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

Abstract

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.

Complicated intra-abdominal infections (cIAIs) remain an important and leading cause of morbidity and death in surgical patients. In intensive care units (ICUs), they hold the second place after pneumonia as infectious cause of mortality [1].

The IAIs are divided into uncomplicated and complicated. Uncomplicated infections are localized in a single abdominal organ and do not extend into the peritoneal cavity. The cIAIs spread beyond the affected organ, which results in localized or diffuse peritonitis [2], and usually the infections lead to sepsis. Sepsis is a life-threatening organ dysfunction (change in Sequential Organ Failure Assessment score ≥2 points) based on dysregulated host response to infection (see sepsis 3 definitions [3]).

Because of the enormous diversity of patient groups affected by complicated intra-abdominal infections, the recommendation of a general treatment algorithm is a difficult task. This necessitates an individual treatment plan for each patient. In predicting the outcome of patients with cIAIs, a wide range of unfavorable circumstances such as poor nutrition, immunosuppression, nosocomial pathogens, pre-existing diseases, advanced age, diffuse peritonitis, delayed treatment, septic shock, organ failures, and poor source control have to be considered [4].

Sepsis is still the main cause of morbidity and death in cIAIs [5]. Despite identical conservative and surgical treatment, some patient populations are distinguished by high mortality rates. Nevertheless, early prognosis and timely therapy in these patients enhance the chances of favorable outcome [6]. All of these facts indicate the necessity for significant methods that could contribute to early prognostic assessment and determine the aggressiveness of treatment regimens. A large number of researchers are still trying to deal with these problems, focusing on the predictive reliability of different anti-inflammatory biomarkers. In this article, we review the prognostic performance of monocyte human leukocyte antigen-DR (mHLA-DR).

The HLA-DR is a glycosylated cell surface membrane protein expressed on antigen presenting cells, constitutively expressed on monocytes as well. The complex of HLA-DR and peptide of nine amino acids in length or longer represents a ligand for the T-cell receptor (TCR). The main role of HLA-DR in the infection is in antigen presentation of T-helper cells that results in releasing of pro-inflammatory cytokines. In patients with sepsis, however, this path could be impaired, and that leads to immunodepression [7].

According to Monneret and Venet [8] and Venet et al [9], the most reliable monitoring biomarker for immune changes in critically ill patients at present is lowered mHLA-DR expression. Moreover, the monocyte functionality and anergy could be assessed perfectly by HLA-DR expression. The mHLA-DR is the most widely evaluated biomarker in different ICU conditions (sepsis, trauma, pancreatitis, surgical procedures, burns); it also provides information for the final outcome and the risk of secondary infections [8,9].

The decreasing of monocyte antigen-presenting capacity through down-regulation of HLA-DR could lead to fatal outcome in septic patients [10]. For this reason, mHLA-DR has been investigated in the last years as a death predictor in sepsis. The HLA-DR expression ≤30% on monocytes correlates with higher risk of poor outcome [11,12].

This review aimed to discover the potential prognostic value of mHLA-DR in patients with cIAIs. For the first time (to our knowledge), we summarized and analyzed the existing data about mHLA-DR association with death.

Methods

We performed an electronic search of PubMed and Google Scholar databases for articles published before January 2019 relating the prognostic value of mHLA-DR in patients with cIAIs and sepsis. The search terms were “HLA-DR,” “monocyte HLA-DR,” “intra-abdominal infections,” “sepsis,”, “outcome,” and “mortality.” The inclusion criteria were: 1. Original studies; 2. studies assessing the prognostic performance of mHLA-DR; 3. studies involving 20 and more cases; 4. studies with patients in Surgical Care Units, ICUs, or Intermediate Care Units, especially surgical patients.

Results and Discussion

Twelve studies with 761 patients met our inclusion criteria. The data we found were quite similar (Table 1).

Table 1.

