The pathogenesis and diagnosis of sepsis post burn injury

Abstract

Burn is an under-appreciated trauma that is associated with unacceptably high morbidity and mortality. Although the survival rate after devastating burn injuries has continued to increase in previous decades due to medical advances in burn wound care, nutritional and fluid resuscitation and improved infection control practices, there are still large numbers of patients at a high risk of death. One of the most common complications of burn is sepsis, which is defined as “severe organ dysfunction attributed to host’s disordered response to infection” and is the primary cause of death in burn patients. Indeed, burn injuries are accompanied by a series of events that lead to sepsis and multiple organ dysfunction syndrome, such as a hypovolaemic state, immune and inflammatory responses and metabolic changes. Therefore, clear diagnostic criteria and predictive biomarkers are especially important in the prevention and treatment of sepsis and septic shock. In this review, we focus on the pathogenesis of burn wound infection and the post-burn events leading to sepsis. Moreover, the clinical and promising biomarkers of burn sepsis will also be summarized.

Keywords

Burn / Infection / Sepsis / Septic shock / Multiple organ dysfunction syndrome / Immune dysregulation / Hypermetabolism / Trauma / Biomaker / Inflammation

References

[1] Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S. Burn injury. Nat. Rev. Dis. Primers. 2020. https://doi.org/10.1038/s41572-020-0145-5.

[2] National Burn Repository 2019 Update, Report of data from 2009-2018 ameriburn.site-ym.com [Internet]. 2019. Available from: https://ameriburn.site-ym.com/store/ViewProduct.aspx?id=14191872.

[3] Pereira RF, Barrias CC, Granja PL, Bartolo PJ. Advanced biofabrication strategies for skin regeneration and repair. Nanomedicine (Lond.) 2013; 8: 603-21.

[4] Peck MD. Epidemiology of burns throughout the world. Part I: distribution and risk factors. Burns 2011; 37: 1087-100.

[5] Cioffi WG. deLemos RA, Coalson JJ, Gerstmann DA, Pruitt BA Jr. decreased pulmonary damage in primates with inhalation injury treated with high-frequency ventilation. Ann. Surg. 1993; 218: 328-35 discussion 35-7.

[6] Finnerty CC, Herndon DN, Jeschke MG. Inhalation injury in severely burned children does not augment the systemic inflammatory response. Crit. Care 2007. https://www.doi.org/10.1186/cc5698.

[7] Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Gao H, et al. A genomic storm in critically injured humans. J. Exp. Med. 2011; 208: 2581-90.

[8] Stanojcic M, Abdullahi A, Rehou S, Parousis A, Jeschke MG. Pathophysiological response to burn injury in adults. Ann. Surg. 2018; 267: 576-84.

[9] Jeschke MG, Gauglitz GG, Kulp GA, Finnerty CC, Williams FN, Kraft R, et al. Long-term persistence of the pathophysiologic response to severe burn injury. PLoS One 2011; 6: e21245. https://www.doi.org/10.1371/journal.pone.0021245.

[10] Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 2003; 348: 1546-54.

[11] Rodríguez-Luna A, Ávila-Román J, González-Rodríguez ML, Cózar MJ, Rabasco AM, Motilva V, et al. Fucoxanthin-containing cream prevents epidermal hyperplasia and UVB-induced skin erythema in mice. Mar. Drugs 2018. https://www.doi.org/10.3390/md16100378.

[12] Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992; 101: 1481-3.

[13] Neely AN, Fowler LA, Kagan RJ, Warden GD. Procalcitonin in pediatric burn patients: an early indicator of sepsis? J. Burn Care Rehabil. 2004; 25: 76-80.

[14] Stanojcic M, Vinaik R, Jeschke MG. Status and challenges of predicting and diagnosing sepsis in burn patients. Surg. Infect. 2018; 19: 168-75.

[15] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315: 801-10.

[16] Li W, Wang M, Zhu B, Zhu Y, Xi X. Prediction of median survival time in sepsis patients by the SOFA score combined with different predictors. Burns Trauma 2020; 8: tkz006.

[17] Jeschke MG, Patsouris D, Stanojcic M, Abdullahi A, Rehou S, Pinto R, et al. Pathophysiologic response to burns in the elderly. EBioMedicine 2015; 2: 1536-48.

