Despite no known infections of H5N1 bird flu among its dairy cows, Missouri recently detected a case in a person with no apparent exposure to possibly infected animals or related products (i.e., raw milk). A close contact and two health workers who cared for the person all developed respiratory symptoms, but were never tested. There has not yet been a wider uptick of other potential cases in the same community to indicate efficient human-to-human transmission — the evolution of which is a prerequisite for a possible human epidemic — but this scare underscores the potential danger posed by the ongoing spread of H5N1.
In recent weeks, California, home to the largest number of dairy cows in the country, became the 14th state to report infected herds. It is possible that H5N1 may be even more widespread, including in states without reported infections among dairy cows, but a lack of testing has made it difficult to know where the virus is circulating. This bottleneck could be resolved by sampling wastewater as close to dairy farms as possible and using genomic sequencing to confirm the presence of H5N1. Sequencing could also assess any detected virus for mutations possibly conducive for human transmission and enable phylogenetic analyses that can help determine from which species it may have originated. The more H5N1 is allowed to circulate, especially among dairy cows that are clustered closely together in large numbers and with close human contact, the greater the chance the virus could evolve for efficient human spread.
Several months into this outbreak, on-farm testing has remained limited. Farm owners remain reluctant to allow testing of bulk milk and animals due to fears of financial loss. Farm workers, many of whom are undocumented, have also been hesitant to get tested due to concerns of losing work, immigration issues, and, in some instances, being unaware that there is an outbreak. After nine poultry workers were infected in July, Colorado mandated routine testing of bulk milk on all dairy farms. This policy quickly led to the detection of 11 infected herds. Colorado required these herds to remain isolated until subsequent testing confirms that viral circulation is no longer present. Massachusetts is the only other state to test all its dairy herds. Other states have not pursued similar directives presumably due to opposition from farm owners and the dairy industry.
Colorado’s approach could be mimicked without mandates by sampling wastewater as close to farms as possible and sequencing it for H5N1. Wastewater is already being tested from about 150 sites for the H5 hemagglutinin gene of the influenza virus, though this approach does not distinguish the neuraminidase (“N”) subtype. Sequencing could be used to delineate the N subtype as well as monitor for several mutations that virologists have identified as potentially necessary for efficient human-to-human transmission. The presence of these mutations could trigger more intensive measures in affected areas, such as testing, vaccination and ensuring workers have personal protective equipment.
The value of a sequencing-based approach was demonstrated by a team from the Texas Epidemic Public Health Institute (TEPHI). In a recent letter in the New England Journal of Medicine, they report on a two-year, 10-city proof-of-concept for a technique that they first described in 2023 (and which won the 2024 STAT Madness contest). Their approach searches for and enriches nearly 100 viruses of “public health concern” in wastewater samples with sequencing conducted on detected viral fragments. The researchers began using this approach in May 2022 and found no trace of H5N1 for nearly two years. Then, in March 2024, they began to see it across 10 Texas cities. Sequencing showed the virus to be from the clade circulating among dairy cows, but did not detect a mutation adaptive for human transmission, consistent with animals as the source.
This type of approach, if decentralized closer to farms and scaled to urban centers, could provide nationwide visibility into H5N1’s geographic distribution and genomic evolution and help get a handle on transmission. Whenever H5N1 is found in a location, the farms in the area could be either mandated or requested to allow on-farm testing with no movement of cattle permitted until they are cleared of ongoing circulation. Sequencing could also be done in other areas where H5N1 may be circulating, like Missouri, or whose wastewater is found positive for H5 influenza without clear links to animal sources, such as in the San Francisco Bay Area.
There are four things needed to apply this strategy. First, a protocol for sequencing should be decided upon or developed for scale. The TEPHI approach is one proven option. At first glance, agnostically sequencing for almost 100 pathogens may be overkill for the purposes of tracking H5N1. It is conceivable that this technique could be adapted into a less expansive approach that augments current H5 wastewater surveillance and only sequences samples found positive. Efforts to create a pared-down protocol of this kind could be pursued, but has not taken place at any level of scale to our knowledge and would need to be validated before wider use, which could take months and require substantial funding to complete. Given the urgency of the current outbreak, it may be more efficient to license and scale the TEPHI protocol that has already been validated in peer-reviewed journals and piloted at scale for two years.
Second, state and county officials should identify sites from which wastewater should be sampled based on the distribution and location of dairy farms and communities with suspected H5N1. This selection should aim to get adequate coverage and, yet, be disaggregated enough to enable sufficiently localized follow-up and control efforts.
Third, this technique would likely cost substantially more than conventional wastewater testing, including initial capital investments for sequencing equipment and bioinformatic computing and recurring costs for reagents, software licenses and trained personnel. The required outlays could be quantified and funds sought from federal and state budgets. Even while awaiting allocations, currently available funds could immediately be targeted to the most strategic sites with others added as more resources become available.
Fourth, the limitations of wastewater sequencing need to be better understood to inform how its results could best be used to guide public health response. For example, it is unclear how much virus needs to be shed into the wastewater in order for this technique to reliably detect it. If low-grade transmission is not readily found, persistent viral circulation could elude control efforts only to surge later. It is also unclear how consistently waste from dairy cows is flushed into routine wastewater as opposed to being discarded separately. These parameters need to be clarified so strategies can be appropriately planned. In the absence of mandates for on-farm testing, even with imperfect sensitivity, wastewater sequencing may be the best — and only — way to track and stifle the dairy outbreak.
Officials in Missouri are pursuing serological testing of the health workers and close contact, which may indicate if human-to-human transmission of H5N1 has already happened. Regardless of the outcome, the lack of a wider footprint of potential cases suggests that it may not yet be efficient enough to cause an epidemic. However, the longer the dairy outbreak is allowed to persist, the higher the odds that such a human transmissible strain may emerge. This current scare should wake us up to finally act more aggressively and creatively in addressing this threat.
Ranu S. Dhillon is an instructor in the Division of Global Health Equity at Brigham and Women’s Hospital and Harvard Medical School. He previously served as a special adviser to the government of Guinea during the 2013-2016 West African Ebola epidemic. Abraar Karan is an infectious disease physician and epidemiologist at Stanford University; he has worked on the Covid-19 and mpox outbreaks at the county, state, and federal levels. Devabhaktuni Srikrishna is founder of Patient Knowhow, which provides how-to information to the public about N95 respirators and indoor air filtration.