Serum biomarkers predictive of cure in Chagas disease patients after nifurtimox treatment

BMC Infectious Diseases

Momar Ndao²  François Chappuis³  Brian J Ward²  Qianqian Miao²  Yves Jackson⁴  Eric Chatelain¹  Cynthia Santamaria² 

[1] Drug for Neglected Diseases initiative (DNDi), Geneva, Switzerland;National Reference Center for Parasitology, Research Institute of the McGill University Health Centre, Department of Medicine, Division of Infectious Diseases, Montreal General Hospital, 1650 Cedar Ave., Room R3-137, Montreal, Quebec H3G 1A4, Canada;Division of international and humanitarian medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland;Division of primary care medicine, Geneva University Hospitals and University of Geneva, Geneva, Switzerland

关键词: Proteomics;    Nifurtimox;    Treatment;    Biomarkers;    Chagas disease;   

Others  :  1127664
DOI  :  10.1186/1471-2334-14-302

 received in 2014-02-19, accepted in 2014-05-28,  发布年份 2014

【 摘 要 】

Background

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, remains an important public health issue in many Central and South American countries, as well as non-endemic areas with high rates of immigration from these countries. Existing treatment options for CD are limited and often unsatisfactory. Moreover the lack of post-treatment tests of cure limits the development of new drugs. To address this issue, we sought to identify serum biomarkers following nifurtimox (Nfx) treatment that could be used as an early test of cure and/or markers of a therapeutic response.

Methods

Human sera from Chagas patients pre- and post-treatment with Nfx (n = 37) were compared to samples from healthy subjects (n = 37) using a range of proteomic and immunologic techniques. Biomarker peaks with the best discriminatory power were further characterized.

Results

Using serum samples (n = 111), we validated the presence of five key biomarkers identified in our previous study, namely human apolipoprotein A-I (APOA1) and specific fragments thereof and one fragment of human fibronectin (FN1). In chagasic serum samples all biomarkers except full-length APOA1 were upregulated. These five biomarkers returned to normal in 43% (16/37) of the patients treated with Nfx at three years after treatment.

Conclusions

The normalization of biomarker patterns strongly associated with CD suggests that these markers can be used to identify patients in whom Nfx treatment is successful. We believe that these are the first biomarkers predictive of cure in CD patients.

