The First Fatal Case of H5N1 Bird Flu in the U.S.

A person in Louisiana who had been hospitalized for bird flu has died, reported the Louisiana Department of Health on Monday, January 6, 2024.  The CDC reported the fatality on the same day. This marks the first ever H5N1 human fatality in the U.S., a grim milestone, to be sure.

It was only a few weeks ago, on December 18, that the CDC first announced this case as the first severe human H5N1 infection in the U.S.  All other cases to date have been “mild” in terms of symptoms. We did a deep dive last month into these mild, or sometimes asymptomatic infections, in The mild and asymptomatic H5N1 cases in some humans, and why it matters.

The Louisiana case, in addition to being the first severe, and now unfortunately, fatal human case in the U.S., this was also the first confirmed human case of H5N1 infection directly from backyard birds. This is unique as, until this case, the human H5N1 cases in the U.S. have been associated with exposure to poultry or dairy cattle. But backyard birds is something new.

But how exactly did the Louisiana patient get infected by birds?

It isn’t supposed to be easy to get infected with H5N1 from birds. Typically there is to be some prolonged or close contact, at least that’s what we have seen historically with H5N1. So how did this happen? We really don’t know.

Per the CDC, all we know is that they “had exposure to sick and dead birds in backyard flocks.”  That is the extent of the details we have as to this person’s route of exposure. We don’t know what type of birds, or what this person was doing at the time, or how long of an exposure, etc.

More information about how this person became infected could tell us a lot about how the virus is behaving in these wild bird populations and even inform other people’s decisions as to risk.  

Why was this patient’s H5N1 case fatal, when other cases in the U.S. have been mild? 

To be sure, the mild nature of recent H5N1 infections are in contrast to historical H5N1 cases, which have seen many fatalities globally.  As the CDC noted in its own announcement of the Louisiana patient’s tragic death, it was “not unexpected because of the known potential for infection with these viruses to cause severe illness and death.”  Indeed, the current global total of human H5N1 bird flu infections is 950 cases with approximately a 50% mortality rate.  

And yet, the majority of the H5N1 cases in the U.S. are “mild” as far as H5N1 goes.  But why?  And why was this Louisiana case, along with the recent human case from Canada, not so lucky?

Again, we really don’t know. It is known that H5N1 can cause a wide range of clinical symptoms and outcomes.  This may be a function of multiple different factors, such as certain “host” differences like vaccination history, existing medical conditions, age, or other factors like differences in access to medical care, exposure route, viral load at infection, etc. 

We know that the Louisiana patient was over the age of 65 and had reported but unspecified “underlying medical conditions.”  So there are some host factors at play that may have made this person at a higher risk.  

Historically, we associate severe or fatal H5N1 infections with close or prolonged contact with household poultry.   In Cambodia for example, a fatal H5N1 infection in a 15 year old girl resulted from the girl handling dead chickens found in her village 5 days before her symptoms began.  For people who just keep backyard flocks, the route to a severe infection seems less clear.  For example, an asymptomatic H5N1 case was discovered in a man who kept a flock of ducks in his backyard in England.  Why was this English case so different from the Louisiana case?

It may also be that the strain from wild birds is inherently more virulent than the strain currently circulating in dairy cattle.  We know that the H5N1 virus that infected the patient in Louisiana was genotype D1.1, the same genotype as the severe human H5N1 case in Canada. However, several mild H5N1 cases with the same genotype were confirmed in Washington state.  

Severity of infection may also be tethered to the properties of the particular virus itself.  An H5 virus that can bind to mammalian receptors and then replicate in that new host to higher levels may also be more virulent in that host if it can replicate to higher levels than its more avian-friendly counterparts.  At least in theory.  Although in the Louisiana patient’s case, they were infected directly from birds after which the virus began to change to favor its human host.

Are there mutations in the H5N1 virus from this fatal case?

Flu viruses mutate incredibly fast. This constant change is monitored by logging any concerning mutations found in novel flu infections. In this case, from the CDC’s report on the sequencing of the H5N1 sample from this patient, we know that three “low frequency” mutations were found in the HA gene: A134A/V, N182N/K, and E186E/D. 

Per the CDC, these changes are “rare in humans,” but the mutations have been “reported in previous cases” of H5N1 infection “in other countries most often during severe disease.” 

Of concern is what the CDC indicated about binding to human receptors. According to the CDC, while the virus on the whole maintained avian-style receptors, these mutations “may result in increased virus binding to α2-6 cell receptors found in the upper respiratory tract of humans.”  

We have seen an increasing concern that H5N1 clade 2.3.4.4b viruses may have an easier time acquiring changes needed to potentially bind to human receptors.  (For a more in depth look at recent receptor binding studies on these viruses, see New study shows how the Q226L mutation makes H5N1 a bigger threat).  What the CDC’s report about the Louisiana case tells us is that there is some evolution going on when these viruses infect humans.  

This viral evolution towards a more “human friendly” bird flu is something that public health authorities look for when evaluating the level of risk a virus holds for humans.  It’s what has been keeping some scientists up at night.

The reason the CDC continually maintains that the risk to public health of H5N1 is “low” is in large part because H5N1 does not bind well to the cells in the upper respiratory tract of humans.  Because it can’t do that well, it can’t transmit between humans.  We’ve already seen some examples of potential adaptation to humans in H5N1 viruses from recent cases exposed to dairy cattle.  Moreover, in the Louisiana patient, there was evidence that the viral samples containing the mutations were from areas in the upper respiratory tract (the oropharyngeal cavity).  

So this H5N1 virus from this Louisiana patient may have, very quickly, gotten better at binding to human cells inside its new human host.  Or is it just that the route of exposure may have been through the upper respiratory tract and therefore more virus could be found there?  We don’t know. Indeed, we really don’t know much about how this person was infected.  But what we do know is that the more H5N1 continues to circulate, through cattle and wild birds and everything in between, the more chances there are for humans to be exposed one way or another, leading to more human cases.  

Every new human case is another opportunity for this bird flu virus to learn to adapt better to a human host. We see that for a fact in the mutations noted above.  This is one more recent demonstration that H5N1 has shown its ability to adapt. The question is: will it adapt to the point that it becomes a true pandemic concern? 

Until next time.