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    As of May 30, 2024, a total of 3 human cases of highly pathogenic avian influenza have been identified in the United States. This ongoing multistate outbreak of influenza A (H5N1) is thus far limited to exposure to infected dairy cows, with 2 cases in Michigan and 1 in Texas. The CDC still considers the health risk assessment for the general US public as low.

    Because 2 patients experienced conjunctivitis and their conjunctival swabs tested positive for the virus, the CDC recommends that clinicians consider the possibility of avian influenza in patients presenting with conjunctivitis and who have a history of relevant exposure to livestock or other animals within 10 days before onset of symptoms.

    CDC Recommendations

    Key Points for the Ophthalmologist

    • Epidemiologic data suggest that H5N1 can be transmitted from patients to healthcare workers.
    • Be alert to H5N1 as a cause of conjunctivitis when a patient presents with a history of exposure to sick birds, livestock, or cattle. Two recent human H5N1 infections, presumably transmitted from sick cows, presented with conjunctivitis as the sole clinical sign and symptom. The third human case also had more typical respiratory illness symptoms.
    • Personal protective equipment (PPE) may be warranted when patients presenting with conjunctivitis meet epidemiological criteria and/or clinical criteria.
    • Gloves, N95 masks or equivalent, and goggles or face shield are recommended for high-risk exposures to H5N1. Hand washing and avoidance of hand-to-eye contact are key.
    When to Be Concerned
    • Patients with conjunctivitis and a history of recent exposure to sick or dead poultry prior to their illness should be suspected of H5N1 infection.
    • Patients with conjunctivitis with close or prolonged, unprotected exposures to infected birds or other animals (including livestock), or to environments contaminated by infected birds or other animals, are at greater risk of infection.

    Clinical Findings in Humans

    • Historically H5N1 can be responsible for a wide range of clinical symptoms including:
      • Mild illness: cough, sore throat, eye redness or eye discharge such as conjunctivitis, fever or feeling feverish, rhinorrhea, fatigue, myalgia, arthralgia, or headache
      • Moderate to severe illness: shortness of breath or difficulty breathing, altered mental status, or seizures
      • Complications: pneumonia, respiratory failure, acute respiratory distress syndrome, multi-organ failure (respiratory and kidney failure), sepsis, or meningoencephalitis 
    • Both H5N1 and H7N9 epidemics presented with acute severe community-acquired pneumonia that did not respond to typical and atypical antimicrobial coverage.

    Testing and Surveillance

    • Influenza A H5N1 can be detected by FDA-cleared and approved assays for influenza A. These tests, however, cannot distinguish H5N1 from other influenza A subtypes.
    • Currently, typing will need to be performed at the state health department laboratories and the CDC.
    Preferred Clinical Specimens
    • One nasopharyngeal swab and one nasal swab combined with an oropharyngeal swab (e.g., two swabs combined into one viral transport media vial)
    • If the patient has conjunctivitis (with or without respiratory symptoms): one conjunctival swab and one nasopharyngeal swab into viral transport media

    Prevention for At-Risk Groups

    Based on the CDC guidelines, workers and other at-risk individuals should avoid the following:
    • Unprotected or close physical contact with sick birds, livestock, and other farm animals
    • Consuming unpasteurized milk or cheese
    • Fecal matter or litter of infected animals
    • Surfaces and water on farms or where sick animals frequent

    Treatment

    Antiviral prophylaxis and outpatient treatment to patients with exposure to H5N1 virus should be provided based on the CDC treatment recommendations:
    • Twice daily oral oseltamivir (available as a generic version or under the trade name Tamiflu) for 5 days.
    • Initiation is based on clinical judgment; treat as soon as possible as clinical benefit is greatest if antiviral is administered early.
    • Antiviral treatment should not be delayed while waiting for laboratory confirmation.
    • If testing is negative for novel H5N1 and clinical suspicion remains high, antiviral treatment should continue, and the patient should be reswabbed for repeat testing
    • In hospitalized patients with suspected or confirmed influenza, initiate oral or enterally administered oseltamivir as soon as possible with supportive care.
    • Co-circulating viruses, including SARS-CoV-2, should be considered for testing, depending on the local epidemiology patterns.
    • Other FDA-approved antivirals that are effective against influenza A and B:
      • Neuraminidase inhibitors: inhaled zanamivir and intravenous peramivir
      • Cap-dependent endonuclease inhibitor: oral baloxavir marboxil

