Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study

Suzanna Attia, Christian J Versloot, Wieger Voskuijl, Sara J van Vliet, Valeria Di Giovanni, Ling Zhang, Susan Richardson, Céline Bourdon, Mihai G Netea, James A Berkley, Patrick F van Rheenen, Robert Hj Bandsma, Suzanna Attia, Christian J Versloot, Wieger Voskuijl, Sara J van Vliet, Valeria Di Giovanni, Ling Zhang, Susan Richardson, Céline Bourdon, Mihai G Netea, James A Berkley, Patrick F van Rheenen, Robert Hj Bandsma

Abstract

Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear.

Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM.

Design: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6-59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling.

Results: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443-535 mg/kg feces) compared with 698 mg/kg feces (1438-244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112-22 ng/mL) compared with 2036 ng/mL (5800-149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831-131 ng/mL) compared with 3174 ng/mL (5819-357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation.

Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at www.controlled-trials.com as ISRCTN13916953.

Keywords: cytokines; diarrhea; inflammation; inflammatory bowel disease; severe acute malnutrition.

Figures

FIGURE 1
FIGURE 1
Concentrations of calprotectin (n = 68; A), propionate (n = 61; B), and butyrate (n = 61; C) in fecal samples from children with severe acute malnutrition who recovered or died. Boxplots summarize the median (midline) and IQRs (upper and lower boxes); overlaid dots indicate all individual data points. Medians (IQRs) for groups that recovered or died were as follows: for calprotectin, 697.5 mg/kg feces (1437.5–243.8 mg/kg feces) compared with 1360 mg/kg feces (2442.5–535 mg/kg feces, P = 0.03); for propionate, 3173.8 ng/mL (5819.2–357.2 ng/mL) compared with 167.2 ng/mL (831.4–130.9 ng/mL, P = 0.04); and for butyrate, 2035.7 ng/mL (5799.6–149.1 ng/mL) compared with 31.3 ng/mL (112.3–21.6 ng/mL), P = 0.02). Group differences were tested by logistic regression. *P < 0.05.
FIGURE 2
FIGURE 2
Serum cytokine concentrations in children (n = 68) with severe acute malnutrition who recovered (n = 54) or died (n = 14). Cytokines presented (n = 7) are those associated with death as obtained through partial least square–based feature selection. Boxplots summarize the medians and IQRs of natural logarithms of cytokine concentrations. Overlaid dots present all individual data points. GCSF, granulocyte-colony stimulating factor.
FIGURE 3
FIGURE 3
Relation between diarrhea, calprotectin, SCFAs, systemic inflammation, and death as estimated by partial least squares path modeling. Children with diarrhea status and both blood and fecal samples (n = 62) were included in this analysis. The path coefficients above each interconnecting arrow indicate the strength and direction of the relation between the nodes of the model. Diarrhea and calprotectin were not directly associated with death but may be linked to mortality through systemic inflammation. Similarly, SCFA shows an indirect association but may also partially contribute to death directly. Pathogens were not included in this model as this did not improve the overall fit (goodness of fit = 0.31), were not found to be associated with any nodes, and caused instability on cross-validation. Solid lines indicate a direct relation with P < 0.05; dashed lines indicate trends with P < 0.1. SCFA, short-chain fatty acid.

