Severe sepsis/septic shock
	in a 65-year-old man

 

Learning Objectives At the conclusion of Case 6, students should be able to … Describe and/or define sepsis/septic shock terms and symptoms Describe which cells are the major components of the innate immune response Describe the primary functions of these cells in innate immunity and the early response to infection Describe the role of TLR receptors in innate immunity Describe what is chemotaxis Describe host innate immune mechanisms for killing bacteria

S. S., a 65-year-old man who lived alone, was cutting vegetables and accidentally cut his finger. He casually washed the bleeding site, put a Band-Aid on the deep cut and continued cooking. Two days later, he removed the Band-Aid but the cut appeared open and oozing. Later that day, he replaced the Band-Aid with a fresh one. A few days later he noticed that his finger had become very red and swollen and he could see a small amount of pus at the site. He had also developed a low grade fever and malaise. The following day he went to see his physician who cleaned the cut and gave him a broad-spectrum antibiotic. However, S. S did not follow the dosing instructions and stopped taking the antibiotic when he felt better after 3 days. A few days later, he developed a high fever, chills, severe fatigue, tachycardia, and growing mental confusion. A relative visiting S. S called 911 and he was taken to the local emergency room. On admission, his temperature was 40 °C, his blood pressure was 88/60 mm Hg, his respiratory rate was 22, his pulse was 111. Blood chemistry revealed a BUN of 55 mg/dl and creatinine of 1.8 mg/dl. Blood cultures grew out Gram-negative rods that were identified as E. coli. He was diagnosed with severe septic shock as a result of inadequate treatment of a wound infection.

Laboratory values on admission:

Table 1. Laboratory Data:
HEMATOLOGY On admission		Normal values
Hematocrit (%)	26	41-50%
Hemoglobin (g/dl)	7	13 - 18 gm/dL
White cells (per mm3)	39,606	5-10,000
Neutrophils (%)	78	48-73
Lymphocytes (%)	8	18 - 48 %
Monocytes (%)	3	0 - 9 %
Eosinophils (%)	0	0 - 5 %
Basophils (%)	0	0 - 2 %
Band forms (%)	11	<3%
Platelets (per mm3)	16,000	150,000-450,000
Mean Corpuscular Volume (fl)	92	80 - 100 fl
BUN	55 mg/dl	7-30mg/dl
Serum creatinine	1.8 mg/dl	0.6-1.2mg/dl
Red Cell morphology	1+schistocytes	none
Prothrombin time (sec)	13.4	10-12.5
Partial Thromboplastin time (sec)	33.2	20-36
D - dimer (mu g/ml)	3.0	<0.25
Fibrinogen (mg/dl)	344	200-400
FDP (mu g/ml)	32	<10
Erythrocyte Sedimentation rate (mm/hr)	60	0-15 millimeters per hour
PA CO2 (mm Hg)	28	40
PA O2 (mm Hg)	68	80-100
MICROBIOLOGY		e coli
Blood culture	E. coli	e. coli
Urine culture	E. coli	e. coli
Urine output (ml/hr)	18	>30ml/hr

S. S was transfused, given fluids, appropriate antibiotics, and PEEP assisted ventilation. It was considered that if he continued to deteriorate, with an increased risk of death as indicated by an acute physiology and chronic health evaluation score (in critically ill patients) APACHE II score greater than or equal to 25 or dysfunction of two or more organs, he would be given activated protein C (Drotrecogrin Alfa), recently reported to decrease mortality and to ameliorate organ dysfunction in patients with severe sepsis.

Septic shock results from a complex progression of disease that is described as severe infection and moves from a systemic inflammatory response syndrome (SIRS) to sepsis and severe sepsis to septic shock. Left untreated, septic shock can lead to death, with or without multiple organ dysfunction syndrome (MODS).

It is particularly important to recognize the problem as early as possible and treat accordingly, especially since mortality rates for sepsis (16 to 20 percent) and septic shock (20 to 50 percent) vary based on the type of infectious organism, underlying illness or complication, timing and the kind of antimicrobial therapy, and degree of system failure present. Thus, it is critical to understand the pathophysiology, symptoms, assessment techniques, and available treatment options.

