STOP! Have you read Zoonotic Potential of Pseudorabies Virus Series: An Emerging Threat – Part 2?
Implications and Future Research Needed:
Prior to the recent case reports of human encephalitis linked to pseudorabies virus (PRV), zoonotic spillover events of PRV were considered rare, and generally only caused mild clinical signs, or in cases of severe disease, were not definitively linked to PRV.1,2 The sudden appearance of multiple cases of viral encephalitis linked to PRV so soon after a major outbreak of a novel PRV variant in Chinese swine herds, indicates a potential evolutionary watershed moment for this virus, and for humanities relationship with it. Alternatively, the spike in cases linked to PRV could be the unintended consequence of developing diagnostic tools with extreme sensitivity for detecting viral nucleic acid; even if only in fragments. While measures to disinfect the sites of cerebrospinal fluid (CSF) collection were undoubtedly taken, these measures may have only inactivated viral particles present on the skin of the patients, and would not necessarily expunge the nucleic acid remnants that would be left behind.3 Contamination of the sample with these remnants could result in a high false positive rate in individuals who are exposed to the virus often (e.g. workers in the pork industry). Furthermore, individuals in the pork industry may also be more likely to have titers for PRV, even though it didn’t necessarily make them ill. However, the fact that researchers were able to isolate a viable, pathogenic virus from the CSF of a patient that had also been diagnosed with PRV infection via metagenomic next-generation sequencing (mNGS) suggests that these alternative explanations for the findings are unlikely.
However, it should be noted, that the mere presence of viable pathogens in CSF does not prove causality. As PRV is an α-herpes virus, it is biologically plausible that it could reside in neurological tissue as a latent commensal organisms, as other α-herpes viruses have been known to do.4 We would expect any commensal latent infections of PRV in pork workers to be analogous to the viruses that exist in the Chinese pork industry. Notwithstanding, demonstrating the viability/cytotoxicity of the human-isolated strain in human derived cell cultures, also suggests a causal relationship.5
Additional research may help to definitively characterize the causality of these novel strains of PRV in humans. A case-control study that examines samples taken from pork workers who were not diagnosed with encephalitis would allow for the establishment of odds ratios that could approximate the risk of encephalitis due to presence of the virus on mNGS. While CSF is the ideal fluid for diagnostic mNGS, owing to its inherent sterility and low background levels of host and/or pathogen nucleic acid, collecting CSF from otherwise healthy individuals would be invasive, costly, and potentially unethical.3,6 A potential work-around would be to collect control samples of CSF from women who work in the pork industry and have spinal taps performed as part of epidural analgesia administered during labor and delivery. As some of the case studies showed the presence of PRV in blood samples, this may also be a sampling medium that would be suitable for such a study.
Alternatively, an occupational cohort study of pork workers could determine the actual risk of developing encephalitis following an injury that breaks the skin. Such a study could examine a wide array of potential risk factors. That said, as we have a high clinical suspicion that PRV may be involved in the pathogenesis of this disease, such a cohort study would have the added benefit of promoting active surveillance for the disease, which may help to detect the symptoms early when treatment may be more beneficial. This might include CSF sampling from at risk patients; a collection protocol that is less ethically questionable. Although to realize the full benefit of collecting these samples, CSF samples would still need to be taken from unaffected individuals in the cohort study who were willing to serve as controls; this could set up a potential nested case-control study within the cohort study.
The one factor in these apparent zoonotic events that has so far been missing is human to human transmission. This is not surprising as humans are a dead-end host for many zoonotic pathogens, especially ones that have only recently started to spillover from animal reservoirs.7 Notwithstanding, if these cases of supposed PRV caused encephalitis started producing secondary cases in close contacts, this would be further evidence that PRV was emerging as a zoonotic threat. Hopefully that day never comes, as zoonotic pathogens that evolve to transmit from human to human have the potential to become pandemics.7 In the meanwhile it might be prudent to determine if these case reports and case series represent a new era for PRV infection in humans, or if they are the result of confounding from ever-increasing diagnostic sensitivity that enables us to detect pathogens that we would otherwise have never considered as being component causes of a disease.
Sawitzky D. Transmission, species specificity, and pathogenicity of Aujeszky’s disease virus. In: Kaaden OR, Czerny CP, Eichhorn W, eds. Viral Zoonoses and Food of Animal Origin. Springer Vienna; 1997:201-206. doi:10.1007/978-3-7091-6534-8_19
Mravak S, Bienzle U, Feldmeier H, Hampl H, Habermehl KO. Pseudorabies in man. The Lancet. 1987;329(8531):501-502. doi:10.1016/S0140-6736(87)92104-0
Simner PJ, Miller S, Carroll KC. Understanding the Promises and Hurdles of Metagenomic Next-Generation Sequencing as a Diagnostic Tool for Infectious Diseases. Clin Infect Dis. 2018;66(5):778-788. doi:10.1093/cid/cix881
Kennedy P, Gershon A. Clinical Features of Varicella-Zoster Virus Infection. Viruses. 2018;10(11):609. doi:10.3390/v10110609
Liu Q, Wang X, Xie C, et al. A Novel Human Acute Encephalitis Caused by Pseudorabies Virus Variant Strain. Clin Infect Dis. 2021;73(11):e3690-e3700. doi:10.1093/cid/ciaa987
Wilson MR, Sample HA, Zorn KC, et al. Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis. N Engl J Med. 2019;380(24):2327-2340. doi:10.1056/NEJMoa1803396
Celentano DD, Szklo. Gordis Epidemiology. 6th Edition. Elsevier; 2019.