Differential susceptibility of Onchocerca volvulus microfilaria to ivermectin in two areas of contrasting history of mass drug administration in Cameroon: relevance of microscopy and molecular techniques for the monitoring of skin microfilarial repopulation within six months of direct observed treatment.
Adolescent
Animals
Antiparasitic Agents
/ therapeutic use
Biopsy
Cameroon
Child
Child, Preschool
Female
Humans
Ivermectin
/ therapeutic use
Male
Mass Drug Administration
Microscopy
Onchocerca volvulus
/ physiology
Onchocerciasis
/ drug therapy
Real-Time Polymerase Chain Reaction
Skin
/ pathology
Young Adult
LAMP
Microfilaricides
Microfilaridemia
Microscopy
Monitoring
O. volvulus
Real-time PCR
Susceptibility
Journal
BMC infectious diseases
ISSN: 1471-2334
Titre abrégé: BMC Infect Dis
Pays: England
ID NLM: 100968551
Informations de publication
Date de publication:
02 Oct 2020
02 Oct 2020
Historique:
received:
04
04
2020
accepted:
23
09
2020
entrez:
3
10
2020
pubmed:
4
10
2020
medline:
8
10
2020
Statut:
epublish
Résumé
Ivermectin is an excellent microfilaricide against Onchocerca volvulus. However, in some regions, long term use of ivermectin has resulted in sub-optimal responses to the treatment. More data to properly document the phenomenon in various contexts of ivermectin mass drug administration (IVM-MDA) is needed. Also, there is a need to accurately monitor a possible repopulation of skin by microfilariae following treatment. Skin snip microscopy is known to have a low sensitivity in individuals with light infections, which can be the case following treatment. This study was designed with two complementary objectives: (i) to assess the susceptibility of O. volvulus microfilariae to ivermectin in two areas undergoing IVM-MDA for different lengths of time, and (ii) to document the repopulation of skin by the O. volvulus microfilariae following treatment, using 3 independent diagnostic techniques. Identified microfilaridermic individuals were treated with ivermectin and re-examined after 1, 3, and 6 months using microscopy, actin real-time PCR (actin-qPCR) and O-150 LAMP assays. Susceptibility to ivermectin and trends in detecting reappearance of skin microfilariae were determined using three techniques. Microscopy was used as an imperfect gold standard to determine the performance of actin-qPCR and LAMP. In Bafia with over 20 years of IVM-MDA, 11/51 (21.6%) direct observe treated microfilaridemic participants were still positive for skin microfilariae after 1 month. In Melong, with 10 years of IVM-MDA, 2/29 (6.9%) treated participants were still positive. The microfilarial density reduction per skin biopsy within one month following treatment was significantly lower in participants from Bafia. In both study sites, the molecular techniques detected higher proportions of infected individuals than microscopy at all monitoring time points. LAMP demonstrated the highest levels of sensitivity and real-time PCR was found to have the highest specificity. Patterns in skin mirofilariae clearance and repopulation were established. O. volvulus worms from Bafia with higher number of annual MDA displayed a lower clearance and higher repopulation rate after treatment with ivermectin. Molecular assays displayed higher sensitivity in monitoring O. volvulus microfilaridemia within six months following treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Ivermectin is an excellent microfilaricide against Onchocerca volvulus. However, in some regions, long term use of ivermectin has resulted in sub-optimal responses to the treatment. More data to properly document the phenomenon in various contexts of ivermectin mass drug administration (IVM-MDA) is needed. Also, there is a need to accurately monitor a possible repopulation of skin by microfilariae following treatment. Skin snip microscopy is known to have a low sensitivity in individuals with light infections, which can be the case following treatment. This study was designed with two complementary objectives: (i) to assess the susceptibility of O. volvulus microfilariae to ivermectin in two areas undergoing IVM-MDA for different lengths of time, and (ii) to document the repopulation of skin by the O. volvulus microfilariae following treatment, using 3 independent diagnostic techniques.
