Monocyte Human Leukocyte antigen-DR Expression Research Articles

Monocytic Human Leukocyte Antigen-DR Expression Levels to Predict Outcome in Children With Severe Sepsis

Monocytic Human Leukocyte Antigen-DR Expression Levels to Predict Outcome in Children With Severe Sepsis

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Immune Profiling Panel Gene Set Identifies Critically Ill Patients With Low Monocyte Human Leukocyte Antigen-DR Expression: Preliminary Results From the REAnimation Low Immune Status Marker (REALISM) Study.

There is a crucial unmet need for biomarker-guided diagnostic and prognostic enrichment in clinical trials evaluating immune modulating therapies in critically ill patients. Low monocyte expression of human leukocyte antigen-DR (mHLA-DR), considered as a reference surrogate to identify immunosuppressed patients, has been proposed for patient stratification in immunostimulation approaches. However, its widespread use in clinic has been somewhat hampered by technical constraints inherent to flow cytometry technology. The objective of the present study was to evaluate the ability of a prototype multiplex polymerase chain reaction tool (immune profiling panel [IPP]) to identify immunosuppressed ICU patients characterized by a low mHLA-DR expression. Retrospective observational cohort study. Adult ICU in a University Hospital, Lyon, France. Critically ill patients with various etiologies enrolled in the REAnimation Low Immune Status Marker study (NCT02638779). None. mHLA-DR and IPP data were obtained from 1,731 blood samples collected from critically ill patients with various etiologies and healthy volunteers. A partial least square regression model combining the expression levels of IPP markers was trained and used for the identification of samples from patients presenting with evidence of immunosuppression, defined here as mHLADR less than 8,000 antibodies bound per cell (AB/C). The IPP gene set had an area under the receiver operating characteristic curve (AUC) of 0.86 (95% CI 0.83-0.89) for the identification of immunosuppressed patients. In addition, when applied to the 123 patients still in the ICU at days 5-7 after admission, IPP similarly enriched the number of patients with ICU-acquired infections in the immunosuppressed group (26%), in comparison with low mHLA-DR (22%). This study reports on the potential of the IPP gene set to identify ICU patients presenting with mHLA-DR less than 8,000 AB/C. Upon further optimization and validation, this molecular tool may help in the stratification of patients that could benefit from immunostimulation in the context of personalized medicine.

Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation.

Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use. To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis. Serial peripheral blood mononuclear cell (PBMC) samples were obtained from 14 sepsis patients (34 total samples) and 7 control patients for this observational study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by tumor necrosis factor-α (TNF-α) production capacity and monocyte human leukocyte antigen DR (HLA-DR) expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type. Sepsis patients were older (15.9 years vs. 10.4 years, P = 0.02) and had higher illness severity by PRISM-III (12.0 vs. 2.0, P < 0.001) compared to controls; demographics were otherwise similar, though control patients were predominately male. Compared to controls, sepsis patients at timepoint 1 demonstrated lower monocyte HLA-DR expression (75% vs. 92%, P = 0.02), loss of peripheral of non-naïve CD4+ T cells (62.4% vs. 77.6%, P = 0.04), and reduced PBMC mitochondrial spare residual capacity (SRC; 4.0 pmol/s/106 cells vs. 8.4 pmol/s/106 cells, P = 0.01). At sepsis onset, immunoparalysis (defined as TNF-α production capacity < 200 pg/mL) was present in 39% of sepsis patients and not identified among controls. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naïve CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen. Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.