【 授权许可】

   
2014 Santamaria et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]World Health Organization: Research priorities for Chagas disease, human African trypanosomiasis and leishmaniasis. World Health Organ Tech Rep Ser 2012, 975(v-xii):1-100.
• [2]Lee BY, Bacon KM, Bottazzi ME, Hotez PJ: Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis 2013, 13:342-348.
• [3]Kirchhoff LV: Epidemiology of American trypanosomiasis (Chagas disease). Adv Parasitol 2011, 75:1-18.
• [4]Esch KJ, Petersen CA: Transmission and epidemiology of zoonotic protozoal diseases of companion animals. Clin Microbiol Rev 2013, 26:58-85.
• [5]Bern C, Montgomery SP: An estimate of the burden of Chagas disease in the United States. Clin Infect Dis 2009, 49:e52-e54.
• [6]Gascon J, Bern C, Pinazo MJ: Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop 2010, 115:22-27.
• [7]Castro JA, de Mecca MM, Bartel LC: Toxic side effects of drugs used to treat Chagas' disease (American trypanosomiasis). Hum Exp Toxicol 2006, 25:471-479.
• [8]Viotti R, Vigliano C, Lococo B, Alvarez MG, Petti M, Bertocchi G, Armenti A: Side effects of benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti Infect Ther 2009, 7:157-163.
• [9]Yun O, Lima MA, Ellman T, Chambi W, Castillo S, Flevaud L, Roddy P, Parreno F, Albajar VP, Palma PP: Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Medecins Sans Frontieres. PLoS Negl Trop Dis 2009, 3:e488.
• [10]Sosa ES, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C: Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. Am J Trop Med Hyg 1998, 59:526-529.
• [11]Alvarez MG, Vigliano C, Lococo B, Petti M, Bertocchi G, Viotti R: Seronegative conversion after incomplete benznidazole treatment in chronic Chagas disease. Trans R Soc Trop Med Hyg 2012, 106:636-638.
• [12]Rodriques CJ, de Castro SL: A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002, 97:3-24.
• [13]Médecins Sans Frontières: International meeting: new diagnostic tests are urgently needed to treat patients with Chagas disease. Rev Soc Bras Med Trop 2008, 41:315-319.
• [14]Zulantay I, Apt W, Valencia C, Torres A, Saavedra M, Rodriguez J, Sandoval L, Martinez G, Thieme P, Sepulveda E: Detection of Trypanosoma cruzi in untreated chronic chagasic patients is improved by using three parasitological methods simultaneously. J Antimicrob Chemother 2011, 66:2224-2226.
• [15]Berrizbeitia M, Ndao M, Bubis J, Gottschalk M, Ache A, Lacouture S, Medina M, Ward BJ: Field evaluation of four novel enzyme immunoassays for Chagas' disease in Venezuela blood banks: comparison of assays using fixed-epimastigotes, fixed-trypomastigotes or trypomastigote excreted-secreted antigens from two Trypanosoma cruzi strains. Transfus Med 2006, 16:419-431.
• [16]Berrizbeitia M, Ndao M, Bubis J, Gottschalk M, Ache A, Lacouture S, Medina M, Ward BJ: Purified excreted-secreted antigens from Trypanosoma cruzi trypomastigotes as tools for diagnosis of Chagas' disease. J Clin Microbiol 2006, 44:291-296.
• [17]da Silveira JF, Umezawa ES, Luquetti AO: Chagas disease: recombinant Trypanosoma cruzi antigens for serological diagnosis. Trends Parasitol 2001, 17:286-291.
• [18]Brasil PE, De CL, Hasslocher-Moreno AM, Sangenis LH, Braga JU: ELISA versus PCR for diagnosis of chronic Chagas disease: systematic review and meta-analysis. BMC Infect Dis 2010, 10:337. BioMed Central Full Text
• [19]Furucho CR, Umezawa ES, Almeida I, Freitas VL, Bezerra R, Nunes EV, Sanches MC, Guastini CM, Teixeira AR, Shikanai-Yasuda MA: Inconclusive results in conventional serological screening for Chagas' disease in blood banks: evaluation of cellular and humoral response. Trop Med Int Health 2008, 13:1527-1533.
• [20]Camargo ME, Segura EL, Kagan IG, Souza JM, Carvalheiro JR, Yanovsky JF, Guimaraes MC: Three years of collaboration on the standardization of Chagas' disease serodiagnosis in the Americas: an appraisal. Bull Pan Am Health Organ 1986, 20:233-244.
• [21]Jackson Y, Chatelain E, Mauris A, Holst M, Miao Q, Chappuis F, Ndao M: Serological and parasitological response in chronic Chagas patients 3 years after nifurtimox treatment. BMC Infect Dis 2013, 13:85. BioMed Central Full Text
• [22]Machado-de-Assis GF, Silva AR, Do Bem VA, Bahia MT, Martins-Filho OA, Dias JC, Albajar-Vinas P, Torres RM, Lana M: Posttherapeutic cure criteria in Chagas' disease: conventional serology followed by supplementary serological, parasitological, and molecular tests. Clin Vaccine Immunol 2012, 19:1283-1291.
• [23]Cancado JR: Criteria of Chagas disease cure. Mem Inst Oswaldo Cruz 1999, 94(Suppl 1):331-335.