METHOD
METHODS
Identified microfilaridermic individuals were treated with ivermectin and re-examined after 1, 3, and 6 months using microscopy, actin real-time PCR (actin-qPCR) and O-150 LAMP assays. Susceptibility to ivermectin and trends in detecting reappearance of skin microfilariae were determined using three techniques. Microscopy was used as an imperfect gold standard to determine the performance of actin-qPCR and LAMP.
RESULTS
RESULTS
In Bafia with over 20 years of IVM-MDA, 11/51 (21.6%) direct observe treated microfilaridemic participants were still positive for skin microfilariae after 1 month. In Melong, with 10 years of IVM-MDA, 2/29 (6.9%) treated participants were still positive. The microfilarial density reduction per skin biopsy within one month following treatment was significantly lower in participants from Bafia. In both study sites, the molecular techniques detected higher proportions of infected individuals than microscopy at all monitoring time points. LAMP demonstrated the highest levels of sensitivity and real-time PCR was found to have the highest specificity.
CONCLUSION
CONCLUSIONS
Patterns in skin mirofilariae clearance and repopulation were established. O. volvulus worms from Bafia with higher number of annual MDA displayed a lower clearance and higher repopulation rate after treatment with ivermectin. Molecular assays displayed higher sensitivity in monitoring O. volvulus microfilaridemia within six months following treatment.
Identifiants
pubmed: 33008333
doi: 10.1186/s12879-020-05444-2
pii: 10.1186/s12879-020-05444-2
pmc: PMC7530974
doi:
Substances chimiques
Antiparasitic Agents
0
Ivermectin
70288-86-7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
726Subventions
Organisme : Wellcome Trust
ID : 201900/Z/16/Z
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Références
WHO: Uniting to Combat Neglected Tropical Diseases. River blindness (Onchocerciasis). 2020 WHO roadmap target: Elimination. https://unitingtocombatntds.org/ntds/onchocerciasis/ . (Accessed 20 Apr 2020). In.; 2020.
Adewole SOaA, S.K. Clinical manifestation of Onchocerciasis in Ise - Orun local government, Ekiti state. Nigeria Pakistan J Nutri. 2009;8:122–4.
Edungbola LD, Watts SJ, Kayode OO. Endemicity and striking manifestations of onchocerciasis in Shao, Kwara state, Nigeria. Afr J Med Med Sci. 1987;16(3):147–56.
Katawa G, Layland LE, Debrah AY, von Horn C, Batsa L, Kwarteng A, Arriens S, D WT, Specht S, Hoerauf A, et al. Hyperreactive onchocerciasis is characterized by a combination of Th17-Th2 immune responses and reduced regulatory T cells. PLoS Negl Trop Dis. 2015;9(1):e3414.
pubmed: 4288720
pmcid: 4288720
Njim T, Ngum JM, Aminde LN. Cutaneous onchocerciasis in Dumbu, a pastoral area in the north-west region of Cameroon: diagnostic challenge and socio-economic implications. Pan African med J. 2015;22:298.
Basanez MG, Pion SD, Boakes E, Filipe JA, Churcher TS, Boussinesq M. Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis. 2008;8(5):310–22.
Osei-Atweneboana MY, Awadzi K, Attah SK, Boakye DA, Gyapong JO, Prichard RK. Phenotypic evidence of emerging ivermectin resistance in Onchocerca volvulus. PLoS Negl Trop Dis. 2011;5(3):e998.
pubmed: 3066159
pmcid: 3066159
Pion SD, Nana-Djeunga HC, Kamgno J, Tendongfor N, Wanji S, Njiokou F, Prichard RK, Boussinesq M. Dynamics of Onchocerca volvulus microfilarial densities after ivermectin treatment in an ivermectin-naive and a multiply treated population from Cameroon. PLoS Negl Trop Dis. 2013;7(2):e2084.
pubmed: 3585010
pmcid: 3585010
Churcher TS, Pion SD, Osei-Atweneboana MY, Prichard RK, Awadzi K, Boussinesq M, Collins RC, Whitworth JA, Basanez MG. Identifying sub-optimal responses to ivermectin in the treatment of river blindness. Proc Natl Acad Sci U S A. 2009;106(39):16716–21.