Monocyte human leukocyte antigen-DR but not \u03b2-d-glucan may help early diagnosing invasive Candida infection in critically ill patients

BackgroundPrecision medicine risk stratification is desperately needed to both avoid systemic antifungals treatment delay and over prescription in the critically ill with risk factors. The aim of the present study was to explore the combination of host immunoparalysis biomarker (monocyte human leukocyte antigen-DR expression (mHLA-DR)) and Candida sp wall biomarker β-d-glucan in risk stratifying patients for secondary invasive Candida infection (IC).MethodsProspective observational study. Two intensive care units (ICU). All consecutive non-immunocompromised septic shock patients. Serial blood samples (n = 286) were collected at day 0, 2 and 7 and mHLA-DR and β-d-glucan were then retrospectively assayed after discharge. Secondary invasive Candida sp infection occurrence was then followed at clinicians’ discretion.ResultsFifty patients were included, 42 (84%) had a Candida score equal or greater than 3 and 10 patients developed a secondary invasive Candida sp infection. ICU admission mHLA-DR expression and β-d-glucan (BDG) failed to predict secondary invasive Candida sp infection. Time-dependent cause-specific hazard ratio of IC was 6.56 [1.24–34.61] for mHLA-DR < 5000 Ab/c and 5.25 [0.47–58.9] for BDG > 350 pg/mL. Predictive negative value of mHLA-DR > 5000 Ab/c and BDG > 350 pg/mL combination at day 7 was 81% [95% CI 70–92].ConclusionsThis study suggests that mHLA-DR may help predicting IC in high-risk patients with septic shock. The added value of BDG and other fungal tests should be regarded according to the host immune function markers.

Up-to-date information on polymyxin B-immobilized fiber column direct hemoperfusion for septic shock.

Endotoxin adsorption therapy by polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) has been used for the treatment of septic shock patients. Endotoxin, an outer membrane component of Gram-negative bacteria, plays an important role in the pathogenesis of septic shock. Endotoxin triggers a signaling cascade for leukocytes, macrophage, and endothelial cells to secrete various mediators including cytokines and nitric oxide, leading to septic shock and multiple organ dysfunction syndrome. PMX-DHP directly adsorbed not only endotoxin but also monocytes and anandamide. It reduced blood levels of inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha and IL-17A, adhesion molecules, plasminogen activator inhibitor 1, and high mobility group box-1. As a result, PMX-DHP increased blood pressure and reduced the dose of vasoactive-inotropic agents. PMX-DHP improved monocyte human leukocyte antigen-DR expression in patients with severe sepsis and septic shock. A post hoc analysis of EUPHRATES (Evaluating the Use of Polymyxin B Hemoperfusion in Randomized Controlled Trial of Adults Treated for Endotoxemia and Septic Shock) trial has shown that PMX-DHP significantly reduced 28-day mortality compared with the control group in septic shock patients with endotoxin activity assay level between 0.60 and 0.89. Longer duration of PMX-DHP may be another strategy to bring out the beneficial effects of PMX-DHP. Further studies are needed to confirm the efficacy of PMX-DHP treatment for septic shock.

Reduced Monocytic Human Leukocyte Antigen-DR Expression Indicates Immunosuppression in Critically Ill COVID-19 Patients.

BACKGROUND:The cellular immune system is of pivotal importance with regard to the response to severe infections. Monocytes/macrophages are considered key immune cells in infections and downregulation of the surface expression of monocytic human leukocyte antigen-DR (mHLA-DR) within the major histocompatibility complex class II reflects a state of immunosuppression, also referred to as injury-associated immunosuppression. As the role of immunosuppression in coronavirus disease 2019 (COVID-19) is currently unclear, we seek to explore the level of mHLA-DR expression in COVID-19 patients.METHODS:In a preliminary prospective monocentric observational study, 16 COVID-19–positive patients (75% male, median age: 68 [interquartile range 59–75]) requiring hospitalization were included. The median Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score in 9 intensive care unit (ICU) patients with acute respiratory failure was 30 (interquartile range 25–32). Standardized quantitative assessment of HLA-DR on monocytes (cluster of differentiation 14+ cells) was performed using calibrated flow cytometry at baseline (ICU/hospital admission) and at days 3 and 5 after ICU admission. Baseline data were compared to hospitalized noncritically ill COVID-19 patients.RESULTS:While normal mHLA-DR expression was observed in all hospitalized noncritically ill patients (n = 7), 89% (8 of 9) critically ill patients with COVID-19–induced acute respiratory failure showed signs of downregulation of mHLA-DR at ICU admission. mHLA-DR expression at admission was significantly lower in critically ill patients (median, [quartiles]: 9280 antibodies/cell [6114, 16,567]) as compared to the noncritically ill patients (30,900 antibodies/cell [26,777, 52,251]), with a median difference of 21,508 antibodies/cell (95% confidence interval [CI], 14,118–42,971), P = .002. Reduced mHLA-DR expression was observed to persist until day 5 after ICU admission.CONCLUSIONS:When compared to noncritically ill hospitalized COVID-19 patients, ICU patients with severe COVID-19 disease showed reduced mHLA-DR expression on circulating CD14+ monocytes at ICU admission, indicating a dysfunctional immune response. This immunosuppressive (monocytic) phenotype remained unchanged over the ensuing days after ICU admission. Strategies aiming for immunomodulation in this population of critically ill patients should be guided by an immune-monitoring program in an effort to determine who might benefit best from a given immunological intervention.

