Immunopathology of Sepsis – 2014
American College of Veterinary Pathologists
Daniel Remick, M.D.
Chair and Professor of Pathology and Laboratory Medicine
Boston University School of Medicine and Boston Medical Center
670 Albany Street
Boston, MA 02118
What is sepsis? A simple definition of sepsis is that it is the systemic host response to a severe
bacterial infection. The concept of the Systemic Inflammatory Response Syndrome (SIRS) was
introduced over 20 years ago by the late Roger
SIRS - Systemic Inflammatory Response
Bone1. There are additional talks in this meeting
Syndrome Criteria (at least 2 criteria are
which will address the clinical aspects of sepsis,
needed)
this presentation will deal with the basic
1. Body Temperature >38° or <36°C
mechanisms of how a host eradicates pathogenic
2. Heart rate > 90 beats/minute
microbes. SIRS is defined as a presence of two
3. Respiratory rate > 20 breaths/minute
of the four criteria listed in table 1. There are
4. WBC >13K or < 4K/mm3, or >10% bands
multiple causes for SIRS including bacterial
infections, noninfectious pancreatitis, major
Table 1. SIRS criteria
trauma and other infections. Severe sepsis is
defined as sepsis with sepsis-induced organ dysfunction or hypotension. Septic shock is when
there is sepsis with refractory hypotension. Septicemia is sepsis when there is a positive blood
culture, while bacteremia merely refers to bacteria within the bloodstream. Colonization refers to
the presence of microbes without an inflammatory response.
Sepsis is a significant clinical problem amongst hospital patients. A 2003 article by Martin2
reviewed 750 million hospital records and show that the incidence of sepsis is increasing every
year. This article also documented that there has been little improvement in sepsis survival
since the introduction of antibiotics. This publication, in addition to other publications, showed
that gram-positive organisms are now in more frequent cause of sepsis than gram-negative
organisms. It should be mentioned that in the past 20 years the mortality caused by sepsis has
stabilized3. When one talks about the mortality of sepsis typically the literature refers to 28 day
mortality. Among septic patients the 28 day mortality is 24%, in other words one out of four
patients with sepsis will die within the month. With this brief background on this devastating
disease, let us now explore the basic pathophysiology mechanisms in sepsis.
Bacterial killing. Eradication of pathogenic bacteria from the host is an excellent idea, and
essential for the survival of the host. There are multiple mechanisms that may be used to kill
pathogens. One of the major mechanisms is phagocytic cells engulfing and killing bacteria. For
this to occur, the bacteria are recognized by antibodies. These antibodies coat the bacteria, a
process called opsonization. In addition to antibodies, fragments of the complement system may
be deposited on the surface of the cell to result in opsonization. The bacteria which have been
opsonized will be more effectively phagocytized by inflammatory cells. The bacteria which have
been phagocytized will increase the production of cytokines by the inflammatory cells.
Additionally, fragments of the bacteria will bind to Toll like receptors on the surface of cells
which will also increase cytokine production.
Cytokine storm. Previously it was believed that sepsis was due to the rapid, explosive
production of cytokines resulted in “cytokine storm”. This cytokine storm resulted in
overwhelming inflammation and tissue injury. The concept was that the host did not die from the
bacterial infection, but rather from the exuberant host response. This concept led to a number of
clinical trials using cytokine inhibitors for the treatment of sepsis. It should be noted that none of
these cytokine inhibitors were effective4-6. However, cytokine inhibitors have been remarkably
effective in treating chronic inflammatory conditions such as rheumatoid arthritis and
inflammatory bowel disease (Crohn’s disease).
Complement. Complement components play an important role in the clearance of bacteria and
we have already discussed opsonization of pathogenic bacteria to improve their eradication.
Activated components of the complement cascade are important in several steps in pathogen
killing. Complement fragments will serve to opsonized bacteria to allow improved phagocytosis.
The terminal components of the complement cascade will form a membrane attack complex.
The membrane attack complex will essentially punch a hole in the cell wall to cause osmotic
lysis of the bacteria. Other activated complement fragments serve as chemotactic factors to
recruit neutrophils. Complement inhibitors have been used to treat other immunologicall
mediated diseases. Specifically hereditary anginoneurotic edema has been treated with a
specifc complement inhibitor, the C1 inhibitor. A small-scale clinical trial reported in 20127
showed an improvement in survival in patients treated with this complement inhibitor, but there
were some important caveats. First, there was a high mortality in the control group and second
the sample size was rather small.