pubmed: 2757820
pmcid: 2757820
Kamga GR, Dissak-Delon FN, Nana-Djeunga HC, Biholong BD, Ghogomu SM, Souopgui J, Kamgno J, Robert A. Audit of the community-directed treatment with ivermectin (CDTI) for onchocerciasis and factors associated with adherence in three regions of Cameroon. Parasit Vectors. 2018;11(1):356.
pubmed: 6009063
pmcid: 6009063
Taylor HR, Munoz B, Keyvan-Larijani E, Greene BM. Reliability of detection of microfilariae in skin snips in the diagnosis of onchocerciasis. Am J Trop Med Hyg. 1989;41(4):467–71.
Thiele EA, Cama VA, Lakwo T, Mekasha S, Abanyie F, Sleshi M, Kebede A, Cantey PT. Detection of Onchocerca volvulus in skin snips by microscopy and real-time polymerase chain reaction: implications for monitoring and evaluation activities. Am J Trop Med Hyg. 2016;94(4):906–11.
pubmed: 4824238
pmcid: 4824238
Kale OO, Bammeke AO, Ayeni O. An evaluation of skin snip techniques used in the quantitative assessment of microfilarial densities of Onchocerca volvulus. Bull World Health Organ. 1974;51(5):547–9.
pubmed: 2366323
pmcid: 2366323
Duke BO. A standard method of assessing microfilarial densities on onchocerciasis surveys. Bull World Health Organ. 1962;27(4–5):629–32.
pubmed: 2555870
pmcid: 2555870
Ta TH, Moya L, Nguema J, Aparicio P, Miguel-Oteo M, Cenzual G, Canorea I, Lanza M, Benito A, Crainey JL, et al. Geographical distribution and species identification of human filariasis and onchocerciasis in Bioko Island, Equatorial Guinea. Acta Trop. 2018;180:12–7.
Nana-Djeunga HC, Fossuo-Thotchum F, Pion SD, Chesnais CB, Kubofcik J, Mackenzie CD, Klion AD, Boussinesq M, Nutman TB, Kamgno J. Loa loa microfilariae in skin snips: consequences for onchocerciasis monitoring and evaluation in L. loa endemic areas. Clin Infect Dis. 2019;69(9):1628-1630.
Basanez MG, Walker M, Turner HC, Coffeng LE, de Vlas SJ, Stolk WA. River blindness: mathematical models for control and elimination. Adv Parasitol. 2016;94:247–341.
Lobos E, Weiss N, Karam M, Taylor HR, Ottesen EA, Nutman TB. An immunogenic Onchocerca volvulus antigen: a specific and early marker of infection. Science. 1991;251(5001):1603–5.
Oguttu D, Byamukama E, Katholi CR, Habomugisha P, Nahabwe C, Ngabirano M, Hassan HK, Lakwo T, Katabarwa M, Richards FO, et al. Serosurveillance to monitor onchocerciasis elimination: the Ugandan experience. Am J Trop Med Hyg. 2014;90(2):339–45.
pubmed: 3919245
pmcid: 3919245
Prince-Guerra JL, Cama VA, Wilson N, Thiele EA, Likwela J, Ndakala N, Muzinga Wa Muzinga J, Ayebazibwe N, Ndjakani YD, Pitchouna NA, et al. Comparison of PCR methods for Onchocerca volvulus detection in skin snip biopsies from the Tshopo Province, Democratic Republic of the Congo. Am J Trop Med Hyg. 2018;98(5):1427–34.
pubmed: 5953380
pmcid: 5953380
Zimmerman PA, Guderian RH, Aruajo E, Elson L, Phadke P, Kubofcik J, Nutman TB. Polymerase chain reaction-based diagnosis of Onchocerca volvulus infection: improved detection of patients with onchocerciasis. J Infect Dis. 1994;169(3):686–9.