Poor Outcome Could Be Predicted by Lower Monocyte Human Leukocyte Antigen-DR Expression in Patients with Complicated Intra-Abdominal Infections: A Review.

Complicated intra-abdominal infections (cIAIs) are still associated with high morbidity and mortality levels. Early prognostic evaluation is a great challenge, and a serious amount of resources have been used to find the perfect mortality predictor. Monocyte human leukocyte antigen-DR (mHLA-DR) expression has been studied as a biomarker in patients with sepsis and other infections. Our aim was to evaluate the potential prognostic performance of mHLA-DR in patients with cIAIs. Methods: We performed an electronic search of Google Scholar and PubMed databases for articles published before January 2019. The search terms were "HLA-DR," "monocyte HLA-DR," "intra-abdominal infections," "sepsis," "outcome," and "mortality." Results: A total of 12 studies with 761 patients met our inclusion criteria. In 10 studies, poor outcome was predicted by lower mHLA-DR expression, and two studies showed no prognostic value. Conclusion: This review found association between lower mHLA-DR expression and mortality. We concluded that mHLA-DR could be a reliable and meaningful predictor of poor outcome in patients with cIAIs. Nevertheless, more large prospective studies with surgical patients exclusively are needed before using this biomarker in a clinical setting.

Si-ni-tang (a Chinese herbal formula) for improving immunofunction in sepsis: study protocol for a pilot randomized controlled trial

BackgroundImmunologic derangement may be the critical pathophysiologic mechanism in sepsis, and immunotherapy might be a potential new treatment. Si-ni-tang (SNT), an ancient Chinese herbal formula documented in Shanghan Lun, has been used for treating severe sepsis for thousands of years. Research shows that it may have a therapeutic benefit for sepsis. This study will evaluate the feasibility of testing the effects of SNT on immune function in sepsis patients.Methods/designThis is a pilot randomized controlled study. Eligible sepsis patients admitted to our medical intensive care unit will be randomly allocated to the control group or the SNT group. Both groups will receive standard therapy according to the recommendations of the Surviving Sepsis Campaign. In addition, the SNT group will receive SNT (150 mL per day for 3 days) orally or by gastric tube, while the control group will receive 150 mL of normal saline. The primary outcome is to assess the feasibility of this treatment. The secondary outcomes include: (1) immune function measured by monocyte human leukocyte antigen-DR (mHLA-DR) expression, procalcitonin, and the ratio of CD4+ to CD8+ T lymphocytes and (2) other clinical data, such as the 28-day all-cause mortality, Sequential Organ Failure Assessment (SOFA) scores, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, both of the latter on days 0 and 3.DiscussionThis study aims to evaluate the feasibility of testing the efficacy of SNT for treating sepsis when used as an adjunctive treatment with the standard therapy recommended by the Surviving Sepsis Campaign.Trial registrationClinicalTrials.gov, NCT02777606. Registered on 22 June 2016. Retrospectively registered. https://clinicaltrials.gov/

Dynamic monitoring of monocyte HLA-DR expression for the diagnosis, prognosis, and prediction of sepsis.

