By Lillian Parr and Saskia Popescu

Overview

The United States and Europe are currently experiencing the most severe outbreaks of avian influenza in their respective histories. On a global scale, this outbreak of the H5N1 avian flu is unprecedented in the variety of mammals impacted, ease of spread, and number of countries impacted. Fueled by a new and especially dangerous clade of H5N1 (a form of highly-pathogenic avian influenza, known as HPAI), this outbreak has been devastating to ecosystems and poultry farms, and has led to the deaths of over 58 million birds in the United States over the past year. More recently, Cambodia reported two human cases of H5N1, including the death of a young girl, who may have been exposed to several sick birds in her family home. Further analysis on the virus isolated from these two human cases by the Cambodian Centers for Disease Control (CDC) revealed that it is from Clade 2.3.2.1c, which is endemic in Cambodia, and not Clade 2.3.4.4b, which is causing so many infections around the world in poultry, wild birds, and mammals.

While most recent coverage of H5N1 is focused on concerning trends over the past few months, the concerning clade (2.3.4.4b) first began circulating in Africa, Asia, and Europe in 2020, and has gradually snowballed into a major biological and ecological threat. H5N1 has the capacity to infect and easily spread through a wide range of avian species, including domestic and wild birds (including migratory species). This makes the outbreak exceptionally difficult to control—any wild bird that comes into contact with an affected poultry farm has the potential to spread H5N1 widely. For example, researchers suspect that H5N1 was first introduced to North America in winter 2021 by a gull migrating from Europe to Canada.

While H5N1 is generally only transmissible in birds, mammals (including humans) may become infected upon direct exposure to an infected bird. However, infected mammals typically cannot transmit or maintain sustained spread of the disease to other mammals. While human infections are rare, they are deadly—the mortality rate is about 56%. The lack of sustained human-to-human transmission has reduced the general threat to humans, but often translates to inadequate risk awareness given the ease at which influenza viruses mutate and evolve.

A concerning shift in the global burden of avian influenza came in October 2022, when an outbreak of H5N1 occurred on a mink farm in Spain. Scientists believe that the circulating variant was being transmitted between mink, an alarming observation that highlights the capability of H5N1 to adapt to mammalian hosts. While all of the 50,000 mink on the affected farm were culled and no workers were infected, the borders of the farm were porous, meaning that contact between mink and free-roaming mammals like cats and dogs may have occurred.

Sequencing of samples from infected mink shows evidence of genetic changes known to enhance the capability of influenza to reproduce in mammals. These same mutations have also been observed in samples from other mammals infected with H5N1 over the past several months.

As of this writing, the Animal and Plant Health Inspection Service in the U.S. Department of Agriculture (USDA) has reported 144 cases of H5N1 in mammals across 22 states, and this is almost certainly an underestimate. Infected mammals include foxes, raccoons, and opossums. H5N1 is causing major issues outside the United States as well—across Peru’s Pacific coastline, nearly 3,500 sea lions have died of H5N1 since November 2022, along with at least 63,000 seabirds. Scientists are concerned that the virus may be spreading in the sea lion population, meaning that this may be another instance of mammal-mammal transmission.

As H5N1 infects more mammals, the risk to humans grows. More infections increase the risk for H5N1 to adapt to mammalian hosts, and creates more chances for a virus to hit the suite of mutations required to become transmissible among mammals—potentially including humans. Mammals being co-infected with H5N1 and another strain of influenza increases this risk, as viral recombination may occur—meaning a daughter virus could potentially have the pathogenicity of H5N1 along with the ability to transmit among mammals. Moreover, infections in mammals and a growing outbreak increase the risk for a spillover event during farming, veterinary care, hunting, and a number of other interactions between species.

Regardless of whether H5N1 evolves to be transmissible among humans, it’s crucial to consider the immense ecological toll it has already taken. North American birds are already facing staggering population decline—and some experts are concerned that the H5N1 outbreak could be a death knell for some avian species. Population decline in birds will have myriad downstream effects—fewer birds may mean reduced seed dispersal, declining populations of animals that prey on birds, and rapid growth in the insects, rodents, and fish that birds prey on. These impacts will also have knock-on effects as ecological phenomena are complex and interdependent, so a mass die-off of birds may have long-lasting and unforeseeable consequences. Furthermore, the surveillance and control efforts required to address this outbreak will place new strain on the already limited resources of public health and ecological services.