Dengue and chikungunya among outpatients with acute undifferentiated fever in Kinshasa, Democratic Republic of Congo: A cross-sectional study

Sam Proesmans, Freddy Katshongo, John Milambu, Blaise Fungula, Hypolite Muhindo Mavoko, Steve Ahuka-Mundeke, Raquel Inocêncio da Luz, Marjan Van Esbroeck, Kevin K Ariën, Lieselotte Cnops, Birgit De Smet, Pascal Lutumba, Jean-Pierre Van Geertruyden, Veerle Vanlerberghe, Sam Proesmans, Freddy Katshongo, John Milambu, Blaise Fungula, Hypolite Muhindo Mavoko, Steve Ahuka-Mundeke, Raquel Inocêncio da Luz, Marjan Van Esbroeck, Kevin K Ariën, Lieselotte Cnops, Birgit De Smet, Pascal Lutumba, Jean-Pierre Van Geertruyden, Veerle Vanlerberghe

Abstract

Background: Pathogens causing acute fever, with the exception of malaria, remain largely unidentified in sub-Saharan Africa, given the local unavailability of diagnostic tests and the broad differential diagnosis.

Methodology: We conducted a cross-sectional study including outpatient acute undifferentiated fever in both children and adults, between November 2015 and June 2016 in Kinshasa, Democratic Republic of Congo. Serological and molecular diagnostic tests for selected arboviral infections were performed on blood, including PCR, NS1-RDT, ELISA and IFA for acute, and ELISA and IFA for past infections.

Results: Investigation among 342 patients, aged 2 to 68 years (mean age of 21 years), with acute undifferentiated fever (having no clear focus of infection) revealed 19 (8.1%) acute dengue-caused by DENV-1 and/or DENV-2 -and 2 (0.9%) acute chikungunya infections. Furthermore, 30.2% and 26.4% of participants had been infected in the past with dengue and chikungunya, respectively. We found no evidence of acute Zika nor yellow fever virus infections. 45.3% of patients tested positive on malaria Rapid Diagnostic Test, 87.7% received antimalarial treatment and 64.3% received antibacterial treatment.

Discussion: Chikungunya outbreaks have been reported in the study area in the past, so the high seroprevalence is not surprising. However, scarce evidence exists on dengue transmission in Kinshasa and based on our data, circulation is more important than previously reported. Furthermore, our study shows that the prescription of antibiotics, both antibacterial and antimalarial drugs, is rampant. Studies like this one, elucidating the causes of acute fever, may lead to a more considerate and rigorous use of antibiotics. This will not only stem the ever-increasing problem of antimicrobial resistance, but will-ultimately and hopefully-improve the clinical care of outpatients in low-resource settings.

Trial registration: ClinicalTrials.gov NCT02656862.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Percentage of participants having an…
Fig 1. Percentage of participants having an acute dengue infection, Lisungi health center, DRCongo, 2015–2016.
Fig 2. Prevalence of flavi- and alphaviruses…
Fig 2. Prevalence of flavi- and alphaviruses infections and their related seroprevalence in patients with acute undifferentiated fever stratified by age at Lisungi health center, DRCongo, 11/2015-06/2016 (n = 235).