Severe sepsis/septic shock is a syndrome that is initiated by the host’s innate immune response. Under normal conditions, bacteria commonly enter the bloodstream but are rapidly removed by leukocytes of the innate immune system (monocytes/macrophages and neutrophils) and no symptoms develop. Similarly, this pathway usually resolves small infections of the skin, etc.. Sometimes, however, due to a variety of conditions including a moderate to severe local infection, gum disease, pneumonia or trauma, particularly to the intestine, possibly coupled with inadequate antibiotic therapy, there are too many bacteria to be removed easily by the host, and large numbers of bacteria enter the bloodstream. An infection that is widespread throughout the bloodstream is called sepsis (or septicemia) and can lead to severe symptoms and a life-threatening condition called septic shock.

Diagnostic Assessment

A CBC and differential

Tests for serum electrolyte levels and renal and hepatic function are recommended

Coagulation status, as calculated by prothrombin time (PT), activated partial thromboplastin time (aPTT or PTT), fibrinogen, FDP and D-dimer can reflect the potential for disseminated intravascular clotting (DIC).

Arterial blood gas (ABG) analysis measures the amount of oxygen, carbon dioxide, and acidity.

Elevated serum lactate levels indicate the presence of hypoperfusion, with higher figures equating to greater degrees of shock and mortality rates.

Urinalysis and culturing can be used to rule out the presence of UTIs.

Gram staining may not only document bacterial infection, but also influence the type of initial antibiotic therapy chosen.

Blood cultures

Etiology Of Sepsis

    Sepsis occurs when pathogenic microorganisms cross host barriers and overwhelm defenses. Gram-negative bacteria - such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Neisseria meningitides - are key pathogens. Other causes include Gram-positive organisms such as Staphylococcus aureus, coagulase-negative Staphylococcus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus. Rickettsiae, viruses, fungi and polymicrobial sepsis have also been noted as causative agents. In neonates, sepsis is most likely caused by group B Streptococci, E. coli bearing a pathogenic K1 capsule, Klebsiella sp. and Enterobacter sp.

    According to the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine, several physiological effects occur as a result of the systemic inflammatory response syndrome (SIRS). Two or more of the following criteria must be present for a SIRS diagnosis: Body temperature can increase above 38C or drop below 36C; individuals might experience tachycardia (over 90 bpm) or tachypnea (more than 20 breaths per minute or PaCO2 less than 32 mm Hg); and white blood cell counts may be greater than 12,000/mm3, less than 4000/mm3, or over 10 percent band cells. It is important to note that sepsis/septic shock can occur without the identification of bacteria in the blood.

    As the disease progresses to severe sepsis, patients generally experience both earlier symptoms, along with organ dysfunction, hypoperfusion, or hypotension. Confusion or altered mental states, elevated plasma lactate levels, and oliguria (decreased urine output of less than 30 ml) are just some examples of the perfusion abnormalities observed.

 

Table 1: Definitions of Sepsis-Related Terms (adapted from the Society for Critical Care Medicine)
Sepsis	A systemic inflammatory response to infection
Severe sepsis	Sepsis with one or more dysfunctional organs or systems (e.g., cardiovascular dysfunction as indicated by hypotension and shock that is resistant to fluid resuscitation, respiratory dysfunction as indicated by hypoxemia, renal dysfunction as indicated by anuria or oliguria)
Systemic inflammatory response syndrome (SIRS)	A syndrome in which inflammatory mediator release, particularly cytokines such as TNF, secondary to an infectious and/or traumatic insult, causes the patient to present with at least two of the following conditions:§ alterations in body temperature (>38°C or <36°C)§ heart rate >90 beats/min§ alterations in respiratory function (rate >20 breaths/min or PaCO2 <32 mmHg) § alterations in WBC count (>12,000/mm3 or <4,000/mm3 or >10% immature forms)
Compensatory anti-inflammatory response syndrome (CARS)	A syndrome in which anti-inflammatory mediator release overcompensates for the systemic inflammatory response to an infectious and/or traumatic insult leading to a state of immune suppression, increased susceptibility of the critically ill patient to infection, and impaired recovery
Septic shock	Severe sepsis with hypotension that is resistant to fluid resuscitation and requires pharmacological intervention (vasopressors and/or inotropic agents)
Multiple organ dysfunction syndrome (MODS)	A syndrome in which the hypotension and hypoperfusion, secondary to the pathophysiological alterations in severe sepsis, result in dysfunction in more than one organ or system

 

Table 2. Clinical Definition of Sepsis/Septic Shock
TYPE	CHARACTERISTICS
Moderate sepsis	Body Temperature >38°C or <36°C§ Heart rate >90 beats/min§ Respiratory rate 20 breaths/min or partial pressure of arterial CO2 <32 mm Hg§ White count >12,000/mm3, or >10% immature band forms§ Evidence of infection
Severe sepsis	Sepsis-associated lactic acidosis, oliguria, or acute alteration of mental status
Septic shock	Sepsis-induced hypotension (i.e., systolic blood pressure <90 mm Hg) despite adequate fluid resuscitation. Patients treated with vasopressors or inotropic medication may not be hypotensive at the time of measurement.