Sepsis, an under-recognized health problem, is a major cause of death. More than 750,000 individuals develop sepsis annually, of whom 215,000 die of the disease. Clinical and experimental evidence indicates that patients with sepsis present with rapid impairment of immune function; biomarkers are therefore needed to enable early detection of this condition. Reduced monocyte human leukocyte antigen-DR (HLA-DR) expression, which is measured by flow cytometry, is currently the most popular biomarker for sepsis detection. In addition, the determination of HLA-DR expression provides valuable information in terms of predicting mortality and risk of secondary infections. HLA-DR levels have been shown to be inversely correlated with the severity of sepsis and immune dysfunction. In this review, we provide an overview of the association between sepsis and HLA-DR expression in terms of the predictive value of the latter in sepsis.

Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study.

BackgroundIdentifying patients in the immunosuppressive phase of sepsis is essential for development of immunomodulatory therapies. Little data exists comparing the ability of the two most well-studied markers of sepsis-induced immunosuppression, human leukocyte antigen (HLA)-DR expression and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-ɑ) production, to predict mortality and morbidity. The purpose of this study was to compare HLA-DR expression and LPS-induced TNF-ɑ production as predictors of 28-day mortality and acquisition of secondary infections in adult septic patients.MethodsA single-center, prospective observational study of 83 adult septic patients admitted to a medical or surgical intensive care unit. Blood samples were collected at three time points during the septic course (days 1–2, days 3–4, and days 6–8 after sepsis diagnosis) and assayed for HLA-DR expression and LPS-induced TNF-ɑ production. A repeated measures mixed model analysis was used to compare values of these immunological markers among survivors and non-survivors and among those who did and did not develop a secondary infection.ResultsTwenty-five patients (30.1 %) died within 28 days of sepsis diagnosis. HLA-DR expression was significantly lower in non-survivors as compared to survivors on days 3–4 (p = 0.04) and days 6–8 (p = 0.002). The change in HLA-DR from days 1–2 to days 6–8 was also lower in non-survivors (p = 0.04). Median HLA-DR expression decreased from days 1–2 to days 3–4 in patients who developed secondary infections while it increased in those without secondary infections (p = 0.054). TNF-ɑ production did not differ between survivors and non-survivors or between patients who did and did not develop a secondary infection.ConclusionsMonocyte HLA-DR expression may be a more accurate predictor of mortality and acquisition of secondary infections than LPS-stimulated TNF-ɑ production in adult medical and surgical critically ill patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1505-0) contains supplementary material, which is available to authorized users.

Inflammation and innate immune function in critical illness.

The purpose of review is to highlight the inflammatory response in critical illness and the importance of immune monitoring and modulation in the diagnosis and treatment of critical illness-induced innate immune suppression. The pro and anti-inflammatory responses are known to be concurrently activated in many patients requiring intensive care, with innate immune suppression emerging as an important, and potentially reversible, complication of critical illness. The initial inflammatory response to critical illness is typically driven by innate immune cells, including neutrophils, monocytes, and macrophages. The proinflammatory mediators made by these cells are responsible for many of the pathophysiologic features of critical illness. Concurrent with this, however, is a compensatory anti-inflammatory response, including the elaboration of anti-inflammatory mediators and impairment of innate immune cell function. This includes reduction of monocyte human leukocyte antigen-DR expression and impairment of the ability of innate immune cells to produce tumor necrosis factor alpha when stimulated ex vivo. In its most severe form this is referred to as immunoparalysis, and is associated with markedly increased risks for secondary infection and death in the ICU. Prospective testing can detect this phenomenon, and immunostimulatory strategies, including the use of granulocyte macrophage-colony stimulating factor, have the potential to restore innate immune function in this setting.