Alhassan A, Osei-Atweneboana MY, Kyeremeh KF, Poole CB, Li Z, Tettevi E, Tanner NA, Carlow CK. Comparison of a new visual isothermal nucleic acid amplification test with PCR and skin snip analysis for diagnosis of onchocerciasis in humans. Mol Biochem Parasitol. 2016;210(1–2):10–2.
Lagatie O, Merino M, Batsa Debrah L, Debrah AY, Stuyver LJ. An isothermal DNA amplification method for detection of Onchocerca volvulus infection in skin biopsies. Parasit Vectors. 2016;9(1):624.
pubmed: 5134125
pmcid: 5134125
Williams JF, el Khalifa M, Mackenzie CD, Sisley B. Antigens of Onchocerca volvulus. Rev Infect Dis. 1985;7(6):831–6.
Toe L, Merriweather A, Unnasch TR. DNA probe-based classification of Simulium damnosum s. l.-borne and human-derived filarial parasites in the onchocerciasis control program area. Am J Trop Med Hyg. 1994;51(5):676–83.
Lloyd MM, Gilbert R, Taha NT, Weil GJ, Meite A, Kouakou IM, Fischer PU. Conventional parasitology and DNA-based diagnostic methods for onchocerciasis elimination programmes. Acta Trop. 2015;146:114–8.
Meredith SE, Lando G, Gbakima AA, Zimmerman PA, Unnasch TR. Onchocerca volvulus: application of the polymerase chain reaction to identification and strain differentiation of the parasite. Exp Parasitol. 1991;73(3):335–44.
Colebunders R, Mandro M, Mokili JL, Mucinya G, Mambandu G, Pfarr K, Reiter-Owona I, Hoerauf A, Tepage F, Levick B, et al. Risk factors for epilepsy in bas-Uele Province, Democratic Republic of the Congo: a case-control study. Int J Infect Dis. 2016;49:1–8.
pubmed: 4973807
pmcid: 4973807
Gilbert J, Nfon CK, Makepeace BL, Njongmeta LM, Hastings IM, Pfarr KM, Renz A, Tanya VN, Trees AJ. Antibiotic chemotherapy of onchocerciasis: in a bovine model, killing of adult parasites requires a sustained depletion of endosymbiotic bacteria (Wolbachia species). J Infect Dis. 2005;192(8):1483–93.
Osue HO, Inabo H, Yakubu S, Audu P, Mamman M. Onchocercal DNA amplification using Beta actin gene primers compared with first internal transcribed spacer sequences for monitoring Onchocerciasis eradication strategy. Afr J Biomed Res. 2018;21:23–8.
Francois P, Tangomo M, Hibbs J, Bonetti EJ, Boehme CC, Notomi T, Perkins MD, Schrenzel J. Robustness of a loop-mediated isothermal amplification reaction for diagnostic applications. FEMS Immunol Med Microbiol. 2011;62(1):41–8.
Kubota R, Vine BG, Alvarez AM, Jenkins DM. Detection of Ralstonia solanacearum by loop-mediated isothermal amplification. Phytopathology. 2008;98(9):1045–51.
Tambo M, Mwinga M, Mumbengegwi DR. Loop-mediated isothermal amplification (LAMP) and polymerase chain reaction (PCR) as quality assurance tools for rapid diagnostic test (RDT) malaria diagnosis in northern Namibia. PLoS One. 2018;13(12):e0206848.
pubmed: 6291133
pmcid: 6291133
Notomi T, Mori Y, Tomita N, Kanda H. Loop-mediated isothermal amplification (LAMP): principle, features, and future prospects. J Microbiol. 2015;53(1):1–5.
Lakwo T, Garms R, Wamani J, Tukahebwa EM, Byamukama E, Onapa AW, Tukesiga E, Katamanywa J, Begumisa S, Habomugisha P, et al. Interruption of the transmission of Onchocerca volvulus in the Kashoya-Kitomi focus, western Uganda by long-term ivermectin treatment and elimination of the vector Simulium neavei by larviciding. Acta Trop. 2017;167:128–36.