[18] Chai J, Sheng Z, Diao L, Yang H, Gao J, Xu M. Effect of extensive excision of burn wound with invasive infection on hypermetabolism in burn patients with sepsis. Zhonghua Wai Ke Za Zhi [Chinese journal of surgery]. 2000; 38: 405-8.

[19] Fitzwater J, Purdue GF, Hunt JL, O’Keefe GE. The risk factors and time course of sepsis and organ dysfunction after burn trauma. J. Trauma 2003; 54: 959-66.

[20] Gomez R, Murray CK, Hospenthal DR, Cancio LC, Renz EM, Holcomb JB, et al. Causes of mortality by autopsy findings of combat casualties and civilian patients admitted to a burn unit. J. Am. Coll. Surg. 2009; 208: 348-54.

[21] Greenhalgh DG.Sepsis in the burn patient: a different problem than sepsis in the general population. Burns Trauma. 2017. https://www.doi.org/10.1186/s41038-017-0089-5.

[22] Atiyeh BS, Gunn SW, Hayek SN. State of the art in burn treatment. World J. Surg. 2005; 29: 131-48.

[23] Ren C, Yao RQ, Ren D, Li Y, Feng YW, Yao YM. Comparison of clinical laboratory tests between bacterial sepsis and SARS-CoV-2-associated viral sepsis. Mil Med Res 2020; 7: 36.

[24] Warner PM, Coffee TL, Yowler CJ. Outpatient burn management. Surg. Clin. North Am. 2014; 94: 879-92.

[25] Lionelli GT, Pickus EJ, Beckum OK, Decoursey RL, Korentager RA. A three decade analysis of factors affecting burn mortality in the elderly. Burns 2005; 31: 958-63.

[26] Thombs BD, Bresnick MG. Mortality risk and length of stay associated with self-inflicted burn injury: evidence from a national sample of 30,382 adult patients. Crit. Care Med. 2008; 36: 118-25.

[27] Church D, Elsayed S, Reid O, Winston B, Lindsay R. Burn wound infections. Clin. Microbiol. Rev. 2006; 19: 403-34.

[28] Kraft R, Herndon DN, Williams FN, Al-Mousawi AM, Finnerty CC, Jeschke MG. The effect of obesity on adverse outcomes and metabolism in pediatric burn patients. Int J Obes (Lond). 2012; 36: 485-90.

[29] Duke JM, Randall SM, Fear MW, Boyd JH, Rea S, Wood FM. Diabetes mellitus after injury in burn and non-burned patients: a population based retrospective cohort study. Burns 2018; 44: 566-72.

[30] Salehi SH, As’adi K, Tabatabaeenezhad SA, Naderan M, Shoar S. Prevalence of HIV infection among burn patients: is there a relationship with patients’ outcomes? Int. Wound J. 2017; 14: 85-8.

[31] Barret JP, Herndon DN. Effects of burn wound excision on bacterial colonization and invasion. Plast. Reconstr. Surg. 2003; 111: 744-50.

[32] Evdokiou A, Kanisicak O, Gierek S, Barry A, Ivey MJ, Zhang X, et al. Characterization of burn eschar pericytes. J. Clin. Med. 2020; 9.

[33] Monsuur HN, van den Broek LJ, Jhingoerie RL, Vloemans A, Gibbs S. Burn eschar stimulates fibroblast and adipose mesenchymal stromal cell proliferation and migration but inhibits endothelial cell sprouting. Int. J. Mol. Sci. 2017. https://www.doi.org/10.3390/ijms18081790.

[34] Costerton JW, Stewart PS, Greenberg EP.Bacterial biofilms: a common cause of persistent infections. Science (New York, N.Y.) 1999; 284: 1318-22.

[35] Flemming HC, Wingender J, Szewzyk U, Steinberg P, Rice SA, Kjelleberg S. Biofilms: an emergent form of bacterial life. Nat. Rev. Microbiol. 2016; 14: 563-75.

[36] Koo H, Allan RN, Howlin RP, Stoodley P, Hall-Stoodley L. Targeting microbial biofilms: current and prospective therapeutic strategies. Nat. Rev. Microbiol. 2017; 15: 740-55.

[37] Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22: 707-10.

[38] Rumbaugh KP, Sauer K. Biofilm dispersion. Nat. Rev. Microbiol. 2020; 18: 571-86.

