Sepsis-induced immunoparalysis: Mechanisms, markers, and treatment options

Minerva Anestesiologica

Volumn 81, Issue 4, 2015, Pages 426-439

  Hamers, L ^a   Kox, M ^a   Pickkers, P ^a  

^a RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Immunomodulation; Immunosuppression; Monitoring, immunologic; Sepsis; Shock, septic

Indexed keywords

BIOLOGICAL MARKER; CASPASE 3; CD163 ANTIGEN; CD4 ANTIGEN; CD69 ANTIGEN; CD8 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; FAS LIGAND; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 15; INTERLEUKIN 7; INTERLEUKIN 7 RECEPTOR; PROGRAMMED DEATH 1 LIGAND 1; PROGRAMMED DEATH 1 LIGAND 2; TUMOR NECROSIS FACTOR ALPHA; IMMUNOLOGICAL ADJUVANT;

ARTICLE; CD8+ T LYMPHOCYTE; CLINICAL TRIAL (TOPIC); HUMAN; IMMUNE DEFICIENCY; IMMUNOMODULATION; IMMUNOPARALYSIS; IMMUNOSUPPRESSIVE TREATMENT; NONHUMAN; SEPSIS; COMPLICATION; IMMUNE SYSTEM DISEASES; IMMUNOCOMPROMISED PATIENT; IMMUNOLOGY; SHOCK, SEPTIC;

ADJUVANTS, IMMUNOLOGIC; HUMANS; IMMUNE SYSTEM DISEASES; IMMUNOCOMPROMISED HOST; SEPSIS; SHOCK, SEPTIC;

EID: 84930007712     PISSN: 03759393     EISSN: 18271596     Source Type: Journal    
DOI: None     Document Type: Article

References (119)