Prolonged suppression of monocytic human leukocyte antigen–DR expression correlates with mortality in pediatric septic patients in a pediatric tertiary Intensive Care Unit

IntroductionImmunoparalysis is a syndrome with no clinical symptoms that occurs in some septic patients. Monocytic human leukocyte antigen–DR (mHLA-DR) expression has been used to identify patients in immunoparalysis and prolonged periods of reduced mHLA-DR expression have been correlated with a poor prognosis in sepsis. However, there is a lack of studies investigating mHLA-DR expression in pediatric septic patients. AimTo determine if mHLA-DR expression correlates with mortality in pediatric septic patients using the QuantiBRITE Anti HLA-DR/Anti-Monocyte,a Bechton Dickinson novel reagent that standardizes flow cytometry values. MethodsWe determined mHLA-DR expression in 30 patients with severe sepsis or septic shock admitted to the pediatric intensive care unit at Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, between January 2013 and February 2015. mHLA-DR expression was quantified between days 3 to 5 and 5 to 7 after the onset of sepsis and the ΔmHLA-DR (mHLA-DR2 − mHLA-DR1) was calculated. We also measured mHLA-DR levels in 21 healthy control patients. ResultsMean mHLA-DR expression was significantly lower in septic patients than in controls (P = .0001). Mortality was 46% in patients with negative ΔHLA-DR or <1000 mAb/cell and 7% in patients with positive ΔHLA-DR or >1000 mAb/cell. Mean ΔmHLA-DR levels were significantly different between survivors and non-survivors (P = .023). ConclusionΔHLA-DR correlates with mortality in pediatric patients with septic shock or severe sepsis. This is the first study to have used the QuantiBRITE Anti HLA-DR/Anti-Monocyte reagent to quantify monocyte HLA-DR expression in pediatric septic patients.

Low-Dose Steroid Therapy Is Associated with Decreased IL-12 Production in PBMCs of Severe Septic Patients.

Background. Sepsis-induced immunosuppression may result in higher mortality rates in patients. Methods. We examined the relationship of cytokine responses from stimulated peripheral blood mononuclear cells (PBMCs) and monocyte human leukocyte antigen-DR (HLA-DR) expression (days 1 and 7) with low-dose steroid therapy in 29 septic patients. Patients were treated according to the guidelines. Thirty healthy controls were enrolled for validation. Results. Eighteen patients were prescribed low-dose steroids and 11 were not. Interleukin- (IL-) 12 responses in patients without low-dose steroid therapy on days 1 and 7 were higher than those with low-dose steroid therapy. Compared to day 1, IL-12 responses significantly increased on day 7 in patients without low-dose steroid therapy. After regression analysis, the change in the IL-12 response from day 7 to day 1 was found to be independently associated with the low-dose steroid therapy. There was no difference in monocyte HLA-DR expression between patients treated with and without low-dose steroid on day 1 or 7. No change in monocyte HLA-DR expression from day 7 to day 1 was observed in patients with or without low-dose steroid therapy. Conclusion. Decreased IL-12 response was associated with the low-dose steroid therapy in PBMCs of septic patients.

Postoperative immunosuppression markers and the occurrence of sepsis in patients with benign and malignant disease

To investigate associations between the postoperative immune response and the levels of extracellular circulating DNA (cDNA), C-reactive protein (CRP), neutrophil/lymphocyte (N/L) ratio, and regulatory T (Treg) cells in the peripheral blood and their role as potential predictors of postoperative septic complications. This was a prospective observational study involving 115 adult patients who underwent elective surgery. Patients were divided into three groups: with benign disease, with malignant disease, and with malignant disease and administration of dexamethasone. Serum CRP levels, N/L ratio, monocyte human leukocyte antigen-DR (HLA-DR) expression, proportion of Treg cells, and cDNA levels were measured at different time points before and after surgery. All patients had increased CRP levels after surgery. Septic patients had higher serum CRP levels at baseline. Compared with the other groups, the dexamethasone group had significantly higher CRP levels before and after surgery, a significantly higher N/L ratio before surgery, a significantly lower rise in the N/L ratio after surgery, and a significantly lower HLA-DR expression at baseline, which remained stable after surgery. In the malignant-disease group, we observed a significant postoperative decrease in the HLA-DR expression. Our results suggest that the immunosuppressive effect of surgery and the presence of a malignant disease may contribute to a higher risk of postoperative sepsis. Preoperative CRP levels may be a reliable predictor of sepsis in oncological patients.

