Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical and Translational Medicine
Published in: Clinical and Translational Medicine 1/2013

Open Access 01-12-2013 | Research

New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients

Authors: Natalia Tiberti, Enock Matovu, Alexandre Hainard, John Charles Enyaru, Veerle Lejon, Xavier Robin, Natacha Turck, Dieudonné Mumba Ngoyi, Sanjeev Krishna, Sylvie Bisser, Bertrand Courtioux, Philippe Büscher, Krister Kristensson, Joseph Mathu Ndung'u, Jean-Charles Sanchez

Published in: Clinical and Translational Medicine | Issue 1/2013

Login to get access

Abstract

Accurate stage determination is crucial in the choice of treatment for patients suffering from sleeping sickness, also known as human African trypanosomiasis (HAT). Current staging methods, based on the counting of white blood cells (WBC) and the detection of parasites in the cerebrospinal fluid (CSF) have limited accuracy. We hypothesized that immune mediators reliable for staging T. b. gambiense HAT could also be used to stratify T. b. rhodesiense patients, the less common form of HAT.
A population comprising 85 T. b. rhodesiense patients, 14 stage 1 (S1) and 71 stage 2 (S2) enrolled in Malawi and Uganda, was investigated. The CSF levels of IgM, MMP-9, CXCL13, CXCL10, ICAM-1, VCAM-1, neopterin and B2MG were measured and their staging performances evaluated using receiver operating characteristic (ROC) analyses.
IgM, MMP-9 and CXCL13 were the most accurate markers for stage determination (partial AUC 88%, 86% and 85%, respectively). The combination in panels of three molecules comprising CXCL13-CXCL10-MMP-9 or CXCL13-CXCL10-IgM significantly increased their staging ability to partial AUC 94% (p value < 0.01).
The present study highlighted new potential markers for stage determination of T. b. rhodesiense patients. Further investigations are needed to better evaluate these molecules, alone or in panels, as alternatives to WBC to make reliable choice of treatment.
Appendix
Available only for authorised users
Literature
1.
Kennedy PG: Cytokines in central nervous system trypanosomiasis: cause, effect or both? Trans R Soc Trop Med Hyg 2009, 103: 213–214. 10.1016/j.trstmh.2008.08.013CrossRefPubMed
2.
Sternberg JM, Maclean L: A spectrum of disease in human African trypanosomiasis: the host and parasite genetics of virulence. Parasitology 2010, 137: 2007–2015. 10.1017/S0031182010000946CrossRefPubMed
3.
Malvy D, Chappuis F: Sleeping sickness. Clin Microbiol Infect. 2011, 17: 986–995. 10.1111/j.1469-0691.2011.03536.xCrossRefPubMed
4.
Simarro PP, Diarra A, Ruiz Postigo JA, Franco JR, Jannin JG: The human African trypanosomiasis control and surveillance programme of the World Health Organization 2000–2009: the way forward. PLoS Negl Trop Dis 2011, 5: e1007. 10.1371/journal.pntd.0001007PubMedCentralCrossRefPubMed
5.
Priotto G, Kasparian S, Mutombo W, Ngouama D, Ghorashian S, Arnold U, Ghabri S, Baudin E, Buard V, Kazadi-Kyanza S, et al.: Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Lancet 2009, 374: 56–64. 10.1016/S0140-6736(09)61117-XCrossRefPubMed
6.
Simarro PP, Franco J, Diarra A, Postigo JA, Jannin J: Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis. Parasitology 2012, 139: 842–846. 10.1017/S0031182012000169CrossRefPubMed
7.
Kennedy PG: An alternative form of melarsoprol in sleeping sickness. Trends Parasitol 2012, 28: 307–310. 10.1016/j.pt.2012.05.003CrossRefPubMed
8.
Burri C: Chemotherapy against human African trypanosomiasis: is there a road to success? Parasitology 2010, 137: 1987–1994. 10.1017/S0031182010001137CrossRefPubMed
9.