1. Martin JN. Diagnosis and epidemiology of human herpes-virus 8 infection. Semin Hematol 2003;40:133-42.
2. Deans KJ, Haley M, Natanson C, Eichacker PQ, Minneci PC. Novel therapies for sepsis: a review. J Trauma 2005;58:867-74.
3. Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 2013;309:1154-62.
4. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011;306:2594-605.
5. Leentjens J, Kox M, van der Hoeven JG, Netea MG, Pickkers P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am J Respir Crit Care Med 2013;187:1287-93.
6. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013;13:862-74.
7. Hotchkiss RS, Opal S. Immunotherapy for sepsis--a new approach against an ancient foe. New Engl J Med 2010;363:87-9.
8. Chong DL, Sriskandan S. Pro-inflammatory mechanisms in sepsis. Contrib Microbiol 2011;17:86-107.
9. Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine C et al. Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev 2013;93:1247-88.
10. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 2000;181:176-80.
11. Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 2006;177:1967-74.
12. Tamayo E, Fernandez A, Almansa R, Carrasco E, Heredia M, Lajo C et al. Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Netw 2011;22:82-7.
13. Martin GS, Mannino DM, Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006;34:15-21.
14. Reber AJ, Chirkova T, Kim JH, Cao W, Biber R, Shay DK et al. Immunosenescence and challenges of vaccination against influenza in the aging population. Aging Dis 2012;3:68-90.
15. Otto GP, Sossdorf M, Claus RA, Rodel J, Menge K, Reinhart K et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Crit Care 2011;15:R183.
16. Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008;300:413-22.
17. Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009;136:1237-48.
18. Torgersen C, Moser P, Luckner G, Mayr V, Jochberger S, Hasibeder WR et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth Analg 2009;108:1841-7.
19. Landelle C, Lepape A, Voirin N, Tognet E, Venet F, Bohe J et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 2010;36:1859-66.
20. Monneret G, Lepape A, Voirin N, Bohe J, Venet F, Debard AL et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 2006;32:1175-83. Epub 2006/06/03. doi: 10.1007/s00134-006-0204-8. PubMed PMID: 16741700.
21. Appoloni O, Vincent JL, Duchateau J. Response of tumour necrosis factor-alpha to delayed in vitro monocyte stimulation in patients with septic shock is related to outcome. Clin Sci (Lond) 2002;102:315-20.
22. Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med 2008;14:64-78.
23. Wolk K, Docke W, von Baehr V, Volk H, Sabat R. Comparison of monocyte functions after LPS- or IL-10-induced reorientation: importance in clinical immunoparalysis. Pathobiology 1999;67:253-6.
24. Nolan A, Kobayashi H, Naveed B, Kelly A, Hoshino Y, Hoshino S et al. Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis. PloS one 2009;4:e6600.
25. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704.
26. Boomer JS, Shuherk-Shaffer J, Hotchkiss RS, Green JM. A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Crit Care 2012;16:R112.
27. Yi JS, Cox MA, Zajac AJ. T-cell exhaustion: characteristics, causes and conversion. Immunology 2010;129:474-81.
28. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-74.
29. Pillay J, Kamp VM, van Hoffen E, Visser T, Tak T, Lammers JW et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. J Clin Invest 2012;122:327-36.
30. Kessel A, Bamberger E, Masalha M, Toubi E. The role of T regulatory cells in human sepsis. J Autoimmun 2009;32:211-5.
31. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531-62.
32. Taams LS, van Amelsfort JM, Tiemessen MM, Jacobs KM, de Jong EC, Akbar AN et al. Modulation of monocyte/ macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 2005;66:222-30.
33. 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.
34. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999;27:1230-51.
35. Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH et al. Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 2002;168:2493-500.
36. Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 2005;174:3765-72.
37. Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE, Jr., Hui JJ, Chang KC et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001;166:6952-63.
38. Peck-Palmer OM, Unsinger J, Chang KC, McDonough JS, Perlman H, McDunn JE et al. Modulation of the Bcl-2 family blocks sepsis-induced depletion of dendritic cells and macrophages. Shock 2009;31:359-66.
39. Benoit M, Desnues B, Mege JL. Macrophage polarization in bacterial infections. J Immunol 2008;181:3733-9.
40. Rigato O, Salomao R. Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin 10 in whole blood of patients with sepsis. Shock 2003;19:113-6.
41. Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regulation of immune cell functions during post-septic immunosuppression. Epigenetics 2011;6:273-83.
42. El Gazzar M, Yoza BK, Chen X, Hu J, Hawkins GA, McCall CE. G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. J Biol Chem 2008;283:32198-208.
43. Lyn-Kew K, Rich E, Zeng X, Wen H, Kunkel SL, Newstead MW et al. IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PloS one 2010;5:e11145.
44. Carson WFt, Cavassani KA, Ito T, Schaller M, Ishii M, Dou Y et al. Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis. Eur J Immunol 2010;40:998-1010.
45. O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010;10:111-22.
46. Caille V, Chiche JD, Nciri N, Berton C, Gibot S, Boval B et al. Histocompatibility leukocyte antigen-D related expression is specifically altered and predicts mortality in septic shock but not in other causes of shock. Shock 2004;22:521-6.