Summary of Studies on Prognostic Performance of mHLA-DR

Year	Author	Department	Patients	Selection criteria	Predictor of death	Poor outcome
1992	Polk et al.	Surgical Trauma Centre	193	Trauma + bacterial contamination	Yes	↓mHLA-DR expression
2000	Hirsh et al.	ICU	23	Sepsis	Yes	↓mHLA-DR expression
2003	Hynninen et al.	ICU	61	Sepsis	Yes	↓mHLA-DR expression
2003	Perry et al.	ICU	70	Sepsis	Not significant	-
2004	Lekkou et al.	Intermediate CU	30	Sepsis	Yes	↓mHLA-DR expression
2006	Monneret et al.	ICU	93	Septic shock	Yes	↓mHLA-DR expression
2008	Abe R et al.	ICU	20	Sepsis	Yes	↓mHLA-DR expression
2009	Fu et al.	Surgical ICU	46	Severe intra-abdominal infections	Yes	↓mHLA-DR expression
2013	Tian Y et al.	Surgical ICU	50	Sepsis	Yes	↓mHLA-DR expression
2016	Skirecki et al	ICU	27	Septic shock	No	-
2016	Drewry et al.	Surgical/ Medical ICU	83	Sepsis	Yes	↓mHLA-DR expression
2018	Wang et al.	ICU	65	Sepsis	Yes	↓mHLA-DR expression

mHLA-DR = monocyte human leukocyte antigen-DR; ICU = intensive care unit.

Ten studies showed a strong association between lower mHLA-DR expression and death. In the first one, Polk et al. [13] evaluated the efficacy of interferon-gamma (IFN-gamma) in 193 patients with major injury and bacterial contamination. They measured mHLA-DR expression in each patient and observed that on the third day, non-survivors in the placebo group had lower mHLA-DR expression (non-survivors vs. infected survivors vs. uninfected survivors – 29% ± 18.9% vs. 39% ± 19.9% vs. 53% ± 22.0%) such as non-survivors in the rIFN-gamma group (non-survivors vs. infected survivors vs. uninfected survivors—45% ± 17.7% vs. 65% ± 22.6% vs. 77% ± 19.0%).

In 2000, Hirsh et al. [14] analyzed mHLA-DR expression in 23 patients with sepsis and a control group of 10 healthy volunteers. Patients with sepsis had a decreased percentage of HLA-DR+ monocytes (32.4% ± 4.9%, p < 0.0001). The group of non-survivors had lower expression compared with survivors (21.3% ± 4.7% vs. 42.5% ± 7.2%, p = 0.026). Hynninen et al. [10] enrolled 61 adult patients with sepsis from two ICUs and measured their mHLA-DR expression, interleukin (IL)-4, and IL-10 levels. The authors found a significant difference of mHLA expression between survivors and non-survivors at admission—84% (interquartile range [IQR] 64%–98%) vs. 62% (IQR 47%–83%), p = 0.025.

In 2003, Lekkou et al. [15] prospectively enrolled 30 patients with sepsis. They tried to analyze the impact of pro-inflammatory and anti-inflammatory molecules and mHLA-DR as biomarkers of immune status for the final outcome. In non-survivors, HLA-DR expression was decreased significantly. All patients with mHLA-DR expression >40% survived, while those with expression <40% died. The mHLA-DR on admission showed good prognostic performance—survivors vs. non-survivors 43.1% ± 25.4% vs. 23.4% ± 20.7%, respectively; p < 0.05.

Monneret et al. [16] performed a measurement of mHLA-DR expression in 93 patients with septic shock. They observed a highly significant difference of mHLA-DR expression at days three to four (survivors vs. non-survivors 43% vs. 18%, respectively; p < 0.001). Multi-variable logistic regression analysis showed that low mHLA-DR (<30%) at days three to four remained an independent outcome predictor after adjustment for usual clinical confounders, adjusted odds ratio (confidence interval [CI]): 6.48 (95% CI: 1.62–25.93). The authors' conclusion was that mHLA-DR was an independent survival predictor in patients with septic shock.

