The mild and asymptomatic H5N1 cases in some humans, and why it matters

The CDC recently published a new study relating to the ongoing H5N1 outbreaks in dairy cattle in the U.S., and the exposure to humans, particularly farm workers, who work closely with cattle. So far, the CDC lists 46 official cases of H5N1 in humans. As of Friday, 11/8/2024, and per the USDA, we are now up to 473 herds of dairy cattle with H5N1 infections.

The CDC study shows the extent of mild and asymptomatic human H5N1 cases:

The aim of the study, published as part of the CDC’s Morbidity and Mortality Weekly Report, was to see whether there was evidence of undetected H5N1 infection in farmworkers. In total, 115 workers from dairy farms in Colorado and Michigan were tested, 8 of which (7%) had “serologic evidence of infection with A(H5) virus.”

That means the blood samples of these 8 workers showed an elevated antibody response to the H5N1 virus used in the study. This would indicate that their bodies had recently mounted an immune response to an H5N1 virus. When there is an antibody response above a certain threshold, the scientists consider that evidence of a recent H5N1 infection. In this case, 8/115 workers had these heightened antibodies in their blood, thus providing evidence of prior H5N1 infection.

The good news is that this is another example of the mild, sometimes very mild, H5N1 human cases we’ve seen in the U.S. so far. I found the mild nature of these cases surprising at first, given the history of H5N1. Although, there have been prior instances of mild cases, even of vintage H5N1.

Other mild or asymptomatic H5N1 human cases:

For example, a study done in 2000 found that two healthcare workers who had treated patients during the 1997 Hong Kong outbreak were seropositive, suggesting they had gotten infected after exposure to the patients. Obviously, the evidence of human transmission is itself noteworthy, but my point in bringing up the study is that the two healthcare workers had not gotten seriously ill and had only later confirmed to have been infected.

A more recent example is the human case in Missouri. H5N1 infection was confirmed only after the patient had been admitted to the hospital for reasons related to underlying conditions. It was later confirmed through serology testing that the patient’s wife had evidence of prior H5N1 infection. Of note, several healthcare workers involved in the patient’s care reported respiratory symptoms around the same time, but they were all seronegative. Although it is concerning that the source of infections was never confirmed, the good news is these were not severe cases of H5N1 infection.

The results of the study and the mild nature of human cases exposed to dairy cattle:

In the current dairy cattle outbreaks, which has now hit 15 states, every human case (that we know of) associated with cattle exposure has been mild or asymptomatic. That isn’t a bad thing, but we don’t really know why.

Interestingly, the CDC study notes that 46 out of the 115 workers reported feeling ill during the time the cattle herds at their respective farms had H5N1 infections. But of those 46, only 4 were among the group with positive test results. So that means 42 other farm workers also felt sick at the same time, but their blood samples did not have the antibodies to meet the threshold for prior H5N1 infection.

It’s possible that some or all of these workers were ill with one of many other respiratory viruses, maybe even probable. It’s also possible that there were more H5N1 infections, but the antibody response was not high enough to be picked up by the tests. 

Indeed, the CDC even notes that one limitation to this study is that “some persons with negative serologic results might have been infected but failed to mount detectable antibody responses for a variety of reasons.” They don’t elaborate on those reasons in this paper.

Anyway, as for the 8 workers that showed positive results, the symptoms they reported were mostly red, draining, or itching eyes. However, 4 workers reported “feverishness, sore throat, runny or stuffy nose, sneezing, diarrhea, and headache.” The study notes that these respiratory symptoms were also reported by people with negative serology results.

Another finding of note was that 66% of all workers in the study had antibodies against seasonal flu, the H1N1 strain, indicating prior infection or vaccination. But only 18% of workers reported getting the flu vaccine. This jumped out at me.

One of the ways that an avian virus, like H5N1, can change into something that infects and transmits in humans is through reassortment: where one flu virus, like H5N1, infects the same cell as another flu virus, like seasonal flu, and they swap some genes and churn out something new. Whether that new virus is actually fit to do anything is another matter. But here, the risk of a human becoming co-infected with H5N1 and a seasonal flu virus is much higher in this setting. The results from the study show that mild cases and asymptomatic H5N1 cases have occurred due to exposure to dairy cattle. If these workers are also infected with another flu virus at the same time, that’s what could lead to a potential reassortment scenario.

One commonality in this study was the 8 workers with positive results all reported cleaning the milking parlor as one work task. We know that H5N1 replicates to high levels in the udder/mammary gland of lactating dairy cattle, and we know high levels of virus has been found in raw milk. So that isn’t surprising that the milking parlor would be an area with heightened exposure risk, maybe even more so than direct contact with dairy cows?

The implications of the study’s findings about asymptomatic cases and H5N1 risk going forward:

As to preparedness, this study helped showcase some gaps in understanding the risks of this virus, as well as gaps in communication. It was discussed several times how PPE usage by farmworkers was reportedly low. Moreover, the majority of workers with positive results apparently DID NOT KNOW that the cows on their farms were infected with H5N1, despite the farms having reported the cases to the USDA. Indeed, as the study notes: “Only one of the persons whose test results indicated antibodies to HPAI A(H5) virus reported working with known HPAI A(H5) virus–infected cows, supporting the need for additional education and outreach to employers and farm workers once HPAI A(H5) is identified in herds.” 

So clearly there are some issues with communicating the risks to farmworkers. There really need to be more proactive efforts here. This includes appropriate outreach, as the study noted that most farmworkers spoke Spanish, and instructions were given in English and Spanish.

In terms of human health, this study showed again how this clade of H5N1 continues to cause mild symptoms in humans infected by dairy cattle. But they don’t know why they are mild. There are also no clear answers as to how or why this virus can so readily spillover into humans like this. Even the authors of the study seemed a bit surprised, as they drew a comparison to prior serology studies before clade 2.3.4.4b emerged, which really highlights how this virus has changed.

To wrap up, we can be glad the cases are mild, but there’s no guarantee it will stay that way. That’s why more studies like this need to be done, and more surveillance in all dairy cattle herds is needed. It seems like every day the USDA is adding dairy herds to its ever growing list of infections. H5N1 does not appear to be burning itself out anytime soon.  With a better strategy to ensure farmworkers are protected on the job, we can hopefully decrease the risks of spillover into humans.

Until next time.