Kuepfer I, Schmid C, Allan M, Edielu A, Haary EP, Kakembo A, Kibona S, Blum J, Burri C: Safety and efficacy of the 10-day melarsoprol schedule for the treatment of second stage rhodesiense sleeping sickness. PLoS Negl Trop Dis 2012, 6: e1695. 10.1371/journal.pntd.0001695PubMedCentralCrossRefPubMed
10.
WHO: Control and surveillance of African trypanosomiasis. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1998, 881(I-VI):1–114.
11.
Kennedy PG: Diagnosing central nervous system trypanosomiasis: two stage or not to stage? Trans R Soc Trop Med Hyg 2008, 102: 306–307. 10.1016/j.trstmh.2007.11.011CrossRefPubMed
12.
Simarro PP, Jannin J, Cattand P: Eliminating human African trypanosomiasis: where do we stand and what comes next? PLoS Med 2008, 5: e55. 10.1371/journal.pmed.0050055PubMedCentralCrossRefPubMed
13.
Amin DN, Ngoyi DM, Nhkwachi GM, Palomba M, Rottenberg M, Buscher P, Kristensson K, Masocha W: Identification of stage biomarkers for human African trypanosomiasis. Am J Trop Med Hyg 2010, 82: 983–990. 10.4269/ajtmh.2010.09-0770PubMedCentralCrossRefPubMed
14.
Kennedy PG: The continuing problem of human African trypanosomiasis (sleeping sickness). Ann Neurol 2008, 64: 116–126. 10.1002/ana.21429CrossRefPubMed
15.
Lejon V, Reiber H, Legros D, Dje N, Magnus E, Wouters I, Sindic CJ, Buscher P: Intrathecal immune response pattern for improved diagnosis of central nervous system involvement in trypanosomiasis. J Infect Dis 2003, 187: 1475–1483. 10.1086/374645CrossRefPubMed
16.
Tiberti N, Hainard A, Lejon V, Robin X, Ngoyi DM, Turck N, Matovu E, Enyaru J, Ndung'u JM, Scherl A, et al.: Discovery and verification of osteopontin and Beta-2-microglobulin as promising markers for staging human African trypanosomiasis. Mol Cell Proteomics 2010, 9: 2783–2795. 10.1074/mcp.M110.001008PubMedCentralCrossRefPubMed
17.
Hainard A, Tiberti N, Robin X, Ngoyi DM, Matovu E, Enyaru JC, Muller M, Turck N, Ndung'u JM, Lejon V, Sanchez JC: Matrix metalloproteinase-9 and intercellular adhesion molecule 1 are powerful staging markers for human African trypanosomiasis. Trop Med Int Health 2011, 16: 119–126. 10.1111/j.1365-3156.2010.02642.xCrossRefPubMed
18.
Hainard A, Tiberti N, Robin X, Lejon V, Ngoyi DM, Matovu E, Enyaru JC, Fouda C, Ndung'u JM, Lisacek F, et al.: A combined CXCL10, CXCL8 and H-FABP panel for the staging of human African trypanosomiasis patients. PLoS Negl Trop Dis 2009, 3: e459. 10.1371/journal.pntd.0000459PubMedCentralCrossRefPubMed
19.
Courtioux B, Pervieux L, Vatunga G, Marin B, Josenando T, Jauberteau-Marchan MO, Bouteille B, Bisser S: Increased CXCL-13 levels in human African trypanosomiasis meningo-encephalitis. Trop Med Int Health 2009, 14: 529–534. 10.1111/j.1365-3156.2009.02263.xCrossRefPubMed
20.
Bisser S, Lejon V, Preux PM, Bouteille B, Stanghellini A, Jauberteau MO, Buscher P, Dumas M: Blood-cerebrospinal fluid barrier and intrathecal immunoglobulins compared to field diagnosis of central nervous system involvement in sleeping sickness. J Neurol Sci 2002, 193: 127–135. 10.1016/S0022-510X(01)00655-4CrossRefPubMed
21.
MacLean L, Odiit M, Sternberg JM: Nitric oxide and cytokine synthesis in human African trypanosomiasis. J Infect Dis 2001, 184: 1086–1090. 10.1086/323479CrossRefPubMed
22.
Maclean L, Odiit M, Sternberg JM: Intrathecal cytokine responses in Trypanosoma brucei rhodesiense sleeping sickness patients. Trans R Soc Trop Med Hyg 2006, 100: 270–275. 10.1016/j.trstmh.2005.03.013CrossRefPubMed
23.
Tiberti N, Hainard A, Lejon V, Courtioux B, Matovu E, Enyaru JC, Robin X, Turck N, Kristensson K, Ngoyi DM, et al.: Cerebrospinal fluid neopterin as marker of the meningo-encephalitic stage of Trypanosoma brucei gambiense sleeping sickness. PLoS One 2012, 7: e40909. 10.1371/journal.pone.0040909PubMedCentralCrossRefPubMed