[39] Edwards R, Harding KG. Bacteria and wound healing. Curr. Opin. Infect. Dis. 2004; 17: 91-6.

[40] Harrison-Balestra C, Cazzaniga AL, Davis SC, Mertz PM. A wound-isolated Pseudomonas aeruginosa grows a biofilm in vitro within 10 hours and is visualized by light microscopy. Dermatol Surg. 2003; 29: 631-5.

[41] Kennedy P, Brammah S, Wills E. Burns, biofilm and a new appraisal of burn wound sepsis. Burns 2010; 36: 49-56.

[42] Erol S, Altoparlak U, Akcay MN, Celebi F, Parlak M. Changes of microbial flora and wound colonization in burned patients. Burns 2004; 30: 357-61.

[43] Norbury W, Herndon DN, Tanksley J, Jeschke MG, Finnerty CC. Infection in Burns. Surg. Infect. 2016; 17: 250-5.

[44] Vollmer W, Blanot D, de Pedro MA. Peptidoglycan structure and architecture. FEMS Microbiol. Rev. 2008; 32: 149-67.

[45] Scott JR, Barnett TC. Surface proteins of gram-positive bacteria and how they get there. Annu. Rev. Microbiol. 2006; 60: 397-423.

[46] Salgado-Pabón W, Breshears L, Spaulding AR, Merriman JA, Stach CS, Horswill AR, et al. Superantigens are critical for Staphylococcus aureus infective endocarditis, sepsis, and acute kidney injury. MBio 2013; 4. https://www.doi.org/10.1128/mBio.00494-13.

[47] Lin YC, Peterson ML. New insights into the prevention of staphylococcal infections and toxic shock syndrome. Expert. Rev. Clin. Pharmacol. 2010; 3: 753-67.

[48] Dayan GH, Mohamed N, Scully IL, Cooper D, Begier E, Eiden J, et al. Staphylococcus aureus: the current state of disease, pathophysiology and strategies for prevention. Expert Rev. Vaccines 2016; 15: 1373-92.

[49] Maresso AW, Schneewind O. Sortase as a target of anti-infective therapy. Pharmacol. Rev. 2008; 60: 128-41.

[50] Foster TJ, Geoghegan JA, Ganesh VK, Höök M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat. Rev. Microbiol. 2014; 12: 49-62.

[51] Kwiecinski J, Jin T, Josefsson E. Surface proteins of Staphylococcus aureus play an important role in experimental skin infection. APMIS. 2014; 122: 1240-50.

[52] McAdow M, Kim HK, Dedent AC, Hendrickx AP, Schneewind O, Missiakas DM. Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood. PLoS Pathog. 2011. https://www.doi.org/10.1371/journal.ppat.1002307.

[53] MacVane SH. Antimicrobial resistance in the intensive care unit: a focus on gram-negative bacterial infections. J. Intensive Care Med. 2017; 32: 25-37.

[54] Kaye KS, Pogue JM. Infections caused by resistant gram-negative bacteria: epidemiology and management. Pharmacotherapy 2015; 35: 949-62.

[55] Dou Y, Huan J, Guo F, Zhou Z, Shi Y. Pseudomonas aeruginosa prevalence, antibiotic resistance and antimicrobial use in Chinese burn wards from 2007 to 2014. J. Int. Med. Res. 2017; 45: 1124-37.

[56] Chevalier S, Bouffartigues E, Bodilis J, Maillot O, Lesouhaitier O, Feuilloley MGJ, et al. Structure, function and regulation of Pseudomonas aeruginosa porins. FEMS Microbiol. Rev. 2017; 41: 698-722.

[57] Tredget EE, Shankowsky HA, Rennie R, Burrell RE, Logsetty S. Pseudomonas infections in the thermally injured patient. Burns 2004; 30: 3-26.

[58] Dzvova N, Colmer-Hamood JA, Griswold JA, Hamood AN. Heparinase is essential for Pseudomonas aeruginosa virulence during thermal injury and infection. Infect. Immun. 2018. https://www.doi.org/10.1128/IAI.00755-17.

[59] Williams FN, Herndon DN, Hawkins HK, Lee JO, Cox RA, Kulp GA, et al. The leading causes of death after burn injury in a single pediatric burn center. Crit. Care 2009. https://www.doi.org/10.1186/cc8170.

