Host Biomarkers Distinguish Dengue from Leptospirosis in Colombia: a Case-control Study

Overview

Journal BMC Infect Dis

Publisher Biomed Central

Specialty Infectious Diseases

Date 2014 Jan 22

PMID 24444080

Citations 11

Authors

Andrea L Conroy

Margarita Gelvez

Michael Hawkes

Nimerta Rajwans

W Conrad Liles

Luis Angel Villar-Centeno

Kevin C Kain

Affiliations

Soon will be listed here.

Abstract

Background: Dengue fever and leptospirosis have partially overlapping geographic distributions, similar clinical presentations and potentially life-threatening complications but require different treatments. Distinguishing between these cosmopolitan emerging pathogens represents a diagnostic dilemma of global importance. We hypothesized that perturbations in host biomarkers can differentiate between individuals with dengue fever and leptospirosis during the acute phase of illness.

Methods: We randomly selected subjects from a prospective cohort study of acute febrile illness in Bucaramanga, Colombia and tested 19 serum biomarkers by ELISA in dengue fever (DF, n = 113) compared to subjects with leptospirosis (n = 47). Biomarkers were selected for further analysis if they had good discriminatory ability (area under the ROC curve (AUC) >0.80) and were beyond a reference range (assessed using local healthy controls).

Results: Nine biomarkers differed significantly between dengue fever and leptospirosis, with higher levels of Angptl3, IL-18BP, IP-10/CXCL10, Platelet Factor 4, sICAM-1, Factor D, sEng and sKDR in dengue and higher levels of sTie-2 in leptospirosis (p < 0.001 for all comparisons). Two biomarkers, sEng and IL18BP, showed excellent discriminatory ability (AUROC >0.90). When incorporated into multivariable models, sEng and IL18BP improved the diagnostic accuracy of clinical information alone.

Conclusions: These results suggest that host biomarkers may have utility in differentiating between dengue and leptospirosis, clinically similar conditions of different etiology.

Citing Articles

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A Rare Complication of Leptospirosis: Weil's Disease Diagnosed in the United States.

Rathi H, Patel A, Beblawy R, Hassoun A Cureus. 2023; 15(8):e43620.

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Demographic and clinical risk factors associated with severity of lab-confirmed human leptospirosis in Colombia, 2015-2020.

Parra Barrera E, Bello Piruccini S, Rodriguez K, Duarte C, Torres M, Undurraga E PLoS Negl Trop Dis. 2023; 17(7):e0011454.

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Role of Platelet Cytokines in Dengue Virus Infection.

Singh A, Bisht P, Bhattacharya S, Guchhait P Front Cell Infect Microbiol. 2020; 10:561366.

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References

Silver K, Conroy A, Leke R, Leke R, Gwanmesia P, Molyneux M . Circulating soluble endoglin levels in pregnant women in Cameroon and Malawi--associations with placental malaria and fetal growth restriction. PLoS One. 2011; 6(9):e24985. PMC: 3178568. DOI: 10.1371/journal.pone.0024985. View

Shapiro N, Yano K, Okada H, Fischer C, Howell M, Spokes K . A prospective, observational study of soluble FLT-1 and vascular endothelial growth factor in sepsis. Shock. 2008; 29(4):452-7. PMC: 5378494. DOI: 10.1097/shk.0b013e31815072c1. View

Pousa I, Mate J, Salcedo-Mora X, Abreu M, Moreno-Otero R, Gisbert J . Role of vascular endothelial growth factor and angiopoietin systems in serum of Crohn's disease patients. Inflamm Bowel Dis. 2007; 14(1):61-7. DOI: 10.1002/ibd.20269. View

Fiedler U, Augustin H . Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006; 27(12):552-8. DOI: 10.1016/j.it.2006.10.004. View

Camenisch G, Pisabarro M, Sherman D, Kowalski J, Nagel M, Hass P . ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo. J Biol Chem. 2002; 277(19):17281-90. DOI: 10.1074/jbc.M109768200. View