Poole CB, Li Z, Alhassan A, Guelig D, Diesburg S, Tanner NA, Zhang Y, Evans TC Jr, LaBarre P, Wanji S, et al. Colorimetric tests for diagnosis of filarial infection and vector surveillance using non-instrumented nucleic acid loop-mediated isothermal amplification (NINA-LAMP). PLoS One. 2017;12(2):e0169011.
pubmed: 5310896
pmcid: 5310896
Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, Doumbia K, Goita SF, Konate L, Mounkoro K, Seck AF, et al. Proof-of-principle of onchocerciasis elimination with ivermectin treatment in endemic foci in Africa: final results of a study in Mali and Senegal. PLoS Negl Trop Dis. 2012;6(9):e1825.
pubmed: 3441490
pmcid: 3441490
Zarroug IM, Hashim K, ElMubark WA, Shumo ZA, Salih KA, ElNojomi NA, Awad HA, Aziz N, Katabarwa M, Hassan HK, et al. The first confirmed elimination of an Onchocerciasis focus in Africa: Abu Hamed, Sudan. Am J Trop Med Hyg. 2016;95(5):1037–40.
pubmed: 5094213
pmcid: 5094213
Kamga GR, Dissak-Delon FN, Nana-Djeunga HC, Biholong BD, Mbigha-Ghogomu S, Souopgui J, Zoure HG, Boussinesq M, Kamgno J, Robert A. Still mesoendemic onchocerciasis in two Cameroonian community-directed treatment with ivermectin projects despite more than 15 years of mass treatment. Parasit Vectors. 2016;9(1):581.
pubmed: 5109673
pmcid: 5109673
Wanji S, Tendongfor N, Nji T, Esum M, Che JN, Nkwescheu A, Alassa F, Kamnang G, Enyong PA, Taylor MJ, et al. Community-directed delivery of doxycycline for the treatment of onchocerciasis in areas of co-endemicity with loiasis in Cameroon. Parasit Vectors. 2009;2(1):39.
pubmed: 2742514
pmcid: 2742514
Taylor HR, Duke BO, Munoz B. The selection of communities for treatment of onchocerciasis with ivermectin. Trop Med Parasitol: official organ of Deutsche Tropenmedizinische Gesellschaft and of Deutsche Gesellschaft fur Technische Zusammenarbeit. 1992;43(4):267–70.
Wanji S, Esum ME, Njouendou AJ, Mbeng AA, Chounna Ndongmo PW, Abong RA, Fru J, Fombad FF, Nchanji GT, Ngongeh G, et al. Mapping of lymphatic filariasis in loiasis areas: a new strategy shows no evidence for Wuchereria bancrofti endemicity in Cameroon. PLoS Negl Trop Dis. 2019;13(3):e0007192.
pubmed: 6436748
pmcid: 6436748
Alexander ND, Cousens SN, Yahaya H, Abiose A, Jones BR. Ivermectin dose assessment without weighing scales. Bull World Health Organ. 1993;71(3–4):361–6.
pubmed: 2393495
pmcid: 2393495
Wanji S, Kengne-Ouafo JA, Esum ME, Chounna PW, Tendongfor N, Adzemye BF, Eyong JE, Jato I, Datchoua-Poutcheu FR, Kah E, et al. Situation analysis of parasitological and entomological indices of onchocerciasis transmission in three drainage basins of the rain forest of south West Cameroon after a decade of ivermectin treatment. Parasit Vectors. 2015;8:202.
pubmed: 4393872
pmcid: 4393872
Ngoumou P, Walsh JF, Mace JM. A rapid mapping technique for the prevalence and distribution of onchocerciasis: a Cameroon case study. Ann Trop Med Parasitol. 1994;88(5):463–74.