References

    1. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, de Onis M, Ezzati M, Grantham-McGregor S, Katz J, Martorell R, et al. . Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 2013;382:427–51.
    1. Irena AH, Mwambazi M, Mulenga V. Diarrhea is a major killer of children with severe acute malnutrition admitted to inpatient set-up in Lusaka, Zambia. Nutr J 2011;10:110.
    1. Talbert A, Thuo N, Karisa J, Chesaro C, Ohuma E, Ignas J, Berkley JA, Toromo C, Atkinson S, Maitland K. Diarrhoea complicating severe acute malnutrition in Kenyan children: a prospective descriptive study of risk factors and outcome. PLoS One 2012;7:e38321.
    1. Maitland K, Berkley JA, Shebbe M, Peshu N, English M, Newton CRJC. Children with severe malnutrition: can those at highest risk of death be identified with the WHO protocol? PLoS Med 2006;3:e500.
    1. Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, Berkley JA, Rollins N, Kelly P, Adamczick C, Maitland K, et al. . Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet 2008;371:1305–7.
    1. World Health Organization. WHO Guideline: Updates on the management of severe acute malnutrition in infants and children. Geneva (Switzerland): World Health Organization; 2013.
    1. Opintan JA, Newman MJ, Ayeh-Kumi PF, Affrim R, Gepi-Attee R, Sevilleja JEAD, Roche JK, Nataro JP, Warren CA, Guerrant RL. Pediatric diarrhea in southern Ghana: etiology and association with intestinal inflammation and malnutrition. Am J Trop Med Hyg 2010;83:936–43.
    1. Campbell DI, Murch SH, Elia M, Sullivan PB, Sanyang MS, Jobarteh B, Lunn PG. Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel function. Pediatr Res 2003;54:306–11.
    1. Sullivan PB. Studies of the small intestine in persistent diarrhea and malnutrition: the Gambian experience. J Pediatr Gastroenterol Nutr 2002;34(Suppl 1):S11–3.
    1. Fakhoury M, Negrulj R, Mooranian A, Al-Salami H. Inflammatory bowel disease: clinical aspects and treatments. J Inflamm Res 2014;7:113–20.
    1. Vinolo MAR, Rodrigues HG, Nachbar RT, Curi R. Regulation of inflammation by short chain fatty acids. Nutrients 2011;3:858–76.
    1. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud D-J, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 2013;54:2325–40.
    1. Macia L, Tan J, Vieira AT, Leach K, Stanley D, Luong S, Maruya M, Ian McKenzie C, Hijikata A, Wong C, et al. . Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nat Commun 2015;6:6734.
    1. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, et al. . Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013;504:451–5.
    1. Rytter MJH, Kolte L, Briend AA, Friis H, Christensen VB. The immune system in children with malnutrition:–a systematic review. PLoS One 2014;9:e105017.
    1. Jones KDJ, Berkley JA. Severe acute malnutrition and infection. Paediatr Int Child Health 2014;34(Suppl 1):S1–29.
    1. González-Torres C, González-Martínez H, Miliar A, Nájera O, Graniel J, Firo VV, Alvarez C, Bonilla E, Rodríguez L. Effect of malnutrition on the expression of cytokines involved in Th1 cell differentiation. Nutrients 2013;5:579–93.
    1. González-Martínez H, Rodríguez L, Nájera O, Cruz D, Miliar A, Domínguez A, Sánchez F, Graniel J, González-Torres MC. Expression of cytokine mRNA in lymphocytes of malnourished children. J Clin Immunol 2008;28:593–9.
    1. Rodríguez L, González C, Flores L, Jiménez-Zamudio L, Graniel J, Ortiz R. Assessment by flow cytometry of cytokine production in malnourished children. Clin Diagn Lab Immunol 2005;12:502–7.
    1. World Health Organization. Pocket book of hospital care for children: second edition [Internet]. [cited 2015 Nov 12]. Available from: .
    1. The R Foundation. The R Project for statistical computing [Internet]. [cited 2015 Sep 30]. Available from: .
    1. Sanchez G. plsdepot: partial least squares (PLS) data analysis methods [Internet]. [cited 2015 Sep 30]. Available from: .
    1. Gonzalez I, Dejean S, Le Cao KA, Rohart F, Gautier B, Monget P, Coquery J, Yao FZ, Liquetey B, Benoit BL. mixOmics: Omics data integration project [Internet]. [cited 2015 Oct 2]. Available from: .
    1. Sanchez G, Trinchera L, Russolillo G. Plspm: tools for partial least squares path modeling (PLS-PM) [Internet]. [cited 2015 Sep 30]. Available from: .
