The Paradigm Shift in Critical Care Immunology
For decades, the clinical management of septic shock focused almost exclusively on dampening the initial hyper-inflammatory response—the so-called cytokine storm. However, contemporary research has revealed that sepsis is a state of simultaneous immune activation and profound immunosuppression. This ‘immunoparalysis’ is often the primary driver of late-stage mortality, characterized by ICU-acquired infections, the reactivation of latent viruses, and impaired wound healing. As we enter the era of precision medicine, identifying the patients who are most likely to benefit from immune-stimulating therapies has become a paramount challenge. Two recent landmark studies have highlighted monocyte HLA-DR (mHLA-DR) expression as the most reliable and actionable biomarker for this stratification.
Monocyte HLA-DR: The Sentinel of Immunoparalysis
Human Leukocyte Antigen-DR (HLA-DR) is a molecule expressed on the surface of antigen-presenting cells, most notably monocytes. Its primary role is to present processed peptides to T-cells, thereby initiating the adaptive immune response. In the context of critical illness, a decrease in the density of mHLA-DR molecules—measured as antibodies per cell (AB/C)—serves as a surrogate for suppressed monocytic function and overall immune incompetence. While many biomarkers have been proposed, mHLA-DR stands out due to its standardized measurement protocols and its direct correlation with the clinical phenomenon of immunoparalysis.
Insights from a 20-Year Septic Shock Cohort
The study by Monneret et al., published in Intensive Care Medicine, provides unprecedented depth into the predictive value of mHLA-DR. By analyzing a real-world cohort of 1,023 septic shock patients over two decades, the researchers demonstrated that mHLA-DR is more than just a diagnostic curiosity; it is a robust enrichment biomarker.
The 8,000 AB/C Threshold
The study confirmed that a threshold of < 8,000 AB/C—a level already utilized in phase II clinical trials—is significantly associated with increased mortality at both day 28 and day 90. Patients falling below this threshold also exhibited a higher incidence of ICU-acquired infections. This data reinforces the use of this specific cut-off for identifying patients at high risk of adverse outcomes.
The Importance of Trajectories
One of the most significant findings from this 20-year analysis is the distinction between early downregulation and persistent immunosuppression. The researchers noted that early immune downregulation (within the first 48 hours) might represent a physiological adaptation to the initial systemic inflammatory response. However, patients who fail to recover their mHLA-DR expression levels over the first week are at the highest risk. Through K-means trajectory clustering, the study showed that tracking mHLA-DR after the initial ICU days is essential. A single measurement taken too early may fail to distinguish between those who will recover naturally and those who are entering a state of chronic immune dysfunction.
A Principal component analysis (PCA) of patients’ main clinical characteristics and mHLA-DR expression at ICU admission. PCA was performed to reduce data dimensionality by retaining quantitative variables commonly used to describe a septic shock cohort and to assess cohort homogeneity over time. The loadings of the eight variables on the first two principal components, together accounting for 41% of the total variance, are shown. B Dots represent individual PCA observations over a 20-year period, with confidence ellipses illustrating group (successive period of inclusion) distributions. Samples were divided into four chronological periods, each comprising approximately 255 patients. C Daily occurrence of mortality and ICU-acquired infections from ICU admission to day 30. Results are shown as the number of events per day using interleaved bar graphs. D Time course of mHLA-DR expression in the whole cohort. Samples were collected at four time points: day 1/2 (n = 899), day 3/4 (n = 886), day 5/7 (n = 650), and at ICU discharge (n = 162). mHLA-DR values are expressed as AB/C (antibodies bound per cell). Results are presented as median with interquartile range (Q1–Q3). The accompanying table shows the numerical values at each time-point. The bottom row indicates the percentage of patients with mHLA-DR ≤ 8000 at each time-point. The dashed line represents the lower limit of reference range of mHLA-DR (i.e., 13,500 AB/C)
Association of mHLA-DR expression with main outcomes. A Time course of mHLA-DR expression according to 28-day mortality (n = 301 deceased patients). B Time course of mHLA-DR expression according to 90-day mortality (n = 378 deceased patients). C Based on cut-off value of 8000 AB/C (antibodies bound per cell) at day 3/4, patients were separated into 2 groups to build Kaplan–Meier survival curves until day 90. The log-rank test was used to test the difference between the curves. D Based on cut-off value of 8000 AB/C (antibodies bound per cell) at day 5/7, patients were separated into 2 groups to build Kaplan–Meier survival curves until day 90. The log-rank test was used to test the difference between the curves. E Time course of mHLA-DR expression according to ICU-acquired infection (n = 190 patients). mHLA-DR values were censored once infection occurred. F Based on cut-off value of 8000 AB/C (antibodies bound per cell) at day 5/7, patients were separated into 2 groups to build Kaplan–Meier infection acquisition curves. The log-rank test was used to test the difference between the curves. G Additional mHLA-DR expression (n = 226 patients for which a fourth sample was available, mean time of sampling = 16 days [Q1–Q3 = 11–22] following ICU admission) according to 90-day mortality. H Based on cut-off value of 8000 AB/C (antibodies bound per cell) for the additional sample, patients were separated into 2 groups to build Kaplan–Meier survival curves until day 90. The log-rank test was used to test the difference between the curves. Results are presented with median and Q1–Q3. Mann–Whitney test was used for comparison between groups. ns: non-significant, *p value < 0.05, **p value < 0.01, ***p value < 0.001, ****p value < 0.0001
