Page 823 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

554 PART 5: Infectious Disorders

■ CLINICAL EVIDENCE AND RELEVANCE OF IMMUNOSUPPRESSION remained independently associated with the development of secondary

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It seems that the majority of shock-related deaths occur during this nosocomial infections (NI). For a given severity, mHLA-DR proved
not a predictive marker of outcome, but delayed or incomplete recovery
secondary hypoimmune state. It has been proposed that patients who
survive the initial hyperinflammatory response but subsequently die of mHLA-DR function was associated with an increased risk of second-
ary infection. Monitoring immune functions through mHLA-DR in
from sepsis are those who do not recover immune function. 23,25,44-48
The clinical relevance of this immunosuppressed state is evidenced intensive care unit patients could therefore be useful to identify a high
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by the frequent occurrence of infection with relatively avirulent risk of secondary infection.
and often multidrug-resistant bacterial, viral, and fungal pathogens
(Stenotrophomonas, Acinetobacter, and Pseudomonas spp, enterococci, CAN IMMUNOPARALYSIS BE MODIFIED?
cytomegalovirus, herpes simplex virus, and Candida spp). 35,49-51 Sepsis-induced immunosuppression is actually a state of functional
This more protracted phase of sepsis is associated with increased length failure of innate and adaptive immunity. Thus, immunomodulation in
of stay, significant morbidity and mortality, and increased costs. 23,25,51-53 sepsis by immunostimulation may benefit patients and possibly improve
Two recent studies in human subjects shed light on one of the most outcomes. Advances in the treatment of septic shock may lie in the
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important and relatively underrecognized mechanisms of sepsis immu- ability to tailor therapies according to the specific immune status of an
nopathology. They provide evidence that the otherwise dormant viruses individual patient (stratification). The discovery and implementation of
cytomegalovirus (CMV) and herpes simplex virus (HSV) are reactivated these therapies are most likely to be successful if studied in more biologi-
in critically ill individuals—adding strength to the concept that a key cally homogeneous patient populations. 69
aspect of critical illness is immunosuppression. Limaye et al examined Based on this concept several issues arise.
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the incidence of reactivation of CMV in 120 CMV-seropositive criti-
cally ill individuals, many of whom apparently had sepsis. Before their • What alterations of immune system mediator and cell numbers and
illness, these people had normal immunity. CMV viremia, as assessed function are observed in sepsis?
by real-time PCR, occurred in 40 subjects (33%), indicating that CMV • What are the appropriate diagnostic tools and monitoring of these
reactivation occurs frequently in the critically ill. CMV reactivation was functions?
associated with prolonged stay and death. These findings dovetail with • What are the appropriate therapeutic approaches to modify
an earlier study by Luyt et al who reported a 21% incidence of HSV
bronchopneumonitis that was attributed to viral reactivation in criti- immunoparalysis?
cally ill, immunocompetent individuals requiring prolonged mechanical ■ MEASUREMENT OF CIRCULATING MEDIATORS
ventilation. 28,54 These studies show that critically ill individuals who had
normal immunity before hospitalization become profoundly immuno- The most consistent data are available for IL-10, which appears to be a
compromised during a protracted illness, thereby enabling reactivation predictor of fatal outcome. Gogos et al showed that IL-10 levels and the
of latent viruses that may become clinically relevant. IL-10/TNF-α ratio were the best indicators of mortality in a panel of
CARS-associated immunosuppression may persist for days, weeks, cytokines, while van Dissel et al reported that a high IL-10/TNF-α ratio
months, or years following the initial SIRS event. This long-term was associated with poor outcome in a group of 450 febrile patients. 70,71
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immunosuppression manifests in patients as a significant decrease in In a separate study of critically ill septic patients, IL-10 levels were found
1- and 8-year survival for patients with severe sepsis compared to age- to be higher in nonsurvivors at admission and provided a more accurate
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matched controls, often due to infections. The poor survival persisted predictor of prognosis than IL-4 levels. Monneret et al demonstrated
when multivariable analysis was conducted to adjust for prehospitaliza- that IL-10 levels remained higher in nonsurvivors than survivors for
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tion comorbid conditions. 56,57 15 days after the onset of septic shock in a group of 38 patients. Given
Also, survivors of septic shock are vulnerable to A fumigatus and the ability of IL-10 to suppress the synthesis of numerous proinflam-
P aeruginosa long after sepsis-induced proinflammatory immune matory cytokines, its continued release may contribute to the immune
response has been resolved, indicating that CARS exists as a long-term dysfunction observed after septic shock and thus may increase suscepti-
phenomenon, which requires its own diagnostic tools and therapies for bility to continuous microbial invasion. 74-76
the patients to survive. Several other studies have also supported the The second counterregulatory phase of sepsis is characterized by
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finding that mortality remains high for several years among hospital increased production of anti-inflammatory cytokines (mainly inter-
survivors of infectious diseases and sepsis. 58-63 When multivariable leukin-10 [IL-10] and transforming growth factor-beta), increased
analyses were used to compare long-term mortality estimates, with and lymphocyte apoptosis, increased proportion of circulating regula-
without chronic health conditions, the long-term estimates remained tory T cells, and a severe downregulation of monocyte HLA-DR
unchanged. Thus, the influence of chronic health conditions on long- expression. 65,77-79 Later phases of sepsis are also characterized by
term survival is small and that the acute illness is more likely to contrib- monocyte/macrophage dysfunction including a decreased capacity to
ute to increased long-term mortality. 63 produce proinflammatory cytokines and an increased expression of
Three potential outcomes are possible following hospitalization anti- inflammatory cytokines. 80-84
for infection and sepsis. Approximately one-fourth of severe sepsis The main advantage of using circulating mediators as markers of
patients die during the hospitalization. The remaining patients who are immune status is the reliability of the majority of currently available
discharged alive either recover completely or experience incomplete assays. These tests are now standardized, reproducible (<10% variability),
recovery. Those with incomplete recovery are at increased risk of sub- and in some cases automated, making them suitable for real-time clinical
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sequent acute illnesses, which eventually leads to death. Several lines decision making. However, measurement of the concentration of only
of evidence suggest that consequences of severe sepsis could be due to one or a few mediators remains questionable as it only provides a limited
immune suppression. Although the exact mechanisms for protracted view of the patient’s condition. In many cases, establishing the dominant
increased susceptibility to infections is unclear, impaired neutrophil response on the basis of serum measurements appears to be impossible
function appears to play an important role. 64 as both pro- and anti-inflammatory responses are enhanced during septic
Another study showed that mHLA-DR is an independent predictor shock. IL-10 acts at the posttranscriptional level to increase endocytosis
of mortality in septic shock patients. Being a marker of immune failure, of monocytic human leukocyte antigen type DR (HLA-DR). 85
immunosuppression. In septic shock patients, after adjustment with ■ MEASUREMENT OF CELL SURFACE MARKERS
low mHLA-DR may provide a rationale for initiating therapy to reverse
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usual clinical confounders (including need for mechanical ventilation A number of cell surface markers are known to vary during sepsis, but
and central venous catheterization), persistent low mHLA-DR expression the data are currently too limited to draw firm conclusions. The largest

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