By Kathy Liszewski
Everyone knows the pandemic headliners: Ebola, plague, and, of course, SARS-CoV-2. But some scientists are tracking lesser-known pandemic threats such as a fungus called Candida auris and, especially, new diseases on the rise in domesticated animals. Such pathogens may represent blind spots in our pandemic preparedness.
A major issue in heading off such threats is that our current regulatory system lacks a clear and comprehensive strategy to prevent disease from spilling over from animals into humans, a process known as zoonosis. Two viruses known to be gaining traction are “cow flu” (influenza D), which is jumping to U.S. cattle workers, and highly pathogenic avian influenza (bird flu), which infects wild birds in all 50 states and has a mortality rate of about 50% in humans. Another concern, newly addressed by the Centers for Disease Control and Prevention (CDC), is that highly lethal and treatment-resistant forms of C. auris are spreading at an alarming rate, especially in healthcare settings.
A fractured regulatory system
In fall 2022, the federal government released a new pandemic preparedness document, the National Biodefense Strategy and Implementation Plan (NBS-22). “It maps a strategy for the American government through which to confront biological threats to the health and safety of its citizens and, more broadly, to improve global health security,” says Ann Linder, JD, a research fellow in the Brooks McCormick Jr. Animal Law and Policy Program at Harvard Law School.
However, Linder believes that some dangerous threats were not fully addressed. “Through its focus on laboratory accidents and deliberate acts of bioterrorism, NBS-22 obscures an important category of threat—a category encompassing predictable but unintended consequences of everyday animal use,” she explains. “These threats involve not some critical error (for example, a cage left unlocked) or a bad actor with malign intentions, but routine practices, many of which are dangerous and poorly regulated.”
More emerging zoonotic diseases originated in the United States than in any other country during the second half of the 20th century. According to Linder, this development is “due in part to the nation’s large and growing systems of animal production.” For example, in 2012, H3N2v influenza spilled over from pigs to humans at livestock exhibitions and infected hundreds of people across 10 states. More recently, in Michigan, mink on fur farms generated a new strain of COVID-19 that jumped to workers.
Linder believes this problem can be addressed even though the current regulatory system is “fractured and insufficient” and lacks a “clear and comprehensive strategy to prevent zoonotic disease.” She maintains, however, that such a strategy can be developed if the appropriate steps are taken. These include steps to gather more and better data about disease risks. Potential reforms include enhanced monitoring of the industries associated with disease risks, and the generation of industry-specific disease prevalence statistics.
Who should drive these reforms? “Policymakers at the state, local, and federal levels could take steps to mitigate zoonotic risk,” Linder says. “What is needed now is a fundamental restructuring of the regulatory regime and a strategy that can bring together the diverse and competing agencies that govern animal, human, and environmental health and break down the silos that divide them.” She adds that the scientists who understand and study these risks should lead the effort to inform both policy and public opinion.
Influenza D spillover
Studies have shown that zoonotic viruses can survive in air, in water, and on surfaces at farms and animal facilities. But is this normal, or dangerous? In a recent small study, Jessica Leibler, DrPH, an associate professor of environmental health at Boston University, and her colleagues found that more than two-thirds of dairy workers surveyed had evidence of influenza D virus in their nasal passages before and after work. An earlier study found that workers in Florida had antibodies in their serum, indicating they had been infected.
“Influenza D is an emerging, zoonotic genus of influenza virus,” Leibler points out. “It was first identified about 10 years ago in industrial swine and cattle.”
Infections to the general population appear limited, and influenza D virus doesn’t appear to cause illness in humans at present. Nonetheless, concern is warranted. “The greater the number of animals that are infected with a virus known to jump to humans,” Leibler warns, “the greater the possibility that the virus could mutate and gain virulence and transmissibility among people.”
What is needed is more comprehensive surveillance of cattle and cattle workers. “It would help clarify exposure sources and identify human health risks posed by this emerging pathogen,” Leibler argues, “but we would need better technology for the rapid detection of influenza D virus.” Moreover, such technology would need to become commercially available. Such a development could be driven by industrial and academic partnerships.
“Perhaps a silver lining from the COVID-19 pandemic is that we are now much more aware of zoonotic spillover,” Leibler reflects. She adds that an improved understanding of zoonotic spillover is of “critical importance in pandemic prevention.”
The rise of avian flu
The World Health Organization has called recent outbreaks of avian flu in humans “worrying.” According to the CDC, highly pathogenic avian influenza (H5N1) has afflicted more than 58 million poultry in 47 states and thousands of wild birds in all 50 states. So far, there has been limited spread of the virus to humans, but “avian influenza has been considered a potential threat to humans for nearly 25 years,” observes Matthew Binnicker, PhD, director of clinical virology at the Mayo Clinic.
