Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection

Abstract

BackgroundLassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF.ResultsAnalyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa.ConclusionOnly LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In addition to suggesting that the current diagnostic paradigm for acute LF should be reconsidered, these studies present new opportunities for therapeutic interventions based on potential prognostic markers in LF.

Laboratory Diagnosis of Lassa Fever

“…Increased levels of antigenemia have been found in fatal cases of Lassa fever compared with those in nonfatal cases (50). The short duration of antigenemia makes the detection of Lassa virus antigen more specific to acute Lassa virus infection than detection with antibody assays.…”

“…Antibody assays have been used to diagnose Lassa fever in those with a clinically consistent illness based on either detectable levels of Lassa virus antibody in a serum sample collected during illness or a rise in Lassa antibody titers (2,63). However, Lassa virus IgM titers remain elevated for months to years following an acute infection (50). One study found that 28% of healthy hosts sampled from a region where the virus is endemic without a recent preceding febrile illness had detectable levels of Lassa virus IgM, suggesting that IgM positivity alone may be insufficient to diagnose Lassa fever in persons residing in regions where it is endemic (50).…”

“…However, Lassa virus IgM titers remain elevated for months to years following an acute infection (50). One study found that 28% of healthy hosts sampled from a region where the virus is endemic without a recent preceding febrile illness had detectable levels of Lassa virus IgM, suggesting that IgM positivity alone may be insufficient to diagnose Lassa fever in persons residing in regions where it is endemic (50). In regions where Lassa virus is endemic, a positive nucleoprotein antigen test, a rise in antibody titers between acuteand convalescent-phase serum, or the development of a new positive IgG titer in combination with a positive IgM titer may more accurately reflect acute Lassa fever than a single positive IgM test.…”

“…A lateral flow assay for Lassa virus nucleoprotein (ReLASV) is one type of rapid diagnostic test that could be used for point-of-care testing. Following initial development and testing efforts (50,57), this assay received the CE mark in 2013, although the assay has not been approved by the U.S. Federal Drug Administration. According to the product insert, the test yields results in 15 to 25 min and has 85% sensitivity and 99% specificity using confirmed Lassa virus-positive blood samples (Lassa virus positive by RT-PCR and IgM negative by ELISA) (58).…”

Factors Associated with Mortality in Febrile Patients in a Government Referral Hospital in the Kenema District of Sierra Leone

“…[2][3][4][5][6] The Kenema District of Sierra Leone is a Lassa-endemic region, although it is currently unknown what the burden of Lassa fever is in relation to other febrile illnesses in the region. In addition, there are no studies to date that broadly examine the etiologies and outcomes of febrile illness in patients seeking healthcare in Sierra Leone.…”