24.
Miezan TW, Meda HA, Doua F, Dje NN, Lejon V, Buscher P: Single centrifugation of cerebrospinal fluid in a sealed pasteur pipette for simple, rapid and sensitive detection of trypanosomes. Trans R Soc Trop Med Hyg 2000, 94: 293. 10.1016/S0035-9203(00)90327-4CrossRefPubMed
25.
Cattand P, Miezan BT, de Raadt P: Human African trypanosomiasis: use of double centrifugation of cerebrospinal fluid to detect trypanosomes. Bull World Health Organ 1988, 66: 83–86.PubMedCentralPubMed
26.
Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Muller M: pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011, 12: 77. 10.1186/1471-2105-12-77PubMedCentralCrossRefPubMed
27.
MacLean LM, Odiit M, Chisi JE, Kennedy PG, Sternberg JM: Focus-specific clinical profiles in human African Trypanosomiasis caused by Trypanosoma brucei rhodesiense . PLoS Negl Trop Dis 2010, 4: e906. 10.1371/journal.pntd.0000906PubMedCentralCrossRefPubMed
28.
Kennedy PG: Difficulties in diagnostic staging of human African trypanosomiasis. J Neuroparasitol 2011, 2: 1–3.CrossRef
29.
Kennedy PG: Diagnostic and neuropathogenesis issues in human African trypanosomiasis. Int J Parasitol 2006, 36: 505–512. 10.1016/j.ijpara.2006.01.012CrossRefPubMed
30.
Gibson W: Will the real Trypanosoma brucei rhodesiense please step forward? Trends Parasitol 2002, 18: 486–490. 10.1016/S1471-4922(02)02390-5CrossRefPubMed
31.
Lejon V, Legros D, Richer M, Ruiz JA, Jamonneau V, Truc P, Doua F, Dje N, N'Siesi FX, Bisser S, et al.: IgM quantification in the cerebrospinal fluid of sleeping sickness patients by a latex card agglutination test. Trop Med Int Health 2002, 7: 685–692. 10.1046/j.1365-3156.2002.00917.xCrossRefPubMed
32.
Lejon V, Roger I, Mumba Ngoyi D, Menten J, Robays J, N'Siesi FX, Bisser S, Boelaert M, Buscher P: Novel markers for treatment outcome in late-stage Trypanosoma brucei gambiense trypanosomiasis . Clin Infect Dis 2008, 47: 15–22. 10.1086/588668CrossRefPubMed
33.
Rodgers J: Trypanosomiasis and the brain. Parasitology. 2010, 137: 1995–2006. 10.1017/S0031182009991806CrossRefPubMed
34.
35.
Gunn MD, Ngo VN, Ansel KM, Ekland EH, Cyster JG, Williams LT: A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 1998, 391: 799–803. 10.1038/35876CrossRefPubMed
36.
Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisakk P, Ransohoff RM, Hofbauer M, Farina C, Derfuss T, Hartle C, et al.: Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 2006, 129: 200–211.CrossRefPubMed
37.
Rainey-Barger EK, Rumble JM, Lalor SJ, Esen N, Segal BM, Irani DN: The lymphoid chemokine, CXCL13, is dispensable for the initial recruitment of B cells to the acutely inflamed central nervous system. Brain Behav Immun 2011, 25: 922–931. 10.1016/j.bbi.2010.10.002PubMedCentralCrossRefPubMed
38.
Dziembowska M, Wlodarczyk J: MMP9: a novel function in synaptic plasticity. Int J Biochem Cell Biol 2012, 44: 709–713. 10.1016/j.biocel.2012.01.023CrossRefPubMed
39.
Ramos-Fernandez M, Bellolio MF, Stead LG: Matrix metalloproteinase-9 as a marker for acute ischemic stroke: a systematic review. J Stroke Cerebrovasc Dis 2011, 20: 47–54. 10.1016/j.jstrokecerebrovasdis.2009.10.008CrossRefPubMed
40.
Unsal Y, Kivilcim G, Aysegul A, Arzu A, Esra G, Ercan D, Ayse S: Matrix metalloproteinase-7 and matrix metalloproteinase-9 in pediatric multiple sclerosis. Pediatr Neurol 2012, 47: 171–176. 10.1016/j.pediatrneurol.2012.05.027CrossRefPubMed
41.