References

    1. World Health Organization, Global Malaria Programme. World malaria report 2017. 2017.
    1. D’Acremont V, Lengeler C, Genton B. Reduction in the proportion of fevers associated with Plasmodium falciparum parasitaemia in Africa: a systematic review. Malar J. 2010;9: 240 10.1186/1475-2875-9-240
    1. Gething PW, Patil AP, Smith DL, Guerra CA, Elyazar IR, Johnston GL, et al. A new world malaria map: Plasmodium falciparum endemicity in 2010. Malaria Journal. 2011;10: 378 10.1186/1475-2875-10-378
    1. D’Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, Kahama-Maro J, et al. Beyond Malaria—Causes of Fever in Outpatient Tanzanian Children. New England Journal of Medicine. 2014;370: 809–817. 10.1056/NEJMoa1214482
    1. Morgan DJ, Okeke IN, Laxminarayan R, Perencevich EN, Weisenberg S. Non-prescription antimicrobial use worldwide: a systematic review. The Lancet Infectious Diseases. 2011;11: 692–701. 10.1016/S1473-3099(11)70054-8
    1. Marston HD, Dixon DM, Knisely JM, Palmore TN, Fauci AS. Antimicrobial Resistance. JAMA. 2016;316: 1193 10.1001/jama.2016.11764
    1. D’Acremont V, Kahama-Maro J, Swai N, Mtasiwa D, Genton B, Lengeler C. Reduction of anti-malarial consumption after rapid diagnostic tests implementation in Dar es Salaam: a before-after and cluster randomized controlled study. Malaria Journal. 2011;10: 107 10.1186/1475-2875-10-107
    1. Dariano DF, Taitt CR, Jacobsen KH, Bangura U, Bockarie AS, Bockarie MJ, et al. Surveillance of Vector-Borne Infections (Chikungunya, Dengue, and Malaria) in Bo, Sierra Leone, 2012–2013. Am J Trop Med Hyg. 2017;97: 1151–1154. 10.4269/ajtmh.16-0798
    1. Amarasinghe A, Kuritsk JN, Letson GW, Margolis HS. Dengue virus infection in Africa. Emerging Infect Dis. 2011;17: 1349–1354. 10.3201/eid1708.101515
    1. Demanou M, Antonio-Nkondjio C, Ngapana E, Rousset D, Paupy C, Manuguerra J-C, et al. Chikungunya outbreak in a rural area of Western Cameroon in 2006: A retrospective serological and entomological survey. BMC Res Notes. 2010;3: 128 10.1186/1756-0500-3-128
    1. Ward T, Samuel M, Maoz D, Runge-Ranzinger S, Boyce R, Toledo J, et al. Dengue data and surveillance in Tanzania: a systematic literature review. Tropical Medicine & International Health. 2017;22: 960–970. 10.1111/tmi.12903
    1. Vairo F, Nicastri E, Meschi S, Schepisi MS, Paglia MG, Bevilacqua N, et al. Seroprevalence of dengue infection: a cross-sectional survey in mainland Tanzania and on Pemba Island, Zanzibar. Int J Infect Dis. 2012;16: e44–46. 10.1016/j.ijid.2011.09.018
    1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496: 504–507. 10.1038/nature12060
    1. Grossi-Soyster EN, Cook EAJ, de Glanville WA, Thomas LF, Krystosik AR, Lee J, et al. Serological and spatial analysis of alphavirus and flavivirus prevalence and risk factors in a rural community in western Kenya. PLoS Negl Trop Dis. 2017;11: e0005998 10.1371/journal.pntd.0005998
    1. Chretien J-P, Anyamba A, Bedno SA, Breiman RF, Sang R, Sergon K, et al. Drought-associated chikungunya emergence along coastal East Africa. Am J Trop Med Hyg. 2007;76: 405–407.
    1. Crump JA, Morrissey AB, Nicholson WL, Massung RF, Stoddard RA, Galloway RL, et al. Etiology of severe non-malaria febrile illness in Northern Tanzania: a prospective cohort study. PLoS Negl Trop Dis. 2013;7: e2324 10.1371/journal.pntd.0002324
