2. BIOMARKERS IN SEPSIS
• Sepsis - major cause of acute illness and death in all age groups
worldwide.
• Early diagnosis and treatment influence the morbidity and mortality.
• Human body's response to sepsis is complex, ( inflammatory and
anti-inflammatory processes, cellular and humoral responses ).
3. • Biomarkers - naturally occurring molecules, genes, or other
characteristics by which particular physiologic or pathologic
processes can be identified.
• Ideal biomarker ?
BIOMARKERS IN SEPSIS
Objective parameter
Easy to measure
Reproducible
Inexpensive
Fast kinetics
high sensitivity & specificity
Short turnaround time
Appropriate response to
therapy
EXISTS OR NOT ?
4. Clinical biomarkers
Diagnostic
Prognostic
• Diagnostic biomarkers for sepsis - which differentiate
infectious from noninfectious causes as well as possible
causative Organism
Can be used for prevention of unnecessary use of
antibiotics.
BIOMARKERS IN SEPSIS
5. Clinical biomarkers
Diagnostic or Prognostic
• Diagnostic biomarkers for sepsis - which differentiate
infectious from noninfectious causes as well as possible
causative Organism - Can be used for prevention of
unnecessary use of antibiotics.
• Prognostic biomarkers - Stratifying patients into risk
groups and predict outcome.
BIOMARKERS IN SEPSIS
6. Other uses of biomarkers
Differentiating local infection, disseminated infection and
sepsis.
Evaluated for differentiation of viral and fungal from
bacterial infection.
Prognosis, guidance of antibiotics.
Determining response to therapy.
Prediction of organ dysfunction and complications.
BIOMARKERS IN SEPSIS
7. Initial biomarkers in sepsis - WBC counts, Lactate,
Erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP).
• Leukocytosis or leukopenia was considered as
response of infection and is a part of the SIRS criteria.
– non infectious causes can lead to leukocytosis – Not
specific
BIOMARKERS IN SEPSIS
8. • Lactate - marker of sepsis?
• Several factors affect hyperlactatemia and lactate
kinetics. – Hypoperfusion leading to anaerobic
glycolysis
• Septic shock - Sepsis with persisting hypotension
requiring vasopressors to maintain mean arterial
pressure >65 mm Hg and having a serum lactate level
>2 mmol/L despite adequate volume resuscitation.
BIOMARKERS IN SEPSIS
9. • Lactate - elevated in hypovolemia and hemorrhage
during trauma and surgery.
• Lactate clearance is used as marker of adequate
resuscitation - not useful biomarkers of sepsis, but
are important indicators of the severity of shock and
hypoperfusion, and the adequacy of resuscitation
BIOMARKERS IN SEPSIS
10. • Erythrocyte sedimentation rate - influenced by
presence of anemia, immunoglobulins, and
changes in erythrocyte size, shape and number.
• Elevated in malignant neoplasms, tissue injury,
and in trauma.
• Limited utility in sepsis.
BIOMARKERS IN SEPSIS
11. C-reactive Protein (CRP) - synthesized in liver in response
to inflammation / tissue injury (Upregulated by Interleukin-6)
• Varies according to age, sex and race; from one laboratory
to another.
• Levels less than 0.3-0.6 mg/L - normal.
• Rise after 6 hours of the inciting stimulus, peaks at about 48
hours and has a plasma half-life of 19-20 hours.
BIOMARKERS IN SEPSIS
12. Modest elevations in CRP - Noninflammatory or low-
grade inflammatory conditions such as atherosclerosis,
obesity, hypertension, diabetes and obstructive sleep
apnea; viral infections
Marked elevations – bacterial infections
• Poor specificity, High sensitivity
• Better marker of inflammation rather than infection.
BIOMARKERS IN SEPSIS
13. PROCALCITONIN ( PCT)
• 116 long AA peptide; molecular weight ~ 13 kDa.
• Produced by the C-cells of thyroid under the control of
the calcitonin gene-related peptide 1 (CALC-1) gene.
• Normally - calcitonin secreted after intracellular
protoeolysis of the PCT.
