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CHAPTER 62: Sepsis and Immunoparalysis 551

form sepo [σήπω], which means “I rot.” The term sepsis is also found in the
• Pea F, Viale P, Pavan F, et al. Pharmacokinetic considerations for
antimicrobial therapy in patients receiving renal replacement Corpus Hippocraticum exchangeably with the word sepidon [σηπεδών]
(“the decay of webs”): Epidemic. B. 2,2, Prorret. I. 99. Aristoteles, Plutarch,
therapy. Clin Pharmacokinet. 2007;46:997-1038. and Galen use the word sepsis [σηψις] in the same meaning as Hippocrates. 1
• Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in This original meaning connoted decay and wound putrefaction and
the critically ill patient. Crit Care Med. 2009;37:840-851; quiz 59. described a process of decomposition of organic matter and tissue break-
• Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring down resulting in disease (foul odor, pus formation, dead tissue) and
of vancomycin in adult patients: a consensus review of the eventually to death. Thus, the word sepsis has persisted for 2700 years
2
American Society of Health-System Pharmacists, the Infectious with more or less unchanged meaning. Subsequent works just confirmed
Diseases Society of America, and the Society of Infectious Diseases the causal link between microbes and suppurative infections or systemic
Pharmacists. Am J Health Syst Pharm. 2009;66:82-98. symptoms and clinical findings from infections establishing the infec-
• Udy AA, Roberts JA, Boots RJ, et al. Augmented renal clearance: tions as the underlying disease. Hugo Schottmuller in 1914 founded
implications for antibacterial dosing in the critically ill. Clin the modern definition of sepsis and was the first to describe that the
Pharmacokinet. 2010;49:1-16. presence of an infection was a fundamental component of the disease. 3
In 1972, Lewis Thomas described sepsis in the following way: “It is
• Udy AA, Varghese JM, Altukroni M, et al. Subtherapeutic initial our response to [the microorganism’s] presence that makes the disease.
beta-lactam concentrations in select critically ill patients: asso- Our arsenals for fighting off bacteria are so powerful … that we are
ciation between augmented renal clearance and low trough drug more in danger from them than the invaders.” and popularizing the the-
concentrations. Chest. 2012;142:30-39. ory that “…it is the [host] response … that makes the disease.” Finally,
4
• Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacoki- the concept entered into daily clinical practice when Roger Bone and
netic and pharmacodynamic issues in the critically ill with severe colleagues defined sepsis as a systemic inflammatory response syndrome
sepsis and septic shock. Crit Care Clin. 2011;27:19-34. that can occur during infection. 5
In recent years this syndromic characterization of sepsis has been
expanded to SIRS (systemic inflammatory response syndrome), CARS
(compensatory anti-inflammatory response syndrome), and MARS
REFERENCES (mixed antagonists response syndrome), with recognition that immune
dysfunction during sepsis may be a significant aspect of pathogenesis. 6,7
Complete references available online at www.mhprofessional.com/hall Currently sepsis is considered a host immune response to infection,
which clinically results in a continuum of disease categorized as sepsis,
severe sepsis, septic shock, and multiorgan failure (MOF). Also, sepsis is
the maladaptive immune response of the host to invading pathogens in
CHAPTER Sepsis and Immunoparalysis normally sterile sites of the body. In severe sepsis and septic shock this
inappropriate immune response to infection leads to mismatch of host
62 Pavlos M. Myrianthefs response to the pathogenic stimuli so profound as to finally lead to cellu-
lar dysfunction and ultimately to organ injury and dysfunction or failure.
Elias Karabatsos
The immune profile of this host-pathogen mismatch can be predomi-
George J. Baltopoulos nately proinflammatory (systemic inflammatory response syndrome,
SIRS), mixed (mixed antagonistic response syndrome, MARS), or
anti- inflammatory (compensatory anti-inflammatory response syn-
KEY POINTS
drome, CARS). The final result is various degrees of hyperinflamma-
• Current paradigms of sepsis include both pro- and anti-inflamma- tion, immunosuppression, abnormal coagulation, and microcirculatory
tory pathway activation to different degrees and at different phases dysfunction, all which may contribute to organ injury and cell death. 2,6
of the syndrome. Clinical diagnosis of severe sepsis or septic shock although valuable
• Failure to recognize and understand the dynamic changes in immune and of significant importance for the management of septic patients may
response in sepsis may in part explain the failure of a number of anti- lead to extremely heterogeneous cohorts in terms of patients’ immuno-
inflammatory drugs and biologics studied in critically ill patients. logical status. This heterogeneity offers one explanation for the failure of
prior trials of biologic therapies for sepsis, since treatments that focused
• The anti-inflammatory or immunosuppressed state associated on attenuating the initial inflammatory response of sepsis in a sense
with sepsis and other forms of critical illness is often protracted ignored and in fact might have exacerbated the progressive development
and places patients at risk for complicating nosocomial infections of immunosuppression in some patients. 8-11
and activation of latent infections. Immune status characterization during the course of sepsis may iden-
• When clinically significant, the anti-inflammatory state associated tify patients who could benefit from immunotherapy tailored to their
with sepsis is termed immunoparesis or immunoparalysis. particular circumstances. These patients may be those who develop
• Cell and humoral biomarkers are needed to properly characterize septic shock and die early from multiorgan failure or those who develop
the individual patient’s immune status to guide targeted and per- late immunosuppression after surviving the initial septic shock but
sonalized therapy to modulate both excessive immune stimulation fail to completely recover from persisting sepsis syndrome. The latter
as well as immune suppression. patients often develop what appears to be chronic sepsis, with recur-
rent nosocomial infections and eventual recurrent and refractory septic
shock. In a sense these patients may be considered to have yet another
organ system failing in the face of sepsis—their immune system.
INTRODUCTION ■
■ HISTORY—DEFINITION Sepsis is a major health care problem due to the high morbidity and
NATURAL HISTORY OF INFECTION AND SEPSIS SYNDROME
Sepsis [σήψις] is the original Greek word for the “decomposition of animal mortality of the syndrome, which has very high health care costs. Despite
or vegetable organic matter in the presence of bacteria.” The word is found intense research and recent advances in treatment, mortality remains
for the first time in Homer’s poems, where Sepsis is a derivative of the verb extremely high, reaching 40% to 60% in high-risk patient populations.

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