47. Wu JF, Ma J, Chen J, Ou-Yang B, Chen MY, Li LF et al. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit Care 2011;15:R220.
48. Docke WD, Hoflich C, Davis KA, Rottgers K, Meisel C, Kiefer P et al. Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. Clin Chem 2005;51:2341-7.
49. Docke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997;3:678-81.
50. Heper Y, Akalin EH, Mistik R, Akgoz S, Tore O, Goral G et al. Evaluation of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, and interleukin-10 levels as diagnostic and prognostic parameters in patients with community-acquired sepsis, severe sepsis, and septic shock. Eur J Clin Microbiol Infect Dis 2006;25:481-91.
51. Suarez-Santamaria M, Santolaria F, Perez-Ramirez A, Aleman-Valls MR, Martinez-Riera A, Gonzalez-Reimers E et al. Prognostic value of inflammatory markers (notably cytokines and procalcitonin), nutritional assessment, and organ function in patients with sepsis. Eur Cytokine Netw 2010;21:19-26.
52. Monneret G, Finck ME, Venet F, Debard AL, Bohe J, Bienvenu J et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Letters 2004;95:193-8.
53. Zhang Y, Li J, Lou J, Zhou Y, Bo L, Zhu J et al. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 2011;15:R70.
54. Guignant C, Lepape A, Huang X, Kherouf H, Denis L, Poitevin F et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 2011;15:R99.
55. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405-13.
56. Inoue S, Bo L, Bian J, Unsinger J, Chang K, Hotchkiss RS. Dose-dependent effect of anti-CTLA-4 on survival in sepsis. Shock 2011;36:38-44.
57. Shubin NJ, Chung CS, Heffernan DS, Irwin LR, Monaghan SF, Ayala A. BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction. J Leukocyte Biol 2012;92:593-603.
58. Squier MK, Sehnert AJ, Cohen JJ. Apoptosis in leukocytes. J Leukocyte Biol 1995;57:2-10.
59. Chung CS, Xu YX, Wang W, Chaudry IH, Ayala A. Is Fas ligand or endotoxin responsible for mucosal lymphocyte apoptosis in sepsis? Arch Surg 1998;133:1213-20.
60. Huttunen R, Syrjanen J, Vuento R, Laine J, Hurme M, Aittoniemi J. Apoptosis markers soluble Fas (sFas), Fas Ligand (FasL) and sFas/FasL ratio in patients with bacteremia: a prospective cohort study. J Infection 2012;64:276-81.
61. Cheadle WG, Pemberton RM, Robinson D, Livingston DH, Rodriguez JL, Polk HC, Jr. Lymphocyte subset responses to trauma and sepsis. J Trauma 1993;35:844-9.
62. Rajan G, Sleigh JW. Lymphocyte counts and the development of nosocomial sepsis. Int Care Med 1997;23:1187.
63. Campbell DJ, Ziegler SF. FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nat Rev Immunol 2007;7:305-10.
64. Hiraki S, Ono S, Tsujimoto H, Kinoshita M, Takahata R, Miyazaki H et al. Neutralization of interleukin-10 or transforming growth factor-beta decreases the percentages of CD4+ CD25+ Foxp3+ regulatory T cells in septic mice, thereby leading to an improved survival. Surgery 2012;151:313-22.
65. Moller HJ, Aerts H, Gronbaek H, Peterslund NA, Hyltoft Petersen P, Hornung N et al. Soluble CD163: a marker molecule for monocyte/macrophage activity in disease. Scand J Clin Lab Invest Suppl 2002;237:29-33.
66. Sulahian TH, Hogger P, Wahner AE, Wardwell K, Goulding NJ, Sorg C et al. Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 2000;12:1312-21.
67. Gaini S, Koldkjaer OG, Pedersen SS, Pedersen C, Moestrup SK, Moller HJ. Soluble haemoglobin scavenger receptor (sCD163) in patients with suspected community-acquired infections. APMIS 2006;114:103-11.
68. Gaini S, Pedersen SS, Koldkaer OG, Pedersen C, Moestrup SK, Moller HJ. New immunological serum markers in bacteraemia: anti-inflammatory soluble CD163, but not proinflammatory high mobility group-box 1 protein, is related to prognosis. Clin Experiment Immunol 2008;151:423-31.
69. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR et al. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Int Med 2007;167:1655-63. E
70. Netea MG, Kullberg BJ, Blok WL, Netea RT, van der Meer JW. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice. Blood 1997;89:577-82.
71. Leentjens J, Kox M, Koch RM, Preijers F, Joosten LA, van der Hoeven JG et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med 2012;186:838-45.
72. Dorresteijn MJ, Draisma A, van der Hoeven JG, Pickkers P. Lipopolysaccharide-stimulated whole blood cytokine production does not predict the inflammatory response in human endotoxemia. Innate Immunity 2010;16:248-53.
73. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med 2010;363:711-23.
74. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med 2012;366:2443-54.
75. Flohe S, Lendemans S, Selbach C, Waydhas C, Ackermann M, Schade FU et al. Effect of granulocyte-macrophage colony-stimulating factor on the immune response of circulating monocytes after severe trauma. Crit Care Med 2003;31:2462-9.
76. Kox WJ, Bone RC, Krausch D, Docke WD, Kox SN, Wauer H et al. Interferon gamma-1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Int Med 1997;157:389-93.
77. Bundschuh DS, Barsig J, Hartung T, Randow F, Docke WD, Volk HD et al. Granulocyte-macrophage colony-stimulating factor and IFN-gamma restore the systemic TNF-alpha response to endotoxin in lipopolysaccharide-desensitized mice. J Immunol 1997;158:2862-71.
78. Bo L, Wang F, Zhu J, Li J, Deng X. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Crit Care 2011;15:R58.
79. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009;180:640-8.
80. Flohe SB, Agrawal H, Flohe S, Rani M, Bangen JM, Schade FU. Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med 2008;14:247-56.
