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Unknown Infectious Syndromes: Fertile Ground for Viral Discovery

Amesh A. Adalja, MD, FACP, FACEP, FIDSA | May 30, 2019

Pandemic preparedness not only includes preparing for known, well-characterized pandemic risks but also anticipating new threats. As such, viral discovery is a task that is prioritized. There are debates, however, regarding the most fruitful areas to search for new viruses with some advocating wide and costly ecological and animal sampling in “hot spots” while others favor determining the etiologies of the myriad undiagnosed clinical syndromes that occur all over the world on a daily basis.

A new paper, published in The New England Journal of Medicine, details the discovery of a novel encephalitis virus by a group pursuing an etiologic diagnosis in a patient with encephalitis in China.

Fever, Headaches, and Tick Bites

The index patient was a 42-year-old woman who presented to a hospital in Inner Mongolia with fever, headache, and a history of tick bites. Initially, tick-borne encephalitis virus (TBEV) was suspected but molecular and serological testing was negative. An effort to identify the etiological agent and search for other similar patients was undertaken. Tick and mosquito samples were also pursued.

Several types of studies were performed including viral cell culture on multiple cell types, electron microscopy, sequencing, and serology.

Alongshan Virus Discovered

Cytopathic effects were seen in Vero cell culture and electron microscopy confirmed the presence of virions with characteristics consistent with flavivirus group viruses. Virus was isolated from the index and 4 other hospitalized patients. Sequencing placed the virus within the Flaviviridae family adjacent, but distinct from, Jingmen tick virus (JMTV).

Further investigation revealed 86 other patients who had symptoms consistent with infection and laboratory evidence of infection with the novel virus. Ticks within the patients’ working environment was a common finding and the virus was also identified in Ixodes persulcatus ticks from the area. No fatal cases were identified though coma was reported in 30 patients and liver injury in 25% of cases. Full recovery was seen in all patients. Interestingly, all patients were treated with intravenous ribavirin plus benzylpenicillin.

This study is a great example of how a systematic approach to an undiagnosed infectious syndrome yielded an important new discovery. By focusing on finding an etiologic agent in a patient with actual clinical symptoms severe enough to merit hospitalization, the likelihood of success is increased as is the likelihood of finding a true (not incidental) pathogen. This type of approach, if replicated in a widespread fashion, has the potential to substantially increase our situational awareness of pathogens and better prepare for future infectious disease emergencies. As Nikos Vasilakis and David Walker write in the accompanying editorial, “although new technologies and broad genomic surveys of viruses will enhance our understanding of virus diversity and evolution, they may provide limited value in understanding the mechanisms of disease emergence. A far more cost-effective way to understand the emergence of diseases and to mitigate their outbreak is a proactive, real-time surveillance of human populations.”


Wang Z-D, Wang B, Wei F, et al. A new segmented virus associated with human febrile illness in China. N Engl J Med 2019;380: 2116-2125.

Vasilikas N, Walker DH. Seek and you shall find—unknown pathogens. N Engl J Med 2019;380: 2174-2175.