    1. Kuhn M, Wing J, Weston S, Williams A, Keefer C, Engelhardt ATC, Mayer Z, Kenkel B, Benesty M, Lescarbeau AZR, et al. . caret: classification and regression training [Internet]. [cited 2015 Oct 2]. Available from: .
    1. Oord T, Hornung N. Fecal calprotectin in healthy children. Scand J Clin Lab Invest 2014;74:254–8.
    1. Ferdous F, Das SK, Ahmed S, Farzana FD, Latham JR, Chisti MJ, Ud-Din AIMS, Azmi IJ, Talukder KA, Faruque ASG. Severity of diarrhea and malnutrition among under five-year-old children in rural Bangladesh. Am J Trop Med Hyg 2013;89:223–8.
    1. Amadi B, Kelly P, Mwiya M, Mulwazi E, Sianongo S, Changwe F, Thomson M, Hachungula J, Watuka A, Walker-Smith J, et al. . Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition. J Pediatr Gastroenterol Nutr 2001;32:550–4.
    1. Jones KDJ, Hünten-Kirsch B, Laving AMR, Munyi CW, Ngari M, Mikusa J, Mulongo MM, Odera D, Nassir HS, Timbwa M, et al. . Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial. BMC Med 2014;12:133.
    1. Hestvik E, Tumwine JK, Tylleskar T, Grahnquist L, Ndeezi G, Kaddu-Mulindwa DH, Aksnes L, Olafsdottir E. Faecal calprotectin concentrations in apparently healthy children aged 0-12 years in urban Kampala, Uganda: a community-based survey. BMC Pediatr 2011;11:9.
    1. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA 2014;111:2247–52.
    1. van der Does AM, Bergman P, Agerberth B, Lindbom L. Induction of the human cathelicidin LL-37 as a novel treatment against bacterial infections. J Leukoc Biol 2012;92:735–42.
    1. Bjerrum JT, Wang Y, Hao F, Coskun M, Ludwig C, Günther U, Nielsen OH. Metabonomics of human fecal extracts characterize ulcerative colitis, Crohn’s disease and healthy individuals. Metabolomics 2015;11:122–33.
    1. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, et al. . Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 2014;510:417–21.
    1. Manokas T, Fromkes JJ, Sundaram U. Effect of chronic inflammation on ileal short-chain fatty acid/bicarbonate exchange. Am J Physiol Gastrointest Liver Physiol 2000;278:G585–90.
    1. Gudmundsson GH, Bergman P, Andersson J, Raqib R, Agerberth B. Battle and balance at mucosal surfaces–the story of Shigella and antimicrobial peptides. Biochem Biophys Res Commun 2010;396:116–9.
    1. Kerac M, Bunn J, Seal A, Thindwa M, Tomkins A, Sadler K, Bahwere P, Collins S. Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind efficacy randomised controlled trial in Malawi. Lancet 2009;374:136–44.
    1. Lotfy OA, Saleh WA, el-Barbari M. A study of some changes of cell-mediated immunity in protein energy malnutrition. J Egypt Soc Parasitol 1998;28:413–28.
    1. Muñoz C, Arévalo M, López M, Schlesinger L. Impaired interleukin-1 and tumor necrosis factor production in protein-calorie malnutrition. Nutr Res 1994;14:347–52.
    1. Bhaskaram P, Sivakumar B. Interleukin-1 in malnutrition. Arch Dis Child 1986;61:182–5.
    1. Pranzatelli MR, Tate ED, McGee NR, Colliver JA. Pediatric reference ranges for proinflammatory and anti-inflammatory cytokines in cerebrospinal fluid and serum by multiplexed immunoassay. J Interferon Cytokine Res 2013;33:523–8.
    1. Kim HO, Kim H-S, Youn J-C, Shin E-C, Park S. Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays. J Transl Med 2011;9:113.
    1. Sack U, Burkhardt U, Borte M, Schädlich H, Berg K, Emmrich F. Age-dependent levels of select immunological mediators in sera of healthy children. Clin Diagn Lab Immunol 1998;5:28–32.
    1. Kleiner G, Marcuzzi A, Zanin V, Monasta L, Zauli G. Cytokine levels in the serum of healthy subjects. Mediators Inflamm 2013;2013:434010.
    1. Salvatore S, Hauser B, Devreker T, Arrigo S, Vandenplas Y. Chronic enteropathy and feeding in children: an update. Nutrition 2008;24:1205–16.
    1. Philbin VJ, Levy O. Developmental biology of the innate immune response: implications for neonatal and infant vaccine development. Pediatr Res 2009;65:98R–105R.
    1. Műzes G, Molnár B, Tulassay Z, Sipos F. Changes of the cytokine profile in inflammatory bowel diseases. World J Gastroenterol 2012;18:5848–61.
    1. Hartman C, Eliakim R, Shamir R. Nutritional status and nutritional therapy in inflammatory bowel diseases. World J Gastroenterol 2009;15:2570–8.

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