In 2008, Abe et al. [17] examined cytokine-related mRNA expression in peripheral leukocytes, cytokine blood levels, and mHLA-DR expression in 20 patients with sepsis. Non-survivors had significantly lower expression of mHLA-DR than survivors (p < 0.05). Abe et al [17] concluded that decreased HLA-DR expression could be a marker of poor outcome.

Fu et al. [18] performed an analysis of mHLA-DR, endotoxin, and CD4(+) CD25(+) Tregs levels in 46 ICU patients with severe intra-abdominal infections. The patients were divided according to their APACHE II score in four groups: mild group (13 patients), medium group (17 patients), severe group (10 patients), and extremely severe group (six patients). The mHLA-DR of mild and medium groups showed a tendency of elevation, but mHLA-DR expression in the critically ill patients was depressed and circulating Treg significantly elevated (p < 0.05). The observed mHLA-DR expression at day one in the severe and extremely severe groups was 33.45% ± 3.52% and 27.84% ± 3.81%, respectively, and the deaths in these two groups were higher than other groups (p < 0.05).

In 2013, Tian et al. [19] included in their prospective study 50 patients with sepsis admitted to a surgical ICU and evaluated their levels of sTNF-related apoptosis-inducing ligand and mHLA-DR expression. The patients were observed for incidence of death in a 28-day period. Patients with sepsis had significantly lower mHLA-DR expression compared with healthy controls (40.6% ± 20.7% vs. 90.7% ± 7.4%, p < 0.01). In addition, expression of mHLA-DR in survivors was significantly higher than that in non-survivors (48.6 ± 22.0 vs. 31.3 ± 14.7, p < 0.01).

Drewry et al. [20] compared HLA-DR expression and LPS-induced TNF-α production as mortality predictors in 83 ICU patients with sepsis. Twenty-five patients (30.1%) died during a 28-day period. In non-survivors compared with survivors, mHLA-DR expression on the third and fourth days (p = 0.04) and sixth, seventh, and eighth days (p = 0.002) was significantly lower. In non-survivors, the change in mHLA-DR from days one to two to days six to eight was also found to be lower (p = 0.04). The authors concluded that mHLA-DR expression could be a better death predictor than LPS-induced TNF-α production in surgical and non-surgical ICU patients.

In 2018, Wang et al. [21] examined the blood lactate acid levels and HLA-DR expression in 65 patients with sepsis and 50 healthy volunteers. Patients with sepsis had decreased HLA-DR expression compared with the control group. In non-survivors, the expression of HLA-DR was significantly lower than in survivors (32.41 ± 12.04 vs. 43.05 ± 11.64, p = 0.011).

We found only two studies in which mHLA-DR showed no prognostic performance. Perry et al. [22] in 2003 analyzed mHLA-DR expression, APACHE II score, age, gender, and outcome in 70 patients with sepsis admitted to a medicosurgical ICU. Twenty-three patients died during hospitalization. The authors found no significant difference in mHLA-DR expression on day one between survivors and non-survivors (p = 0.85). In the second study, Skirecki et al. [23] compared the mHLA-DR and neutrophil CD64 expression in 27 patients with septic shock and analyzed their prognostic performance. Sixteen patients died. The mHLA-DR expression did not discriminate non-survivors from survivors at all (p = 1.00).

Ten of 12 studies found mHLA-DR a good death predictor, and the poor outcome was associated with lower expression. Only two studies showed lack of prognostic performance. None of the studies reported that poor outcome correlated with higher expression.

Conclusion

Finding the perfect biomarker for early prognostic evaluation is a difficult task. At present, many efforts are directed at searching different multi-marker panels. Our opinion, however, is that mHLA-DR could be a reliable and most important independent prognostic biomarker in patients with complicated intra-abdominal infections. Certainly, future large multi-center studies with surgical patients exclusively are needed before using this biomarker in clinical practice.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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