Novel H5N1 Bird Flu Outbreak

Key Points for the Ophthalmologist

• Be alert to H5N1 as a cause of conjunctivitis when a patient presents with a history of exposure to sick birds, dairy cows or livestock. Two recent human H5N1 infections, presumably transmitted from sick cows, presented with conjunctivitis as the sole clinical sign and symptom. The third human case had more typical upper respiratory illness symptoms and eye discharge. The fourth human case had only eye symptoms. An additional four cases, presumably transmitted from H5N1 virus-infected poultry, presented with conjunctivitis and tearing as well as more typical flu 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.

• Patients with conjunctivitis and a history of recent exposure to sick or dead poultry or sick cows or unpasteurized (raw) cow milk prior to their illness should be suspected of H5N1 infection. Heat treatment of milk appears to inactivate avian influenza A (H5N1) virus.
• Patients with conjunctivitis with close or prolonged, unprotected exposures to infected birds or other animals (including livestock) or to unpasteurized (raw) milk, 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 and cannot be used with conjunctival swab specimens.
• Currently, influenza A virus subtyping will need to be performed at a public health laboratory using the CDC real-time RT-PCR assays.

• For patients with conjunctivitis (with or without respiratory symptoms): one conjunctival swab and one nasopharyngeal swab into separate viral transport media
• For patients without conjunctivitis: one nasopharyngeal swab and one nasal swab combined with an oropharyngeal swab (e.g., two swabs combined into one viral transport media vial)

Prevention

• Unprotected or close physical contact with sick birds, livestock such as dairy cattle, and other farm animals (workers can wear recommended PPE, including N95 mask and goggles or face shield)
• Consuming unpasteurized (raw) cow milk or cheese
• Fecal matter or litter of infected animals
• Surfaces and water on farms or where sick animals frequent

Treatment

• 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.

Highly pathogenic avian influenza (HPAI) A (H5N1) virus has spread widely through migratory birds to many regions of the world, causing infections of many wild bird species, poultry outbreaks, with spillover to mammals. 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. Conjunctivitis has been rarely reported in humans infected with HPAIA (H5N1) viruses since 1997. 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.

Currently, in the US, since February 2022, there have been widespread poultry outbreaks, with nearly 97 million commercial poultry and backyard flocks dying or culled to contain the spread. In March 2024, the first multistate outbreak of avian influenza A H5N1 in cows was documented in the United States. As of July 19, 2024, there were 10 reported United States cases of influenza A (H5N1) in humans, 1 in Texas, 2 in Michigan and 7 in Colorado. All were farm workers who came in contact with sick cows or poultry. 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) and Low Pathogenic Avian Influenza A Viruses

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 can be highly pathogenic strains. 

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

H5N1 Outbreaks

The first human outbreak of avian influenza A (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 the conjunctiva, which likely explains the 2 recent cases with only ocular symptoms or signs. H5N1 can be transmitted from birds to cows and can be detected in cow’s milk. There was sero-epidemiologic evidence that H5N1 can be transmitted from patients to healthcare workers from this 1997 H5N1 outbreak in Hong Kong.

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. The Texas case was a patient with isolated bilateral conjunctivitis and subconjunctival hemorrhage. Testing of both conjunctival and nasopharyngeal swabs was positive for H5N1 virus. The first Michigan case presented with isolated unilateral conjunctivitis with diagnosis made by conjunctival swab specimen. The second Michigan case presented with acute non-febrile upper respiratory tract symptoms and diagnosis was made by nasopharyngeal swab.
• Four recent cases have been reported on July 14, 2024 (Colorado). All 4 cases occurred in farm workers at a poultry facility experiencing an outbreak of H5N1 virus. These workers reported conjunctivitis and eye tearing, as well as more typical symptoms of flu, including fever, chills, coughing, sore throat/runny rose. Another 2 cases in poultry workers were reported on July 19, 2024 (Colorado).

H7N9 and H7N7 Outbreaks

The first human outbreak of avian influenza A (H7N9) was reported in China in 2013, causing more than 1500 human infections with nearly 40% case fatality, although a few cases were exported to other countries. The vast majority of these cases were caused by the low pathogenic avian influenza A (H7N9) virus. Unlike H5N1, there were no reported avian outbreaks before the human outbreak. Avian influenza A (H7) viruses have tropism for ocular receptors in humans. 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, including the outbreak of the highly pathogenic avian influenza A (H7N7) virus infections in the Netherlands in 2003. Out of the 453 people who might have been exposed to the avian influenza virus, 349 met a case definition of conjunctivitis. H7N7 was detected in ~22% (78/349) of patients who presented with conjunctivitis as their only clinical signs and symptoms. Thus, it was concluded that H7N7 was likely the etiologic agent causing 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
• Timothy Uyeki, MD, MPH, MPP, Chief Medical Officer, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention