Causes of fever in primary care in Southeast Asia and the performance of C-reactive protein in discriminating bacterial from viral pathogens

Thomas Althaus, Janjira Thaipadungpanit, Rachel C Greer, Myo Maung Maung Swe, Sabine Dittrich, Pimnara Peerawaranun, Pieter W Smit, Tri Wangrangsimakul, Stuart Blacksell, Jonas M Winchell, Maureen H Diaz, Nicholas P J Day, Frank Smithuis, Paul Turner, Yoel Lubell, Thomas Althaus, Janjira Thaipadungpanit, Rachel C Greer, Myo Maung Maung Swe, Sabine Dittrich, Pimnara Peerawaranun, Pieter W Smit, Tri Wangrangsimakul, Stuart Blacksell, Jonas M Winchell, Maureen H Diaz, Nicholas P J Day, Frank Smithuis, Paul Turner, Yoel Lubell

Abstract

Objectives: This study investigated causes of fever in the primary levels of care in Southeast Asia, and evaluated whether C-reactive protein (CRP) could distinguish bacterial from viral pathogens.

Methods: Blood and nasopharyngeal swab specimens were taken from children and adults with fever (>37.5 °C) or history of fever (<14 days) in Thailand and Myanmar.

Results: Of 773 patients with at least one blood or nasopharyngeal swab specimen collected, 227 (29.4%) had a target organism detected. Influenza virus type A was detected in 85/227 cases (37.5%), followed by dengue virus (30 cases, 13.2%), respiratory syncytial virus (24 cases, 10.6%) and Leptospira spp. (nine cases, 4.0%). Clinical outcomes were similar between patients with a bacterial or a viral organism, regardless of antibiotic prescription. CRP was higher among patients with a bacterial organism compared with those with a viral organism (median 18 mg/L, interquartile range [10-49] versus 10 mg/L [≤8-22], p = 0.003), with an area under the curve of 0.65 (95% CI 0.55-0.75).

Conclusions: Serious bacterial infections requiring antibiotics are an exception rather than the rule in the first line of care. CRP testing could assist in ruling out such cases in settings where diagnostic uncertainty is high and routine antibiotic prescription is common. The original CRP randomised controlled trial was registered with ClinicalTrials.gov, number NCT02758821.

Keywords: Antibiotic prescription; C-reactive protein; Causes of fever; Primary care; Southeast Asia.

Conflict of interest statement

The funders had no role in study design, data collection, data interpretation or writing the manuscript. The corresponding author had full access to all the data and took the final decision to submit for publication.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Study flowchart. RNP3, Ribonuclease P3 gene as an extraction and specimen integrity control.
Figure 2
Figure 2
C-reactive protein (CRP) concentration (mg/L) using a log scale per aetiological group in Chiang Rai, northern Thailand and Hlaing Tha Yar, Lower Myanmar, 2016–2017. CRP concentrations (all in log-scale) are coloured in blue for viruses, red for bacteria and in grey when no organisms were detected neither in blood specimens nor in nasopharyngeal (NP) swabs. Box boundaries show 25th and 75th percentiles of CRP concentrations and lines within the boxes show the medians. The whiskers indicate the 10th and 90th percentile of CRP concentrations.
Figure 3
Figure 3
Diagnostic accuracy of C-reactive protein (CRP)-testing for distinguishing bacterial from viral targeted organisms in Chiang Rai, northern Thailand and Hlaing Tha Yar, Lower Myanmar, 2016–2017.

References

    1. Althaus T., Greer R.C., Swe M.M.M., Cohen J., Tun N.N., Heaton J. Effect of point-of-care C-reactive protein testing on antibiotic prescription in febrile patients attending primary care in Thailand and Myanmar: an open-label, randomised, controlled trial. Lancet Glob Health. 2019;7(1):e119–e131. doi: 10.1016/s2214-109x(18)30444-3.
    1. Bénet T., Sánchez Picot V., Messaoudi M., Chou M., Eap T., Wang J. Microorganisms associated with pneumonia in children <5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study. Clin Infect Dis. 2017;65(4):604–612.
    1. Birger R., Morita H., Comito D., Filip I., Galanti M., Lane B. Asymptomatic shedding of respiratory virus among an ambulatory population across seasons. mSphere. 2018;3(4)
    1. Bosch A.A., Biesbroek G., Trzcinski K., Sanders E.A., Bogaert D. Viral and bacterial interactions in the upper respiratory tract. PLoS Pathog. 2013;9(1)
    1. Campbell G. Advances in statistical methodology for the evaluation of diagnostic and laboratory tests. Stat Med. 1994;13(5–7):499–508. Epub 1994/03/15. PubMed PMID: 8023031.
    1. Capeding M.R., Chua M.N., Hadinegoro S.R., Hussain I.I., Nallusamy R., Pitisuttithum P. Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. PLoS Negl Trop Dis. 2013;7(7) doi: 10.1371/journal.pntd.0002331.
    1. Castonguay-Vanier J., Davong V., Bouthasavong L., Sengdetka D., Simmalavong M., Seupsavith A. Evaluation of a simple blood culture amplification and antigen detection method for diagnosis of Salmonella enterica serovar typhi bacteremia. J Clin Microbiol. 2013;51(1):142–148. doi: 10.1128/jcm.02360-12.
    1. Chartrand C., Tremblay N., Renaud C., Papenburg J. Diagnostic accuracy of rapid antigen detection tests for respiratory syncytial virus infection: systematic review and meta-analysis. J Clin Microbiol. 2015;53(12):3738–3749. doi: 10.1128/jcm.01816-15.
    1. Chen L., Evans T., Anand S., Boufford J.I., Brown H., Chowdhury M. Human resources for health: overcoming the crisis. Lancet. 2004;364(9449):1984–1990.
    1. Chheng K., Carter M.J., Emary K., Chanpheaktra N., Moore C.E., Stoesser N. A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia. PLoS One. 2013;8(4)
    1. Choo K.E., Davis T.M., Henry R.L., Chan L.P. Serum C-reactive protein concentrations in Malaysian children with enteric fever. J Trop Pediatr. 2001;47(4):211–214. doi: 10.1093/tropej/47.4.211.
    1. Cohen J.F., Bertille N., Cohen R., Chalumeau M. Rapid antigen detection test for group A streptococcus in children with pharyngitis. Cochrane Database Syst Rev. 2016;7 doi: 10.1002/14651858.
    1. Cunnington A.J. The importance of pathogen load. PLoS Pathogens. 2015;11(1) doi: 10.1371/journal.ppat.1004563.
    1. D’Acremont V., Kilowoko M., Kyungu E., Philipina S., Sangu W., Kahama-Maro J. Beyond malaria--causes of fever in outpatient Tanzanian children. New Engl J Med. 2014;370(9):809–817. doi: 10.1056/NEJMoa1214482.
    1. Decker L.L., Klaman L.D., Thorley-Lawson D.A. Detection of the latent form of Epstein-Barr virus DNA in the peripheral blood of healthy individuals. J Virol. 1996;70(5):3286–3289.
    1. Do N.T., Ta N.T., Tran N.T., Than H.M., Vu B.T., Hoang L.B. Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. Lancet Glob Health. 2016;4(9):e633–e641.
    1. Drexler J.F., Helmer A., Kirberg H., Reber U., Panning M., Müller M. Poor clinical sensitivity of rapid antigen test for influenza A pandemic (H1N1) 2009 virus. Emerg Infect Dis. 2009;15(10):1662.
    1. Hackett S.J., Guiver M., Marsh J., Sills J.A., Thomson A.P., Kaczmarski E.B. Meningococcal bacterial DNA load at presentation correlates with disease severity. Arch Dis Child. 2002;86(1):44–46. Epub 2002/01/25. PubMed PMID: 11806883; PubMed Central PMCID: PMCPMC1719043.
    1. Hildenwall H., Amos B., Mtove G., Muro F., Cederlund K., Reyburn H. Causes of non-malarial febrile illness in outpatients in Tanzania. Trop Med Int Health. 2016;21(1):149–156. doi: 10.1111/tmi.12635.
    1. Htwe T., Oo W.M., Lwin N., Win K.H., Dar H.T. Poverty among households living in slum area of Hlaing Tharyar Township, Yangon City, Myanmar. Int J Res Med Sci. 2017;5(6):2497–2501.
    1. Jansen R.R., Wieringa J., Koekkoek S.M., Visser C.E., Pajkrt D., Molenkamp R. Frequent detection of respiratory viruses without symptoms: toward defining clinically relevant cutoff values. J Clin Microbiol. 2011;49(7):2631–2636.
    1. Jiang L., Lee V.J.M., Cui L., Lin R., Tan C.L., Tan L.W.L. Detection of viral respiratory pathogens in mild and severe acute respiratory infections in Singapore. Sci Rep. 2017;7:42963.
    1. Kanchanachitra C., Lindelow M., Johnston T., Hanvoravongchai P., Lorenzo F.M., Huong N.L. Human resources for health in southeast Asia: shortages, distributional challenges, and international trade in health services. Lancet. 2011;377(9767):769–781.
    1. Kapasi A.J., Dittrich S., González I.J., Rodwell T.C. Host biomarkers for distinguishing bacterial from non-bacterial causes of acute febrile illness: a comprehensive review. PLoS One. 2016;11(8)
    1. Kasper M.R., Blair P.J., Touch S., Sokhal B., Yasuda C.Y., Williams M. Infectious etiologies of acute febrile illness among patients seeking health care in south-central Cambodia. Am J Trop Med Hyg. 2012;86(2):246–253. doi: 10.4269/ajtmh.2012.11-0409. PubMed PMID: 22302857; PubMed Central PMCID: PMC3269275.
    1. Keitel K., Kagoro F., Samaka J., Masimba J., Said Z., Temba H. A novel electronic algorithm using host biomarker point-of-care tests for the management of febrile illnesses in Tanzanian children (e-POCT): a randomized, controlled non-inferiority trial. PLoS Med. 2017;14(10) doi: 10.1371/journal.pmed.1002411.
    1. Keitel K., Samaka J., Masimba J., Temba H., Said Z., Kagoro F. Safety and efficacy of C-reactive protein–guided antibiotic use to treat acute respiratory infections in Tanzanian children: a planned subgroup analysis of a randomized controlled noninferiority trial evaluating a novel electronic clinical decision algorithm (ePOCT) Clin Infect Dis. 2019;69(11):1926–1934.
    1. Koh G.C., Maude R.J., Paris D.H., Newton P.N., Blacksell S.D. Diagnosis of scrub typhus. Am J Trop Med Hyg. 2010;82(3):368–370.
    1. Kuijpers L.M.F., Chung P., Peeters M., Phoba M.F., Kham C., Barbe B. Diagnostic accuracy of antigen-based immunochromatographic rapid diagnostic tests for the detection of Salmonella in blood culture broth. PLoS One. 2018;13(3) doi: 10.1371/journal.pone.0194024.
    1. Laras K., Cao B.V., Bounlu K., Nguyen T.K., Olson J.G., Thongchanh S. The importance of leptospirosis in Southeast Asia. Am J Trop Med Hyg. 2002;67(3):278–286. doi: 10.4269/ajtmh.2002.67.278.
    1. Lim J.K., Alexander N., Di Tanna G.L. A systematic review of the economic impact of rapid diagnostic tests for dengue. BMC Health Services Res. 2017;17(1):850.
    1. Lubell Y., Blacksell S.D., Dunachie S., Tanganuchitcharnchai A., Althaus T., Watthanaworawit W. Performance of C-reactive protein and procalcitonin to distinguish viral from bacterial and malarial causes of fever in Southeast Asia. BMC Infect Dis. 2015;15(1):511.
    1. Lubell Y., Althaus T., Blacksell S.D., Paris D.H., Mayxay M., Pan-Ngum W. Modelling the impact and cost-effectiveness of biomarker tests as compared with pathogen-specific diagnostics in the management of undifferentiated fever in remote tropical settings. PLoS One. 2016;11(3) doi: 10.1371/journal.pone.0152420.
    1. Mayxay M., Sengvilaipaseuth O., Chanthongthip A., Dubot-Pérès A., Rolain J.-M., Parola P. Causes of fever in rural Southern Laos. Am J Trop Med Hyg. 2015;93(3):517–520.
    1. McHugh L.C., Snyder K., Yager T.D. The effect of uncertainty in patient classification on diagnostic performance estimations. PLoS One. 2019;14(5)
    1. Mendelson M., Rottingen J.A., Gopinathan U., Hamer D.H., Wertheim H., Basnyat B. Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries. Lancet. 2016;387(10014):188–198. doi: 10.1016/s0140-6736(15)00547-4.
    1. Mueller T.C., Siv S., Khim N., Kim S., Fleischmann E., Ariey F. Acute undifferentiated febrile illness in rural Cambodia: a 3-year prospective observational study. PLoS One. 2014;9(4)
    1. O’Brien K.L., Baggett H.C., Brooks W.A., Feikin D.R., Hammitt L.L., Higdon M.M. Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study. Lancet. 2019;394(10200):757–779.
    1. Picardeau M., Bertherat E., Jancloes M., Skouloudis A.N., Durski K., Hartskeerl R.A. Rapid tests for diagnosis of leptospirosis: current tools and emerging technologies. Diagn Microbiol Infect Dis. 2014;78(1):1–8.
    1. Pretorius M.A., Tempia S., Walaza S., Cohen A.L., Moyes J., Variava E. The role of influenza, RSV and other common respiratory viruses in severe acute respiratory infections and influenza-like illness in a population with a high HIV sero-prevalence, South Africa 2012-2015. J Clin Virol. 2016;75:21–26. doi: 10.1016/j.jcv.2015.12.004.
    1. Reimer L.G., Wilson M.L., Weinstein M.P. Update on detection of bacteremia and fungemia. Clin Microbiol Rev. 1997;10(3):444–465.
    1. Renati S., Linder J.A. Necessity of office visits for acute respiratory infections in primary care. Fam Pract. 2016;33(3):312–317.
    1. Saha S.K., Schrag S.J., El Arifeen S., Mullany L.C., Islam M.S., Shang N. Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study. Lancet. 2018;392(10142):145–159.
    1. Saraswati K., Day N.P., Mukaka M., Blacksell S.D. Scrub typhus point-of-care testing: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2018;12(3)
    1. Schmidt C., Schneble N., Wetzker R. The fifth dimension of innate immunity. J Cell Commun Signal. 2014;8(4):363–367. doi: 10.1007/s12079-014-0246-6.
    1. Shrestha P., Roberts T., Homsana A., Myat T.O., Crump J.A., Lubell Y. Febrile illness in Asia: gaps in epidemiology, diagnosis and management for informing health policy. Clin Microbiol Infect. 2018;24(8):815–826. doi: 10.1016/j.cmi.2018.03.028.
    1. Southeast Asia Infectious Disease Clinical Research Network Causes and outcomes of sepsis in southeast Asia: a multinational multicentre cross-sectional study. Lancet Glob Health. 2017;5(2):e157–e167. doi: 10.1016/s2214-109x(17)30007-4.
    1. Sutinen J., Sombrero L., Paladin F.J., Julkunen I., Leinikki P., Hernandez E. Etiology of central nervous system infections in the Philippines and the role of serum C-reactive protein in excluding acute bacterial meningitis. Int J Infect Dis. 1998;3(2):88–93. Epub 1999/05/04. PubMed PMID: 10225986.
    1. Trombetta V.K., Chan Y.L., Bankowski M.J. Are rapid influenza antigen tests still clinically useful in today’s molecular diagnostics world? Hawaii J Med Public Health. 2018;77(9):226.
    1. Van den Bruel A., Hall H., Aertgeerts B., Bruyninckx R., Aerts M., Buntinx F. Signs and symptoms for diagnosis of serious infections in children: a prospective study in primary careCommentary. Br J Gen Pract. 2007;57(540):538–546.
    1. Van den Bruel A., Thompson M.J., Haj-Hassan T., Stevens R., Moll H., Lakhanpaul M. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ. 2011;342:d3082.
    1. Verbakel J.Y., Lemiengre M.B., De Burghgraeve T., De Sutter A., Aertgeerts B., Shinkins B. Should all acutely ill children in primary care be tested with point-of-care CRP: a cluster randomised trial. BMC Med. 2016;14(1):131.
    1. Waikar S.S., Betensky R.A., Emerson S.C., Bonventre J.V. Imperfect gold standards for biomarker evaluation. Clin Trials. 2013;10(5):696–700.
    1. Wangdi K., Kasturiaratchi K., Nery S.V., Lau C.L., Gray D.J., Clements A.C.A. Diversity of infectious aetiologies of acute undifferentiated febrile illnesses in south and Southeast Asia: a systematic review. BMC Infect Dis. 2019;19(1):577. doi: 10.1186/s12879-019-4185-y.
    1. Wangrangsimakul T., Althaus T., Mukaka M., Kantipong P., Wuthiekanun V., Chierakul W. Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand. PLoS Negl Trop Dis. 2018;12(5)
    1. Warhurst G., Maddi S., Dunn G., Ghrew M., Chadwick P., Alexander P. Diagnostic accuracy of SeptiFast multi-pathogen real-time PCR in the setting of suspected healthcare-associated bloodstream infection. Int Care Med. 2015;41(1):86–93.
    1. Waterer G., Rello J. Why should we measure bacterial load when treating community-acquired pneumonia? Curr Opin Infect Dis. 2011;24(2):137–141. doi: 10.1097/QCO.0b013e328343b70d.
    1. Weller S.A., Cox V., Essex-Lopresti A., Hartley M.G., Parsons T.M., Rachwal P.A. Evaluation of two multiplex real-time PCR screening capabilities for the detection of Bacillus anthracis, Francisella tularensis and Yersinia pestis in blood samples generated from murine infection models. J Med Microbiol. 2012;61(11):1546–1555.
    1. WHO . World Health Organization; Geneva: 2006. The world health report 2006: working together for health.
    1. WHO . World Health Organization; Geneva: 2011. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents and children: December 2011.
    1. Williams J.A., Ofner S., Batteiger B.E., Fortenberry J.D., Van Der Pol B. Duration of polymerase chain reaction–detectable DNA after treatment of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis infections in women. Sex Transm Dis. 2014;41(3):215–219.
    1. World Health Organization . 2017. Key points: world malaria report.
    1. Xu G., Walker D.H., Jupiter D., Melby P.C., Arcari C.M. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis. 2017;11(11)
    1. Ying G-s, Maguire M., Quinn G., Kulp M.T., Cyert L. ROC analysis of the accuracy of Noncycloplegic retinoscopy, Retinomax Autorefractor, and SureSight Vision Screener for preschool vision screening. Investig Ophthalmol Vis Sci. 2011;52(13):9658–9664.

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