Immunomonitoring of Monocyte and Neutrophil Function in Critically Ill Patients: From Sepsis and/or Trauma to COVID-19

Udovičić, Ivo; Stanojević, Ivan; Djordjević, Dragan; Zeba, Snježana; Rondović, Goran; Abazovic, Tanja; Lazic, Srdjan; Vojvodić, Danilo; To, Kendrick; Abazović, Džihan; Khan, Wasim; Šurbatović, Maja

doi:10.3390/jcm10245815

Cited by 7 publications

(6 citation statements)

References 420 publications

(456 reference statements)

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“…Third, the strength of the association between Neu1 and clinical severity was modifiable by the presence of other cell types such as monocyte. The negative impact of the neutrophil fraction on disease severity was not observed in the presence of a high monocyte fraction, suggesting the importance of the interaction between monocyte and neutrophils in the pathogenesis of sepsis ( Udovicic et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptome profiling reveals heterogeneous neutrophils with prognostic values in sepsis

Hong¹,

Chen²,

Sun³

et al. 2022

iScience

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Section: Discussionmentioning

confidence: 99%

Single-cell transcriptome profiling reveals heterogeneous neutrophils with prognostic values in sepsis

Hong¹,

Chen²,

Sun³

et al. 2022

iScience

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Section: Blood Monocyte Hla-dr Expressionmentioning

confidence: 99%

“…Finally, several studies support that dynamic changes by serial mHLA-DR monitoring might predict mortality better than static mHLA-DR monitoring (80,113,114). Correspondingly, persistence of low mHLA-DR levels suggests slow or no recovery from sepsis IP (4,12,13,113,115,116). Given inter-individual variability of mHLA-DR in sepsis, dynamic change or HLA-DR slope might increase prognostic significance of low mHLA-DR expression for mortality prediction (4,13,93,98,117).…”

Section: Blood Monocyte Hla-dr Expressionmentioning

confidence: 99%

Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis

Joshi¹,

Carney

Rock³

2023

Front. Immunol.

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Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.

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“…Therefore, instead of this therapeutic approach, the inflammatory process should be treated, bearing in mind that innate inflammatory response is initiated by pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) produced by damaged cells. DAMPs are released in sepsis, trauma and various other states [ 47 ].…”

Section: Aspects Of Host Response—how Specific Are They For Covid-19?mentioning

confidence: 99%

“…Biological drugs against IL-6 can target the cytokine directly (siltuximab, clazakizumab, sirukumab and olokizumab) while membrane-bound IL-6 receptor is blocked by tocilizumab and sarilumab [ 47 , 95 ]. Soluble IL-6R is blocked by olamkicept, resulting in the arrest of IL-6 trans-signaling [ 95 ].…”

Section: Immunomodulatory Treatment Of Moderate-to-severe Covid-19—di...mentioning

confidence: 99%

From Cytokine Storm to Cytokine Breeze: Did Lessons Learned from Immunopathogenesis Improve Immunomodulatory Treatment of Moderate-to-Severe COVID-19?

et al. 2022

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Complex immune response to infection has been highlighted, more than ever, during the COVID-19 pandemic. This review explores the immunomodulatory treatment of moderate-to-severe forms of this viral sepsis in the context of specific immunopathogenesis. Our objective is to analyze in detail the existing strategies for the use of immunomodulators in COVID-19. Immunomodulating therapy is very challenging; there are still underpowered or, in other ways, insufficient studies with inconclusive or conflicting results regarding a rationale for adding a second immunomodulatory drug to dexamethasone. Bearing in mind that a “cytokine storm” is not present in the majority of COVID-19 patients, it is to be expected that the path to the adequate choice of a second immunomodulatory drug is paved with uncertainty. Anakinra, a recombinant human IL-1 receptor antagonist, is a good choice in this setting. Yet, the latest update of the COVID-19 Treatment Guidelines Panel (31 May 2022) claims that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19. EMA’s human medicines committee recommended extending the indication of anakinra to include treatment of COVID-19 in adult patients only recently (17 December 2021). It is obvious that this is still a work in progress, with few ongoing clinical trials. With over 6 million deaths from COVID-19, this is the right time to speed up this process. Our conclusion is that, during the course of COVID-19, the immune response is changing from the early phase to the late phase in individual patients, so immunomodulating therapy should be guided by individual responses at different time points.

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Immunomonitoring of Monocyte and Neutrophil Function in Critically Ill Patients: From Sepsis and/or Trauma to COVID-19

Cited by 7 publications

References 420 publications

Single-cell transcriptome profiling reveals heterogeneous neutrophils with prognostic values in sepsis

Single-cell transcriptome profiling reveals heterogeneous neutrophils with prognostic values in sepsis

Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis

From Cytokine Storm to Cytokine Breeze: Did Lessons Learned from Immunopathogenesis Improve Immunomodulatory Treatment of Moderate-to-Severe COVID-19?

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