Monocyte Human Leukocyte Antigen–DR Expression—A Tool to Distinguish Intestinal Bacterial Infections From Inflammatory Bowel Disease?

We sought to determine the quantitative expression of human leukocyte antigen-DR (HLA-DR) on monocytes in patients with acute intestinal bacterial infections and inflammatory bowel disease (IBD). The quantitative expression of HLA-DR on monocytes was determined by fluorescence-activated cell sorting analysis in patients with IBD, patients with acute intestinal bacterial infections (bact.), and healthy subjects (contr.). The quantitative expression of HLA-DR in patients with bact. (n = 20; 90,000 molecules per monocyte; confidence interval [CI], 79,000-102,000) was significantly higher than that in patients with ulcerative colitis (n = 40, 30,000; CI, 30,000-38,000; P < 0.0001), Crohn disease (n = 80, 31,000; CI, 32,000-39,000; P < 0.0001), or in contr. (n = 28, 39,000; CI, 36,000-46,000; P < 0.0001). In patients with ulcerative colitis and Crohn disease, HLA-DR expression was significantly decreased, as compared with contr. (P < 0.05 and P < 0.01, respectively). With a cutoff point of 50,000, HLA-DR showed a sensitivity of 95% and a specificity of 92% in discriminating between bact. and active IBD. The quantitative measurement of HLA-DR expression could serve as a valuable tool to discriminate between bact. and active IBD.

The Role of Fas Expression on the Occurrence of Immunosuppression in Severe Acute Pancreatitis

Severe acute pancreatitis (SAP) is a dangerous illness with high mortality where most patients do not die of excessive inflammation, but die of immunosuppression and multiple infections at a later stage. The mechanism of immunosuppression in SAP is unknown. The purpose of this study was to analyze the role of Fas expression on the occurrence of immunosuppression in patients with SAP. Forty-eight patients with pancreatitis were divided into two groups: 20 cases with SAP (7 cases with sepsis, 13 cases without sepsis) and 28 cases with mild acute pancreatitis (MAP). Twenty-eight healthy volunteers were selected as controls. Fas mRNA expression in peripheral blood was detected by qPCR and Fas protein of lymphocyte membranes; T lymphocyte subsets and expression of monocyte Human leukocyte antigen DR (HLA-DR) in peripheral blood were detected by flow cytometry. Compared with MAP and control groups, expression level of Fas mRNA and lymphocyte Fas protein in peripheral blood were significantly increased in the SAP group (all P < 0.01). There was a further significant increase in the SAP group with sepsis compared to those without sepsis (all P < 0.01). The CD4(+) T cell ratio, CD4(+)/CD8(+) ratio and monocyte HLA-DR expression in the SAP group were decreased significantly compared with MAP and control groups (all P < 0.01). Significant negative relationships were observed between Fas mRNA expression and CD4(+) T-cell ratio, CD4(+)/CD8(+) ratio, and monocyte HLA-DR expression in SAP patients with sepsis (all P < 0.05). The results suggest that expression level of Fas is related to severity and immune status of pancreatitis. Overexpression of Fas may lead to the occurrence of immunosuppression and sepsis.

Low monocyte HLA-DR expression as an indicator of immunodepression in very low birth weight infants

