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. 2023 Nov 8;27(2):63–70. doi: 10.1016/j.cjtee.2023.11.001

Clinical practice of sepsis-induced immunosuppression: Current immunotherapy and future options

Fei Pei a,b, Bin Gu a,b, Shu-Min Miao a,b, Xiang-Dong Guan a,b, Jian-Feng Wu a,b,∗
PMCID: PMC11075145  PMID: 38040590

Abstract

Sepsis is a potentially fatal condition characterized by the failure of one or more organs due to a disordered host response to infection. The development of sepsis is closely linked to immune dysfunction. As a result, immunotherapy has gained traction as a promising approach to sepsis treatment, as it holds the potential to reverse immunosuppression and restore immune balance, thereby improving the prognosis of septic patients. However, due to the highly heterogeneous nature of sepsis, it is crucial to carefully select the appropriate patient population for immunotherapy. This review summarizes the current and evolved treatments for sepsis-induced immunosuppression to enhance clinicians' understanding and practical application of immunotherapy in the management of sepsis.

Keywords: Sepsis, Sepsis-induced immunosuppression, Immunotherapy, Enrichment, Classifier

1. Introduction

Sepsis is a life-threatening condition characterized by organ dysfunction due to a disordered host response to infection.1 It is a major global health concern affecting 50 million people annually and leading to over 11 million deaths.2 Despite the standard treatment approach that includes antibacterial agents, fluid resuscitation, and organ function support, sepsis continues to have high overall mortality, highlighting the need for a new therapeutic approach.3 Immune dysfunction is an important factor in the development and progression of sepsis, as patients present with hyperinflammatory response and/or immunosuppression.4, 5, 6 A hyperinflammatory response initiates tissue damage and organ injury, while immunosuppression exacerbates lethal complications, increasing overall mortality throughout sepsis.7, 8, 9 However, the implementation of anti-inflammatory strategies in clinical trials has not proven to be effective. In recent years, there has been growing interest in approaches that can effectively address immunosuppression in patients with sepsis.4,5,10 The main mechanism of sepsis-induced immunosuppression is an imbalance of immune homeostasis, manifested by an excessive inflammatory response and a depressed immune response.11,12 Under immune homeostasis conditions, immune cells in contact with pathogen-associated-molecular patterns and damage-associated molecular patterns cause immune cells activation and release of inflammatory cytokines that promote the immune system to eliminate pathogenic microorganisms.11,12 Following the initiation of sepsis, the excessive release of inflammatory cytokines in some patients has the potential to induce immune cell exhaustion and diminished function as a consequence of persistent activation, ultimately culminating in tissue damage and organ failure. Enhancing immune cell function through the amelioration of immune cells exhaustion and diminished function holds the potential to eradicate pathogenic microorganisms and mitigate secondary infections, thereby leading to reduced mortality rates.5,12 Immunotherapy offers a promising alternative for sepsis-induced immunosuppression, as it reinstates immune homeostasis and counteracts immunosuppressive effects. This review provides an overview of the current and future treatments for sepsis-induced immunosuppression and supports the use of immunotherapy as a promising option for sepsis treatment in clinical practice.

2. Current immunotherapy for sepsis-induced immunosuppression

Administering immunotherapy for sepsis has become a widely researched area in recent years, with several immunomodulatory drugs entering clinical trials.4,5,13,14 These drugs include intravenous immunoglobulin (IVIG), recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), thymosin α1 (Tα1), recombinant interleukin-7 (rIL-7), anti-programmed death (PD)-1 or anti-PD-ligand (L) 1 antibodies, recombinant interferon-γ (rIFN-γ) and mesenchymal stem cells (MSCs) (Table 1).5,8,15

Table 1.

Current advances in immunotherapy for sepsis.

Drugs Mechanisms Clinical evidences Ongoing trials Potential side effects
IVIG/IVIGMA Improve phagocytic ability, neutralize endotoxin,
attenuate neutrophil apoptosis18,78, 79, 80, 81 		IVIG does not reduce mortality,
IVIGMA potential reduce mortality20, 21, 22, 23,82, 83, 84, 85, 86 		NCT04182737 Skin reactions, heart failure, and pleural effusion20,21
rGM-CSF Enhance phagocytosis and cytokine release, promote proliferation of immune cells28, 29, 30, 31, 32 Do not reduce mortality, improve mHLA-DR expression,
reduce secondary infection29,35,36 		NCT02361528 Fever, rash, thrombocytopenia; nausea29,34
Tα1 Activate natural immune cells, stimulate T cell proliferation,
enhance antibacterial ability,
reverse T cell exhaustion37,40, 41, 42,87, 88, 89, 90, 91, 92 		Reduce mortality, improve mHLA-DR expression,
mitigate excessive inflammation43,45,47 		NCT02867267 Not reported45
rIL-7 Promote proliferation of lymphocyte, reduce lymphocyte apoptosis48, 49, 50, 51 Increase the count and function of lymphocyte50 NCT03821038 Fever, injection site reactions50,93
Anti-PD-(L)1 Restore immune function, reverse immune cell exhaustion55, 56, 57, 58, 59, 60 No drug-induced cytokine storm and unexpected safety incidents were found64,65 – Not reported64,65
rIFN-γ Enhance phagocytosis and cytokine release66,68,69,94,95 Improve mHLA-DR expression66,68 NCT03332225 Potential cytokine storm69
MSCs Improve bacterial clearance, modulate immune responses,
reduce cell apoptosis, promote damage repair70, 71, 72, 73, 74, 75, 76 		No inflammatory storm77 NCT03369275
NCT02883803 		Not reported77
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IVIG: intravenous immunoglobulin; IVIGMA: IVIG enriched with IgM and IgA; rGM-CSF: recombinant granulocyte-macrophage colony-stimulating factor; Tα1: thymosin α1; rIL-7: recombinant interleukin-7; PD-(L)1: programmed cell death (1 ligand) 1; rIFN-γ: recombinant interferon-γ; MSCs: mesenchymal stem cells.

