Towards Improving Point-of-Care Diagnosis of Non-malaria Febrile Illness: A Metabolomics Approach
Saskia Decuypere, Jessica Maltha, Stijn Deborggraeve, Nicholas J W Rattray, Guiraud Issa, Kaboré Bérenger, Palpouguini Lompo, Marc C Tahita, Thusitha Ruspasinghe, Malcolm McConville, Royston Goodacre, Halidou Tinto, Jan Jacobs, Jonathan R Carapetis, Saskia Decuypere, Jessica Maltha, Stijn Deborggraeve, Nicholas J W Rattray, Guiraud Issa, Kaboré Bérenger, Palpouguini Lompo, Marc C Tahita, Thusitha Ruspasinghe, Malcolm McConville, Royston Goodacre, Halidou Tinto, Jan Jacobs, Jonathan R Carapetis
Abstract
Introduction: Non-malaria febrile illnesses such as bacterial bloodstream infections (BSI) are a leading cause of disease and mortality in the tropics. However, there are no reliable, simple diagnostic tests for identifying BSI or other severe non-malaria febrile illnesses. We hypothesized that different infectious agents responsible for severe febrile illness would impact on the host metabolome in different ways, and investigated the potential of plasma metabolites for diagnosis of non-malaria febrile illness.
Methodology: We conducted a comprehensive mass-spectrometry based metabolomics analysis of the plasma of 61 children with severe febrile illness from a malaria-endemic rural African setting. Metabolite features characteristic for non-malaria febrile illness, BSI, severe anemia and poor clinical outcome were identified by receiver operating curve analysis.
Principal findings: The plasma metabolome profile of malaria and non-malaria patients revealed fundamental differences in host response, including a differential activation of the hypothalamic-pituitary-adrenal axis. A simple corticosteroid signature was a good classifier of severe malaria and non-malaria febrile patients (AUC 0.82, 95% CI: 0.70-0.93). Patients with BSI were characterized by upregulated plasma bile metabolites; a signature of two bile metabolites was estimated to have a sensitivity of 98.1% (95% CI: 80.2-100) and a specificity of 82.9% (95% CI: 54.7-99.9) to detect BSI in children younger than 5 years. This BSI signature demonstrates that host metabolites can have a superior diagnostic sensitivity compared to pathogen-detecting tests to identify infections characterized by low pathogen load such as BSI.
Conclusions: This study demonstrates the potential use of plasma metabolites to identify causality in children with severe febrile illness in malaria-endemic settings.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
References
- Nadjm B, Amos B, Mtove G, Ostermann J, Chonya S, et al. (2010) WHO guidelines for antimicrobial treatment in children admitted to hospital in an area of intense Plasmodium falciparum transmission: prospective study. BMJ 340: c1350 10.1136/bmj.c1350
- Sigauque B, Roca A, Mandomando I, Morais L, Quinto L, et al. (2009) Community-acquired bacteremia among children admitted to a rural hospital in Mozambique. Pediatr Infect Dis J 28: 108–113. 10.1097/INF.0b013e318187a87d
- Chheng K, Carter MJ, Emary K, Chanpheaktra N, Moore CE, et al. (2013) A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia. PLoS One 8: e60634 10.1371/journal.pone.0060634
- Punjabi NH, Taylor WR, Murphy GS, Purwaningsih S, Picarima H, et al. (2012) Etiology of acute, non-malaria, febrile illnesses in Jayapura, northeastern Papua, Indonesia. Am J Trop Med Hyg 86: 46–51. 10.4269/ajtmh.2012.10-0497
- Gething PW, Kirui VC, Alegana VA, Okiro EA, Noor AM, et al. (2010) Estimating the number of paediatric fevers associated with malaria infection presenting to Africa's public health sector in 2007. PLoS Med 7: e1000301 10.1371/journal.pmed.1000301
- Church J, Maitland K (2014) Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review. BMC Med 12: 31 10.1186/1741-7015-12-31
- Deen J, von Seidlein L, Andersen F, Elle N, White NJ, et al. (2012) Community-acquired bacterial bloodstream infections in developing countries in south and southeast Asia: a systematic review. Lancet Infect Dis 12: 480–487. 10.1016/S1473-3099(12)70028-2
- Reddy EA, Shaw AV, Crump JA (2010) Community-acquired bloodstream infections in Africa: a systematic review and meta-analysis. Lancet Infect Dis 10: 417–432. 10.1016/S1473-3099(10)70072-4
- Maltha J, Guiraud I, Kabore B, Lompo P, Ley B, et al. (2014) Frequency of Severe Malaria and Invasive Bacterial Infections among Children Admitted to a Rural Hospital in Burkina Faso. PLoS One 9: e89103 10.1371/journal.pone.0089103
- Graham SM, English M (2009) Non-typhoidal salmonellae: a management challenge for children with community-acquired invasive disease in tropical African countries. Lancet 373: 267–269. 10.1016/S0140-6736(09)60073-8
- Bottieau E, Gillet P, De Weggheleire A, Scheirlinck A, Stokx J, et al. (2013) Treatment practices in patients with suspected malaria in Provincial Hospital of Tete, Mozambique. Trans R Soc Trop Med Hyg 107: 176–182. 10.1093/trstmh/trs012
- Phoba MF, De Boeck H, Ifeka BB, Dawili J, Lunguya O, et al. (2014) Epidemic increase in Salmonella bloodstream infection in children, Bwamanda, the Democratic Republic of Congo. Eur J Clin Microbiol Infect Dis 33: 79–87. 10.1007/s10096-013-1931-8
- Iqbal J, Siddique A, Jameel M, Hira PR (2004) Persistent histidine-rich protein 2, parasite lactate dehydrogenase, and panmalarial antigen reactivity after clearance of Plasmodium falciparum monoinfection. J Clin Microbiol 42: 4237–4241.