As a protective response to an inflammatory stimulus, the antigen-presenting molecules (human leukocyte antigen-DR (HLA-DR)) on monocytes are downregulated. If severe, the response may lead to immunodepression or immunoparalysis, associated with an increased rate of morbidity and mortality in adults. In very low birth weight (VLBW) infants, birth and intensive care present major immunological challenges. We measured monocyte HLA-DR expression by flow cytometry and determined 13 plasma cytokines in 56 VLBW infants (gestational age (GA): 23.7-31.8 wk) and 25 controls (GA: 34.1-41.4 wk). HLA-DR expression decreased postnatally both in VLBW and in control infants. In VLBW infants, GA and respiratory distress syndrome (RDS) both showed associations with HLA-DR nadir on day 3, when 45% of them met the criteria of immunodepression. HLA-DR expression was lower in those infants subsequently developing infection (74 vs. 49% (day 3) and 85 vs. 68% (day 7); both P = 0.002). Interleukin (IL)-6 on day 1 was a predictor of the HLA-DR nadir. VLBW infants are in a state of immunodepression postnatally. This immunodepression correlated with GA and was a predisposing factor for late infections. The downregulation of HLA-DR during RDS probably indicates an RDS-induced antigen load on the immune system.

Importance of Monocyte Deactivation in Determining Early Outcome after Ventricular Assist Device Implantation

Patients undergoing mechanical circulatory support using ventricular assist devices (VADs) experience a postoperative mixed antagonistic (proinflammatory and antiinflammatory) response syndrome. This response can result in immunoparalysis, exposing VAD recipients to infection and interfering with patient recovery despite adequate hemodynamic support. We undertook the present study to evaluate whether postoperative monocytic human leukocyte antigen-DR (mHLA-DR) expression is of prognostic value for mortality or infection of VAD recipients during their initial intensive care unit (ICU) stay after implantation. Since 2004, we have monitored postoperative mHLA-DR expression in 50 VAD recipients using flow cytometry. Thirty-seven patients (74%) developed infection, and 22 patients (44%) died during their initial ICU stay. mHLA-DR expression was lowest in the immediate postoperative period (postoperative days [PODs] 1-3) but increased progressively thereafter. Multiple regression analysis showed that preoperative aspartate aminotransferase level was the only significant and independent predictor of the percentage of HLA-DR-positive monocytes on PODs 1-3 (β = -0.726, p = 0.0001). ICU death and infection were associated with significantly lower percentages of HLA-DR-positive monocytes on PODs 1-3. ROC curve analysis revealed that the percentage of HLA-DR-positive monocytes on PODs 1-3 had significant discriminative power for ICU death (area under the curve = 0.73, 95% confidence interval, 0.545-0.912, p = 0.037), but not for infection. Postoperative mHLA-DR expression was closely related to preoperative hepatic cytolysis. It appeared to be the only early postoperative biological parameter that had some predictive power for death of VAD recipients in the ICU.

Clinical Outcome of Critically Ill Patients Cannot Be Defined by Cutoff Values of Monocyte Human Leukocyte Antigen-DR Expression

Septic shock is the most common cause of death in intensive care units. During the last two decades, new strategies have focused on the diagnosis and on the immunological changes in critically ill patients. There have been conflicting reports whether monocyte human leukocyte antigen (HLA) DR expression poses a useful parameter to characterize clinical outcome of these patients. To elucidate the role of monocyte HLA-DR expression, we hypothesized that low expression of HLA-DR on circulating human monocytes in critically ill patients correlates with higher mortality and that cutoff values of HLA-DR discriminate surviving from nonsurviving patients. In this retrospective study, monocyte HLA-DR expression in 413 critically ill patients was investigated during their intensive care unit stay. Human leukocyte antigen DR was determined in a quantitative and standardized procedure by flow cytometry (anti-HLA-DR monoclonal antibodies bound per cell [mABs/cell]) at least every third day or when clinical changes in the patients conditions were observed. Healthy probands served as control group to determine the range of "normal" values. As expected, HLA-DR expression was significantly higher in the group of survivors (n = 279) than in the group of nonsurvivors (n = 134; mABs/cell: 23,038 [SD, 11,150] vs. 18,070 [SD, 8,906]; P < 0.001). When minimal HLA-DR values per patient were compared, no cutoff values could be identified between the groups of survivors and nonsurvivors (mABs/cell: 19,611 [SD, 11,129] vs. 14,944 [SD, 8,013]; P < 0.001). In conclusion, in this sizable cohort we could again show that HLA-DR expression is decreased in critically ill patients but it is not suitable as a prognostic or predictive parameter for clinical outcome.