[60] Greenhalgh DG, Saffle JR, Holmes JH, Gamelli RL, Palmieri TL, Horton JW, et al. American burn association consensus conference to define sepsis and infection in burns. J Burn Care Res. 2007; 28: 776-90.

[61] Mann-Salinas EA, Baun MM, Meininger JC, Murray CK, Aden JK, Wolf SE, et al. Novel predictors of sepsis outperform the American burn association sepsis criteria in the burn intensive care unit patient. J Burn Care Res. 2013; 34: 31-43.

[62] Yan J, Hill WF, Rehou S, Pinto R, Shahrokhi S, Jeschke MG. Sepsis criteria versus clinical diagnosis of sepsis in burn patients: a validation of current sepsis scores. Surgery 2018; 164: 1241-5.

[63] Jeschke MG, Chinkes DL, Finnerty CC, Kulp G, Suman OE, Norbury WB, et al. Pathophysiologic response to severe burn injury. Ann. Surg. 2008; 248: 387-401.

[64] Hart DW, Wolf SE, Mlcak R, Chinkes DL, Ramzy PI, Obeng MK, et al. Persistence of muscle catabolism after severe burn. Surgery 2000; 128: 312-9.

[65] Kottke MA, Walters TJ. Where’s the leak in vascular barriers? A review. Shock (Augusta, Ga) 2016; 46: 20-36.

[66] Arbuthnot MK, Garcia AV. Early resuscitation and management of severe pediatric burns. Semin. Pediatr. Surg. 2019; 28: 73-8.

[67] Ashina K, Tsubosaka Y, Nakamura T, Omori K, Kobayashi K, Hori M, et al. Histamine induces vascular hyperpermeability by increasing blood flow and endothelial barrier disruption in vivo. PLoS One 2015. https://www.doi.org/10.1371/journal.pone.0132367.

[68] Mikelis CM, Simaan M, Ando K, Fukuhara S, Sakurai A, Amornphimoltham P, et al. RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock. Nat. Commun. 2015. https://www.doi.org/10.1038/ncomms7725.

[69] Ma T, Liu L, Wang P, Xue Y. Evidence for involvement of ROCK signaling in bradykinin-induced increase in murine blood-tumor barrier permeability. J. Neuro-Oncol. 2012; 106: 291-301.

[70] Liu LB, Xue YX, Liu YH, Wang YB. Bradykinin increases blood-tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. J. Neurosci. Res. 2008; 86: 1153-68.

[71] Duah E, Adapala RK, Al-Azzam N, Kondeti V, Gombedza F, Thodeti CK, et al. Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT2 and CysLT1 receptors. Sci. Rep. 2013. https://www.doi.org/10.1038/srep03274.

[72] Lee KS, Kim SR, Park HS, Jin GY, Lee YC. Cysteinyl leukotriene receptor antagonist regulates vascular permeability by reducing vascular endothelial growth factor expression. J. Allergy Clin. Immunol. 2004; 114: 1093-9.

[73] Antonetti DA, Barber AJ, Hollinger LA, Wolpert EB, Gardner TW. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J. Biol. Chem. 1999; 274: 23463-7.

[74] Chen XL, Nam JO, Jean C, Lawson C, Walsh CT, Goka E, et al. VEGF-induced vascular permeability is mediated by FAK. Dev. Cell 2012; 22: 146-57.

[75] Vasile E, Qu H, Dvorak HF, Dvorak AM. Caveolae and vesiculo-vacuolar organelles in bovine capillary endothelial cells cultured with VPF/VEGF on floating Matrigel-collagen gels. J. Histochem. Cytochem. 1999; 47: 159-67.

[76] Feng D, Nagy JA, Hipp J, Dvorak HF, Dvorak AM. Vesiculovacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J. Exp. Med. 1996; 183: 1981-6.

[77] van der Flier M, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI, Geelen SP. Plasma vascular endothelial growth factor in severe sepsis. Shock (Augusta, Ga) 2005; 23: 35-8.

[78] Zang Q, Maass DL, White J, Horton JW. Cardiac mitochondrial damage and loss of ROS defense after burn injury: the beneficial effects of antioxidant therapy. J Appl Physiol. 2007; 102: 103-12.

[79] Willis MS, Carlson DL, Dimaio JM, White MD, White DJ, Adams GA, et al. Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury. Am. J. Physiol. Heart Circ. Physiol. 2005; 288: H795-804.

