Zoonotic potential of pseudorabies virus series: An Emerging Threat – Part 2

Posted on June 15, 2023 by

STOP! Have you read Zoonotic Potential of Pseudorabies Virus Series: An Emerging Threat – Part 1? 

Zoonotic potential of pseudorabies virus series: An Emerging Threat – Part 1

Continue Reading: Part 2 

Porcine Outbreak

China is by far the world’s largest pork producer, with a national herd one-time inventory in excess of 400 million hogs. To put the scale of the Chinese pork industry in perspective, the next two largest pork producers are the European Union with ~140 million hogs, and the United States with ~75 million.1 Furthermore, China harvests ~700 million pig per year, compared to ~240 million for the European Union, and ~135 million for the United States.1 In 2011 there was a severe outbreak of pseudorabies virus (PRV) in the Chinese swine industry that continued through at least 2017, and likely continues to be an issue today.2–4 In swine, PRV typically causes reproductive failure and stillbirths in sows, neurologic, respiratory, and gastrointestinal disease in piglets, and respiratory disease and failure to thrive in growers.4 A prevalence study published in 2018 determined that approximately 8% of pigs in 27 provinces harbored PRV as determined by PCR.3 Genetic and proteomic analysis of the detected strains revealed changes in the codon for glycoprotein E (gE), a viral protein that is absent in the attenuated-live Bartha-K61 vaccine strain that was widely used in the Chinese pork industry at the time.2,3,5 Antibodies against gE in diagnostic samples are used as a serologic marker to differentiate wild-type strains from the vaccine strain. A more recent review of studies that used these types of serologic tests determined that the average seropositive rate across 29 Chinese provinces for wild-type PRV-gE antibodies was ~30%.4 However, the seroprevalence against PRV is not uniform, and the same review identified non-vaccine related management factors that were associated with higher seroprevalence.4 Notwithstanding, phylogenetic and selection pressure analysis showed that this novel variant of the gE codon appeared to give the newer strains of PRV an advantage that enabled them to evade the host defenses induced with Bartha-K61 vaccination.2,3

Case Reports:

The first case reports of possible zoonotic PRV occurring in China were published in 2018. One report was a case of endophthalmitis that yielded PRV in the vitreous humor of the affected eye on metagenomic next-generation sequencing (mNGS), the other was a case series of 4 individuals who were diagnosed with encephalitis. Both of the cases described in these reports occurred in 2017, all of the affected individuals were between the ages of 38-54 years, and all of them worked in the pork industry and had direct contact with pigs.6,7 In the 4 cases of encephalitis, only 2 of the cases produced PRV on mNGS, though 3 of the 4 had positive titers to PRV on serology. Further details were not available for the 4 encephalitis cases diagnosed in 2017, as the publication was in Mandarin and only the abstract was available in English.7 In 2019 another case series was published that described 5 cases of encephalitis in individuals in the same age range and with similar occupational exposure to pigs in Shandong province. In this case series, 4 of the individuals were positive on mNGS of cerebrospinal fluid (CSF) for PRV and the results of the 5th were weakly suggestive of PRV.  The 4 cases that were positive on mNGS also shared a common link of a recent injury at work that broke the skin; the case with the weakly suggestive result denied any injury.8 A case study published in 2020 detailed a 2019 case of encephalitis in a 44 year old man in Anhui province that was positive for PRV on mNGS of CSF and blood, and also had positive titers against PRV on serology; the mNGS was confirmed with Sanger sequencing.9 A 2022 case study documented a 2021 case of encephalitis in a 54 year old man in Hunan province that was positive for PRV on mNGS of the CSF, blood, and vitreous humor, and was also positive on Sanger sequencing.10 Consistent with previous reports, both of the individuals in these case reports worked in the pork industry, and had recent history (within past month) of a hand injury at work.9,10 Some of the commonly reported clinical signs in these cases included headaches, memory loss, seizures, vision impairment, and respiratory failure. While follow up information was not available for all of the cases described, many of the affected individuals died, or were left with debilitating clinical conditions.6,8–11

