What Infectious Disease Physicians Need to Know

Avian influenza A viruses, particularly the H5N1 subtype, continue to grab headlines — raising concerns for the public who is likely leery of another pandemic. Yet many infectious disease experts say that the risk for human-to-human transmission is low.

Still, recent viral mutations have shown the pathogen’s adaptability to mammalian hosts, prompting infectious disease, animal health, and environmental health experts to remain vigilant.

“For years, we’ve seen avian influenza circulating in birds, but 2024 brought an increase in infections among mammals — including cows, cats, and raccoons,” said David J. Cennimo, MD, an associate professor of medicine and pediatrics in the Division of Infectious Diseases at Rutgers New Jersey Medical School, Newark, New Jersey. “The more this virus infects mammals, the greater the opportunity for mutations that enhance mammalian transmissibility.”

H5N1 is not yet efficient at spreading between mammals; however, sporadic cases of transmission between cows and from cows to cats suggest a concerning trend. “Each time the virus adapts to a new mammalian host, it takes a step closer to potentially infecting humans more efficiently,” Cennimo told Medscape Medical News.

Another key concern is reassortment — the mixing of H5N1 with human-adapted influenza viruses such as H1N1 or H3N2, potentially leading to a novel, more transmissible strain. “While reassortments are rare, they could occur in an intermediary species like pigs, which have historically been effective ‘mixing vessels’ for influenza strains,” Cennimo explained.

Fortunately, H5N1 has shown limited ability to infect pigs so far.

Clinical Presentation 

H5N1 in humans can present with a range of clinical manifestations with some needing intensive care and others showing mild or even subclinical infections. “One striking feature in recent case reports is the high prevalence of conjunctivitis, which is somewhat unusual compared to seasonal influenza,” Cennimo said. This raises the possibility of underdiagnosed or misdiagnosed cases.

For suspected cases, he recommends infectious disease specialists maintain a high index of suspicion, particularly in patients with recent exposure to birds or cattle. Infectious disease specialists should follow local health department protocols for reporting and testing suspected cases.

Oseltamivir remains the primary antiviral treatment for H5N1, with a recommended extended 10-day course for hospitalized patients, Cennimo said. “If a patient is severely ill, combination therapy with baloxavir could be considered, though data on its added benefit remain inconclusive.”

Biosecurity Measures for At-Risk Populations

Infectious disease physicians should advise individuals working closely with poultry, livestock, or wild game on preventive measures.

“Basic precautions such as hand hygiene, gloves, and masks should be standard when handling potentially infected animals,” Cennimo advised.

He also noted that while the virus has been detected in unpasteurized milk, no human cases have been definitively linked to milk consumption.

Monitoring for the Tipping Point

A key factor enabling human-to-human transmission of H5N1 would be an adaptive mutation allowing efficient replication in human respiratory tissue. “Right now, H5N1 does not have that capability — but if it develops, we could see a shift in the pandemic potential of this virus,” Cennimo cautioned.

Cennimo’s recommendations for infectious disease physicians include:

• Suspect H5N1 in patients with recent exposure to birds, cattle, or infected animals.
• Test for influenza A subtypes and pursue additional H5N1 testing if H1N1 and H3N2 are ruled out.
• Follow public health protocols for notification and containment.
• Educate at-risk populations on biosecurity measures.
• Monitor evolving epidemiologic trends to stay ahead of potential transmission shifts.

“The threat of H5N1 is not just hypothetical. It’s a rapidly evolving situation that requires close monitoring and proactive preparedness,” Cennimo concluded.

Surveillance Remains Key

While vigilance for zoonotic events remains essential, there is currently no immediate threat of a pandemic, added James Lowe, DVM, MS, DABVP, professor of veterinary clinical medicine at the University of Illinois Urbana-Champaign.

Though the H5N1 virus can infect many species, including humans, how or whether it spreads varies greatly because the virus must bind to the sialic acid (SA) receptor, which differs across species. Consider these differences:

• Humans: SA receptors are deep in the lungs, making human infection rare but more severe because of where the virus replicates.
• Pigs: Have mostly human-like receptors and some avian-like receptors in their respiratory tracts. The longstanding theory was that bird flu would first infect pigs before jumping to humans, but the predominant transmission pattern has been the other way around.
• Poultry: Spreads rapidly and is highly lethal.
• Cattle: Infects the udder, but not the respiratory track.
• Marine mammals (eg, seals): Highly susceptible due to birdlike SA receptors in their respiratory tracts.
• Cats (and other wild carnivorous mammals): Causes neurological disease, not respiratory illness because the SA receptors are in the brain.

“These species differences explain why H5N1 is devastating in some animals while relatively benign in others,” Lowe said.

In short, livestock face the greatest threat from H5N1, but federal regulatory frameworks differ significantly for poultry and cattle. While poultry benefit from established federal disease-control programs, cattle infected with H5N1 fall into a regulatory gap. The US Department of Agriculture enforces strict containment policies for avian flu in poultry, primarily to safeguard exports. However, influenza type A was not historically considered a cattle disease, leaving cattle without a structured federal control program.

“As a result, H5N1 in poultry is well-controlled with no evidence of flock-to-flock transmission,” Lowe said. “But in cattle, we’re seeing what looks like an endemic disease pattern. Eliminating it entirely may no longer be possible.”

Emerging Data

More viruses in animals mean higher risk for humans.

“Zoonotic disease spillover risk to humans increases with more virus activity in animals, but among the sporadic human infections, we have not seen any evidence of human-to-human transmission,” added Sarah Michaels, PhD, an infectious disease researcher at Tulane University in New Orleans.

If this were to happen, she said, “it would be a sign that the mutations were allowing the virus to be more easily transmitted. This is why it is important to continue robust surveillance systems to identify infections among people and animals. This allows us to detect animal epizootics, work rapidly to contain them, investigate new routes of transmission between animals, and offer guidance to reduce the likelihood of transmission to humans.”

In January, Centers for Disease Control and Prevention issued a Health Alert Network advisory to clinicians and laboratories to remain alert for sporadic H5N1 cases, particularly amid high seasonal influenza activity. Still, few additional H5N1 cases have been found, and have been attributed to contact with infected commercial poultry or backyard flocks.

Other influenza surveillance systems like emergency room admissions, public health laboratory testing and wastewater surveillance have also expanded to include H5N1 detection. Wastewater surveillance has identified some positive samples but isn’t able to distinguish human from animal infections.

“Human infections of H5N1 are rare, and testing should be prioritized for those with contact with known or suspected H5N1-infected animals,” Michaels said.

“The risk to the general public remains low, but infectious disease surveillance systems need to remain robust enough to detect any emerging changes in influenza A distribution or magnitude of human infections.”

Cennimo, Lowe, and Michaels had no financial conflicts to disclose.