2.1. IVIG

Immunoglobulin (Ig) is a macromolecular protein produced by B cells. It is composed of several types of antibodies, such as IgG, IgM, and IgA, which are extracted from blood plasma.16 A meta-analysis reported that about 70% of septic patients present with low plasma IG on the day of sepsis onset.17 Given this finding, IVIG was used in clinical trials to evaluate the therapeutic potential in sepsis patients.18,19 The score-based IG therapy of sepsis20 (n = 624) and early supplemental severe systemic inflammatory response syndrome treatment with IVIG in score-identified high-risk patients after cardiac surgery21 (n = 218) trials are 2 large randomized controlled trials (RCTs) that have studied the efficiency of IVIG for sepsis. The score-based IG therapy of sepsis trial administered IgG twice when enrollment (initial 0.6 g/kg and then 0.3 g/kg), and found no prognostic benefit for septic patients. At the same time, the early supplemental severe systemic inflammatory response syndrome treatment with IVIG in score-identified high-risk patients after cardiac surgery trial enrolled 218 cardiac surgery patients with a hyperinflammatory response and the IgG for patients with necrotizing soft tissue infection trial enrolled 100 patients with skin and soft tissue infections also found the similar results.21,22 Interestingly, a meta-analysis of 10 clinical studies with polyclonal IVIG (n = 1430) and 7 studies using IgM-enriched IVIG (IVIGM) (n = 528) found that IVIG reduced the 28 – 180 days mortality of septic patients, but both IVIG and IVIGM studies were found to have a moderate to high risk of bias.23 However, another meta-analysis included only high-quality studies that found no improvement in the prognosis of sepsis patients when treated with IVIG.24 Thus, the surviving sepsis campaign guidelines do not recommend IVIG for sepsis treatment, but further research is required.3 In recent years, IVIG enriched with IgM and IgA (IVIGMA) was used to treat septic patients with chemotherapy-induced neutropenia but found no improvement in the prognosis.25 On the contrary, when IVIGMA was applied to patients with community-acquired pneumonia, subgroup analysis revealed IVIGMA reduced mortality in patients with elevated C-reactive protein levels and low IgM.26 Then, a recent meta-analysis of 5 clinical studies indicated that IVIG treatment reduced mortality in patients with streptococcal toxic shock syndrome.27 Therefore, the efficacy of IVIG may depend on the characteristics of the infection and the pathogens involved, and this is worthy of further clinical confirmation.

2.2. rGM-CSF

As a growth factor, granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes the growth and differentiation of immune cells such as granulocytes and myeloid stem cells.28, 29, 30, 31, 32 Given its important role, clinical trials of rGM-CSF were conducted in sepsis patients in the early 2000s. In 2002, a phase II study in septic patients showed that low-dose (3 μg/kg) intravenous infusions of GM-CSF improved the oxygenation index within 5 days of treatment, but did not reduce the 30-day mortality.33 In 2006, Orozco et al.34 conducted a RCT using rGM-CSF (3 μg/kg/day) to treat sepsis and abdominal infections. The study found rGM-CSF reduced the antibiotic duration and infection-induced complications but did not improve overall survival. In 2009, Meisel et al.35 conducted a RCT using rGM-CSF (4 μg/kg/day) and observed significant increases in monocyte human leukocyte antigen (mHLA)-DR and reductions in the duration of a ventilator, hospital stay, and intensive care unit stay. A meta-analysis included 2380 patients with sepsis who received rGM-CSF showed no improvement in the overall prognosis, and subgroup analysis revealed that rGM-CSF enhanced pathogenic bacteria clearance.36 Then, Pinder et al.29 designed a study to evaluate the effect of rGM-CSF treatment in increasing neutrophil phagocytosis and found that neutrophil phagocytosis enhanced in over half of patients in rGM-CSF group, while only 44% in the control group. These findings suggest that rGM-CSF may improve phagocytosis and potentially reduce secondary infections in patients with sepsis. Notably, cytokine levels need to be monitored dynamically during the treatment.

2.3. Tα1

Tα1 plays a crucial role in the regulation of innate and adaptive immune systems.37 As an immunomodulatory peptide, Tα1 has multiple effects on the immune system during infections, including the promotion of naive T cell maturation38, reversal of T cell depletion39, alleviation of cytokine storms40,41, and enhancement of Th1-dependent antifungal immunity42. In the last 2 decades, several studies were conducted to evaluate the value of Tα1 in sepsis.43, 44, 45 In 2007, a multicenter RCT was conducted in China to assess the efficacy of Tα1 and ulinastatin in sepsis.46 The trial designed 2 phases based on the dose of drugs. In the first phase, septic patients in the treatment group received 100,000 units ulinastatin 3 times per day and 1.6 mg Tα1 once daily. Unfortunately, the 28-day mortality between the treatment and the control groups was not significantly different. Then, the second phase doubled the doses of the therapeutic drugs. The results showed that the treatment significantly reduced the short mortality (28-day and 90-day) compared to the control group. In 2013, another multicenter RCT was conducted to evaluate the efficacy of Tα1 in sepsis.45 This study also demonstrated that Tα1 can improve the survival of patients with sepsis. Similarly, meta-analysis further confirmed that Tα1 can reduce the mortality of patients with sepsis.47 Recently, a large, multicenter, randomized, double-blind, controlled trial was designed to evaluate the efficacy of Tα1 for sepsis (ClinicalTrials number: NCT02867267). These current available findings suggest that Tα1 can benefit patients with sepsis, but the mechanism needs to be further explored.

2.4. rIL-7

rIL-7 improves the lymphocyte count by fostering lymphopoiesis and suppressing lymphocyte apoptosis.48, 49, 50, 51 A phase II, randomized, double-blind, controlled clinical trial investigating the safety and efficacy of rIL-7 treatment in septic patients was recently completed.50 The study enrolled 27 septic shock patients with severe lymphopenia and evaluated the impact of rIL-7 on lymphopoiesis. The results showed that rIL-7 treatment did not induce a hyperinflammatory response or worsen organ dysfunction. Additionally, the total lymphocyte counts and lymphocyte subset (CD4+ and CD8+ T cells) significantly increased in septic patients after rIL-7 treatment, and the activated T cells displayed good functionality. However, the efficacy of rIL-7 in reversing sepsis-induced organ dysfunction and reducing sepsis-related mortality still requires further evaluation through phase II/III clinical trials (ClinicalTrials number: NCT03821038).

