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US Agencies Team Up to Prioritize Top Zoonotic Diseases

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This story has been updated to include additional information about the diagnostics challenges for Brucellosis infections.

NEW YORK (GenomeWeb) – A coordinated effort by 15 state and federal groups has, for the first time, identified a set of priority zoonotic diseases in the US.

Among the eight diseases identified in recently-published report of the US workshop results are a few presenting diagnostics challenges — and opportunities — for both animal and human health testing.

The zoonotic diseases that will be prioritized by coordinated US government efforts going forward include zoonotic influenza viruses, salmonella infections, West Nile virus, plague, a class of emerging coronaviruses that includes severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), rabies virus, brucellosis, and Lyme disease.

The effort used a workshop format that had been developed and deployed by the US Centers for Disease Control and Prevention to help other countries address so-called "One Health" issues and focus limited resources on key problems.

One Health is an important concept in addressing existing and emerging infectious disease health threats. It posits that the health of humans is inextricably linked to the health of animals and the environment, and that the complex interplay of disease transmission between species requires vigilance on all fronts — from all veterinary, wildlife, agriculture, and public health agencies and experts — in order to save lives and prevent epidemic outbreaks.

Casey Barton Behravesh, the director of CDC’s One Health Office, which is part of the National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), was one of the driving forces behind the workshop. The motivation to bring such a large group together in the US stemmed, in part, from CDC's success in other parts of the world.

"There is increasing attention and excitement around One Health all around the world at the moment," Barton Behravesh said in an interview.

The CDC has had a One Health office since 2009, she said, and has developed a tool it calls a One Health Zoonotic Disease Prioritization Workshop.

The approach is intended to bring experts together to help government agencies break out of their silos and coordinate strategies for complex One Health issues among a disparate group of stakeholders.

Although the CDC had been part of successful applications of this tool in different countries and regions — such as in Ethiopia, Uganda, and Burkina Faso, and recently in Uzbekistan, as well as regionally in West Africa, among US Southern border states, and in Alaska and the arctic — the tool had never been applied to the US as a whole.

"We started talking to One Health partners in the US about the value of holding a workshop for our country as a way to bring together key players from different agencies and partners from states so we could have these important discussions, prioritize zoonotic diseases, and make some plans to address them," Barton Behravesh said.

The US workshop was also motivated by a 2016 Joint External Evaluation of the country that was overseen by the World Health Organization.

The JEE process is focused on identifying public health risks in a country. It consists of a self-assessment by the country and an evaluation by a team of independent international assessors, to score a country in several areas and ultimately strengthen health security, Barton Behravesh explained. The recent JEE assessment of the US found that there was a need for more emphasis on One Health and better coordination among agencies.  

The US workshop was held in December of 2017. At the federal level, it brought together representatives from the US Department of Health and Human Services (HHS), the US Department of Agriculture (USDA), Department of the Interior (DOI), the Environmental Protection Agency (EPA), and National Oceanic and Atmospheric Association (NOAA).

Specific agencies within these larger organizations were also represented, including the CDC, the US Food and Drug Administration, and the Assistant Secretary for Preparedness and Response (ASPR) from HHS; the Animal and Plant Health Inspection Service (APHIS), the Food Safety and Inspection Service (FSIS), and the Agricultural Research Service (ARS) from USDA; and the US Geological Survey (USGS), National Park Service (NPS), Fish and Wildlife Service (FWS), and the Office of Emergency Management from the DOI.

At the state level, there were also representatives from the Delaware Department of Agriculture, the Virginia Department of Public Health, and the Maryland Department of Natural Resources.

The workshop tool that CDC developed has a semi-quantitative and semi-qualitative piece to it, Barton Behravesh said. It is based on data as well as on expert opinion and a collaborative discussion process. It does not involve each agency bringing a list of their favorite targets; rather, it starts with an extensive literature search to identify the top 60 or so diseases that are of greatest concern in the country.

"There are thousands of zoonotic diseases, and all of them are important," she said, but to determine priorities, that list has to first be narrowed down a bit. The participants then have thorough discussions about the characteristics that constitute a disease of concern for them.

These characteristics can include pathogens that are potential bioterrorism agents, for example, or that have worldwide pandemic potential, or that cause severe disease in people, domestic animals, or wildlife for which there might not be good therapeutics or vaccines.

Finally, the participants use the characteristics that they've collectively decided are important in order to winnow the list to the top five or so priorities.

"The nice thing about doing it that way is it really focuses in on the issues and concerns for the country," Barton Behravesh said. Every country will develop its own unique list because it is not a cookie cutter approach, and the process also helps to eliminate any bias or chance that any group will promote special interests.

Rabies is the No. 1 zoonotic disease around the world and is on almost every list developed so far, Barton Behravesh noted, as are zoonotic influenza viruses like avian or swine flu. In Africa, viral hemorrhagic fevers like Marburg and Ebola also commonly make the top priorities lists.

One of the hoped-for outcomes of these workshops is enhanced collaboration between government agencies.

"Participating in this process, and the way that we do it — where everyone actually comes together in the same room and develops their own criteria — really brings partners together and gives them a foundation of trust that can help strengthen One Health collaboration, coordination, and communication to best address these shared health risks," said Barton Behravesh. 

Another real-time outcome from the workshop is that government agencies can "really start to take advantage of the momentum of coming up with a priority list in order to talk about next steps and action items," Barton Behravesh said. "It's really exciting," she said.

In its prior applications in other countries, the transparent and collaborative process has helped support creation of new One Health platforms, and it also helped countries focus limited personnel and financial resources for things like surveillance and lab needs, outbreak response, and preparedness planning.

