Immunoparalysis and adverse outcomes from critical illness

Abstract

Proper immunologic balance between pro- and anti-inflammatory forces is necessary for recovery from critical illness. Persistence of a marked compensatory anti-inflammatory innate immune response after an insult is termed immunoparalysis. Critically ill patients demonstrating prolonged, severe reductions in monocyte HLA-DR expression or ex vivo tumor necrosis factor alpha production are at high risk for nosocomial infection and death. Reversal of immunoparalysis can be accomplished through the administration of immunostimulatory agents or tapering of exogenous immunosuppression. Evidence suggests that this may be associated with improved clinical outcomes. Immune-monitoring protocols are needed to identify patients who may benefit from immunomodulatory trials.

Figure 1. Functions of the activated monocyte

A normal monocyte, upon activation, is capable of ingesting pathogens; effecting intracellular killing and processing the foreign proteins into antigenic peptides; presenting these peptides on its cell surface in conjunction with HLA-DR molecules; and producing proinflammatory cytokines such as TNFα. An immunoparalyzed monocyte demonstrates reduced HLA-DR expression and impaired TNFα production capacity.

Figure 2. Immunologic homeostasis vs. immunoparalysis

A transient compensatory anti-inflammatory response typically follows a proinflammatory insult, but the immunologic balance between pro- and anti-inflammatory forces should be restored within a few days (A). If the anti-inflammatory response is severe and prolonged it is termed immunoparalysis (B).

Figure 3. Prolonged suppression of monocyte HLA-DR expression predicts outcome

In 86 adult patients with septic shock, monocyte HLA-DR expression was suppressed on Days 1 – 2 in all patients, but to a greater degree in nonsurvivors. By Days 3 – 4, survivors had begun to recover HLA-DR expression whereas it remained low in nonsurvivors. *p < 0.001 vs. survivors, Mann – Whitney test. Data represent median (25^th – 75^th %). Data from Monneret G, Lepape A, Voirin N, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. Aug 2006;32(8):1175–1183.

Figure 4. The ex vivo LPS-induced TNFα response is lower over time in nonsurvivors of pediatric MODS

Thirty children with MODS underwent serial measurement of their whole blood ex vivo LPS-induced TNFα response in the first and second weeks of illness. Nonsurvivors demonstrated a reduced capacity to produce TNFα when stimulated ex vivo over time compared to survivors (p = 0.017; 2-way ANOVA on log transformed data). Data represent mean (standard error). Data from Hall MW, Gavrilin MA, Knatz, NL et al. Monocyte mRNA phenotype and adverse outcomes from pediatric multiple organ dysfunction syndrome. Pediatric Research. Nov 2007; 62(5):597–603.