2.5. Anti-PD-1 and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies

Anti-PD-1 and anti-PD-L1 antibodies have been used as a novel form of immunotherapy for tumors, as they restore T cell function by blocking the PD-1/PD-L1 pathway.52, 53, 54 This is because both sepsis and cancer share similar immune mechanisms, including lymphocyte depletion.55, 56, 57, 58, 59, 60 Therefore, novel immunotherapy is being evaluated for use in sepsis-induced immunosuppression through clinical trials.61, 62, 63 A recent phase I RCT assessed the safety of anti-PD-L1 antibody in sepsis treatment.64 The study enrolled 24 patients with sepsis-induced immunosuppression whose lymphocyte count was lower than 1.1 × 109/L. Participants were randomized into the treatment group and the placebo group. Results showed that treatment with anti-PD-L1 antibody significantly increased mHLA-DR expression and maintained it for over 28 days, without causing an increase in cytokine levels. Another phase I, multicenter RCT assessed the safety of anti-PD-1 antibody in sepsis treatment, enrolling 31 patients with decreased lymphocyte count (absolute lymphocyte count ≤ 1.1 × 109/L).65 Participants were randomized into 2 dose groups (480 – 960 mg) and received a single-dose intravenous infusion for 90 min. The study showed that anti-PD-1 antibody did not cause any unexpected adverse events or severe inflammatory responses, and improved mHLA-DR expression in both dose groups. Although these studies suggest the preliminary safety of anti-PD-1 and anti-PD-L1 antibodies in the treatment of sepsis-induced immunosuppression, further investigation through phase II/III clinical trials is necessary to confirm their safety and efficacy.

2.6. rIFN-γ

rIFN-γ is an important cytokine released by immune cells that promotes the clearance of pathogenic microorganisms by increasing the phagocytic bactericidal capacity of macrophages.12,66 However, when immunocompromised, interferon release is reduced, resulting in rapid progression of infection.67 As early as the end of the 20th century, a study recruited 9 patients with low mHLA-DR expression and found that rIFN-γ treatment significantly up-regulated mHLA-DR expression, increased monocyte secretion of TNF-α, and enhanced pathogenic bacteria clearance.66 Case series demonstrated that rIFN-γ treatment improved host immune defense in immunosuppressed septic patients, and the treatment was well tolerated.68,69 An ongoing large clinical trial (ClinicalTrials number: NCT03332225) is currently designed to further confirm the value of rIFN-γ in improving sepsis-induced immunosuppression. In terms of safety, rIFN-γ, similar to rGM-CSF, may induce an inflammatory storm, which is a concern.

2.7. MSCs

MSCs can reverse immune dysfunction in sepsis by improving bacterial clearance, modulating immune responses, reducing apoptosis, and promoting damage repair.70, 71, 72, 73, 74, 75, 76 A clinical trial in 9 patients with sepsis demonstrated that MSCs do not induce an elevation of inflammatory cytokines, suggesting that the administration of MSCs in patients with sepsis is safe.77 Currently, 2 ongoing phase II RCTs are aimed at evaluating the role of MSCs on the immune response and organ failure in patients with infectious shock (ClinicalTrials number: NCT03369275, NCT02883803). In summary, the safety of MSCs has been preliminarily demonstrated in the current phase I clinical studies, and we look forward to more clinical trials to confirm the efficacy of MSCs in reversing immune dysfunction in sepsis.

3. Future immunotherapy strategies

The efficacy of existing immunomodulatory drugs for sepsis-induced immunosuppression is not universally applicable to all sepsis patients. Consequently, it is imperative to establish more precise criteria for determining the appropriate patient population for each drug. Currently, the prevailing method involves employing biomarkers to identify eligible individuals. The 2 most commonly used immune monitoring biomarkers in clinical practice are the mHLA-DR and lymphocyte count.96, 97, 98, 99 These are widely used in clinical trials to assess the immune status of patients with sepsis.100, 101, 102, 103 In a clinical trial, rGM-CSF was used for sepsis treatment. This study not only identified septic patients with immunosuppression by mHLA-DR (below 8000 antibodies/cell) for 2 consecutive days, but also took mHLA-DR over 15,000 antibodies/cell as the treatment endpoint for administering rGM-CSF.35 Cheng et al.104 selected patients with COVID-19 and lymphocyte counts below 800/μL for treatment with rGM-CSF. Another study selected septic patients with lymphocyte counts below 900/μL for treatment with rIL-7 and continuously monitored changes in lymphocyte count.50 Although several clinical monitoring indicators, such as mHLA-DR and lymphocyte count, have been applied to identify sepsis-induced immunosuppression, they still cannot perfectly reflect the immune status of septic patients.105,106 Recently, omics approaches have been utilized to study immune monitoring and identify more precise sepsis-related biomarkers, but these approaches require validation through large-scale clinical trials.107,108 In addition to precise biomarkers, it is important to note that these biomarkers can be affected by many confounding factors, such as age and disease status, so specific therapy strategies for immunotherapy are required in the future.

3.1. Enrichment strategy

Classifying patients with sepsis based on indicators such as pathophysiology and clinical characteristics can aid in selecting a homogeneous patient population for research and evaluating drug efficacy in clinical settings.109 Enrichment strategies, which select patients most likely to respond to investigational drug treatment based on patient characteristics, diseases, or medications, can improve the efficiency of a study (Fig. 1).110 As sepsis is a highly heterogeneous clinical syndrome, high-dimensional data analysis is necessary to understand its complexity and to objectively evaluate the effects of medications.111 Thus, enrichment strategies are effective for patient selection in therapeutic clinical trials of highly heterogeneous syndromes. Wong et al.112 conducted a post-hoc analysis of 288 children with septic shock and found that children with type B septic shock (compared with type A, classified based on the genetic characteristics of adaptive immunity and glucocorticoid receptor signals) were more likely to benefit from corticosteroid therapy. The ongoing personalized immunotherapy in sepsis study is a phase II randomized, placebo-controlled trial evaluating the efficacy of personalized immunotherapy for patients with sepsis and macrophage activation-like syndrome or immunoparalysis.113 In this study, immunotherapy regimens will be assigned based on patients' specific immunotypes, with patients with macrophage activation-like syndrome receiving IL-1 antagonist treatment and patients with immunoparalysis receiving rINF-γ treatment. Compared to inflexible immunotherapy regimens, immunotype-based immunotherapy has the potential to provide greater therapeutic benefits for patients with sepsis. The adoption of enrichment strategies in selecting the appropriate treatment population can further improve therapeutic outcomes in patients with sepsis.

Fig. 1.