[80] Nielson CB, Duethman NC, Howard JM, Moncure M, Wood JG. Burns: pathophysiology of systemic complications and current management. J Burn Care Res. 2017; 38: e469-81.

[81] Griswold JA.White blood cell response to burn injury. Semin. Nephrol. 1993; 13: 409-15.

[82] Grogan JB.Altered neutrophil phagocytic function in burn patients. J. Trauma 1976; 16: 734-8.

[83] ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, et al. Recommendations for the management of autoinflammatory diseases. Ann. Rheum. Dis. 2015; 74: 1636-44.

[84] Schildt BE. Function of the RES after thermal and mechanical trauma in mice. Acta Chir. Scand. 1970; 136: 359-64.

[85] Qiu T, Li M, Tanner MA, Yang Y, Sowers JR, Korthuis RJ, et al. Depletion of dendritic cells in perivascular adipose tissue improves arterial relaxation responses in type 2 diabetic mice. Metab. Clin. Exp. 2018; 85: 76-89.

[86] Vignesh P, Rawat A, Sharma M, Singh S. Complement in autoimmune diseases. Clinica Chimica Acta. 2017; 465: 123-30.

[87] Hammad A, Westacott L, Zaben M. The role of the complement system in traumatic brain injury: a review. J. Neuroinflammation 2018. https://www.doi.org/10.1186/s12974-018-1066-z.

[88] Hugli TE.Complement and cellular triggering reactions. Introductory remarks. Federation proceedings. 1984; 43: 2540-2.

[89] Conde P, Rodriguez M, van der Touw W, Jimenez A, Burns M, Miller J, et al. DC-SIGN(+) macrophages control the induction of transplantation tolerance. Immunity 2015; 42: 1143-58.

[90] Donnelly RP, Fenton MJ, Kaufman JD, Gerrard TL. IL-1 expression in human monocytes is transcriptionally and posttranscriptionally regulated by IL-4. J. Immunol. 1991; 146: 3431-6.

[91] Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 1991; 147: 3815-22.

[92] Oswald IP, Wynn TA, Sher A, James SL. Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 8676-80.

[93] Heideman M, Bengtsson A. The immunologic response to thermal injury. World J. Surg. 1992; 16: 53-6.

[94] Sheridan RL, Weber JM, Pasternak MM, Mulligan JM, Tompkins RG. A 15-year experience with varicella infections in a pediatric burn unit. Burns 1999; 25: 353-6.

[95] Gosain A, Gamelli RL. A primer in cytokines. J. Burn Care Rehabil. 2005; 26: 7-12.

[96] Schwacha MG.Macrophages and post-burn immune dysfunction. Burns 2003; 29: 1-14.

[97] Burleson DG, Mason AD, Jr, Pruitt BA, Jr. Lymphoid subpopulation changes after thermal injury and thermal injury with infection in an experimental model. Ann. Surg. 1988; 207: 208-12.

[98] Rendon JL, Choudhry MA. Th17 cells: critical mediators of host responses to burn injury and sepsis. J. Leukoc. Biol. 2012; 92: 529-38.

[99] Deitch EA, Bridges RM, Dobke M, McDonald JC. Burn wound sepsis may be promoted by a failure of local antibacterial host defenses. Ann. Surg. 1987; 206: 340-8.

[100] Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J, Lepape A, et al. Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J. Immunol. 2006; 177: 6540-7.

[101] Porter C, Tompkins RG, Finnerty CC, Sidossis LS, Suman OE, Herndon DN. The metabolic stress response to burn trauma: current understanding and therapies. Lancet (London, England) 2016; 388: 1417-26.

[102] Porter C, Herndon DN, Børsheim E, Bhattarai N, Chao T, Reidy PT, et al. Long-term skeletal muscle mitochondrial dysfunction is associated with hypermetabolism in severely burned children. J Burn Care Res. 2016; 37: 53-63.

[103] Porter C, Herndon DN, Børsheim E, Chao T, Reidy PT, Borack MS, et al. Uncoupled skeletal muscle mitochondria contribute to hypermetabolism in severely burned adults. Am. J. Physiol. Endocrinol. Metab. 2014; 307: E462-7.