Hathirat P, Isarangkura P, SRICHAIKUL T, Suvatte V, MITRAKUL C . Abnormal hemostasis in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 1993; 24 Suppl 1:80-5. View

Murray C, Rosenfeld L, Lim S, Andrews K, Foreman K, Haring D . Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet. 2012; 379(9814):413-31. DOI: 10.1016/S0140-6736(12)60034-8. View

Conroy A, Glover S, Hawkes M, Erdman L, Seydel K, Taylor T . Angiopoietin-2 levels are associated with retinopathy and predict mortality in Malawian children with cerebral malaria: a retrospective case-control study*. Crit Care Med. 2012; 40(3):952-9. PMC: 3284252. DOI: 10.1097/CCM.0b013e3182373157. View

Levine R, Lam C, Qian C, Yu K, Maynard S, Sachs B . Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006; 355(10):992-1005. DOI: 10.1056/NEJMoa055352. View

10.

Avirutnan P, Hauhart R, Marovich M, Garred P, Atkinson J, Diamond M . Complement-mediated neutralization of dengue virus requires mannose-binding lectin. mBio. 2011; 2(6). PMC: 3236064. DOI: 10.1128/mBio.00276-11. View

11.

Page A, Tarr P, Watkins S, Rajwans N, Petruzziello-Pellegrini T, Marsden P . Dysregulation of angiopoietin 1 and 2 in Escherichia coli O157:H7 infection and the hemolytic-uremic syndrome. J Infect Dis. 2013; 208(6):929-33. PMC: 3749007. DOI: 10.1093/infdis/jit268. View

12.

Farr R . Leptospirosis. Clin Infect Dis. 1995; 21(1):1-6; quiz 7-8. DOI: 10.1093/clinids/21.1.1. View

13.

Nascimento E, Silva A, Cordeiro M, Brito C, Gil L, Braga-Neto U . Alternative complement pathway deregulation is correlated with dengue severity. PLoS One. 2009; 4(8):e6782. PMC: 2728508. DOI: 10.1371/journal.pone.0006782. View

14.

Erdman L, Dhabangi A, Musoke C, Conroy A, Hawkes M, Higgins S . Combinations of host biomarkers predict mortality among Ugandan children with severe malaria: a retrospective case-control study. PLoS One. 2011; 6(2):e17440. PMC: 3045453. DOI: 10.1371/journal.pone.0017440. View

15.

Daher E, Lima R, Silva Junior G, Silva E, Karbage N, Kataoka R . Clinical presentation of leptospirosis: a retrospective study of 201 patients in a metropolitan city of Brazil. Braz J Infect Dis. 2010; 14(1):3-10. View

16.

Kuller L, Tracy R, Belloso W, De Wit S, Drummond F, Lane H . Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008; 5(10):e203. PMC: 2570418. DOI: 10.1371/journal.pmed.0050203. View

17.

Morgan J, Bornstein S, Karpati A, Bruce M, Bolin C, Austin C . Outbreak of leptospirosis among triathlon participants and community residents in Springfield, Illinois, 1998. Clin Infect Dis. 2002; 34(12):1593-9. DOI: 10.1086/340615. View

18.

Zhang C, Kaba M, Ge G, Xie K, Tong W, Hug C . Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nat Med. 2006; 12(2):240-5. PMC: 2771412. DOI: 10.1038/nm1342. View

19.

Butthep P, Chunhakan S, Yoksan S, Tangnararatchakit K, Chuansumrit A . Alteration of cytokines and chemokines during febrile episodes associated with endothelial cell damage and plasma leakage in dengue hemorrhagic fever. Pediatr Infect Dis J. 2012; 31(12):e232-8. DOI: 10.1097/INF.0b013e31826fd456. View

20.

Mosbruger T, Duggal P, Goedert J, Kirk G, Hoots W, Tobler L . Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus. J Infect Dis. 2010; 201(9):1371-80. PMC: 2853721. DOI: 10.1086/651606. View