Fig. 1

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Future immunotherapy strategy for sepsis. “Enrichment strategy” refers to the treatment of different subgroups, which are classified based on clinical characteristics, biological features, and the clinical course of a disease. “Classifier strategy”, on the other hand, involves treating patients based on their therapeutic responsiveness to specific immune drugs. In this approach, clinical characteristics, biological features, and omics information are used to identify the characteristics of therapeutic responsiveness and establish a classifier for the specific immune drug.

3.2. Classifier strategy

Cancer and sepsis are complex diseases with high levels of heterogeneity. To select the best patients for clinical treatment, multi-omics approaches are commonly utilized to categorize patients based on their response to treatment. These approaches are essential tools in identifying reliable and effective markers, as they help in gaining a complete understanding of the molecular mechanism underlying the disease and determining the right therapy strategy. The VeriStrat plasma test is one such example, which selects patients to receive epidermal growth factor receptor tyrosine kinase inhibitors based on their serum proteomic profile.114, 115, 116 This test classifies patients as “Good” or “Poor” based on the analysis of 8 signature peptide peaks, and predicts overall survival and progression-free survival in patients with non-small cell lung cancer. Several validation studies have shown that patients with “Good” ratings have significantly higher overall survival and progression-free survival compared to those with “Poor” ratings.114, 115, 116 A study published in Cell presents a resource of Staphylococcus aureus bacteremia (SaB) prognostic biomarkers. In this study, proteomic and metabolomic techniques were used to analyze serum samples from 25 uninfected controls, 99 SaB survivors, and 76 fatalities.117 Over 10,000 characteristic markers were screened and analyzed in-depth. The study evaluated serum complexity using multiple computational strategies, providing a comprehensive view of the early host response to infection. The biomarkers identified in this study exceeded the predictive capabilities of previously reported biomarkers, supporting the development of the enrichment strategy. The use of multiple biomarkers can help identify high-risk patients early enough to trigger immunotherapy. In conclusion, multi-omics approaches can aid in the development of specific classification tests for the selection of immunotherapy drugs for sepsis.

In summary, the enrichment strategy is suitable as an initial screening strategy for the assessment of immune status for grouping patients with sepsis. However, the grouping under this strategy is highly influenced by the accuracy and sensitivity of the enrichment indicators and results in poor grouping stability. The classifier strategy helps to find the sensitive group of a particular drug with stable efficacy. However, this strategy has the disadvantage that only the sensitivity of a single drug can be assessed, so it is not suitable as a primary screening strategy.

4. Summary

The advancement in the understanding of the underlying pathophysiology of sepsis has indicated that relying solely on antibiotics to eliminate pathogenic bacteria may not be sufficient. The host's immune dysfunction induced by pathogenic bacteria must also be taken into consideration. Several current RCTs have confirmed that immunotherapy can help to improve immune function and reduce mortality in patients with sepsis. However, due to the long duration of immune dysfunction after infection and the large inter-individual heterogeneity in sepsis patients, the fixed therapeutic dosage and course of immunomodulatory drugs in the RCT studies may be difficult to apply to the entire sepsis population. Therefore, we need to further explore the appropriate therapeutic regimens of those drugs through real-world study, which is complimentary and expends beyond RCT. Additionally, enrichment strategy and classifier strategy can help us to provide precise treatment for specific patients with sepsis. In the future, the integration of artificial intelligence and multi-omics techniques holds the potential for the development of precision immunotherapy for sepsis.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No.82302415, No.82272186 and No.82002076), the Natural Science Foundation of Guangdong Province (Grant No.2016A030313269), the Sun Yat-sen University Clinical Research Program 5010 (Grant No.2019002) and the Guangdong Clinical Research Center for Critical Care Medicine (Grant No.2020B1111170005).

Ethical statement

This is a review article and thus ethical approval is not applicable.

Declaration of competing interest

The authors declare that there is no conflict of interest.

Author contributions

Fei Pei and Bin Gu wrote the manuscript. Jian-Feng Wu and Xiang-Dong Guan corrected the manuscript. All authors read and approved the final version.

Acknowledgments

We express our gratitude to Lu-Yue Li from the Anhui Vocational College of Grain Engineering for her assistance in drawing the figures.

Footnotes

Peer review under responsibility of Chinese Medical Association.

