Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 1,442

The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.

Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach

Open access
Hotchkiss, Richard S, Monneret, Guillaume, Payen, Didier·2013·The Lancet Infectious Diseases
DOI 10.1016/s1473-3099(13)70001-x
Open this paper in CoChat — free account

Abstract

Failures of highly touted trials have caused experts to call for re-evaluation of the current approach toward sepsis. New research has revealed key pathogenic mechanisms; autopsy results have shown that most patients admitted to intensive care units for treatment of sepsis had unresolved septic foci at post mortem, suggesting that patients were unable to eradicate invading pathogens and were more susceptible to nosocomial organisms, or both. These results suggest that therapies that improve host immunity might increase survival. Additional work showed that cytokine production by splenocytes taken post mortem from patients who died of sepsis is profoundly suppressed, possibly because of so-called T-cell exhaustion—a newly recognised immunosuppressive mechanism that occurs with chronic antigenic stimulation. Results from two clinical trials of biomarker-guided therapeutic drugs that boosted immunity showed promising findings in sepsis. Collectively, these studies emphasise the degree of immunosuppression that occurs in sepsis, and explain why many previous sepsis trials which were directed at blocking inflammatory mediators or pathogen recognition signalling pathways failed. Finally, highly encouraging results from use of the new immunomodulatory molecules interleukin 7 and anti-programmed cell death 1 in infectious disease point the way for possible use in sepsis. We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s1473-3099(13)70001-x