[104] Auger C, Samadi O, Jeschke MG. The biochemical alterations underlying post-burn hypermetabolism. Biochim. Biophys. Acta Mol. basis Dis. 2017; 1863: 2633-44.

[105] Wieser V, Moschen AR, Tilg H. Inflammation, cytokines and insulin resistance: a clinical perspective. Arch. Immunol. Ther. Exp. 2013; 61: 119-25.

[106] Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006; 440: 944-8.

[107] Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 2011; 17: 179-88.

[108] Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N. Engl. J. Med. 2001; 345: 1223-9.

[109] Wang Y, Viscarra J, Kim SJ, Sul HS. Transcriptional regulation of hepatic lipogenesis. Nat. Rev. Mol. Cell Biol. 2015; 16: 678-89.

[110] Jeschke MG, Herndon DN, Wolf SE, DebRoy MA, Rai J, Thompson JC, et al. Hepatocyte growth factor modulates the hepatic acute-phase response in thermally injured rats. Crit. Care Med. 2000; 28: 504-10.

[111] Yu YM, Tompkins RG, Ryan CM, Young VR. The metabolic basis of the increase of the increase in energy expenditure in severely burned patients. JPEN J. Parenter. Enteral Nutr. 1999; 23: 160-8.

[112] Matthias A, Ohlson KB, Fredriksson JM, Jacobsson A, Nedergaard J, Cannon B. Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty acid-induced thermogenesis. J. Biol. Chem. 2000; 275: 25073-81.

[113] Jeschke MG, Finnerty CC, Herndon DN, Song J, Boehning D, Tompkins RG, et al. Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response. Ann. Surg. 2012; 255: 370-8.

[114] Wang C, Huang Z, Du Y, Cheng Y, Chen S, Guo F. ATF4 regulates lipid metabolism and thermogenesis. Cell Res. 2010; 20: 174-84.

[115] Kraft R, Herndon DN, Finnerty CC, Hiyama Y, Jeschke MG. Association of postburn fatty acids and triglycerides with clinical outcome in severely burned children. J. Clin. Endocrinol. Metab. 2013; 98: 314-21.

[116] Abdullahi A, Jeschke MG. White adipose tissue browning: a double-edged sword. Trends Endocrinol Metab 2016; 27: 542-52.

[117] Meier JA, Larner AC. Toward a new STATe: the role of STATs in mitochondrial function. Semin. Immunol. 2014; 26: 20-8.

[118] Porter C, Herndon DN, Chondronikola M, Chao T, Annamalai P, Bhattarai N, et al. Human and mouse brown adipose tissue mitochondria have comparable UCP1 function. Cell Metab. 2016; 24: 246-55.

[119] Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM consensus conference committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101: 1644-55.

[120] Yarema TC, Yost S. Low-dose corticosteroids to treat septic shock: a critical literature review. Crit. Care Nurse 2011; 31: 16-26.

[121] Burns JP. Septic shock in the pediatric patient: pathogenesis and novel treatments. Pediatr. Emerg. Care 2003; 19: 112-5.

[122] Vincent JL, Zhang H, Szabo C, Preiser JC. Effects of nitric oxide in septic shock. Am. J. Respir. Crit. Care Med. 2000; 161: 1781-5.

[123] Zardi EM, Zardi DM, Dobrina A, Afeltra A. Prostacyclin in sepsis: a systematic review. Prostaglandins Other Lipid Mediat. 2007; 83: 1-24.

[124] Araújo AV, Ferezin CZ, Rodrigues GJ, Lunardi CN, Vercesi JA, Grando MD, et al. Prostacyclin, not only nitric oxide, is a mediator of the vasorelaxation induced by acetylcholine in aortas from rats submitted to cecal ligation and perforation (CLP). Vasc. Pharmacol. 2011; 54: 44-51.

[125] Galley HF.Oxidative stress and mitochondrial dysfunction in sepsis. Br. J. Anaesth. 2011; 107: 57-64.

[126] Alvarez S, Evelson PA. Nitric oxide and oxygen metabolism in inflammatory conditions: sepsis and exposition to polluted ambients. Front Biosci. 2007; 12: 964-74.

[127] Hattori Y, Kasai K. Induction of mRNAs for ICAM-1, VCAM-1, and ELAM-1 in cultured rat cardiac myocytes and myocardium in vivo. Biochem. Mol. Biol. Int. 1997; 41: 979-86.