References

  • 1.Singer M., Deutschman C.S., Seymour C.W., et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3) JAMA. 2016;315:801–810. doi: 10.1001/jama.2016.0287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Rudd K.E., Johnson S.C., Agesa K.M., et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395:200–211. doi: 10.1016/S0140-6736(19)32989-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Evans L., Rhodes A., Alhazzani W., et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–1247. doi: 10.1007/s00134-021-06506-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.van der Poll T., Shankar-Hari M., Wiersinga W.J. The immunology of sepsis. Immunity. 2021;54:2450–2464. doi: 10.1016/j.immuni.2021.10.012. [DOI] [PubMed] [Google Scholar]
  • 5.Torres L.K., Pickkers P., van der Poll T. Sepsis-induced immunosuppression. Annu Rev Physiol. 2022;84:157–181. doi: 10.1146/annurev-physiol-061121-040214. [DOI] [PubMed] [Google Scholar]
  • 6.Hotchkiss R.S., Monneret G., Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–874. doi: 10.1038/nri3552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.van der Poll T., van de Veerdonk F.L., Scicluna B.P., et al. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17:407–420. doi: 10.1038/nri.2017.36. [DOI] [PubMed] [Google Scholar]
  • 8.Venet F., Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol. 2018;14:121–137. doi: 10.1038/nrneph.2017.165. [DOI] [PubMed] [Google Scholar]
  • 9.Pei F., Zhang G.R., Zhou L.X., et al. Early immunoparalysis was associated with poor prognosis in elderly patients with sepsis: secondary analysis of the ETASS study. Infect Drug Resist. 2020;13:2053–2061. doi: 10.2147/IDR.S246513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Zeni F., Freeman B., Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med. 1997;25:1095–1100. doi: 10.1097/00003246-199707000-00001. [DOI] [PubMed] [Google Scholar]
  • 11.Torres L.K., Pickkers P., van der Poll T. Sepsis-induced immunosuppression. Annu Rev Physiol. 2022;84:157–181. doi: 10.1146/annurev-physiol-061121-040214. [DOI] [PubMed] [Google Scholar]
  • 12.Liu D., Huang S.Y., Sun J.H., et al. Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options. Mil Med Res. 2022;9:56. doi: 10.1186/s40779-022-00422-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Zhang Y.Y., Ning B.T. Signaling pathways and intervention therapies in sepsis. Signal Transduct Targeted Ther. 2021;6:407. doi: 10.1038/s41392-021-00816-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Lin H.Y. The severe COVID-19: a sepsis induced by viral infection? And its immunomodulatory therapy. Chin J Traumatol. 2020;23:190–195. doi: 10.1016/j.cjtee.2020.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Welte T., Dellinger R.P., Ebelt H., et al. Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study) Intensive Care Med. 2018;44:438–448. doi: 10.1007/s00134-018-5143-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Tocut M., Kolitz T., Shovman O., et al. Outcomes of ICU patients treated with intravenous immunoglobulin for sepsis or autoimmune diseases. Autoimmun Rev. 2022;21 doi: 10.1016/j.autrev.2022.103205. [DOI] [PubMed] [Google Scholar]
  • 17.Bermejo-Martin J.F., Giamarellos-Bourboulis E.J. Endogenous immunoglobulins and sepsis: new perspectives for guiding replacement therapies. Int J Antimicrob Agents. 2015;46:S25–S28. doi: 10.1016/j.ijantimicag.2015.10.013. [DOI] [PubMed] [Google Scholar]
  • 18.Busani S., Damiani E., Cavazzuti I., et al. Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness. Minerva Anestesiol. 2016;82:559–572. [PubMed] [Google Scholar]
  • 19.Shankar-Hari M., Culshaw N., Post B., et al. Endogenous IgG hypogammaglobulinaemia in critically ill adults with sepsis: systematic review and meta-analysis. Intensive Care Med. 2015;41:1393–1401. doi: 10.1007/s00134-015-3845-7. [DOI] [PubMed] [Google Scholar]
  • 20.Werdan K., Pilz G., Bujdoso O., et al. Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study. Crit Care Med. 2007;35:2693–2701. [PubMed] [Google Scholar]
  • 21.Werdan K., Pilz G., Müller-Werdan U., et al. Immunoglobulin G treatment of postcardiac surgery patients with score-identified severe systemic inflammatory response syndrome--the ESSICS study. Crit Care Med. 2008;36:716–723. doi: 10.1097/01.CCM.0B013E3181611F62F. [DOI] [PubMed] [Google Scholar]
  • 22.Madsen M.B., Hjortrup P.B., Hansen M.B., et al. Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med. 2017;43:1585–1593. doi: 10.1007/s00134-017-4786-0. [DOI] [PubMed] [Google Scholar]
  • 23.Alejandria M.M., Lansang M.A., Dans L.F., et al. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;2013:CD001090. doi: 10.1002/14651858.CD001090.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Laupland K.B., Kirkpatrick A.W., Delaney A. Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis. Crit Care Med. 2007;35:2686–2692. [PubMed] [Google Scholar]
  • 25.Hentrich M., Fehnle K., Ostermann H., et al. IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial. Crit Care Med. 2006;34:1319–1325. doi: 10.1097/01.CCM.0000215452.84291.C6. [DOI] [PubMed] [Google Scholar]
  • 26.Welte T., Dellinger R.P., Ebelt H., et al. Concept for a study design in patients with severe community-acquired pneumonia: a randomised controlled trial with a novel IGM-enriched immunoglobulin preparation - the CIGMA study. Respir Med. 2015;109:758–767. doi: 10.1016/j.rmed.2015.03.008. [DOI] [PubMed] [Google Scholar]
  • 27.Parks T., Wilson C., Curtis N., et al. Polyspecific intravenous immunoglobulin in clindamycin-treated patients with streptococcal toxic shock syndrome: a systematic review and meta-analysis. Clin Infect Dis. 2018;67:1434–1436. doi: 10.1093/cid/ciy401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Zhou Y., Fu B., Zheng X., et al. Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv. 2020 doi: 10.1101/2020.02.12.945576. [DOI] [Google Scholar]
  • 29.Pinder E.M., Rostron A.J., Hellyer T.P., et al. Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis. Thorax. 2018;73:918–925. doi: 10.1136/thoraxjnl-2017-211323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Lendemans S., Kreuzfelder E., Waydhas C., et al. Differential immunostimulating effect of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and interferon gamma (IFNgamma) after severe trauma. Inflamm Res. 2007;56:38–44. doi: 10.1007/s00011-007-6069-7. [DOI] [PubMed] [Google Scholar]
  • 31.Drossou-Agakidou V., Kanakoudi-Tsakalidou F., Sarafidis K., et al. In vivo effect of rhGM-CSF and rhG-CSF on monocyte HLA-DR expression of septic neonates. Cytokine. 2002;18:260–265. doi: 10.1006/cyto.2002.1037. [DOI] [PubMed] [Google Scholar]