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 7 references

Research works printed but not linked: 77

  1. Cohen, 2012, Sepsis studies need new direction, Lancet Infect Dis, 12, 503, 10.1016/S1473-3099(12)70136-6 · DOI
  2. Wenzel, 2012, Septic shock: evaluating another failed treatment, N Engl J Med, 366, 2122, 10.1056/NEJMe1203412 · DOI
  3. Williams, 2012, After Xigris, researchers look to new targets to combat sepsis, Nat Med, 18, 1001, 10.1038/nm0712-1001 · doi:10.1038/nm0712-1001
  4. Dolgin, 2012, Trial failure prompts soul-searching for critical-care specialists, Nat Med, 18, 1000, 10.1038/nm0712-1000 · doi:10.1038/nm0712-1000
  5. Angus, 2011, The search for effective therapy for sepsis: back to the drawing board?, JAMA, 306, 2614, 10.1001/jama.2011.1853 · DOI · Paper page
  6. Vincent, 2012, The rise and fall of drotrecogin alfa (activated), Lancet Infect Dis, 12, 649, 10.1016/S1473-3099(12)70175-5 · doi:10.1016/s1473-3099(12)70175-5
  7. Torgersen, 2009, Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis, Anesth Analg, 108, 1841, 10.1213/ane.0b013e318195e11d · DOI · Paper page
  8. Boomer, 2011, Immunosuppression in patients who die of sepsis and multiple organ failure, JAMA, 306, 2594, 10.1001/jama.2011.1829 · DOI · Paper page
  9. Meisel, 2009, Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial, Am J Respir Crit Care Med, 180, 640, 10.1164/rccm.200903-0363OC · DOI · Paper page
  10. Hall, 2011, Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome, Intensive Care Med, 37, 525, 10.1007/s00134-010-2088-x · DOI · Paper page
  11. Unsinger, 2010, IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis, J Immunol, 184, 3768, 10.4049/jimmunol.0903151 · DOI · Paper page
  12. Cheever, 2008, Twelve immunotherapy drugs that could cure cancers, Immunol Rev, 222, 357, 10.1111/j.1600-065X.2008.00604.x · DOI · Paper page
  13. Hotchkiss, 2003, The pathophysiology and treatment of sepsis, N Engl J Med, 348, 138, 10.1056/NEJMra021333 · DOI · Paper page
  14. van Dissel, 1998, Anti-inflammatory cytokine profile and mortality in febrile patients, Lancet, 351, 950, 10.1016/S0140-6736(05)60606-X · doi:10.1016/s0140-6736(05)60606-x · Paper page
  15. Ertel, 1995, Downregulation of proinflammatory cytokine release in whole blood from septic patients, Blood, 85, 1341, 10.1182/blood.V85.5.1341.bloodjournal8551341 · DOI · Paper page
  16. Munoz, 1991, Dysregulation of in vitro cytokine production by monocytes during sepsis, J Clin Invest, 88, 1747, 10.1172/JCI115493 · DOI · Paper page
  17. Rigato, 2003, Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin 10 in whole blood of patients with sepsis, Shock, 19, 113, 10.1097/00024382-200302000-00004 · DOI
  18. Sinistro, 2008, Downregulation of CD40 ligand response in monocytes from sepsis patients, Clin Vaccine Immunol, 15, 1851, 10.1128/CVI.00184-08 · DOI
  19. Weighardt, 2000, Sepsis after major visceral surgery is associated with sustained and interferon-gamma-resistant defects of monocyte cytokine production, Surgery, 127, 309, 10.1067/msy.2000.104118 · DOI
  20. Barochia, 2010, Bundled care for septic shock: an analysis of clinical trials, Crit Care Med, 38, 668, 10.1097/CCM.0b013e3181cb0ddf · DOI · Paper page
  21. Monneret, 2008, Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony, Mol Med, 14, 64, 10.2119/2007-00102.Monneret · DOI · Paper page
  22. Hotchkiss, 2009, Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction, Crit Care Med, 27, 1230, 10.1097/00003246-199907000-00002 · DOI · Paper page
  23. Fink, 2002, Mechanisms of organ dysfunction in critical illness: report from a round table conference held in Brussels, Intensive Care Med, 28, 369, 10.1007/s00134-001-1205-2 · DOI
  24. Abraham, 2007, Mechanisms of sepsis-induced organ dysfunction, Crit Care Med, 35, 2408, 10.1097/01.CCM.0000282072.56245.91 · DOI · Paper page
  25. Kethireddy, 2012, Mortality due to septic shock following early, appropriate antibiotic therapy: can we do better?, Crit Care Med, 40, 2228, 10.1097/CCM.0b013e318256bb99 · doi:10.1097/ccm.0b013e318256bb99
  26. Otto, 2011, The late phase of sepsis is characterized by an increased microbiological burden and death rate, Crit Care, 15, R183, 10.1186/cc10332 · DOI · Paper page