[128] Li Y, Chen B, Yang X, Zhang C, Jiao Y, Li P, et al. S100a8/a9 Signaling causes mitochondrial dysfunction and cardiomyocyte death in response to ischemic/reperfusion injury. Circulation 2019; 140: 751-64.

[129] Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N. Engl. J. Med. 2013; 368: 1845-6.

[130] Abdullahi A, Chen P, Stanojcic M, Sadri AR, Coburn N, Jeschke MG. IL-6 signal from the bone marrow is required for the browning of white adipose tissue post burn injury. Shock (Augusta, Ga) 2017; 47: 33-9.

[131] Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N. Engl. J. Med. 1999; 340: 448-54.

[132] Thomas S, Wolf SE, Chinkes DL, Herndon DN. Recovery from the hepatic acute phase response in the severely burned and the effects of long-term growth hormone treatment. Burns 2004; 30: 675-9.

[133] Pruchniewski D, Pawlowski T, Morkowski J, Mackiewicz S. C-reactive protein in management of children’s burns. Ann. Clin. Res. 1987; 19: 334-8.

[134] Lavrentieva A, Kontakiotis T, Lazaridis L, Tsotsolis N, Koumis J, Kyriazis G, et al. Inflammatory markers in patients with severe burn injury. What is the best indicator of sepsis? Burns 2007; 33: 189-94.

[135] Jeschke MG, Finnerty CC, Kulp GA, Kraft R, Herndon DN. Can we use C-reactive protein levels to predict severe infection or sepsis in severely burned patients? Int J Burns Trauma. 2013; 3: 137-43.

[136] Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet (London, England) 1993; 341: 515-8.

[137] Long B, Koyfman A. Ready for prime time? Biomarkers in sepsis. Emerg. Med. Clin. North Am. 2017; 35: 109-22.

[138] Brunkhorst FM, Eberhard OK, Brunkhorst R. Discrimination of infectious and noninfectious causes of early acute respiratory distress syndrome by procalcitonin. Crit. Care Med. 1999; 27: 2172-6.

[139] Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit. Care Med. 2006; 34: 1996-2003.

[140] Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect. Dis. 2013; 13: 426-35.

[141] Nunez Lopez O, Cambiaso-Daniel J, Branski LK, Norbury WB, Herndon DN. Predicting and managing sepsis in burn patients: current perspectives. Ther. Clin. Risk Manag. 2017; 13: 1107-17.

[142] Meisner M. Pathobiochemistry and clinical use of procalcitonin. Clin Chim Acta. 2002; 323: 17-29.

[143] Schneider HG, Lam QT. Procalcitonin for the clinical laboratory: a review. Pathology 2007; 39: 383-90.

[144] Brunkhorst FM, Wegscheider K, Forycki ZF, Brunkhorst R. Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock. Intensive Care Med. 2000; 26: S148-52.

[145] Seoane L, Pértega S, Galeiras R, Astola I, Bouza T.Procalcitonin in the burn unit and the diagnosis of infection. Burns 2014; 40: 223-9.

[146] Paratz JD, Lipman J, Boots RJ, Muller MJ, Paterson DL. A new marker of sepsis post burn injury?^*. Crit. Care Med. 2014; 42: 2029-36.

[147] Finnerty CC, Herndon DN, Przkora R, Pereira CT, Oliveira HM, Queiroz DM, et al. Cytokine expression profile over time in severely burned pediatric patients. Shock (Augusta, Ga) 2006; 26: 13-9.

[148] Abdel-Hafez NM, Saleh Hassan Y, El-Metwally TH. A study on biomarkers, cytokines, and growth factors in children with burn injuries. Ann. Burns Fire Disasters 2007; 20: 89-100.

[149] Kraft R, Herndon DN, Finnerty CC, Cox RA, Song J, Jeschke MG. Predictive value of IL-8 for sepsis and severe infections after burn injury: a clinical study. Shock (Augusta, Ga) 2015; 43: 222-7.

[150] Pileri D, Accardo Palombo A, D’Amelio L, D’Arpa N, Amato G, Masellis A, et al. Concentrations of cytokines IL-6 and IL-10 in plasma of burn patients: their relationship to sepsis and outcome. Ann. Burns Fire Disasters 2008; 21: 182-5.