Diagnostic needs

Diagnostics are a critical component to detecting and tracking diseases.

"One Health is a concept that links the health of humans to what is happening with the health of animals and the health of our environment," emphasized Jennifer McQuiston, the deputy director of the Division of High Consequence Pathogens and Pathology at NCEZID.

"A lot of the pathogens that affect humans can't be controlled or prevented without addressing what is happening in the animal populations or in the environment," McQuiston said.

Rabies is a great example. The virus can be transmitted by animals to people, and without post-exposure prophylaxis, a rabies infection is almost universally fatal. "It is the most highly fatal virus that I'm aware of," McQuiston said.

And, even though the general population has a perception that rabies is no longer an issue in the US, "Many thousands of people every year are exposed to rabid animals," she said.  

From McQuiston's perspective as a pathogen expert at CDC with veterinary training, the new US priorities list now gives a pathway for collaboration with other agencies also focused on the same goals. For example, because rabies has such a strong wildlife component, it is critical that the CDC-situated NCEZID office works together with the Department of the Interior and the USDA.

Having the priorities list front and center can also help in "making decisions about how we spend the money that Congress has authorized us to spend on emerging infections," she said.

The NCEZID also studies and monitors Brucella bacteria, among other high-consequence pathogens.

McQuiston noted that a species called Brucella abortus has been targeted for elimination in the US, and USDA has had a very active campaign vaccinating calves.

Unfortunately, there are now emerging cases of infection with a strain called RB51, which is the vaccine strain and may be caused by the vaccine shedding from a small number of animals into the environment. The RB51 strain causes less severe human infections, but can still potentially lead to miscarriage in pregnant women who are exposed through consuming unpasteurized milk.

"The problem is, this is a strain of Brucella that was developed specifically so it would not show up on traditional diagnostic tests," McQuiston said. It is a so-called rough strain of Brucella, and "the only way we can pick this up right now is through culture, and there are probably more cases that we are missing because we don't have a good serologic assay," she said.

Brucella canis is another rough strain of the virus. It is currently causing an outbreak among dogs that were bred in a particular Iowa kennel and auctioned to multiple states. The dogs "pose a risk to humans who come in contact with them," McQuiston said, "But we don't have a good serologic test to see if a person has been exposed or not."

Rebekah Tiller of NCEZID's Zoonoses and Select Agents Lab also commented that isolation of Brucella from patient samples depends on the stage of the disease, with isolation rates as low as 30 percent in later stages of infection. "Due to the low isolation rates, presump­tive clinical diagnosis is usually confirmed by serologic tests," Tiller said, including traditional agglutination tests and ELISAs.

But the serologic tests are not reliable and can't accurately detect anti-Brucella antibodies or differentiate acute and chronic stages of the disease, she said. The field also lacks "serological tests that can detect antibodies against B. canis and the B. abortus RB51 vaccine strain that has become an emerging public health issue," Tiller said. And, from a zoonotic transmission perspective, there is also a lack of easy and quick tests, such as antigen detection tests, to detect Brucella spp. that have been shed into animal milk, Tiller added.

While Brucella diagnosis is still a challenge, rabies, a member of the Lyssavirus family of RNA viruses, is a great example of a recent diagnostic success for the specialists at CDC.

The agency recently published a multisite global evaluation of a pan-Lyssavirus multiplex real-time PCR assay called LN34 that is the first to reliably detect all strains of the viral family.

In the US, widespread vaccination of dogs has eliminated canine rabies, but wildlife rabies continues to be a problem, particularly among animals like bats and raccoons.

If a person is bitten by a wild animal, the animal is typically caught and put down, if possible, and tested to determine whether the person needs to be treated.

But the diagnostic test for animal tissue that has been used for the past 50 years is cumbersome and necessitates a highly trained expert to interpret. It requires making an impression from intact necropsy brain tissue onto a slide, followed by a direct fluorescent antibody (DFA) test that is a microscope-based assay.

Decomposed brain tissue can't be reliably tested with the method, so the tissue has to be maintained frozen from the point of collection through to testing, which can also be a challenge in low-resource settings.

Crystal Gigante, one of the developers of the qPCR test and a member of the Genomics and Molecular Diagnostics Team of the Poxvirus and Rabies Branch of NCEZID, explained in an interview that there are 16 species that can cause rabies. The LN34 test was "specially developed, targeting a very conserved portion of the genome, using degenerate primers and a very short probe, which helps to make the assay work in all of the different species that cause rabies," Gigante said, including in a few new species that have recently been discovered.

The potential impact of the LN34 PCR test on rabies elimination in the US could be particularly significant for activities being carried out by the USDA, especially if the test can somehow be incorporated into field testing for raccoon rabies, for example.

"Right now, a lot of their testing requires a microscope … and they are looking for something that they can do in the field," Gigante said.

Companies coming out with portable qPCR machines might provide a good alternative for lab-based testing, and CDC has been working with USDA to test instruments from several companies, she said.

McQuiston noted that to eliminate canine rabies globally, which is what is driving human deaths worldwide, there also has to be an excellent surveillance program, and the qPCR test could be very helpful there, as well. Although the virus is highly fatal, if a person knows that they have been exposed to a rabid animal and can begin the post-exposure prophylaxis before symptoms start, they can survive.

And, in addition to diagnostics challenges among the priorities list, there are also some data challenges that might now get new attention.

"We need information from diagnostic tests to help us with our surveillance efforts," Barton Behravesh said. A process for data and information sharing, or a real-time "trends tool" that works bi-directionally across animal and human sectors, would be really useful, she said. If, for example, the human health agencies could be aware of outbreak among livestock of die-offs of wildlife, they could be on the alert for potential impacts on people.