    1. Mugabe VA, Ali S, Chelene I, Monteiro VO, Guiliche O, Muianga AF, et al. Evidence for chikungunya and dengue transmission in Quelimane, Mozambique: Results from an investigation of a potential outbreak of chikungunya virus. Roques P, editor. PLOS ONE. 2018;13: e0192110 10.1371/journal.pone.0192110
    1. Pastorino B, Muyembe-Tamfum JJ, Bessaud M, Tock F, Tolou H, Durand JP, et al. Epidemic resurgence of Chikungunya virus in democratic Republic of the Congo: identification of a new central African strain. J Med Virol. 2004;74: 277–282. 10.1002/jmv.20168
    1. Ido E, Ahuka S, Karhemere S, Ibuki K, Shibata M, Kameoka M, Muyembe JJ. Dengue virus infection during an outbreak of chikungunya virus in Democratic Republic of Congo. Annals of African Medicine. 2016; vol 10, n 1.
    1. Moyen N, Thiberville S-D, Pastorino B, Nougairede A, Thirion L, Mombouli J-V, et al. First Reported Chikungunya Fever Outbreak in the Republic of Congo, 2011. Rénia L, editor. PLoS ONE. 2014;9: e115938 10.1371/journal.pone.0115938
    1. Sharp TM, Moreira R, Soares MJ, Miguel da Costa L, Mann J, DeLorey M, et al. Underrecognition of Dengue during 2013 Epidemic in Luanda, Angola. Emerging Infectious Diseases. 2015;21: 1311–1316. 10.3201/eid2108.150368
    1. Grobbelaar AA, Weyer J, Moolla N, Jansen van Vuren P, Moises F, Paweska JT. Resurgence of Yellow Fever in Angola, 2015–2016. Emerging Infectious Diseases. 2016;22: 1854–1855. 10.3201/eid2210.160818
    1. Kraemer MUG, Brady OJ, Watts A, German M, Hay SI, Khan K, et al. Zika virus transmission in Angola and the potential for further spread to other African settings. Transactions of The Royal Society of Tropical Medicine and Hygiene. 2017;111: 527–529. 10.1093/trstmh/try001
    1. Mbanzulu KM, Wumba R, Mukendi J-PK, Zanga JK, Shija F, Bobanga TL, et al. Mosquito-borne viruses circulating in Kinshasa, Democratic Republic of the Congo. International Journal of Infectious Diseases. 2017;57: 32–37. 10.1016/j.ijid.2017.01.016
    1. Fritzell C, Rousset D, Adde A, Kazanji M, Van Kerkhove MD, Flamand C. Current challenges and implications for dengue, chikungunya and Zika seroprevalence studies worldwide: A scoping review. Clapham H, editor. PLOS Neglected Tropical Diseases. 2018;12: e0006533 10.1371/journal.pntd.0006533
    1. Van Den Bossche D, Cnops L, Meersman K, Domingo C, Van Gompel A, Van Esbroeck M. Chikungunya virus and West Nile virus infections imported into Belgium, 2007–2012. Epidemiology and Infection. 2015;143: 2227–2236. 10.1017/S0950268814000685
    1. Franco L, Di Caro A, Carletti F, Vapalahti O, Renaudat C, Zeller H, et al. Recent expansion of dengue virus serotype 3 in West Africa. Euro Surveill. 2010;15.
    1. Nur YA, Groen J, Heuvelmans H, Tuynman W, Copra C, Osterhaus AD. An outbreak of West Nile fever among migrants in Kisangani, Democratic Republic of Congo. Am J Trop Med Hyg. 1999;61: 885–888. 10.4269/ajtmh.1999.61.885
    1. Makiala-Mandanda S, Ahuka-Mundeke S, Abbate JL, Pukuta-Simbu E, Nsio-Mbeta J, Berthet N, et al. Identification of Dengue and Chikungunya Cases Among Suspected Cases of Yellow Fever in the Democratic Republic of the Congo. Vector-Borne and Zoonotic Diseases. 2018; 10.1089/vbz.2017.2176