- Wongsrichanalai C, Barcus MJ, Muth S, Sutamihardja A, Wernsdorfer WH (2007) A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg 77: 119–127.
- Visser BJ, Wieten RW, Nagel IM, Grobusch MP (2013) Serum lipids and lipoproteins in malaria—a systematic review and meta-analysis. Malar J 12: 442 10.1186/1475-2875-12-442
- Surowiec I, Orikiiriza J, Karlsson E, Nelson M, Bonde M, et al. (2015) Metabolic Signature Profiling as a Diagnostic and Prognostic Tool in Pediatric Plasmodium falciparum Malaria. Open Forum Infect Dis 2: ofv062 10.1093/ofid/ofv062
- Parola P, Gazin P, Patella F, Badiaga S, Delmont J, et al. (2004) Hypertriglyceridemia as an indicator of the severity of falciparum malaria in returned travelers: a clinical retrospective study. Parasitol Res 92: 464–466.
- Webster JI, Sternberg EM (2004) Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products. J Endocrinol 181: 207–221.
- Silverman MN, Pearce BD, Biron CA, Miller AH (2005) Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 18: 41–78.
- Ibrahim EA, Kheir MM, Elhardello OA, Almahi WA, Ali NI, et al. (2011) Cortisol and uncomplicated Plasmodium falciparum malaria in an area of unstable malaria transmission in eastern Sudan. Asian Pac J Trop Med 4: 146–147. 10.1016/S1995-7645(11)60056-4
- Shwe T, Khin M, Min H, Hla KK, Win YY, et al. (1998) Serum cortisol levels in patients with uncomplicated and cerebral malaria. Southeast Asian J Trop Med Public Health 29: 46–49.
- Libonati RM, de Mendonca BB, Maues JA, Quaresma JA, de Souza JM (2006) Some aspects of the behavior of the hypothalamus-pituitary-adrenal axis in patients with uncomplicated Plasmodium falciparum malaria: Cortisol and dehydroepiandrosterone levels. Acta Trop 98: 270–276.
- Wilson M, Davis TM, Binh TQ, Long TT, Danh PT, et al. (2001) Pituitary-adrenal function in uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health 32: 689–695.
- Davis TM, Li TA, Tran QB, Robertson K, Dyer JR, et al. (1997) The hypothalamic-pituitary-adrenocortical axis in severe falciparum malaria: effects of cytokines. J Clin Endocrinol Metab 82: 3029–3033.
- Seymour CW, Yende S, Scott MJ, Pribis J, Mohney RP, et al. (2013) Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study. Intensive Care Med 39: 1423–1434. 10.1007/s00134-013-2935-7
- Annane D (2008) Adrenal insufficiency in sepsis. Curr Pharm Des 14: 1882–1886.
- Green RM, Beier D, Gollan JL (1996) Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology 111: 193–198.
- Trauner M, Arrese M, Lee H, Boyer JL, Karpen SJ (1998) Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J Clin Invest 101: 2092–2100.
- Penno EC, Crump JA, Baird SJ (2015) Performance Requirements to Achieve Cost-Effectiveness of Point-of-Care Tests for Sepsis Among Patients with Febrile Illness in Low-Resource Settings. Am J Trop Med Hyg.
- Peeling RW, Mabey D (2010) Point-of-care tests for diagnosing infections in the developing world. Clin Microbiol Infect 16: 1062–1069. 10.1111/j.1469-0691.2010.03279.x
- Chin CD, Cheung YK, Laksanasopin T, Modena MM, Chin SY, et al. (2013) Mobile device for disease diagnosis and data tracking in resource-limited settings. Clin Chem 59: 629–640. 10.1373/clinchem.2012.199596
- Xu ZL, Shen YD, Beier RC, Yang JY, Lei HT, et al. (2009) Application of computer-assisted molecular modeling for immunoassay of low molecular weight food contaminants: A review. Anal Chim Acta 647: 125–136. 10.1016/j.aca.2009.06.003
- D'Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, et al. (2014) Beyond malaria—causes of fever in outpatient Tanzanian children. N Engl J Med 370: 809–817. 10.1056/NEJMoa1214482
Source: PubMed