. Personal protective equipment and antiviral drug use during hospitalization for suspected avian or pandemic influenza. Emerg Infect Dis. 2007;13(10):1541-7.  [PMID:18258004]

    Comment: Estimates of personal protective equipment (PPE) needs for a pandemic flu patient during the first 6 hours: A mean number of close contacts -- 12 (10 HCWs), mean exposures -- 19, requirements 20-25 PPE sets/patient. Up to 41% of HCW would qualify for antiviral prophylaxis.

  18. Beigel JH, Farrar J, Han AM, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005;353(13):1374-85.  [PMID:16192482]

    Comment: Review of all facets of the disease showing: 1) limited human-human transmission, 2) high lethality: 34/59, 3) 80% of cases report poultry contact, 4) death due to ARDS at a median of 10 days post-onset symptoms, 5) poor response to oseltamivir.

  19. Taubenberger JK, Reid AH, Lourens RM, et al. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005;437(7060):889-93.  [PMID:16208372]

    Comment: Reconstruction of the 1918 pandemic flu strain (!) showed it was an avian-like virus that adapted to humans, had unusual virulence in mice, and shared some sequences conferring virulence with H5N1.

  20. Tran TH, Nguyen TL, Nguyen TD, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med. 2004;350(12):1179-88.  [PMID:14985470]

    Comment: Review of 10 cases in Vietnam. Most had flu symptoms followed by ARDS and death.

  21. WHO. Avian and other zoonotic influenza http://www.emro.who.int/health-topics/avian-influenza/avian-influenza.html (accessed 1/13/2025)

    Comment: The page leads to linked pages, including updates on regional avian disease outbreaks in poultry and human cases (weekly reports), though the outbreak page was last update was in 2016.

Last updated: January 16, 2025