    1. World Health Organization, Global Malaria Programme. World malaria report 2018. 2018.
    1. Mavoko HM, Nabasumba C, da Luz RI, Tinto H, D’Alessandro U, Kambugu A, et al. Efficacy and safety of re-treatment with the same artemisinin-based combination treatment (ACT) compared with an alternative ACT and quinine plus clindamycin after failure of first-line recommended ACT (QUINACT): a bicentre, open-label, phase 3, randomised controlled trial. Lancet Glob Health. 2017;5: e60–e68. 10.1016/S2214-109X(16)30236-4
    1. Litzba N, Schuffenecker I, Zeller H, Drosten C, Emmerich P, Charrel R, et al. Evaluation of the first commercial chikungunya virus indirect immunofluorescence test. Journal of Virological Methods. 2008;149: 175–179. 10.1016/j.jviromet.2008.01.004
    1. Prat CM, Flusin O, Panella A, Tenebray B, Lanciotti R, Leparc-Goffart I. Evaluation of Commercially Available Serologic Diagnostic Tests for Chikungunya Virus. Emerging Infectious Diseases. 2014;20: 2129–2132. 10.3201/eid2012.141269
    1. Pezzi L, Reusken CB, Weaver SC, Drexler JF, Busch M, LaBeaud AD, et al. GloPID-R report on Chikungunya, O’nyong-nyong and Mayaro virus, part I: Biological diagnostics. Antiviral Research. 2019;166: 66–81. 10.1016/j.antiviral.2019.03.009
    1. Cnops L, Jacobs J, Esbroeck MV. Validation of a four-primer real-time PCR as a diagnostic tool for single and mixed Plasmodium infections. Clinical Microbiology and Infection. 2011;17: 1101–1107. 10.1111/j.1469-0691.2010.03344.x
    1. de la C Sierra B, Kourí G, Guzmán MG. Race: a risk factor for dengue hemorrhagic fever. Arch Virol. 2007;152: 533–542. 10.1007/s00705-006-0869-x
    1. Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, et al. OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans. Kuhn RJ, editor. PLOS Pathogens. 2017;13: e1006220 10.1371/journal.ppat.1006220
    1. Chanama S, Anantapreecha S, A-nuegoonpipat A, Sa-gnasang A, Kurane I, Sawanpanyalert P. Analysis of specific IgM responses in secondary dengue virus infections: levels and positive rates in comparison with primary infections. Journal of Clinical Virology. 2004;31: 185–189. 10.1016/j.jcv.2004.03.005
    1. Van Esbroeck M, Meersman K, Michiels J, Ariën KK, Van den Bossche D. Letter to the editor: Specificity of Zika virus ELISA: interference with malaria. Eurosurveillance. 2016;21 10.2807/1560-7917.ES.2016.21.21.30237
    1. Johnson BW, Russell BJ, Goodman CH. Laboratory Diagnosis of Chikungunya Virus Infections and Commercial Sources for Diagnostic Assays. Journal of Infectious Diseases. 2016;214: S471–S474. 10.1093/infdis/jiw274
    1. Gibney KB, Kosoy OI, Fischer M, Edupuganti S, Lanciotti RS, Delorey MJ, et al. Detection of Anti-Yellow Fever Virus Immunoglobulin M Antibodies at 3–4 Years Following Yellow Fever Vaccination. The American Journal of Tropical Medicine and Hygiene. 2012;87: 1112–1115. 10.4269/ajtmh.2012.12-0182
    1. Monath TP, Vasconcelos PFC. Yellow fever. Journal of Clinical Virology. 2015;64: 160–173. 10.1016/j.jcv.2014.08.030
    1. Bingham AM, Cone M, Mock V, Heberlein-Larson L, Stanek D, Blackmore C, et al. Comparison of Test Results for Zika Virus RNA in Urine, Serum, and Saliva Specimens from Persons with Travel-Associated Zika Virus Disease—Florida, 2016. MMWR Morbidity and Mortality Weekly Report. 2016;65: 475–478. 10.15585/mmwr.mm6518e2
