Systems analysis-based assessment of post-treatment adverse events in lymphatic filariasis

Background: Lymphatic filariasis (LF) is a neglected tropical disease, and the Global Program to Eliminate LF delivers mass drug administration (MDA) to 500 million people every year. Adverse events (AEs) are common after LF treatment. Methodology/Principal findings: To better understand the pathogenesis of AEs, we studied LF-patients from a treatment trial. Plasma levels of many filarial antigens increased post-treatment in individuals with AEs, and this is consistent with parasite death. Circulating immune complexes were not elevated in these participants, and the classical complement cascade was not activated. Multiple cytokines increased after treatment in persons with AEs. A transcriptomic analysis was performed for nine individuals with moderate systemic AEs and nine matched controls. Differential gene expression analysis identified a significant transcriptional signature associated with post-treatment AEs; 744 genes were upregulated. The transcriptional signature was enriched for TLR and NF-κB signaling. Increased expression of seven out of the top eight genes upregulated in persons with AEs were validated by qRT-PCR, including TLR2. Conclusions/Significance: This is the first global study of changes in gene expression associated with AEs after treatment of lymphatic filariasis. Changes in cytokines were consistent with prior studies and with the RNAseq data. These results suggest that Wolbachia lipoprotein is involved in AE development, because it activates TLR2-TLR6 and downstream NF-κB. Additionally, LPS Binding Protein (LBP, which shuttles lipoproteins to TLR2) increased post-treatment in individuals with AEs. Improved understanding of the pathogenesis of AEs may lead to improved management, increased MDA compliance, and accelerated LF elimination. Author summary: Lymphatic filariasis (LF) is a disabling parasitic disease that affects millions of people in the developing world. The Global Programme to Eliminate Lymphatic Filariasis (coordinated by the World Health Organization) uses mass administration of antifilarial medications to cure infections, prevent disease, and reduce transmission. Some individuals develop adverse events (AEs) after treatment, and this can reduce willingness of persons in endemic areas to accept treatment. The purpose of this study was to improve understanding of the cause of AEs following treatment. We hypothesized that parasite antigens released into the blood following treatment trigger inflammatory responses that lead to AEs. To test this hypothesis we collected blood from LF-infected individuals before and after treatment and clinically assessed them for AEs. We measured parasite antigens, cytokines and other components of the immune system in blood samples and compared post-treatment changes in persons with and without AEs. We also assessed changes in transcription profiles in peripheral blood leukocytes that were associated with post-treatment AEs. Post-treatment changes in transcription profiles and in immune proteins and parasite components in plasma suggest that systemic AEs are triggered by death of the parasites following treatment with release of parasite antigens and Wolbachia bacteria into the circulation. Improved understanding of the pathogenesis of post-treatment AEs may help to improve messaging related to mass drug administration programs and lead to improved AE management.