81. Jarvis JN, Meintjes G, Rebe K, Williams GN, Bicanic T, Williams A et al. Adjunctive interferon-gamma immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS 2012;26:1105-13.
82. Zhang Y, Zhou Y, Lou J, Li J, Bo L, Zhu K et al. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care 2010;14:R220.
83. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukocyte Biol 2010;88:233-40.
84. Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 2009;106:6303-8.
85. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011;480:480-9.
86. Iwata A, Stevenson VM, Minard A, Tasch M, Tupper J, Lagasse E et al. Over-expression of Bcl-2 provides protection in septic mice by a trans effect. J Immunol 2003;171:3136-41.
87. Chung CS, Song GY, Lomas J, Simms HH, Chaudry IH, Ayala A. Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity. J Leukocyte Biol 2003;74:344-51.
88. Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, Klender P et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 2000;1:496-501.
89. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 2011;11:330-42.
90. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 2011;144:601-13.
91. Unsinger J, Burnham CA, McDonough J, Morre M, Prakash PS, Caldwell CC et al. Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis. J Infect Dis 2012;206:606-16.
92. Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 2010;184:3768-79.
93. Venet F, Foray AP, Villars-Mechin A, Malcus C, Poitevin-Later F, Lepape A et al. IL-7 restores lymphocyte functions in septic patients. J Immunol 2012;189:5073-81.
94. Morre M, Beq S. Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival. Target Oncol 2012;7:55-68.
95. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 2007;26:503-17.
96. Maeurer MJ, Trinder P, Hommel G, Walter W, Freitag K, Atkins D et al. Interleukin-7 or interleukin-15 enhances survival of Mycobacterium tuberculosis-infected mice. Infect Immun 2000;68:2962-70.
97. Hiromatsu T, Yajima T, Matsuguchi T, Nishimura H, Wajjwalku W, Arai T et al. Overexpression of interleukin-15 protects against Escherichia coli-induced shock accompanied by inhibition of tumor necrosis factor-alpha-induced apoptosis. J Infect Dis 2003;187:1442-51.
98. Ma LL, Spurrell JC, Wang JF, Neely GG, Epelman S, Krensky AM et al. CD8 T cell-mediated killing of Cryptococcus neoformans requires granulysin and is dependent on CD4 T cells and IL-15. J Immunol 2002;169:5787-95.
99. Eckmann L, Kagnoff MF. Cytokines in host defense against Salmonella. Microbes and infection Institut Pasteur 2001;3:1191-200.
100. Inoue S, Unsinger J, Davis CG, Muenzer JT, Ferguson TA, Chang K et al. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis. J Immunol 2010;184:1401-9.
101. Sherwood ER, Williams DL, McNamee RB, Jones EL, Browder IW, Di Luzio NR. Enhancement of interleukin-1 and interleukin-2 production by soluble glucan. Int J Immunopharmacol 1987;9:261-7.
102. Tzianabos AO. Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function. Clin Microbiol Rev 2000;13:523-33.
103. Onderdonk AB, Cisneros RL, Hinkson P, Ostroff G. Anti-infective effect of poly-beta 1-6-glucotriosyl-beta 1-3-glucopyranose glucan in vivo. Infect Immun 1992;60:1642-7.
104. Adams DS, Pero SC, Petro JB, Nathans R, Mackin WM, Wakshull E. PGG-Glucan activates NF-kappaB-like and NF-IL-6-like transcription factor complexes in a murine monocytic cell line. J Leukocyte Biol 1997;62:865-73.
105. Nakagawa Y, Ohno N, Murai T. Suppression by Candida albicans beta-glucan of cytokine release from activated human monocytes and from T cells in the presence of monocytes. J Infect Dis 2003;187:710-3.
106. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 1994;271:698-702.
107. Shann F. The non-specific effects of vaccines. Arch Dis Childhood 2010;95:662-7.
108. Ritz N, Mui M, Balloch A, Curtis N. Non-specific effect of Bacille Calmette-Guerin vaccine on the immune response to routine immunisations. Vaccine 2013;31:3098-103.
109. Roth A, Jensen H, Garly ML, Djana Q, Martins CL, Sodemann M et al. Low birth weight infants and Calmette-Guerin bacillus vaccination at birth: community study from Guinea-Bissau. Pediatric Infect Dis J 2004;23:544-50.
110. Breiman RF, Streatfield PK, Phelan M, Shifa N, Rashid M, Yunus M. Effect of infant immunisation on childhood mortality in rural Bangladesh: analysis of health and demographic surveillance data. Lancet 2004;364:2204-11.
111. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ 2000;321:1435-8.
112. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245-52.
113. Shann F, Nohynek H, Scott JA, Hesseling A, Flanagan KL, Working Group on Nonspecific Effects of V. Randomized trials to study the nonspecific effects of vaccines in children in low-income countries. Pediatric Infect Dis J 2010;29:457-61.
114. Sylvester RJ, van der MA, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964-70.
115. Kolmel KF, Grange JM, Krone B, Mastrangelo G, Rossi CR, Henz BM et al. Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients. Eur J Cancer 2005;41:118-25.
116. El-Zein M, Parent ME, Benedetti A, Rousseau MC. Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta-analysis of epidemiological studies. Int J Epidemiol 2010;39:469-86.
117. Huppmann M, Baumgarten A, Ziegler AG, Bonifacio E. Neonatal Bacille Calmette-Guerin vaccination and type 1 diabetes. Diab Care 2005;28:1204-6.
118. Kleinnijenhuis J, Quintin J, Preijers F, Joosten LA, Ifrim DC, Saeed S et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A 2012;109:17537-42.
119. Netea MG, Quintin J, van der Meer JW. Trained immunity: a memory for innate host defense. Cell Host Microbe 2011;9:355-61.