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

Andersen, Britt; Rosa, Bruce A.; Kupritz, Jonah; Meïté, Aboulaye; Serge, Traye; Hertz, Marla I.; Curtis, Kurt C.; King, Christopher L.; Mitreva, Makedonka; Fischer, Peter; Weil, Gary J.

doi:10.1371/journal.pntd.0007697

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…The mechanism by which doxycycline mediates antimorbidity effects in filariasis is difficult to determine in the clinic, due to its curative activity via targeting filarial Wolbachia ( 52 ), and its broad-spectrum antibiotic properties that reduce secondary skin bacterial infections and cellulitis complications ( 53 ). Further, Wolbachia can directly activate classical inflammatory processes upon liberation from filarial tissues ( 32 ) and have been identified as mediators of systemic adverse reactions in LF patients after filaricidal treatment ( 54 , 55 ). Therefore, Wolbachia may contribute to filarial LE via triggering classical inflammation ( 56 ) and doxycycline may prevent this disease pathway.…”

Section: Discussionmentioning

confidence: 99%

Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor–mediated lymphangiogenesis

Furlong-Silva¹,

Cross²,

Marriott³

et al. 2021

Journal of Clinical Investigation

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Lymphatic filariasis is the major global cause of nonhereditary lymphedema. We demonstrate that the filarial nematode Brugia malayi induced lymphatic remodeling and impaired lymphatic drainage following parasitism of limb lymphatics in a mouse model. Lymphatic insufficiency was associated with elevated circulating lymphangiogenic mediators, including vascular endothelial growth factor C. Lymphatic insufficiency was dependent on type 2 adaptive immunity, the interleukin-4 receptor, and recruitment of C-C chemokine receptor-2–positive monocytes and alternatively activated macrophages with a prolymphangiogenic phenotype. Oral treatments with second-generation tetracyclines improved lymphatic function, while other classes of antibiotic had no significant effect. Second-generation tetracyclines directly targeted lymphatic endothelial cell proliferation and modified type 2 prolymphangiogenic macrophage development. Doxycycline treatment impeded monocyte recruitment, inhibited polarization of alternatively activated macrophages, and suppressed T cell adaptive immune responses following infection. Our results determine a mechanism of action for the antimorbidity effects of doxycycline in filariasis and support clinical evaluation of second-generation tetracyclines as affordable, safe therapeutics for lymphedemas of chronic inflammatory origin.

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Section: Discussionmentioning

confidence: 99%

Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor–mediated lymphangiogenesis

Furlong-Silva¹,

Cross²,

Marriott³

et al. 2021

Journal of Clinical Investigation

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“…After treatment with antifilarial drugs, systemic adverse events (AEs) such as fever, headache, and myalgia can occur as a result of the death of microfilaria (Mf). The risk of AEs is associated with Mf density [19][20][21]. Given the high endemicity of LF in PNG and lack of prior treatment for LF in most areas, the greater efficacy of IDA might lead to a higher rate of AEs as had been observed in clinical trials in PNG with heavy LF infections [15,16].…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole + diethylcarbamazine + ivermectin for lymphatic filariasis in Papua New Guinea: An open-label, cluster-randomised trial

et al. 2022

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Background Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. Methodology All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. Principal findings Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 97% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007). Conclusion IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. Trial registration Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.

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“…Bancroftian filariasis after microfilaricidal treatment further arguing that worm death is responsible in both cases (25).…”

Section: Discussionmentioning

confidence: 99%

Brugia malayi Glycoproteins Detected by the Filariasis Test Strip Antibody AD12.1

Hertz¹,

Hamlin²,

Rush³

et al. 2021

Front. Trop. Dis

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BackgroundRapid and accurate prevalence mapping of lymphatic filariasis (LF) is necessary to eliminate this disfiguring and disabling neglected tropical disease. Unfortunately, rapid tests such as the filariasis test strip (FTS) for Wuchereria bancrofti, the causative agent of LF in Africa, can cross-react with antigens circulating in some persons infected by the African eye worm, Loa loa, rendering the test unreliable in eleven co-endemic nations. The intended target of the FTS is a heavily glycosylated W. bancrofti circulating filarial antigen (Wb-CFA). Previously, we determined that the FTS monoclonal antibody, AD12.1, which detects a carbohydrate epitope on Wb-CFA, also detects multiple L. loa proteins in cross-reactive sera from persons with loiasis. Since the carbohydrate epitope recognized by AD12.1 is present on glycoproteins of other parasitic nematodes, including Brugia species, it is unclear why reactive glycoproteins are not detected in infections with other filarial parasites.MethodsTo gain a better understanding of the proteins recognized by the FTS diagnostic antibody, we used proteomics and lectin array technology to characterize filarial glycoproteins that are bound by the AD12.1 antibody using Brugia malayi as a model.ResultsDistinct but overlapping sets of AD12 glycoproteins were identified from somatic and excretory/secretory worm products. One of the identified proteins, Bm18019 was confirmed as a secreted AD12-reactive glycoprotein by in-gel proteomics and immunoassays. Based on lectin binding patterns, Brugia AD12-reactive glycoproteins express glycans including core fucose, galactose, N-acetylglucosamine and galactose(β1-3)N-acetylgalactosamine in addition to the epitope recognized by AD12.1. None of the lectins that bound B. malayi AD12 glycoproteins had affinity for the Wb-CFA, highlighting a key difference between it and other AD12 glycoproteins.ConclusionsB. malayi somatic and excretory/secretory proteins are similar to L. loa antigens found in FTS-positive human sera, bolstering the hypothesis that circulating L. loa AD12 antigens result from worm tissue damage or death. The difference in glycan and protein composition between the Wb-CFA and other AD12 glycoproteins can be used to differentiate LF from cross-reactive loiasis.

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

Cited by 14 publications

References 49 publications

Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor–mediated lymphangiogenesis

Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor–mediated lymphangiogenesis

Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole + diethylcarbamazine + ivermectin for lymphatic filariasis in Papua New Guinea: An open-label, cluster-randomised trial

Brugia malayi Glycoproteins Detected by the Filariasis Test Strip Antibody AD12.1

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