“Certain strains of avian influenza, such as H5N1 and H7N9, may be highly pathogenic and cause severe disease in humans,” he continues. “Initial symptoms may be similar to human influenza, but the mortality rate of avian influenza can be about 50%. Antivirals used to treat human flu may be effective in treating cases of avian influenza, but routine flu vaccines are not believed to provide protection against avian influenza strains.”
However, if avian influenza develops the ability to spread efficiently to and within humans, we are unprepared to handle it. Binnicker notes, “Currently, the vast majority of monitoring and testing for avian influenza is being performed in poultry and wild birds. Very little testing has been performed in humans, and this is typically only done when an individual develops flu-like symptoms after interacting with an ill or dead bird.”
Binnicker says the main reason that testing in humans is not more common is that there are no commercially available tests specifically designed to detect avian influenza. Testing is currently limited to the CDC and public health laboratories. He advises that rapid and at-home tests for avian influenza need to be devised. Additionally, candidate vaccines need to be developed and readied for potential widespread distribution. Finally, poultry should be vaccinated against avian flu to reduce the number of infections and the potential for humans to be exposed.
Binnicker remains optimistic: “Strong partnerships are being formed between public health, clinical laboratories, industry, and the government to discuss how to prevent a future outbreak or pandemic from avian influenza. My hope is we’ll learn important lessons from the COVID-19 pandemic and apply those lessons to prevent future pandemics, including a possible avian influenza outbreak.”
Last March, the CDC issued a warning on C. auris, a fungus spreading at an alarming rate, especially in healthcare settings. The first U.S. cases of C. auris were reported in 2016, but a retrospective review identified cases that dated back to 2013. Now the pathogen has been documented in at least 26 states. Between 2016 and 2019, the number of clinical cases rose from 13 to 476. Occurrences have continued to climb dramatically, with the CDC reporting 5,754 clinical cases in 2022.
Further, the mortality rate for C. auris is high, estimated at 30–72%. The CDC’s Meghan Lyman, MD, a medical officer in the Mycotic Diseases Branch, warns, “C. auris acts differently from other Candida species and is an urgent public health threat because it is often resistant to multiple antifungal medications, spreads easily in healthcare settings, and can cause serious, invasive infections. People with C. auris are very sick at baseline and require high-acuity care (including mechanical ventilation and invasive medical devices). They have had many exposures to antimicrobial medications. And they have had long or frequent stays in healthcare facilities.”
Lyman says that transmission at present mostly occurs in healthcare settings. She adds that “there is no evidence that transmission in the community is a concern.”
To help contain the spread of the deadly fungus, Lyman shares some advice: “Early identification of cases, strong adherence to infection control practices, and good communication about a patient’s C. auris status are all important to prevent spread. In general, it’s best to identify C. auris in an area before there is widespread transmission. It’s important to have proactive case identification through colonization screening and enhanced surveillance of clinical specimens by conducting Candida species identification from all specimens, not just those that are invasive.”
According to Lyman, facilities will need to be proactive to monitor potential infections, even if they are in low-burden areas. She explains, “Containment generally seems to be easier in places that identify cases early, before there is transmission.”
Different fungal clades
There are at least four major clades of C. auris: Clade 1, South Asian; Clade 2, East Asian; Clade 3, South African; and Clade 4, South American. Samantha Jacobs, MD, an associate professor of medicine (infectious diseases) at the Icahn School of Medicine at Mount Sinai, and colleagues from the American Type Culture Collection and the New York State Department of Health’s Wadsworth Center recently performed a case study of C. auris isolates from a transplant patient who evolved pandrug resistance to four classes of antifungal therapeutics. “Part of the treatment dilemma,” Jacobs points out, “is that we have fewer fungal treatment options as compared to the larger armamentarium against bacteria.”
The researchers characterized the genomes and performed drug resistance analyses of multiple C. auris isolates in the infected patient over a 72-day period. They found a distinct subcluster of South Asia Clade 1, and they identified common and novel genetic changes driving resistance to the antifungal agents (azoles, echinocandins, polyene, and flucytosine). They concluded that the “emergence of pandrug-resistant C. auris in a patient over time is alarming.”
Reflecting on the study’s findings, Jacobs notes, “What is needed is improvement in fungal diagnostics that can perform antifungal susceptibility testing in concert with rapid genomic screens to assess resistance markers. The real issue, though, is the need to develop more effective and safe therapies. There are several promising candidates now undergoing clinical trials. We also must focus on raising awareness, especially in the medical community, about the continued and increasing threat of C. auris.”
Although the experts who spoke with GEN all felt that more scrutiny and technological advances are critically needed to avoid the next pandemic, they are uniformly hopeful that we have learned valuable lessons from COVID-19. They share the conviction that increased collaboration among academia, industry, and government, along with scientific innovation, will be critical to preventing or mitigating the next pandemic.