  • 32.Flohé S., Börgermann J., Domínguez F.E., et al. Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass, and severe sepsis. Shock. 1999;12:17–24. doi: 10.1097/00024382-199907000-00003. [DOI] [PubMed] [Google Scholar]
  • 33.Presneill J.J., Harris T., Stewart A.G., et al. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med. 2002;166:138–143. doi: 10.1164/rccm.2009005. [DOI] [PubMed] [Google Scholar]
  • 34.Orozco H., Arch J., Medina-Franco H., et al. Molgramostim (GM-CSF) associated with antibiotic treatment in nontraumatic abdominal sepsis: a randomized, double-blind, placebo-controlled clinical trial. Arch Surg. 2006;141:150–153. doi: 10.1001/archsurg.141.2.150. discussion 154. [DOI] [PubMed] [Google Scholar]
  • 35.Meisel C., Schefold J.C., Pschowski R., 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;180:640–648. doi: 10.1164/rccm.200903-0363OC. [DOI] [PubMed] [Google Scholar]
  • 36.Bo L., Wang F., Zhu J., et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Crit Care. 2011;15:R58. doi: 10.1186/cc10031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Romani L., Bistoni F., Montagnoli C., et al. Thymosin alpha1: an endogenous regulator of inflammation, immunity, and tolerance. Ann N Y Acad Sci. 2007;1112:326–338. doi: 10.1196/annals.1415.002. [DOI] [PubMed] [Google Scholar]
  • 38.Shehadeh F., Benitez G., Mylona E.K., et al. A pilot trial of thymalfasin (Thymosin-α-1) to treat hospitalized patients with hypoxemia and lymphocytopenia due to coronavirus disease 2019 infection. J Infect Dis. 2023;227:226–235. doi: 10.1093/infdis/jiac362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Liu Y., Pan Y., Hu Z., et al. Thymosin alpha 1 reduces the mortality of severe coronavirus disease 2019 by restoration of lymphocytopenia and reversion of exhausted T cells. Clin Infect Dis. 2020;71:2150–2157. doi: 10.1093/cid/ciaa630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Matteucci C., Minutolo A., Balestrieri E., et al. Thymosin alpha 1 mitigates cytokine storm in blood cells from coronavirus disease 2019 patients. Open Forum Infect Dis. 2021;8:ofaa588. doi: 10.1093/ofid/ofaa588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Yu K., He J., Wu Y., et al. Dysregulated adaptive immune response contributes to severe COVID-19. Cell Res. 2020;30:814–816. doi: 10.1038/s41422-020-0391-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Romani L., Bistoni F., Gaziano R., et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood. 2004;103:4232–4239. doi: 10.1182/blood-2003-11-4036. [DOI] [PubMed] [Google Scholar]
  • 43.Pei F., Guan X., Wu J. Thymosin alpha 1 treatment for patients with sepsis. Expet Opin Biol Ther. 2018;18:71–76. doi: 10.1080/14712598.2018.1484104. [DOI] [PubMed] [Google Scholar]
  • 44.Pei F., Liu Y., Zuo L., et al. Thymosin alpha 1 therapy alleviates organ dysfunction of sepsis patients: a retrospective cohort study. Exploration of Immunology. 2022;22:200–210. doi: 10.37349/ei.2022.00045. [DOI] [Google Scholar]
  • 45.Wu J., Zhou L., Liu J., et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Crit Care. 2013;17:R8. doi: 10.1186/cc11932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Lin H.Y. Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin. Zhonghua Yixue Zazhi. 2007;87:451–457. [PubMed] [Google Scholar]
  • 47.Liu F., Wang H.M., Wang T., et al. The efficacy of thymosin α1 as immunomodulatory treatment for sepsis: a systematic review of randomized controlled trials. BMC Infect Dis. 2016;16:488. doi: 10.1186/s12879-016-1823-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Winer H., Rodrigues G., Hixon J.A., et al. IL-7: comprehensive review. Cytokine. 2022;160 doi: 10.1016/j.cyto.2022.156049. [DOI] [PubMed] [Google Scholar]
  • 49.Chen D., Tang T.X., Deng H., et al. Interleukin-7 biology and its effects on immune cells: mediator of generation, differentiation, survival, and homeostasis. Front Immunol. 2021;12 doi: 10.3389/fimmu.2021.747324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Francois B., Jeannet R., Daix T., et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3 doi: 10.1172/jci.insight.98960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.de Roquetaillade C., Monneret G., Gossez M., et al. IL-7 and its beneficial role in sepsis-induced T lymphocyte dysfunction. Crit Rev Immunol. 2018;38:433–451. doi: 10.1615/CritRevImmunol.2018027460. [DOI] [PubMed] [Google Scholar]
  • 52.Yi M., Zheng X., Niu M., et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21:28. doi: 10.1186/s12943-021-01489-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Yamaguchi H., Hsu J.M., Yang W.H., et al. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol. 2022;19:287–305. doi: 10.1038/s41571-022-00601-9. [DOI] [PubMed] [Google Scholar]
  • 54.Doroshow D.B., Bhalla S., Beasley M.B., et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18:345–362. doi: 10.1038/s41571-021-00473-5. [DOI] [PubMed] [Google Scholar]
  • 55.Shindo Y., McDonough J.S., Chang K.C., et al. Anti-PD-L1 peptide improves survival in sepsis. J Surg Res. 2017;208:33–39. doi: 10.1016/j.jss.2016.08.099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Wang J.F., Li J.B., Zhao Y.J., et al. Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: an animal study and a prospective case-control study. Anesthesiology. 2015;1224:852–863. doi: 10.1097/ALN.0000000000000525. [DOI] [PubMed] [Google Scholar]
  • 57.Liu Q., Lu J.Y., Wang X.H., et al. Changes in the PD-1 and PD-L1 expressions of splenic dendritic cells in multiple-organ dysfunction syndrome mice and their significance. Genet Mol Res. 2014;13:7666–7672. doi: 10.4238/2014.September.26.4. [DOI] [PubMed] [Google Scholar]
  • 58.Chang K., Svabek C., Vazquez-Guillamet C., et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care. 2014;18:R3. doi: 10.1186/cc13176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Zhang Y., Li J., Lou 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;151:R70. doi: 10.1186/cc10059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Brahmamdam P., Inoue S., Unsinger J., et al. Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol. 2010;88:233–240. doi: 10.1189/jlb.0110037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Rienzo M., Skirecki T., Monneret G., et al. Immune checkpoint inhibitors for the treatment of sepsis:insights from preclinical and clinical development. Expet Opin Invest Drugs. 2022;31:885–894. doi: 10.1080/13543784.2022.2102477. [DOI] [PubMed] [Google Scholar]