    1. Maeda A, Maeda J. Review of diagnostic plaque reduction neutralization tests for flavivirus infection. Vet J. 2013;195: 33–40. 10.1016/j.tvjl.2012.08.019
    1. Wong W-Y, Tan L-K, Ng L-C, Lam S, Low S-L, Teo D. Dengue Seroprevalence of Healthy Adults in Singapore: Serosurvey Among Blood Donors, 2009. The American Journal of Tropical Medicine and Hygiene. 2015;93: 40–45. 10.4269/ajtmh.14-0671
    1. Punjabi NH, Taylor WRJ, Murphy GS, Purwaningsih S, Picarima H, Sisson J, et al. Etiology of acute, non-malaria, febrile illnesses in Jayapura, northeastern Papua, Indonesia. Am J Trop Med Hyg. 2012;86: 46–51. 10.4269/ajtmh.2012.10-0497
    1. Leslie T, Martin NJ, Jack-Roosberg C, Odongo G, Beausoleil E, Tuck J, et al. Dengue Serosurvey in Sint Eustatius. Jin X, editor. PLoS ONE. 2014;9: e95002 10.1371/journal.pone.0095002
    1. Carabali M, Lim JK, Velez DC, Trujillo A, Egurrola J, Lee KS, et al. Dengue virus serological prevalence and seroconversion rates in children and adults in Medellin, Colombia: implications for vaccine introduction. International Journal of Infectious Diseases. 2017;58: 27–36. 10.1016/j.ijid.2017.02.016
    1. Dhanoa A, Hassan SS, Jahan NK, Reidpath DD, Fatt QK, Ahmad MP, et al. Seroprevalence of dengue among healthy adults in a rural community in Southern Malaysia: a pilot study. Infectious Diseases of Poverty. 2018;7 10.1186/s40249-017-0384-1
    1. Mumba D, Jadi R, de Silva AM, Collins MH, Meshnick SR, Tshefu A, et al. Seroepidemiology of Dengue, Zika, and Yellow Fever Viruses among Children in the Democratic Republic of the Congo. The American Journal of Tropical Medicine and Hygiene. 2018; 10.4269/ajtmh.18-0156
    1. Mengesha Tsegaye M, Beyene B, Ayele W, Abebe A, Tareke I, Sall A, et al. Sero-prevalence of yellow fever and related Flavi viruses in Ethiopia: a public health perspective. BMC Public Health. 2018;18 10.1186/s12889-018-5726-9
    1. Mavoko H, Kalabuanga M, Maketa V, Effa J, Luz R, Mukele R, et al. Short communication: Non-malaria related acute fever, a preliminary study from Kinshasa the Democratic Republic of the Congo. International Journal of Tropical Medicine and Public Health. 2017;7: 7.
    1. Barbazan P, Yoksan S, Gonzalez J-P. Dengue hemorrhagic fever epidemiology in Thailand: description and forecasting of epidemics. Microbes Infect. 2002;4: 699–705.
    1. Morrison AC, Minnick SL, Rocha C, Forshey BM, Stoddard ST, Getis A, et al. Epidemiology of Dengue Virus in Iquitos, Peru 1999 to 2005: Interepidemic and Epidemic Patterns of Transmission. Tesh RB, editor. PLoS Neglected Tropical Diseases. 2010;4: e670 10.1371/journal.pntd.0000670
    1. Ntamabyaliro NY, Burri C, Nzolo DB, Engo AB, Lula YN, Mampunza SM, et al. Drug use in the management of uncomplicated malaria in public health facilities in the Democratic Republic of the Congo. Malaria Journal. 2018;17 10.1186/s12936-018-2332-3
    1. Hopkins H, Bruxvoort KJ, Cairns ME, Chandler CIR, Leurent B, Ansah EK, et al. Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings. BMJ. 2017; j1054. 10.1136/bmj.j1054
    1. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of Artemisinin Resistance in Plasmodium falciparum Malaria. New England Journal of Medicine. 2014;371: 411–423. 10.1056/NEJMoa1314981

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