Noma M, Zoure HG, Tekle AH, Enyong PA, Nwoke BE, Remme JH. The geographic distribution of onchocerciasis in the 20 participating countries of the African Programme for Onchocerciasis control: (1) priority areas for ivermectin treatment. Parasit Vectors. 2014;7:325.
pubmed: 4223657
pmcid: 4223657
Zoure HG, Noma M, Tekle AH, Amazigo UV, Diggle PJ, Giorgi E, Remme JH. The geographic distribution of onchocerciasis in the 20 participating countries of the African Programme for Onchocerciasis control: (2) pre-control endemicity levels and estimated number infected. Parasit Vectors. 2014;7:326.
pubmed: 4222889
pmcid: 4222889
Schulz-Key H. A simple technique to assess the total number of Onchocerca volvulus microfilariae in skin snips. Tropenmedizin und Parasitologie. 1978;29(1):51–4.
Lim C, Wannapinij P, White L, Day NPJ, Cooper BS, Peacock SJ, Limmathurotsakul D. Using a Web-Based Application to Define the Accuracy of Diagnostic Tests When the Gold Standard Is Imperfect. PloS one. 2013. https://doi.org/10.1371/journal.pone.0079489 .
Limmathurotsakul D, Jamsen K, Arayawichanont A, Simpson JA, White LJ, Lee SJ, Wuthiekanun V, Chantratita N, Cheng A, Day NP, et al. Defining the true sensitivity of culture for the diagnosis of melioidosis using Bayesian latent class models. PLoS One. 2010;5(8):e12485.
pubmed: 2932979
pmcid: 2932979
Trikalinos TA, Balion CM. Options for Summarizing Medical Test Performance in the Absence of a "Gold Standard". In: Chang SM, Matchar DB, Smetana GW, Umscheid CA, editors. Methods Guide for Medical Test Reviews. Rockville (MD): Oxford University Press; 2012.
Basanez MG. Mathematical modelling of parasitic infections: from data and parameter estimation to evolutionary implications. Preface Parasitol. 2008;135(13):1487–8.
Basanez MG, Boussinesq M. Population biology of human onchocerciasis. Philos Trans R Soc Lond Ser B Biol Sci. 1999;354(1384):809–26.
Plaisier AP, van Oortmarssen GJ, Habbema JD, Remme J, Alley ES. ONCHOSIM: a model and computer simulation program for the transmission and control of onchocerciasis. Comput Methods Prog Biomed. 1990;31(1):43–56.
Alhassan A, Makepeace BL, LaCourse EJ, Osei-Atweneboana MY, Carlow CK. A simple isothermal DNA amplification method to screen black flies for Onchocerca volvulus infection. PLoS One. 2014;9(10):e108927.
pubmed: 4191976
pmcid: 4191976
Kaneko H, Kawana T, Fukushima E, Suzutani T. Tolerance of loop-mediated isothermal amplification to a culture medium and biological substances. J Biochem Biophys Methods. 2007;70(3):499–501.
Martzy R, Kolm C, Brunner K, Mach RL, Krska R, Sinkovec H, Sommer R, Farnleitner AH, Reischer GH. A loop-mediated isothermal amplification (LAMP) assay for the rapid detection of Enterococcus spp. in water. Water Res. 2017;122:62–9.
Notomi T, Okayama H, Masubuchi H, Yonekawa T, Watanabe K, Amino N, Hase T. Loop-mediated isothermal amplification of DNA. Nucleic Acids Res. 2000;28(12):E63..
pubmed: 102748
pmcid: 102748
Takagi H, Itoh M, Kasai S, Yahathugoda TC, Weerasooriya MV, Kimura E. Development of loop-mediated isothermal amplification method for detecting Wuchereria bancrofti DNA in human blood and vector mosquitoes. Parasitol Int. 2011;60(4):493–7.
Senyonjo L, Oye J, Bakajika D, Biholong B, Tekle A, Boakye D, Schmidt E, Elhassan E. Factors associated with Ivermectin non-compliance and its potential role in sustaining Onchocerca volvulus transmission in the west region of Cameroon. PLoS Negl Trop Dis. 2016;10(8):e0004905.
pubmed: 4986942
pmcid: 4986942