  • 62.Nakamori Y., Park E.J., Shimaoka M. Immune deregulation in sepsis and septic shock: reversing immune paralysis by targeting PD-1/PD-L1 pathway. Front Immunol. 2020;11 doi: 10.3389/fimmu.2020.624279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.McBride M.A., Patil T.K., Bohannon J.K., et al. Immune checkpoints: novel therapeutic targets to attenuate sepsis-induced immunosuppression. Front Immunol. 2020;11 doi: 10.3389/fimmu.2020.624272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Hotchkiss R.S., Colston E., Yende S., et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand 1 antibody (BMS-936559) Crit Care Med. 2019;47:632–642. doi: 10.1097/CCM.0000000000003685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Hotchkiss R.S., Colston E., Yende S., et al. Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med. 2019;45:1360–1371. doi: 10.1007/s00134-019-05704-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Döcke W.D., Randow F., Syrbe U., et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3:678–681. doi: 10.1038/nm0697-678. [DOI] [PubMed] [Google Scholar]
  • 67.Assendorp E.L., Gresnigt M.S., Sprenkeler E., et al. Adjunctive interferon-γ immunotherapy in a pediatric case of Aspergillus terreus infection. Eur J Clin Microbiol Infect Dis. 2018;37:1915–1922. doi: 10.1007/s10096-018-3325-4. [DOI] [PubMed] [Google Scholar]
  • 68.Payen D., Faivre V., Miatello J., et al. Multicentric experience with interferon gamma therapy in sepsis induced immunosuppression. A case series. BMC Infect Dis. 2019;19:931. doi: 10.1186/s12879-019-4526-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Delsing C.E., Gresnigt M.S., Leentjens J., et al. Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series. BMC Infect Dis. 2014;14:166. doi: 10.1186/1471-2334-14-166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Mei S.H., Haitsma J.J., Dos Santos C.C., et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182:1047–1057. doi: 10.1164/rccm.201001-0010OC. [DOI] [PubMed] [Google Scholar]
  • 71.Walter J., Ware L.B., Matthay M.A. Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet Respir Med. 2014;2:1016–1026. doi: 10.1016/S2213-2600(14)70217-6. [DOI] [PubMed] [Google Scholar]
  • 72.Pedrazza L., Cubillos-Rojas M., de Mesquita F.C., et al. Mesenchymal stem cells decrease lung inflammation during sepsis, acting through inhibition of the MAPK pathway. Stem Cell Res Ther. 2017;8:289. doi: 10.1186/s13287-017-0734-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Rabani R., Volchuk A., Jerkic M., et al. Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis. Eur Respir J. 2018;51 doi: 10.1183/13993003.02021-2017. [pii] [DOI] [PubMed] [Google Scholar]
  • 74.Saeedi P., Halabian R., Fooladi A. Mesenchymal stem cells preconditioned by staphylococcal enterotoxin B enhance survival and bacterial clearance in murine sepsis model. Cytotherapy. 2019;21:41–53. doi: 10.1016/j.jcyt.2018.11.002. [DOI] [PubMed] [Google Scholar]
  • 75.Khosrojerdi A., Soudi S., Hosseini A.Z., et al. Immunomodulatory and therapeutic effects of mesenchymal stem cells on organ dysfunction in sepsis. Shock. 2021;55:423–440. doi: 10.1097/SHK.0000000000001644. [DOI] [PubMed] [Google Scholar]
  • 76.Daniel M., Bedoui Y., Vagner D., et al. Pathophysiology of sepsis and genesis of septic shock: the critical role of mesenchymal stem cells (MSCs) Int J Mol Sci. 2022;23:9274. doi: 10.3390/ijms23169274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Schlosser K., Wang J.P., Dos Santos C., et al. Effects of mesenchymal stem cell treatment on systemic cytokine levels in a phase 1 dose escalation safety trial of septic shock patients. Crit Care Med. 2019;47:918–925. doi: 10.1097/CCM.0000000000003657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Zhao Z., Jiang X., Kang C., et al. Blockade of the T cell immunoglobulin and mucin domain protein 3 pathway exacerbates sepsis-induced immune deviation and immunosuppression. Clin Exp Immunol. 2014;178:279–291. doi: 10.1111/cei.12401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Aoyama-Ishikawa M., Seishu A., Kawakami S., et al. Intravenous immunoglobulin-induced neutrophil apoptosis in the lung during murine endotoxemia. Surg Infect. 2014;15:36–42. doi: 10.1089/sur.2012.227. [DOI] [PubMed] [Google Scholar]
  • 80.Djoumerska-Alexieva I., Pashova S., Vassilev T., et al. The protective effect of modified intravenous immunoglobulin in LPS sepsis model is associated with an increased IRA B cells response. Autoimmun Rev. 2013;12:653–656. doi: 10.1016/j.autrev.2012.10.010. [DOI] [PubMed] [Google Scholar]
  • 81.Hagiwara S., Iwasaka H., Hasegawa A., et al. High-dose intravenous immunoglobulin G improves systemic inflammation in a rat model of CLP-induced sepsis. Intensive Care Med. 2008;34:1812–1819. doi: 10.1007/s00134-008-1161-1. [DOI] [PubMed] [Google Scholar]
  • 82.Carr R., Brocklehurst P., Doré C.J., et al. Granulocyte-macrophage colony stimulating factor administered as prophylaxis for reduction of sepsis in extremely preterm, small for gestational age neonates (the PROGRAMS trial): a single-blind, multicentre, randomised controlled trial. Lancet. 2009;373:226–233. doi: 10.1016/S0140-6736(09)60071-4. [DOI] [PubMed] [Google Scholar]
  • 83.Cavazzuti I., Serafini G., Busani S., et al. Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock. Intensive Care Med. 2014;40:1888–1896. doi: 10.1007/s00134-014-3474-6. [DOI] [PubMed] [Google Scholar]
  • 84.Cui J., Wei X., Lv H., et al. The clinical efficacy of intravenous IgM-enriched immunoglobulin (pentaglobin) in sepsis or septic shock: a meta-analysis with trial sequential analysis. Ann Intensive Care. 2019;9:27. doi: 10.1186/s13613-019-0501-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Nierhaus A., Berlot G., Kindgen-Milles D., et al. Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis. Ann Intensive Care. 2020;10:132. doi: 10.1186/s13613-020-00740-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Tian L., Zhu J., Jin J., et al. Prognostic value of circulating lymphocyte B and plasma immunoglobulin M on septic shock and sepsis: a systematic review and meta-analysis. Am J Transl Res. 2019;11:7223–7232. [PMC free article] [PubMed] [Google Scholar]
  • 87.Serafino A., Pica F., Andreola F., et al. Thymosin α1 activates complement receptor-mediated phagocytosis in human monocyte-derived macrophages. J Innate Immun. 2014;6:72–88. doi: 10.1159/000351587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Serafino A., Pierimarchi P., Pica F., et al. Thymosin α1 as a stimulatory agent of innate cell-mediated immune response. Ann N Y Acad Sci. 2012;1270:13–20. doi: 10.1111/j.1749-6632.2012.06707.x. [DOI] [PubMed] [Google Scholar]
  • 89.Yao Q., Doan L.X., Zhang R., et al. Thymosin-alpha1 modulates dendritic cell differentiation and functional maturation from human peripheral blood CD14+ monocytes. Immunol Lett. 2007;110:110–120. doi: 10.1016/j.imlet.2007.04.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Bozza S., Gaziano R., Bonifazi P., et al. Thymosin alpha1 activates the TLR9/MyD88/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo. Int Immunol. 2007;19:1261–1270. doi: 10.1093/intimm/dxm097. [DOI] [PubMed] [Google Scholar]