[151] Csontos C, Foldi V, Pálinkas L, Bogar L, Röth E, Weber G, et al. Time course of pro-and anti-inflammatory cytokine levels in patients with burns-prognostic value of interleukin-10. Burns 2010; 36: 483-94.

[152] Yaegashi Y, Shirakawa K, Sato N, Suzuki Y, Kojika M, Imai S, et al. Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis. J Infect Chemother. 2005; 11: 234-8.

[153] Wu J, Hu L, Zhang G, Wu F, He T. Accuracy of presepsin in sepsis diagnosis: a systematic review and meta-analysis. PLoS One 2015. https://www.doi.org/10.1371/journal.pone.0133057.

[154] Bellos I, Fitrou G, Pergialiotis V, Thomakos N, Perrea DN, Daskalakis G. The diagnostic accuracy of presepsin in neonatal sepsis: a meta-analysis. Eur. J. Pediatr. 2018; 177: 625-32.

[155] Memar MY, Baghi HB. Presepsin: a promising biomarker for the detection of bacterial infections. Biomed Pharmacother 2019; 111: 649-56.

[156] Miyoshi M, Inoue Y, Nishioka M, Ikegame A, Nakao T, Kishi S, et al. Clinical evaluation of presepsin considering renal function. PLoS One 2019. https://www.doi.org/10.1371/journal.pone.0215791.

[157] Yoon SH, Kim EH, Kim HY, Ahn JG. Presepsin as a diagnostic marker of sepsis in children and adolescents: a systemic review and meta-analysis. BMC Infect. Dis. 2019. https://www.doi.org/10.1186/s12879-019-4397-1.

[158] Gille J, Schmidt J, Kremer T, Sablotzki A. Evaluation of MR-proANP and copeptin for sepsis diagnosis after burn injury. J. Crit. Care 2019; 52: 149-55.

[159] Hampson P, Dinsdale RJ, Wearn CM, Bamford AL, Bishop JRB, Hazeldine J, et al. Neutrophil dysfunction, immature granulocytes, and cell-free DNA are early biomarkers of sepsis in burn-injured patients: a prospective observational cohort study. Ann. Surg. 2017; 265: 1241-9.

[160] Guo H, Tang L, Xu J, Lin C, Ling X, Lu C, et al. MicroRNA-495 serves as a diagnostic biomarker in patients with sepsis and regulates sepsis-induced inflammation and cardiac dysfunction. Eur. J. Med. Res. 2019. https://www.doi.org/10.1186/s40001-019-0396-3.

[161] Nishiguchi T, Ito I, Lee JO, Suzuki S, Suzuki F, Kobayashi M. Macrophage polarization and MRSA infection in burned mice. Immunol. Cell Biol. 2017; 95: 198-206.

[162] Lourtet-Hascoët J, Félicé MP, Bicart-See A, Bouige A, Giordano G, Bonnet E. Species and antimicrobial susceptibility testing of coagulase-negative staphylococci in periprosthetic joint infections. Epidemiol. Infect. 2018; 146: 1771-6.

[163] Shen WC, Wang X, Qin WT, Qiu XF, Sun BW. Exogenous carbon monoxide suppresses Escherichia coli vitality and improves survival in an Escherichia coli-induced murine sepsis model. Acta Pharmacol. Sin. 2014; 35: 1566-76.

[164] Chadha P, Katare OP, Chhibber S. Liposome loaded phage cocktail: enhanced therapeutic potential in resolving Klebsiella pneumoniae mediated burn wound infections. Burns 2017; 43: 1532- 43.

[165] Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur. Respir. J. 2016; 47: 45-68.

[166] Katz T, Wasiak J, Cleland H, Padiglione A. Incidence of non-candidal fungal infections in severe burn injury: an Australian perspective. Burns 2014; 40: 881-6.

[167] Sobouti B, Momeni M, Masalegooyan N, Ansari I, Rahbar H. Herpes simplex virus infection in minor burn injury: a case report. Int J Burns Trauma. 2018; 8: 149-52.

[168] Gibbs JT, Zieger M, Sood R. Cytomegalovirus colitis in a burn patient. J Burn Care Res. 2016; 37: e298-300.

[169] Kubota Y, Kosaka K, Hokazono T, Yamaji Y, Tezuka T, Akita S, et al. Disseminated zoster in an adult patient with extensive burns: a case report. Virol. J. 2019; 16: 68.