أستاذنا الدكتور سمير الأنصاري

1. Sepsis markers

2. Introduction
• Sepsis can occur suddenly and
deteriorate rapidly
• Timely diagnosis of sepsis is the key
of success

3. How to improve the outcome of
sepsis?
• Early diagnosis and
treatment
• Surviving Sepsis
Campaign .

4. Sepsis markers
• Diagnostic
– Useful for identifying or ruling out sepsis
– Identifying patients who may benefit from
specific therapies
• Assessing the response to therapy
• Prognostic

6. Ideal sepsis markers
• High sensitivity (increase pathologically in
the presence of disease)
• High specificity (does not increase in the
absence of disease)
• Related to the disease burden and extent
• Changes in accordance with the clinical
evolution
• Anticipates clinical changes before it
happens

7. Ideal sepsis markers
• Adds independent information
about the risk or prognosis
• Reproducible
• Easy and cheap

8. What do we have now?
• WCC
• Lactate
– Tissue perfusion variables
• Biomarkers
– C-reactive protein (CRP)
– Procalcitonin (PCT)
– Cytokines
– New markers

9. What do we have now?
• Large numbers of markers
– Cytokines
– Receptors biomarkers
– Coagulation biomarkers
– Biomarkers related to vascular endothelial
damage
– Markers related to organ dysfunction
– Acute phase protein biomarkers
– others

10. Sepsis markers
• Lactate
• C-reactive protein (CRP)
• Procalcitonin (PCT)
• Newer sepsis markers

11. Lactate production
Critical illness leading to increased tissue oxygen extraction
Oxygen delivery Oxygen consumption
Oxygen debt
Global tissue hypoxia
Anaerobic metabolism
Lactate production

12. Lactate
• Raised in severe sepsis and septic shock
– Hypoperfusion (secondary to anaerobic
metabolism)
– Cellular metabolic failure
– Decrease clearance by the liver

14. Prognostic and predict mortality
• It can be used as …
– Monitoring response of septic patients to resuscitation
– Stratification and prognosis
• Serial lactate level monitoring is recommended
– High lactate clearance:
• less required vasopressors therapy, greater improvements in
APACHE II scores and decreased mortality rates

15. Lactate clearance
• In patients with septic shock
– Survivors vs non-survivors
• Initial lactate level did not differ much
•Survivors had a significant
decrease in lactate levels and
less “lactate clearance time”

16. Lactate clearance
• Lactate clearance
– The percentage lactate decrease over the
initial 6 hr ED evaluation and treatment period

17. Lactate clearance
The higher the lactate
clearance, the lower the
mortality

18. CRP
• Acute phase protein
• Synthesized in liver
• IL-6 (and IL-1 and TNFα) stimulate
synthesis
• Binds bacterial polysaccharide/ chromatin
– Activates the classical complement pathway
– Increase the immune inflammatory response
• Esp. in bacteria infection (vs viral)

19. CRP
• Level of CRP begins within 4-6hrs after
stimulus
• Doubles every 8hrs
• Peaks at 36-50 hrs
• Half-life 19hrs

20. CRP
• A sensitive marker of inflammation and tissue damage
• Other conditions result in raised in CRP
– Rheumatological disease
• SLE
• Systemic sclerosis
• Dermatomyositis
• Sjogren’s disease
– Inflammatory bowel disease
– Haematological disease
• E.g. leukaemia
– Graft-versus-host disease

21. Procalcitonin
• A peptide precursor of calcitonin
• Produced by
– parafollicular cells of the thyroid
– neuroendocrine cells of the lung and the
intestine (extrathyroidal)
• It raises in a response to a
proinflammatory stimulus
– Esp of bacterial origin (mainly from the cells of
lung and the intestine)

22. PCT- characteristics
•Fast response (2-4hrs)
•Peak values 8-24hr

23. PCT- characteristics
• Short half-life (~24hrs) independent of
renal function
• Easy to measure in serum and plasma
(stable in vivo and in vitro)
• Plasma concentration ~ <0.05-1000ng/ml

24. • In systemic inflammation or in infection
– Persists as long as inflammatory process
continues
• Mechanical trauma
– Increase within 2-4hrs
– Peak in 1st
or 2nd
day then diminish

25. Procalcitonin (PCT)
• Reference values (except newborn)
– Significantly lower in leukopenic patients
< 0.05ng/ml Healthy individuals
< 0.5ng/ml Probability of sepsis
is low, local infection
possible
0.5-2ng/ml Grey zone, recheck
6-12hrs later
>2ng/ml Probability of sepsis
is high