From: Schrier and Wang, NEJM 2004, 35:159-169.

 

References:

Russell, J.A. Management of Sepsis. 2006. NEJM. 355:1699-1713.

Bone, R. C., C. L. Sprung, and W. J. Sibbald. 1992. Definitions for sepsis and organ failure. Crit Care Med
20:724-726.

Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee.1992. Definitions for sepsis and organ failure and guidelines for the use of
innovative therapies in sepsis. Crit Care Med 20: 864–874

Levy, M. M., M. P. Fink, J. C. Marshall, E. Abraham, D. Angus, D. Cook, J. Cohen, S. M. Opal, J. L. Vincent, and G. Ramsay. 2003. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530-538.

Hotchkiss, R. S., and I. E. Karl. 2003. The pathophysiology and treatment of sepsis. N Engl J Med
348:138-150.

Janeaway JA, Travers P, Walport M and M.J. Shlomchik (eds). Immunobiology, 6th ed. Garland Science, NY 2005.

 

Internet Links - Microbiology:

QUESTIONS and ANSWERS:

QUESTIONS: The innate immune response to bacteria is initially driven by the interaction of bacteria and/or their products with innate immune cells. Severe sepsis/septic shock can result from an early, overactive innate immune response following bacterial infection resulting in overproduction of inflammatory mediators that lead to a cascade of events, potentially ending in death, often within only a few days.

1. What cells are the major components of the innate immune response and what is their primary function?

Answer 1.

2. Describe how endotoxin (LPS) from Gram-negative bacteria activates cells of the innate immune system?

Answer 2.

 2a.) What products are produced by this activation?

Answer 2a).

 2b.) Which of these products contribute to the cascade of events leading to further deterioration of the patient?

Answer 2b).

3. What is chemotaxis?

Answer 3.

3a.) How do neutrophils get from the blood to sites of infection? What molecules are involved in transmigration (diapedesis) across the endothelium?

Answer 3a).

  Fig. 1 and Table 1.

Figure 1

 

Table 1: Adhesion molecules that play a role in emigration of neutrophils through the endothelium to site of infection.

FAMILY	ENDOTHELIAL CELLS	NEUTROPHILS	FAMILY	EFFECT ON EMIGRATION
Selectins	GlyCAM-1, MAdCAM-1, CD34 (sialyl Lewis-X type structures) [*activ EC]	L-selectin (CD62L) [†PMN]	Selectins	Rolling (light adhesion)
	P-selectin (CD62P) [activ EC]	PSGL-1 (CD162) [PMN]
	E-selectin (CD62E) [activ EC]	CD44 [PMN]
+IgSF	ICAM-1 [activ EC]	Mac-1 (CD11b/CD18, CR3 or aM/b2) [PMN]	b2-Integrins	Stopping (firm adhesion) and transmigration across EC
		LFA-1 (CD11a/CD18 or aL/b2) [PMN]
	ICAM-2 [activ EC]	LFA-1 (also called CD11a/CD18 or aL/b2) [PMN]
	VCAM-1 [activ EC]	VLA-4 (also known as a4/b1 or CD49d/CD29) [PMN]	b1-Integrins
IgSF	PECAM-1 (CD31) (cell-cell junctions) [activ EC]	PECAM-1 (CD31) Homotypic interaction  [PMN]	IgSF	Transmigration across EC

*Activ EC: present on activated endothelial cells
†PMN: present on activated neutrophils
+IgSF: immunoglobulin superfamily

4. Complement plays an important role in innate immunity. What are three major functions of complement in innate immunity and describe them.

Answer 4.

The complement fragments C3a and C5a act as chemotactic factors for neutrophils.

Opsonin/Ligand	Receptor	Cell type	Function
C3b, C4b, iC3b	CR1 (CD35)	Monocytes/macrophages, neutrophils	Stimulates phagocytosis
iC3b	CR3 (CD11b/CD18)	Monocytes/macrophages, neutrophils	Stimulates phagocytosis
iC3b	CR4 (CD11c/CD18)	Monocytes/macrophages, neutrophils	Stimulates phagocytosis

 

5. What is phagocytosis? Describe in detail the events leading to killing of bacteria by phagocytosis.

Answer 5.

 

6. What did S. S. do wrong?

Answer 6.