Perhaps the most significant of these reports was a 2021 case series that documented 4 cases of encephalitis in 2 veterinarians and 2 pig butchers. All of the affected individuals were male and ranged in age from 25-43 years, and all were diagnosed via mNGS. Two of the cases were from Henan province, 1 was from Hubei province, and the 4th case was from Shandong province. A viable strain of PRV, with close phylogenetic relation to novel strains of PRV circulating in pigs at the time, was isolated from the 4th case, a 43-year-old male veterinarian who persisted in a vegetative state following the clinical onset of disease. Phylogenetic analysis of this stain showed that it was closely related to the variant strains of PRV that were circulating in the Chinese pork industry at that time, and the virus also showed significant cytopathic effects in human derived cell cultures. Furthermore, challenge studies that inoculated PRV free mice and piglets with the isolated strain showed that it was highly pathogenic to these species.11 While it is theoretically possible that the detection of PRV via mNGS as described in the case reports was the result of contamination of the reagents, or an artifact of the collection process, this latest development adds strength to the argument for a causal relationship between the variant strains of PRV in the Chinese swine industry and human cases of encephalitis and edopthalmitis.4,11,12

Continue Reading Part 3 of the Zoonotic Potential of Pseudorabies Virus Series: An Emerging Threat

Zoonotic potential of pseudorabies virus series: an evolutionary shift? – Part 3

References:

  1. United States Department of Agriculture. Livestock and Poultry: World Markets and Trade. Published online April 11, 2023. Accessed May 12, 2023. https://downloads.usda.library.cornell.edu/usda-esmis/files/73666448x/cn69nh059/zs25zp436/livestock_poultry.pdf

  2. Gu J, Hu D, Peng T, et al. Epidemiological investigation of pseudorabies in Shandong Province from 2013 to 2016. Transbound Emerg Dis. 2018;65(3):890-898. doi:10.1111/tbed.12827

  3. Sun Y, Liang W, Liu Q, et al. Epidemiological and genetic characteristics of swine pseudorabies virus in mainland China between 2012 and 2017. PeerJ. 2018;6:e5785. doi:10.7717/peerj.5785

  4. Tan L, Yao J, Yang Y, et al. Current Status and Challenge of Pseudorabies Virus Infection in China. Virol Sin. 2021;36(4):588-607. doi:10.1007/s12250-020-00340-0

  5. An TQ, Peng JM, Tian ZJ, et al. Pseudorabies Virus Variant in Bartha-K61–Vaccinated Pigs, China, 2012. Emerg Infect Dis. 2013;19(11):1749-1755. doi:10.3201/eid1911.130177

  6. Ai JW, Weng SS, Cheng Q, et al. Human Endophthalmitis Caused By Pseudorabies Virus Infection, China, 2017. Emerg Infect Dis. 2018;24(6):1087-1090. doi:10.3201/eid2406.171612

  7. Zhao, Weili, Wu, Yihan, Li, Hongfang, et al. Clinical experience and next-generation sequencing analysis of encephalitis caused by pseudorabies virus. Natl Med J China. 2018;98(15):1152-1157.

  8. Yang X, Guan H, Li C, et al. Characteristics of human encephalitis caused by pseudorabies virus: A case series study. Int J Infect Dis. 2019;87:92-99. doi:10.1016/j.ijid.2019.08.007

  9. Wang D, Tao X, Fei M, et al. Human encephalitis caused by pseudorabies virus infection: a case report. J Neurovirol. 2020;26(3):442-448. doi:10.1007/s13365-019-00822-2

  10. Yan W, Hu Z, Zhang Y, Wu X, Zhang H. Case Report: Metagenomic Next-Generation Sequencing for Diagnosis of Human Encephalitis and Endophthalmitis Caused by Pseudorabies Virus. Front Med. 2022;8:753988. doi:10.3389/fmed.2021.753988

  11. 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

  12. 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