26. Use of PCT
• Sepsis diagnosis
• Antibiotic guidance
• Patient prognosis

27. • Antibiotics were started/ stopped based on
a predefined cut-off ranges of PCT value
• Primary end point
– 28 and 60 days mortality
– No. of days without antibiotics

28. • PCT is also associated with other
conditions
– VAP
– Severe acute pancreatitis
– Acute exacerbation of COPD

29. Nonbacterial infection: Viruses, Fungi,
Parasites
• PCT tend to be low in viral infection
– However, in systemic viral infection, PCT value can
as high as 16 ng/ml
• A low serum PCT cannot be used to exclude
bacterial from viral infections but that a
combination of PCT, CRP, white blood cell
count, and clinical illness scoring might be more
useful

30. Nonbacterial infection: Viruses, Fungi,
Parasites
• In patients with fungal infections, results have
been variable
• Infection with the malaria parasite often leads to
very high levels of serum, as high as 662 ng/mL

31. Sepsis and PCT: The Pediatric Experience
• Variable in sensitivity and specificity
• Some authors recommended against the use of
PCT in routine diagnosis of bacterial sepsis in
neonates, because of more complicated PCT
measurement and its expense in comparison
with CRP.

32. Different features of CRP and PCT
• CRP levels may not further increase
during more severe stages of sepsis.
• PCT rises in proportion to the severity of
sepsis and reaches its highest levels in
septic shock.
Therefore, the diagnostic capacity of PCT isTherefore, the diagnostic capacity of PCT is
superior to that of CRP due to the closesuperior to that of CRP due to the close
correlation between PCT levels and thecorrelation between PCT levels and the
severity of sepsis and outcome.severity of sepsis and outcome.
Therefore, the diagnostic capacity of PCT isTherefore, the diagnostic capacity of PCT is
superior to that of CRP due to the closesuperior to that of CRP due to the close
correlation between PCT levels and thecorrelation between PCT levels and the
severity of sepsis and outcome.severity of sepsis and outcome.

33. Different features of CRP and PCT
• PCT reacted more quickly than CRP
• PCT concentrations had their maximum
levels prior to those of CRP
Allows anticipation of a
diagnosis of sepsis 24-48 hours
before the CRP level would
Allows anticipation of a
diagnosis of sepsis 24-48 hours
before the CRP level would

34. Different features of CRP and PCT
• CRP concentrations were high already during
the less severe stages of organ dysfunction and
systemic inflammation
– values were not much further increased during the
more severe stages of disease.
• PCT levels correlates with the stages of disease
(especially increased in patients with organ
dysfunction, severe sepsis or septic shock.)
CRP less useful in distinguishing evolution of
sepsis in severe sepsis and septic shock
CRP less useful in distinguishing evolution of
sepsis in severe sepsis and septic shock

35. Different features of CRP and PCT
• PCT concentrations more rapidly declined
as compared with CRP
CRP remained high even in the late
stage of disease
CRP remained high even in the late
stage of disease

37. Prognosis
• PCT levels were significantly associated with
– admission to a special care unit
– duration of intravenous antibiotic use
– total duration of antibiotic treatment
– length of hospital stay, whereas CRP was
related only to the latter two variables.
• These data suggest that PCT may be a valuable
addition to currently used markers of infection
for diagnosis of infection and prognosis in
patients with fever at the AED

38. New sepsis markers
• Soluble CD14 subtype
(Generic name- Presepsin)
• Heparin-Binding protein
• Others

39. Soluble CD14 subtype

42. Early diagnosis and prognosis
{ Presepsin }

43. Quick turn around time-
for emergency and intensive
care use
Quick turn around time-
for emergency and intensive
care use

44. Heparin-binding protein
• An early marker of circulatory failure in
sepsis
• Release from activated neutrophils
–A potent inducer of vascular leakage
–Resulted in extravasation of plasma and
WBC to the focus of infection

45. How about other markers?

46. • TNF-a
– The initiating factor in the activation of host
response and subsequent cytokine release
during infection
– Concentration increase 24 times after LPS
challenge during in vivo experimental
endotoxemia

47. • Short half-life of 17 min
– Short-term concentration in response to
bacterial challenge
However, the diagnostic utility of TNF is
insufficient for distinguishing infectious
inflammation
Why?

48. • Interleukin-6
– Increased concentrations correlating to infection
– Activation time: very short
– Half-life time ~ 1hr
– Sensitive early diagnosis of neonatal sepsis
– Adult values
• Sepsis 300-2700ng/L
• SIRS 100ng/L
– Usefulness in adult diagnosis has not well
established.

49. THANK YOU
SAMIR EL ANSARY