  27. Martin, 2006, The effect of age on the development and outcome of adult sepsis, Crit Care Med, 34, 15, 10.1097/01.CCM.0000194535.82812.BA · DOI · Paper page
  28. Reber, 2012, Immunosenescence and challenges of vaccination against influenza in the aging population, Aging Dis, 3, 68
  29. Meakins, 1977, Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma, Ann Surg, 186, 241, 10.1097/00000658-197709000-00002 · DOI · Paper page
  30. Hotchkiss, 2001, Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans, J Immunol, 166, 6952, 10.4049/jimmunol.166.11.6952 · DOI · Paper page
  31. Hotchkiss, 2002, Depletion of dendritic cells, but not macrophages, in patients with sepsis, J Immunol, 168, 2493, 10.4049/jimmunol.168.5.2493 · DOI · Paper page
  32. Felmet, 2005, Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure, J Immunol, 174, 3765, 10.4049/jimmunol.174.6.3765 · DOI · Paper page
  33. Toti, 2004, Spleen depletion in neonatal sepsis and chorioamnionitis, Am J Clin Pathol, 122, 765, 10.1309/RV6E9BMC9954A2WU · doi:10.1309/rv6e9bmc9954a2wu
  34. Venet, 2008, Regulatory T cell populations in sepsis and trauma, J Leukoc Biol, 83, 523, 10.1189/jlb.0607371 · DOI · Paper page
  35. Venet, 2009, Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients, Intensive Care Med, 35, 678, 10.1007/s00134-008-1337-8 · DOI · Paper page
  36. Leng, 2012, Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during the early-stage sepsis in ICU patients, J Microbiol Immunol Infect
  37. Delano, 2007, MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis, J Exp Med, 204, 1463, 10.1084/jem.20062602 · DOI · Paper page
  38. Hotchkiss, 1999, Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis, J Immunol, 162, 4148, 10.4049/jimmunol.162.7.4148 · DOI · Paper page
  39. Hotchkiss, 1999, Prevention of lymphocyte cell death in sepsis improves survival in mice, Proc Natl Acad Sci USA, 96, 14541, 10.1073/pnas.96.25.14541 · DOI · Paper page
  40. Wesche-Soldato, 2007, The apoptotic pathway as a therapeutic target in sepsis, Curr Drug Targets, 8, 493, 10.2174/138945007780362764 · DOI
  41. Kollef, 2008, Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria, Chest, 134, 281, 10.1378/chest.08-1116 · DOI · Paper page
  42. Luyt, 2007, Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation, Am J Respir Crit Care Med, 175, 935, 10.1164/rccm.200609-1322OC · DOI · Paper page
  43. Limaye, 2008, Cytomegalovirus reactivation in critically ill immunocompetent patients, JAMA, 300, 413, 10.1001/jama.2008.697 · DOI · Paper page
  44. Xiao, 2011, A genomic storm in critically injured humans, J Exp Med, 208, 2581, 10.1084/jem.20111354 · DOI · Paper page
  45. Boomer, 2012, A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis, Crit Care, 16, R112, 10.1186/cc11404 · DOI · Paper page
  46. Lukaszewicz, 2009, Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction, Crit Care Med, 37, 2746
  47. Venet, 2011, Clinical review: flow cytometry perspectives in the ICU - from diagnosis of infection to monitoring of injury-induced immune dysfunctions, Crit Care, 15, 231, 10.1186/cc10333 · DOI
  48. Guignant, 2011, Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients, Crit Care, 15, R99, 10.1186/cc10112 · DOI · Paper page
  49. Monneret, 2010, Additional bad news from regulatory T cells in sepsis, Crit Care, 14, 453, 10.1186/cc9357 · doi:10.1186/cc9357
  50. Belikova, 2007, Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis, Crit Care Med, 35, 2702
  51. Sprent, 2012, Interleukin 7, maestro of the immune system, Semin Immunol, 24, 149, 10.1016/j.smim.2012.04.011 · doi:10.1016/j.smim.2012.04.011
  52. Mackall, 2011, Harnessing the biology of IL-7 for therapeutic application, Nat Rev Immunol, 11, 330, 10.1038/nri2970 · DOI · Paper page
  53. Kim, 2008, IL-7 and IL-15: biology and roles in T-cell immunity in health and disease, Crit Rev Immunol, 28, 325, 10.1615/CritRevImmunol.v28.i4.40 · DOI
  54. Morre, 2012, Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival, Target Oncol, 7, 55, 10.1007/s11523-012-0210-4 · DOI