Epithelial barriers. An important, but often overlooked, aspect in the development of sepsis is
maintaining intact epithelial barriers. If the skin or the mucosa of the intestine is not broken, the
bacteria will remain outside of the host and cannot initiate an infection. Breaching the epithelial
barriers will result in the introduction of pathogenic bacteria into a normally sterile space. If there
is a small infection, the host rapidly eradicates the bacteria and there is complete resolution. An
example is found in everyday life. It has been estimated that nearly half of people developed
bacteremia when they brush their teeth. Despite having bacteria in the bloodstream, the host
response is rapid and appropriate to eradicate the bacteria without causing illness or injury.
Lymphocyte apoptosis. Apoptosis refers to programed cell death with the lymphocytes
undergo an orderly demise. Several studies have demonstrated that in septic patients or
experimental animals lymphocytes undergo substantial apoptosis8, 9. Landmark studies done by
Richard Hotchkiss evaluated trauma patients who were not septic and septic patients10. Rapid
autopsies were done in order to determine the degree of lymphocyte apoptosis, since after
death these cells are no longer functional. Lymphocyte apoptosis was found in virtually every
organ in the body. In fact, even small aggregates of lymphocytes such as those in the Peyer’s
patches in the intestine underwent apoptosis in septic patients. There are several reasons why
apoptotic lymphocytes contribute to the pathogenesis of sepsis. First of all, lymphocytes provide
assistance to the immune system in the clearance of pathogen. Specifically, CD4 positive helper
T lymphocytes will produce stimulating cytokines that will activate macrophages to clear
bacteria. Secondly, there are classes lymphocytes called T helper 17 cells. These cells produce
interleukin 17 (IL-17) and IL-22 which act on the epithelial cells. The IL-17 and IL-22 help
increase production of antimicrobial peptides and improve the barrier function. Finally, B cells
are the lymphocytes responsible for the production of antibodies which are important in
recognizing clearing the bacteria. If these B cells undergo apoptosis there will be reduced
antibodies directed against the pathogenic bacteria.
There are many excellent reviews on sepsis11-13.
Bibliography
1.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald
WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in
sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest
Physicians/Society of Critical Care Medicine [see comments], Chest 1992, 101:1644-1655,
PMID:
2.
Martin GS, Mannino DM, Eaton S, Moss M: The epidemiology of sepsis in the United
States from 1979 through 2000, New England Journal of Medicine. 2003, 348:1546-1554,
PMID:
3.
Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ: Two decades of
mortality trends among patients with severe sepsis: a comparative meta-analysis*, Crit Care
Med 2014, 42:625-631, PMID: 24201173
4.
Fisher CJ, Jr., Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ,
Rackow EC, Shapiro MJ, Greenman RL, et al.: Recombinant human interleukin 1 receptor
antagonist in the treatment of patients with sepsis syndrome. Results from a randomized,
double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.[see
comment], JAMA 1994, 271:1836-1843, PMID: 8196140
5.
Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel
RP, Balk R, Allred R, Pennington JE, Wherry JC: Efficacy and safety of monoclonal antibody to
human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled,
double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group., JAMA 1995,
273:934-941, PMID:
6.
Fisher CJ, Jr., Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein
RM, Benjamin E: Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion
protein. The Soluble TNF Receptor Sepsis Study Group, N. Engl. J. Med. 1996, 334:1697-1702,
PMID:
7.
Igonin AA, Protsenko DN, Galstyan GM, Vlasenko AV, Khachatryan NN, Nekhaev IV,
Shlyapnikov SA, Lazareva NB, Herscu P: C1-esterase inhibitor infusion increases survival rates
for patients with sepsis*, Crit Care Med 2012, 40:770-777, PMID: 22080632
8.
Ayala A, Xu YX, Chung CS, Chaudry IH: Does Fas ligand or endotoxin contribute to
thymic apoptosis during polymicrobial sepsis?, Shock 1999, 11:211-217, PMID:
9.
Chung CS, Xu YX, Wang W, Chaudry IH, Ayala A: Is Fas ligand or endotoxin
responsible for mucosal lymphocyte apoptosis in sepsis?, Archives of Surgery. 1998, 133:12131220, PMID:
10.
Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM,
Buchman TG, Karl IE: Apoptotic cell death in patients with sepsis, shock, and multiple organ
dysfunction [see comments], Critical Care Medicine 1999, 27:1230-1251, PMID:
11.
Hotchkiss RS, Monneret G, Payen D: Sepsis-induced immunosuppression: from cellular
dysfunctions to immunotherapy, Nat Rev Immunol 2013, 13:862-874, PMID: 24232462
12.
King EG, Bauza GJ, Mella JR, Remick DG: Pathophysiologic mechanisms in septic
shock, Lab Invest 2014, 94:4-12, PMID: 24061288
13.
Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine
C, Remick DG: Sepsis: multiple abnormalities, heterogeneous responses, and evolving
understanding, Physiol Rev 2013, 93:1247-1288, PMID: 23899564