• [24]Pinazo MJ, Tassies D, Munoz J, Fisa R, Posada EJ, Monteagudo J, Ayala E, Gallego M, Reverter JC, Gascon J: Hypercoagulability biomarkers in Trypanosoma cruzi -infected patients. Thromb Haemost 2011, 106:617-623.
• [25]Moreira MC, Wang Y, Heringer-Walther S, Wessel N, Walther T: Prognostic value of natriuretic peptides in Chagas' disease: a head-to-head comparison of the 3 natriuretic peptides. Congest Heart Fail 2009, 15:75-81.
• [26]Fernandez-Villegas A, Pinazo MJ, Maranon C, Thomas MC, Posada E, Carrilero B, Segovia M, Gascon J, Lopez MC: Short-term follow-up of chagasic patients after benzonidazole treatment using multiple serological markers. BMC Infect Dis 2011, 11:206. BioMed Central Full Text
• [27]Krautz GM, Kissinger JC, Krettli AU: The targets of the lytic antibody response against Trypanosoma cruzi. Parasitol Today 2000, 16:31-34.
• [28]Endimiani A, Hujer KM, Hujer AM, Kurz S, Jacobs MR, Perlin DS, Bonomo RA: Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia? Clin Infect Dis 2011, 52(Suppl 4):S373-S383.
• [29]Desai AP, Stanley T, Atuan M, McKey J, Lipuma JJ, Rogers B, Jerris R: Use of matrix assisted laser desorption ionisation-time of flight mass spectrometry in a paediatric clinical laboratory for identification of bacteria commonly isolated from cystic fibrosis patients. J Clin Pathol 2012, 65:835-838.
• [30]Ndao M: Biomarker discovery in serum/plasma using surface enhanced laser desorption ionization time of flight (SELDI-TOF) mass spectrometry. Methods Mol Biol 2012, 818:67-79.
• [31]Wolk DM, Kaleta EJ, Wysocki VH: PCR-electrospray ionization mass spectrometry: the potential to change infectious disease diagnostics in clinical and public health laboratories. J Mol Diagn 2012, 14:295-304.
• [32]van Belkum A, Welker M, Erhard M, Chatellier S: Biomedical mass spectrometry in today's and tomorrow's clinical microbiology laboratories. J Clin Microbiol 2012, 50:1513-1517.
• [33]Ndao M, Rainczuk A, Rioux MC, Spithill TW, Ward BJ: Is SELDI-TOF a valid tool for diagnostic biomarkers? Trends Parasitol 2010, 26:561-567.
• [34]Rioux MC, Carmona C, Acosta D, Ward B, Ndao M, Gibbs BF, Bennett HP, Spithill TW: Discovery and validation of serum biomarkers expressed over the first twelve weeks of Fasciola hepatica infection in sheep. Int J Parasitol 2008, 38:123-136.
• [35]Deckers N, Dorny P, Kanobana K, Vercruysse J, Gonzalez AE, Ward B, Ndao M: Use of ProteinChip technology for identifying biomarkers of parasitic diseases: the example of porcine cysticercosis (Taenia solium). Exp Parasitol 2008, 120:320-329.
• [36]Ndao M, Spithill TW, Caffrey R, Li H, Podust VN, Perichon R, Santamaria C, Ache A, Duncan M, Powell MR, Ward BJ: Identification of novel diagnostic serum biomarkers for Chagas' disease in asymptomatic subjects by mass spectrometric profiling. J Clin Microbiol 2010, 48:1139-1149.
• [37]Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F: Tolerance and safety of nifurtimox in patients with chronic chagas disease. Clin Infect Dis 2010, 51:e69-e75.
• [38]Coura JR, Borges-Pereira J: Chagas disease. What is known and what should be improved: a systemic review. Rev Soc Bras Med Trop 2012, 45:286-296.
• [39]Murcia L, Carrilero B, Albajar VP, Segovia M: Nifurtimox chemotherapy: collateral effects in treated Trypanosoma cruzi infected patients. Rev Esp Quimioter 2012, 25:74-75.
• [40]Jannin J, Villa L: An overview of Chagas disease treatment. Mem Inst Oswaldo Cruz 2007, 102(Suppl 1):95-97.
• [41]Luquetti AO, Ponce C, Ponce E, Esfandiari J, Schijman A, Revollo S, Anez N, Zingales B, Ramgel-Aldao R, Gonzalez A, Levin MJ, Umezawa ES, Franco da Silveira J: Chagas' disease diagnosis: a multicentric evaluation of Chagas Stat-Pak, a rapid immunochromatographic assay with recombinant proteins of Trypanosoma cruzi. Diagn Microbiol Infect Dis 2003, 46:265-271.
• [42]Gonzalez VD, Garcia VS, Vega JR, Marcipar IS, Meira GR, Gugliotta LM: Immunodiagnosis of Chagas disease: synthesis of three latex-protein complexes containing different antigens of Trypanosoma cruzi. Colloids Surf B: Biointerfaces 2010, 77:12-17.
• [43]Carmona SJ, Sartor PA, Leguizamon MS, Campetella OE, Aguero F: Diagnostic peptide discovery: prioritization of pathogen diagnostic markers using multiple features. PLoS One 2012, 7:e50748.
• [44]Jimenez V, Docampo R: Molecular and electrophysiological characterization of a novel cation channel of Trypanosoma cruzi. PLoS Pathog 2012, 8:e1002750.
• [45]Vitelli-Avelar DM, Sathler-Avelar R, Wendling AP, Rocha RD, Teixeira-Carvalho A, Martins NE, Dias JC, Rassi A, Luquetti AO, Eloi-Santos SM, Martins-Filho OA: Non-conventional flow cytometry approaches to detect anti-Trypanosoma cruzi immunoglobulin G in the clinical laboratory. J Immunol Methods 2007, 318:102-112.