  55. Rosenberg, 2006, IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells, J Immunother, 29, 313, 10.1097/01.cji.0000210386.55951.c2 · DOI · Paper page
  56. Levy, 2012, Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study, Clin Infect Dis, 55, 291, 10.1093/cid/cis383 · DOI · Paper page
  57. Pellegrini, 2011, IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology, Cell, 144, 601, 10.1016/j.cell.2011.01.011 · DOI · Paper page
  58. Kasten, 2010, Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis, Infect Immun, 78, 4714, 10.1128/IAI.00456-10 · DOI
  59. Patel, 2010, A case of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia, J Antimicrob Chemother, 65, 2697, 10.1093/jac/dkq359 · doi:10.1093/jac/dkq359
  60. Unsinger, 2012, Interleukin-7 ameliorates immune dysfunction and improves survival in a 2-hit model of fungal sepsis, J Infect Dis, 206, 606, 10.1093/infdis/jis383 · DOI
  61. Venet, 2012, IL-7 restores lymphocyte functions in septic patients, J Immunol, 189, 5073, 10.4049/jimmunol.1202062 · DOI · Paper page
  62. Nishimura, 2001, Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice, Science, 291, 319, 10.1126/science.291.5502.319 · DOI · Paper page
  63. Sharpe, 2007, The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection, Nat Immunol, 8, 239, 10.1038/ni1443 · DOI · Paper page
  64. Huang, 2009, PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis, Proc Natl Acad Sci USA, 106, 6303, 10.1073/pnas.0809422106 · DOI · Paper page
  65. Brahmamdam, 2010, Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis, J Leukoc Biol, 88, 233, 10.1189/jlb.0110037 · DOI · Paper page
  66. Zhang, 2010, PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction, Crit Care, 14, R220, 10.1186/cc9354 · DOI · Paper page
  67. Nalos, 2012, Immune effects of interferon gamma in persistent staphylococcal sepsis, Am J Respir Crit Care Med, 185, 110, 10.1164/ajrccm.185.1.110 · DOI
  68. Inoue, 2010, IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis, J Immunol, 184, 1401, 10.4049/jimmunol.0902307 · DOI · Paper page
  69. Adler, 2011, B and T lymphocyte attenuator restricts the protective immune response against experimental malaria, J Immunol, 187, 5310, 10.4049/jimmunol.1101456 · DOI
  70. Shubin, 2012, BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction, J Leukoc Biol, 92, 593, 10.1189/jlb.1211641 · DOI
  71. Hotchkiss, 2010, Immunotherapy for sepsis—a new approach against an ancient foe, N Engl J Med, 363, 87, 10.1056/NEJMcibr1004371 · DOI · Paper page
  72. Ward, 2011, Immunosuppression in sepsis, JAMA, 306, 2618, 10.1001/jama.2011.1831 · DOI
  73. Christaki, 2011, Immunomodulatory therapy for sepsis: an update, Expert Rev Anti Infect Ther, 9, 1013, 10.1586/eri.11.122 · DOI
  74. Stearns-Kurosawa, 2011, The pathogenesis of sepsis, Annu Rev Pathol, 6, 19, 10.1146/annurev-pathol-011110-130327 · DOI · Paper page
  75. Waterer, 2012, Community-acquired pneumonia: genomics, epigenomics, transcriptomics, proteomics, and metabolomics, Semin Respir Crit Care Med, 33, 257, 10.1055/s-0032-1315637 · doi:10.1055/s-0032-1315637
  76. Nelson, 1998, A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia, J Infect Dis, 178, 1075, 10.1086/515694 · DOI · Paper page
  77. Root, 2003, Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis, Crit Care Med, 31, 367, 10.1097/01.CCM.0000048629.32625.5D · DOI · Paper page

Cited by

See all 1,442

Metadata

Authors
Hotchkiss, R. S., Monneret, G., & Payen, D.
Venue
The Lancet Infectious Diseases
Publisher
Elsevier BV
Published
2013-03
Volume
13
Issue
3
Pages
260-268
ISSN
1473-3099 (ISSN-L)
DOI
10.1016/s1473-3099(13)70001-x
OpenAlex
W2097476575
Cited by
1,442
References
7
FWCI
79.56
Type
journal article
Language
en
Open access
green
Licence
  • www.elsevier.com/tdm/userlicense/1.0/ (tdm)
  • www.elsevier.com/legal/tdmrep-license (tdm)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. https://app.cochat.ai/papers/10.1016/s1473-3099(13)70001-x
The paper
Hotchkiss, R. S., Monneret, G., & Payen, D. (2013). Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. The Lancet Infectious Diseases. https://doi.org/10.1016/s1473-3099(13)70001-x

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.