    Avian Influenza Disease Background

    Waterfowl are the natural reservoir of all known influenza A viruses. Influenza A viruses belong to the family Orthomyxoviridae, whose genomes are composed of eight negative-sense, single-stranded RNA segments. The subtypes of influenza A viruses are based on the antigenicity of the 2 surface glycopeptides, hemagglutinin (HA) and neuraminidase (NA). Because some influenza A subtypes infect both nonhuman hosts and humans, reassortments of genes can occur and result in antigenic shift. Given that humans typically have little or no antibodies against these viruses, the potential for pandemics is a concern.

    Since 1997, multiple outbreaks of avian influenza A H5N1 and H7N9 in domestic poultry have been reported. The most recent outbreak of H5N1 started at the end of 2020 and killed more than 100 million birds. Human infections were rare and occurred in those with unprotected exposure to sick birds. According to the World Health Organization (WHO), there have been fewer than 900 cases and 493 deaths (>50%) in humans due to H5N1 from 2003 to April 2024.

    In March 2024, the first multistate outbreak of avian influenza A H5N1 in cows was documented in the United States. As of May 30, 2024, there were 3 reported United States cases of influenza A (H5N1) in humans, 1 in Texas and 2 in Michigan. All were farm workers who came in contact with sick cows and each reported ocular symptoms. In the first two patients, H5N1 viruses were detected at higher levels in conjunctival swabs compared with samples from the upper respiratory tract.

    Highly Pathogenic Avian Influenza A Viruses (HPAIV)

    Avian influenza A viruses are classified into two categories: low pathogenic and highly pathogenic. Highly pathogenic refers to the virus’s ability to cause disease in chickens in a laboratory setting. Both H5N1 and H7N9 are highly pathogenic strains. 

    No human vaccines against highly pathogenic avian influenza A viruses are presently available.

    H5N1 Outbreaks

    The first human outbreak of H5N1 occurred in Hong Kong in 1997. Prior to this outbreak, several avian outbreaks occurred on farms. H5N1 appears to be more readily transmitted from poultry to people than H7N9. This virus has a strong affinity for α-2,3-linked sialic acid receptors, which are present in the lower respiratory tract of humans. These receptors are also present on conjunctiva, which likely explains recent cases with only ocular symptoms or signs. H5N1 can be transmitted from birds to cows and can be detected in cow’s milk. H5N1 can be transmitted from patients to healthcare workers.

    Recent Cases of H5N1 (2022 to 2024)

    • The first human case was reported in the United Kingdom in January 2022. The affected person lived with a large flock of ducks who became ill. This patient was asymptomatic.
    • The second reported case (first in the United States) was reported in the spring of 2022, involving an incarcerated 40-year-old man culling poultry who presented with fatigue.
    • Three recent cases have been reported in March 2024 (Texas) and May 2024 (Michigan). All 3 cases occurred in adult dairy farm workers exposed to sick cows. Two patients presented with only red eyes and without systemic symptoms. Subconjunctival hemorrhage was described in the Texas case.

    H7N9 Outbreaks

    The first human outbreak of H7N9 was reported in China in 2013. Unlike H5N1, there were no reported avian outbreaks before the human outbreak. The H7 subtype replicates robustly on the conjunctiva and can serve as the portal for systemic entry. Other H7 viruses prior to the 2013 outbreak were reported to cause conjunctivitis.

    Acknowledgements

    The Academy thanks the following contributing authors:

    • Thuy Doan, MD, PhD, Director, Ralph and Sophie Heintz Laboratory, Francis I. Proctor Foundation for Research in Ophthalmology, University of California, San Francisco
    • Gerami Seitzman, MD, Medical Director, Francis I. Proctor Foundation for Research in Ophthalmology, University of California, San Francisco
    • Thomas M. Lietman, MD, Ruth Lee and Phillips Thygeson Distinguished Professor, Director, Francis I. Proctor Foundation for Research in Ophthalmology, University of California, San Francisco