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Moving Lassa Fever Research and Care Into the 21st Century.

Lassa fever, a viral hemorrhagic disease, is a growing threat to public health in West Africa and beyond. While Ebola virus disease (EVD) recently captured the attention of the global community, Lassa fever arguably represents an even more concerning cause of viral hemorrhagic fever (VHF). Unlike EVD, which causes sporadic outbreaks, Lassa virus (LASV) is endemic in West Africa and is responsible for an estimated 300 000 infections and >5000 deaths annually—figures that are likely underestimates, given the challenge of collecting epidemiologic data due to civil conflict and limited clinical research infrastructure in endemic countries [1–3]. As a result, in a given 3 year period, Lassa fever kills more people than all the known outbreaks of EVD combined. Moreover, the World Health Organization (WHO) reports an upward trend in the incidence of Lassa fever this past year, perhaps as a consequence of climate change, with an increase in severity and case fatality rate [4]. Many of these deaths could be prevented with better diagnostics, supportive clinical care, and therapeutics [4, 5]. Furthermore, with >32 reported cases of Lassa fever imported into nonendemic countries—one-third of which were fatal—the significance of enhanced detection and management of this virus extends beyond West Africa [6–10]. For these reasons, in 2016, the WHO released a research and development blueprint call to action that identified LASV as a “top priority emerging pathogen” likely to cause a severe outbreak in the near future and consequently urgently needing to be studied [11]. Despite being a major cause of infection in West Africa, Lassa fever remains underdiagnosed and understudied. It has been almost 50 years since LASV was first identified during a 1969 outbreak in Nigeria, but the mechanisms underlying its pathogenesis and the role that host and viral factors play remain unclear. With the notable exception of tenacious efforts by research groups at Kenema Government Hospital in Sierra Leone a Irrua Specialist Teaching Hospital in Nigeria, Lassa fever clinical research has been largely petrified. Limited studies from the 1980s suggest that uncontrolled viremia is highly predictive of disease severity [12]. Patients presenting with systemic viral loads <103 median 50% tissue culture infective dose (TCID50)/mL were 3.7 times more likely to survive than those admitted with higher levels [13]. Additionally, survival has also been linked to the induction of a LASV-specific cell-mediated immune response, rather than a humoral immune response, as the appearance of antibodies does not seem to impact viremia and neutralizing antibodies do not appear until months to years after the acute infection [13]. Beyond this, there is limited understanding of human immune responses to LASV infection, as civil conflict in Sierra Leone and Liberia and the subsequent decimation of the healthcare infrastructure in the region have effectively halted Lassa fever research and, importantly, impeded the care of infected patients. The report by McElroy and colleagues in this issue of The Journal of Infectious Diseases provides an alternative strategy to advance the science of Lassa fever and the care of infected patients. Capitalizing on the opportunity presented when a healthcare worker with acute Lassa fever was repatriated from West Africa to Emory University Hospital in Atlanta, McElroy and colleagues, in a collaboration with the Centers for Disease Control and Prevention, conducted an in-depth investigation to characterize the kinetics, magnitude, and quality of the innate and cellular immune response during primary LASV infection, while also providing advanced clinical care. Although they detail the immune response of a single patient, the comprehensive nature of their analysis offers a rare insight into the interaction of a high-consequence pathogen with a human host and an opportunity to identify critical aspects that require further investigation. After a tragically prolonged pause in Lassa fever research, the work reported by these investigators is an important step in moving the science of this neglected virus into the 21st century. The detailed analysis of the kinetics of the immune response revealed a correlation between multiple components of the immune response and viral clearance including interferon alpha (IFN-α) expression, the appearance of LASV-specific immunoglobulin M (IgM), and increasing activated CD8+ T cells. The IFN-α findings support prior work in nonhuman primate models of Lassa fever linking IFN-α levels with survival as well as E D I T O R I A L C O M M E N T A R Y