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

Abstract

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.

Monocyte HLA‐DR level on admission predicting in‐hospital mortality rate in exertional heatstroke: A 12‐year retrospective study

“…This study revealed that mHLA‐DR was an independent risk factor (OR = 0.939; 95% CI: 0.892–0.988; p = 0.016) for poor outcomes in EHS patients. We found that mHLA‐DR levels had a modest prognostic effect for in‐hospital mortality rate (AUC = 0.880, 95% CI: 0.780–0.945, cut‐off value = 53.6%, p < 0.0001) in EHS, which was consistent with the previous studies illustrating that decreased mHLA‐DR expression predicted poor outcomes in patients with severe burns, 20 and sepsis 15 . Berres et al have described that individuals with decompensated liver cirrhosis had greater ICU mortality rate when their mHLA‐DR levels were decreased 10 .…”

“…Besides, platelet (PLT), hemoglobin (Hb), and hematocrit (HCT) levels were lower in nonsurvivors (p < 0.05), indicating possible massive destruction of red blood cells in nonsurvivors. Furthermore, the length of ICU stays and hospital stays in those nonsurvivors (16 [9-20] days and 18 [9-46] days) were both longer than those in survivors (5 [3][4][5][6][7][8] days, p < 0.001 and 11 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] days, p = 0.045). Mean arterial pressure, white blood cell, neutrophil count and percentage, prolonged activated partial thromboplastin time, fibrinogen, serum creatinine, creatine kinase, lymphocyte count and percentage, SIRS and International Society of Thrombosis and Hemostasis score, underlying disease, monocyte count and percentage, and RM between survivors and nonsurvivors were not significantly different.…”

“…13 Current research has verified that the expression of mHLA-DR below 30% indicates that the individual is immunologically paralyzed and vulnerable to secondary infection, MODS, and even death. 14,15 The signature of the "sepsis-like syndrome," such as postcardiac arrest syndrome (PCAS), is systemic hyperinflammation, 16 which may be mediated by monocytes with several pattern recognition receptors (PRRs), such as coreceptor CD14. 17 However, another feature is the immunosuppressive phenotype, identified by the downregulation of mHLA-DR. 16,17 HS, a "like-sepsis" pathophysiological process, 1 presents a more swift and intense inflammatory response and immune disorder.…”

“…Low monocyte HLA‐DR (mHLA‐DR) levels have been observed in critically ill individuals with severe burns, 9 hepatitis, 10 pancreatitis 11 and trauma, 12 as well as sepsis particularly 13 . Current research has verified that the expression of mHLA‐DR below 30% indicates that the individual is immunologically paralyzed and vulnerable to secondary infection, MODS, and even death 14,15 …”

Das Immunsystem des kritisch Kranken

“…Einerseits konnte eine therapeutische Stimulation der mHLA-DR-Expression mittels Substitution von Interferonγ bereits positive Effekte erzielen [54], was aktuell in weiteren Studien erneut evaluiert wird [55]. Andererseits zeigten sich auch positive Effekte einer GM-CSF-Gabe als myelopoetischem Wachstumsfaktor mit konsekutiver immunaktivierender Wirkung bei primärer Immunparalyse [56,57,58]. Im Fokus der immunaktivierenden Therapiekonzepte steht hierbei die Restitution des Immunsystems.…”