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CHAPTER 62: Sepsis and Immunoparalysis 555

body of literature is available for mHLA-DR expression, and it has been correlate different markers with functional testing and to determine a
proposed that diminished mHLA-DR expression provides a reliable link with outcome or septic nosocomial complications. 44
reflection of immunosuppression in critically ill patients, in terms of Current tools to identify and monitor immune function include
both its magnitude and persistence. Monocytes from septic patients
with decreased levels of mHLA-DR have been shown to produce small 1. Anti-inflammatory serum cytokine measurement, with current
amounts of TNF-α and IL-1 in response to bacterial challenges such attention focused upon IL-10
as stimulation with LPS, staphylococcal enterotoxin B, and phorbol 2. Ex-vivo LPS stimulation of whole blood and subsequent measure-
myristate acetate, and a decrease in antigen presenting capacity partly ment of proinflammatory cytokines (TNF-α)
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due to a reduced HLA-DR expression. 65,66,87-89 3. HLA-DR expression on the monocyte surface
To date, mHLA-DR levels have mainly been assessed as a predic-
tor of septic complications after trauma, surgery, and pancreatitis. Monocyte Dysfunction: Monocytes from septic patients have been shown
Low levels of mHLA-DR were found in patients who subsequently to have a decreased capacity to mount a proinflammatory reaction upon
developed nosocomial infections. In contrast, mHLA-DR levels nor- secondary bacterial challenge and impairment in antigen presentation
malized rapidly (generally within 1 week) in patients who recovered likely due to the lowered expression of major histocompatibility class II
103
uneventfully. Diminished mHLA-DR expression has previously been molecules (MHC class II). Several groups have investigated the capac-
identified as an independent predictor of septic complications in ity of septic patients’ monocytes to release proinflammatory cytokines in
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multiple logistical regression analysis after correction for clinical response to LPS, other TLR agonists, or whole bacteria in vitro. These
parameters. 90 tests represent reliable methods to assess the phenomenon of endotoxin
■ APOPTOSIS tolerance defined as a reduced responsiveness to a secondary LPS chal-
lenge following a first inflammatory response. Monocytes from patients
Apoptosis is another promising, indicator of immunoparalysis. In experi- usually present with a diminished capacity to release tumor necrosis
mental models, excess apoptosis was associated with deleterious effect and factor (TNF-α), interleukin (IL)-1a, IL-6, IL-12, whereas the release of
blockade of apoptosis reduced mortality rates. 91,92 In septic patients who anti-inflammatory mediators (IL-1 receptor antagonist [IL-1ra], IL-10)
died, Hotchkiss et al observed lymphocyte apoptosis in the spleen and a is not affected or is even slightly increased. However, although this test is
decrease in the number of circulating lymphocytes. Similar observations considered a good method to assess monocyte hyporesponsiveness after
93
have been made in animal models of sepsis, and adoptive transfer of apop- sepsis, it is not yet suitable for routine analysis/diagnosis. 104
totic splenocytes induced immunosuppression by downregulating IFN-γ T-Lymphocyte Dysfunction: Lymphocyte anergy is illustrated by the
production that was associated with facilitated bacterial dissemination. 78,91,94 observation of the loss of the delayed-type hypersensitivity reaction
Le Tulzo et al demonstrated that apoptosis rapidly follows the onset to recall skin test antigens in patients.
of septic shock and leads to profound lymphopenia that is associated However, the investigation of lymphocyte anergy is neither easy nor
with death. It is not clear, however, that apoptotic pathways involve all practical for the diagnosis of sepsis immunosuppression.
95
lymphocyte subclasses since divergent findings have been reported for
B-lymphocyte populations. 96-98 Apoptosis and Gene Expression: It is generally agreed that apoptotic cell
Importantly, lymphopenia is accompanied by modifications of the death represents the major mechanism triggering sepsis-induced lym-
CD4 /CD8 ratio and the relative percentage of cellular subsets. phocyte anergy/dysfunction. Recently it was shown that gene signatures
+
+
Lymphopenia has also been associated with bacteremia. Hotchkiss and gene expression mosaics obtained from patients within the first
99
and colleagues showed that apoptosis was affecting circulating NK cells, 24 hours of septic shock can be used to stratify patients into subclasses
B lymphocytes, and CD4 and CD8 T lymphocytes. The reduced having their own particular severity of illness, rate of organ failure, and
+
+
100
HLA-DR expression on CD14 monocytes is another hallmark of sepsis mortality. This work shows that gene expression methods may represent a
+
and SIRS. It shows promise as a prognostic marker for the development robust and achievable process by which patients with sepsis can be strati-
of sepsis in hospitalized patients. The preliminary cutoff levels for fied. Similarly, Turrel-Davin and colleagues have shown that mRNA
106
101
monocytic HLA-DR expression compatible with immunoparalysis have expression can be used to monitor subsequent response to treatment. 107
been shown to be : The Cell Surface Marker mHLA-DR: HLA-DR is a glycosylated cell surface
102
• >15,000 Ab/cell (antibodies per cell) indicates immunocompetence. membrane protein expressed on antigen presenting cells, constitutively
• 10-15,000 Ab/cell (antibodies per cell) indicates moderate immuno- expressed on monocytes. Expression of HLA-DR by monocytes is essen-
depression. tial for the processing and presentation of peptides derived from ingested
+
• <10,000 Ab/cell (antibodies per cell) indicates severe immunodepression. microbes. Its function is to present processed antigen to CD4 T cells to
initiate a specific immune response, which will eliminate the potential
• <5000 Ab/cell (antibodies per cell) indicates immunoparalysis. pathogens. Lower expression of HLA-DR has been associated with
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■ APPROPRIATE DIAGNOSTIC TOOLS AND MONITORING higher mortality in sepsis. 87,109,110 There appears to be general consensus
that diminished mHLA-DR is a reliable marker for the development of
As our capacity to treat patients during the very first hours of shock has immunosuppression in critically ill patients. Indeed, decreased expres-
improved, many patients now survive this initial phase only to die later sion of this marker is reported to be associated with higher mortality/
in a state of immunosuppression. It is to this population that immu- risk for nosocomial infections in critically ill patients. 111
nostimulatory therapies are now considered an innovative strategy for These findings suggest that a critical point signaling recovery
the treatment of sepsis, if we can identify which patients would actually of immune function after insults such as critical illness is restitution of
benefit from these therapies. Indeed, in the absence of specific clinical HLA-DR expression. mHLA-DR rapidly returns to normal values (gen-
signs of immune status, it is critical to determine the best biological erally in < week) in injured patients with uneventful recovery, whereas
tools to stratify patients according to their immune status . This would this parameter remains constantly decreased in patients with adverse
then permit the testing of the various interventions—stimulating innate outcome or secondary septic complications. 111-115
immunity and/or adaptive immunity, blocking apoptosis, restoring A challenge for future study is to determine the extent to which
other altered functions—at the proper time in the right patient, bringing compensatory anti-inflammatory reaction can be an appropriate brake
us to individualized tailored therapy. 103 on the immune system and how and when these phenomena become
There is a lack of clinical signs associated with immunoparalysis and inappropriate with adverse effects on the patient. 112-115 mHLA-DR offers
moreover, there is currently no biological “gold standard” for the diag- promise as a biomarker to investigate both the mechanisms and time
nosis of immunoparalysis. Clinical studies are consequently required to course of these events. The HLA-DR molecule is encoded by the major

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