Multivariate analysis. A Association with mortality over time. mHLA-DR expression was modeled as a time-dependent covariate using a Cox proportional hazards model, incorporating repeated measurements as a longitudinal exposure. The threshold of 8000 AB/C (antibodies bound per cell) was applied. The model was adjusted for age, SAPS II, and SOFA scores at admission. B Association with mortality at discrete time points. Three separate landmark Cox regression models were performed at days 1/2, 3/4, and 5/7. The threshold of 8000 AB/C (antibodies bound per cell) was applied. Models were adjusted for age, SAPS II, and SOFA scores at admission. C Association with ICU-acquired infections. Cumulative incidence of ICU-acquired infections was analyzed at days 1/2, 3/4, and 5/7 using Fine and Gray competing risk models, treating death and ICU discharge as competing events. Subdistribution hazard ratios were adjusted for age, SAPS II, and SOFA scores
Predicting Outcomes in Liver Transplantation
The utility of mHLA-DR extends beyond the general sepsis population into specialized fields such as solid organ transplantation. In a prospective observational study by Delignette et al., the focus was shifted to patients undergoing liver transplantation (LT). These patients are uniquely vulnerable due to cirrhosis-associated immune dysfunction (CAID) existing prior to surgery.
Infection Risk and mHLA-DR Recovery
Among 99 patients who underwent LT, over 35% experienced early post-operative infections. The study found that neither lymphocyte counts nor functional T-cell assays were predictive of these outcomes. Instead, the kinetics of mHLA-DR were the defining factor. Specifically, a delayed recovery of mHLA-DR (defined as < 11,000 AB/C by Day 7) was associated with a 12-fold increase in the risk of infection (OR 12.1).
Survival and Clinical Correlation
The clinical impact of delayed immune restoration was stark. Patients who failed to reach the mHLA-DR threshold by post-operative day 7 had a significantly lower one-year survival rate (77.8% compared to 98.3% in those with normal recovery). When combined with a pre-transplant MELD score of > 30, mHLA-DR monitoring provided a powerful predictive model for identifying patients who require intensive post-operative surveillance and potentially modified immunosuppressive regimens.
Expert Commentary and Clinical Integration
The convergence of these two studies suggests that mHLA-DR should be integrated into standard critical care and transplant monitoring protocols. However, several clinical considerations remain.
Methodological Standardization
The strength of these findings rests on the use of standardized flow cytometry. For mHLA-DR to be used as a universal enrichment biomarker, laboratories must adhere to strictly calibrated protocols to ensure that AB/C measurements are comparable across different institutions.
Therapeutic Implications
The identification of ‘low-expressors’ opens the door for targeted immunostimulatory therapies, such as Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) or Interferon-gamma (IFN-γ). By using mHLA-DR trajectories, clinicians can avoid over-treating patients who are already on a path to natural recovery, focusing instead on those with persistent immunoparalysis.
Study Limitations
While the 20-year cohort provides massive scale, it is inherently retrospective in its data collection, which may introduce bias regarding changes in standard sepsis care over two decades. In the liver transplant study, the sample size, while prospective, is smaller and based at a single center. Further multi-center validation of the 11,000 AB/C threshold in transplantation is warranted.
Conclusion: The Future of Immune-Guided Medicine
The evidence is clear: mHLA-DR is a critical tool for navigating the complexities of the ICU. Whether managing the aftermath of septic shock or the recovery phase of a liver transplant, clinicians must look beyond static snapshots of the immune system. By monitoring mHLA-DR trajectories, we can identify the ‘window of opportunity’ for intervention, potentially reducing the burden of secondary infections and improving long-term survival for the most vulnerable patients.
Funding and Clinical Trial Information
The liver transplantation study was registered in the ClinicalTrials.gov registry under NCT03995537 (June 20, 2019). The septic shock cohort research was supported by institutional funding and represents one of the largest real-world datasets of its kind.
References
1. Monneret G, Lafon T, Gossez M, et al. Monocyte HLA-DR expression in septic shock patients: insights from a 20-year real-world cohort of 1023 cases. Intensive Care Med. 2025;51(10):1820-1832.
2. Delignette MC, Riff A, Antonini T, et al. Individual mHLA-DR trajectories in the ICU as predictors of early infections following liver transplantation: a prospective observational study. Crit Care. 2025;29(1):79.