  • 91.Giuliani C., Napolitano G., Mastino A., et al. Thymosin-alpha1 regulates MHC class I expression in FRTL-5 cells at transcriptional level. Eur J Immunol. 2000;30:778–786. doi: 10.1002/1521-4141(200003)30:3<778::AID-IMMU778>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  • 92.Baumann C.A., Badamchian M., Goldstein A.L. Thymosin alpha 1 antagonizes dexamethasone and CD3-induced apoptosis of CD4+ CD8+ thymocytes through the activation of cAMP and protein kinase C dependent second messenger pathways. Mech Ageing Dev. 1997;94:85–101. doi: 10.1016/s0047-6374(96)01860-x. [DOI] [PubMed] [Google Scholar]
  • 93.Daix T., Mathonnet A., Brakenridge S., et al. Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial. Ann Intensive Care. 2023;13:17. doi: 10.1186/s13613-023-01109-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Flohé S.B., Agrawal H., Flohé S., et al. 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;14:247–256. doi: 10.2119/2007-00120.Flohe. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Leentjens J., Kox M., Koch R.M., et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med. 2012;186:838–845. doi: 10.1164/rccm.201204-0645OC. [DOI] [PubMed] [Google Scholar]
  • 96.Pei F., Yao R.Q., Ren C., et al. Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression. Mil Med Res. 2022;9:74. doi: 10.1186/s40779-022-00430-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Pei F., Song W., Wang L., et al. Lymphocyte trajectories are associated with prognosis in critically ill patients: a convenient way to monitor immune status. Front Med. 2022;9 doi: 10.3389/fmed.2022.953103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Wu J.F., Ma J., Chen J., et al. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit Care. 2011;15:R220. doi: 10.1186/cc10457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Liu S., Li Y., She F., et al. Predictive value of immune cell counts and neutrophil-to-lymphocyte ratio for 28-day mortality in patients with sepsis caused by intra-abdominal infection. Burns Trauma. 2021;9:tkaa040. doi: 10.1093/burnst/tkaa040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Misra A.K., Levy M.M., Ward N.S. Biomarkers of immunosuppression. Crit Care Clin. 2020;36:167–176. doi: 10.1016/j.ccc.2019.08.013. [DOI] [PubMed] [Google Scholar]
  • 101.Yao R.Q., Ren C., Zheng L.Y., et al. Advances in immune monitoring approaches for sepsis-induced immunosuppression. Front Immunol. 2022;13 doi: 10.3389/fimmu.2022.891024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.de Roquetaillade C., Dupuis C., Faivre V., et al. Monitoring of circulating monocyte HLA-DR expression in a large cohort of intensive care patients: relation with secondary infections. Ann Intensive Care. 2022;12:39. doi: 10.1186/s13613-022-01010-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Bodinier M., Peronnet E., Brengel-Pesce K., et al. Monocyte trajectories endotypes are associated with worsening in septic patients. Front Immunol. 2021;12 doi: 10.3389/fimmu.2021.795052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Cheng L.L., Guan W.J., Duan C.Y., et al. Effect of recombinant human granulocyte colony-stimulating factor for patients with coronavirus disease 2019 (COVID-19) and lymphopenia: a randomized clinical trial. JAMA Intern Med. 2021;181:71–78. doi: 10.1001/jamainternmed.2020.5503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Venet F., Lukaszewicz A.C., Payen D., et al. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol. 2013;25:477–483. doi: 10.1016/j.coi.2013.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Rubio I., Osuchowski M.F., Shankar-Hari M., et al. Current gaps in sepsis immunology: new opportunities for translational research. Lancet Infect Dis. 2019;19:e422–e436. doi: 10.1016/S1473-3099(19)30567-5. [DOI] [PubMed] [Google Scholar]
  • 107.Reyes M., Filbin M.R., Bhattacharyya R.P., et al. An immune-cell signature of bacterial sepsis. Nat Med. 2020;26:333–340. doi: 10.1038/s41591-020-0752-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.Yao R.Q., Li Z.X., Wang L.X., et al. Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis. Theranostics. 2022;12:4606–4628. doi: 10.7150/thno.72760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Wong H.R. Intensive care medicine in 2050: precision medicine. Intensive Care Med. 2017;43:1507–1509. doi: 10.1007/s00134-017-4727-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Stanski N.L., Wong H.R. Prognostic and predictive enrichment in sepsis. Nat Rev Nephrol. 2020;16:20–31. doi: 10.1038/s41581-019-0199-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.Schuurman A.R., Reijnders T., Kullberg R., et al. Sepsis: deriving biological meaning and clinical applications from high-dimensional data. Intensive Care Med Exp. 2021;9:27. doi: 10.1186/s40635-021-00383-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Wong H.R., Atkinson S.J., Cvijanovich N.Z., et al. Combining prognostic and predictive enrichment strategies to identify children with septic shock responsive to corticosteroids. Crit Care Med. 2016;44:e1000–e1003. doi: 10.1097/CCM.0000000000001833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Kotsaki A., Pickkers P., Bauer M., et al. ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol. BMJ Open. 2022;12 doi: 10.1136/bmjopen-2022-067251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Taguchi F., Solomon B., Gregorc V., et al. Mass spectrometry to classify non-small-cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study. J Natl Cancer Inst. 2007;99:838–846. doi: 10.1093/jnci/djk195. [DOI] [PubMed] [Google Scholar]
  • 115.Lara P.N., Jr., Moon J., Hesketh P.J., et al. SWOG S0709: randomized phase II trial of erlotinib versus erlotinib plus carboplatin/paclitaxel in patients with advanced non-small cell lung cancer and impaired performance status as selected by a serum proteomics assay. J Thorac Oncol. 2016;11:420–425. doi: 10.1016/j.jtho.2015.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.Rich P., Mitchell R.B., Schaefer E., et al. Real-world performance of blood-based proteomic profiling in first-line immunotherapy treatment in advanced stage non-small cell lung cancer. J Immunother Cancer. 2021;9 doi: 10.1136/jitc-2021-002989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.Wozniak J.M., Mills R.H., Olson J., et al. Mortality risk profiling of Staphylococcus aureus bacteremia by multi-omic serum analysis reveals early predictive and pathogenic signatures. Cell. 2020;182:1311–1327.e14. doi: 10.1016/j.cell.2020.07.040. [DOI] [PMC free article] [PubMed] [Google Scholar]

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