Prato M, Giribaldi G: Matrix metalloproteinase-9 and haemozoin: wedding rings for human host and Plasmodium falciparum parasite in complicated malaria. J Trop Med 2011, 2011: 628435.PubMedCentralCrossRefPubMed
42.
Szklarczyk A, Stins M, Milward EA, Ryu H, Fitzsimmons C, Sullivan D, Conant K: Glial activation and matrix metalloproteinase release in cerebral malaria. J Neurovirol 2007, 13: 2–10. 10.1080/13550280701258084CrossRefPubMed
43.
Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, Sorokin LM: Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med 2006, 203: 1007–1019. 10.1084/jem.20051342PubMedCentralCrossRefPubMed
44.
Robin X, Turck N, Hainard A, Lisacek F, Sanchez JC, Muller M: Bioinformatics for protein biomarker panel classification: what is needed to bring biomarker panels into in vitro diagnostics? Expert Rev Proteomics 2009, 6: 675–689. 10.1586/epr.09.83CrossRefPubMed
45.
Weng Y, Siciliano SJ, Waldburger KE, Sirotina-Meisher A, Staruch MJ, Daugherty BL, Gould SL, Springer MS, DeMartino JA: Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors. J Biol Chem 1998, 273: 18288–18291. 10.1074/jbc.273.29.18288CrossRefPubMed
46.
Amin DN, Rottenberg ME, Thomsen AR, Mumba D, Fenger C, Kristensson K, Buscher P, Finsen B, Masocha W: Expression and role of CXCL10 during the encephalitic stage of experimental and clinical African trypanosomiasis. J Infect Dis 2009, 200: 1556–1565. 10.1086/644597CrossRefPubMed
47.
Kristensson K, Nygard M, Bertini G, Bentivoglio M: African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions. Prog Neurobiol 2010, 91: 152–171. 10.1016/j.pneurobio.2009.12.001CrossRefPubMed
48.
49.
Hunter CA, Jennings FW, Kennedy PG, Murray M: Astrocyte activation correlates with cytokine production in central nervous system of Trypanosoma brucei brucei -infected mice. Lab Invest 1992, 67: 635–642.PubMed
50.
Chappuis F, Loutan L, Simarro P, Lejon V, Buscher P: Options for field diagnosis of human African trypanosomiasis. Clin Microbiol Rev 2005, 18: 133–146. 10.1128/CMR.18.1.133-146.2005PubMedCentralCrossRefPubMed
51.
Maclean L, Reiber H, Kennedy PG, Sternberg JM: Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response. PLoS Negl Trop Dis 2012, 6: e1857. 10.1371/journal.pntd.0001857PubMedCentralCrossRefPubMed
52.
Ngotho M, Kagira JM, Jensen HE, Karanja SM, Farah IO, Hau J: Immunospecific immunoglobulins and IL-10 as markers for Trypanosoma brucei rhodesiense late stage disease in experimentally infected vervet monkeys. Trop Med Int Health 2009, 14: 736–747. 10.1111/j.1365-3156.2009.02285.xCrossRefPubMed
Metadata
Title
New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients
Authors
Natalia Tiberti
Enock Matovu
Alexandre Hainard
John Charles Enyaru
Veerle Lejon
Xavier Robin
Natacha Turck
Dieudonné Mumba Ngoyi
Sanjeev Krishna
Sylvie Bisser
Bertrand Courtioux
Philippe Büscher
Krister Kristensson
Joseph Mathu Ndung'u
Jean-Charles Sanchez
Publication date
01-12-2013
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2013
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/2001-1326-2-1

Other articles of this Issue 1/2013

Clinical and Translational Medicine 1/2013 Go to the issue

Research

Establishing a Southern Swedish Malignant Melanoma OMICS and biobank clinicalcapability

Review

Regenerative medicine for the kidney: stem cell prospects & challenges

Research

A pilot study demonstrating a non-invasive method for the measurement of protein turnover in skin disorders: application to psoriasis

Perspective

Mapping the translational science policy ‘valley of death’

Review

A glow of HLA typing in organ transplantation

Research

Evaluation of lung flute in sputum samples for molecular analysis of lung cancer