• Microbial infections - increase in CALC-1 gene
expression in various extra-thyroid tissues and cells
which is mediated by TNF- α and IL-6.
14. • Lung, liver and kidney - principal sources of circulating PCT
in sepsis.
• Either microbial toxins directly or the host response by
humoral or cell-mediated indirectly - release of PCT.
• Rises by 2 hours after stimulus, peaks around 6 hours, and
maintains a plateau through 8 and 24 hours and decreases
to baseline after 2 days.
• Half-life of PCT - 20-24 hours.
PROCALCITONIN ( PCT)
15. Pro calcitonin level (ng/mL) Interpretation
< 0.05 Normal
0.05-0.5 (Retest) Localised infection possible
0.5-2 (Retest) Systemic bacterial infection possible
2-10 ( high risk for severe sepsis ) Systemic bacterial infection possible
>10 Severe bacterial sepsis
PROCALCITONIN ( PCT)
• 1000 fold increase - active infection and sepsis.
• Viral infections - IFN - γ released suppresses PCT -
high levels are not observed in viral sepsis.
• Gram-negative bacteremia causes > elevation than
gram-positive.
16. • Elevated in absence of bacterial infections in -
PROCALCITONIN ( PCT)
Neonates <48 hours age
First days after major surgery
Trauma, Burns, Pancreatitis
Treatment with OKT3
antibodies, interleukins, TNF-a
Invasive fungal infections
Acute falciparum malaria
Severe cardiogenic shock
Malignancies - medullary C-
cell carcinoma of thyroid,
small cell Ca lung, bronchial
carcinoid
• falsely low in early course of infection, localized infections and
subacute bacterial endocarditis
17. • Diagnosis of Bacterial Infection and Sepsis
• Differentiation of Bacterial and Viral Infections
• De-escalation of Antibiotics
UTILITY OF PROCALCITONIN
18. Diagnosis of Bacterial Infection and Sepsis
• A prospective controlled trial concluded that procalcitonin
is a reliable diagnostic and prognostic marker in patients
with septic shock compared to nonseptic shock
• In a study, PCT, CRP, IL-6 and lactate were evaluated for
diagnosis of sepsis and PCT was found to be the most
reliable marker for the diagnosis of sepsis, with 89%
sensitivity and 94% specificity.
Crit Care Med. 2004;32:1166-9
Crit Care Med. 2000;28:977-83
19. Differentiation of Bacterial & Viral Infections
• Pro calcitonin - produced in response to endotoxin
or inflammatory mediators such as ILs, TNF -
response classically seen in bacterial infections.
• Viral infections - release of interferon (IF), a
cytokine which attenuates PCT production.
20. De-escalation of Antibiotics
• Rampant usage of antibiotics in past few decades, -
Antibiotic resistance
• The concept of antibiotic stewardship for optimal usage
of antibiotics and early de-escalation of antibiotics is
accepted and encouraged.
• Due to favorable kinetics of PCT - evaluated for
discontinuation of antibiotics.
21. • Randomized 621 adult patients with suspected bacterial
infection and utilized an algorithm in which initial procalcitonin
was used to assess whether to start antibiotics. Subsequent
antibiotics were discontinued when PCT levels were <0.5 g/L
or decreased from peak value by >= 80%.
De-escalation of Antibiotics
22. • Algorithm used was similar to PRORATA
• Significant reduction in antibiotic requirement with no increased
rates of complications or mortality.
• Mild increase in reinfection rates in PCT arm.
• Strong evidence for use of PCT based algorithms in sepsis
De-escalation of Antibiotics
23. Procalcitonin in post op. period
• Depending on the degree of tissue injury during surgery, levels of
PCT rise in postoperative period.
• Normally levels rise up to 9 ng/mL in the postoperative period.
• Persistently high levels should raise suspicion of post op.
infection.
• Any PCT more than 10 ng/mL in the postoperative non-transplant
patient is considered to be abnormal.
24. • Site of surgery influences levels of PCT.
• Greatest with abdominal and retroperitoneal surgery and minor in
thoracotomy.
• More useful than CRP, white cell count, and IL6 in detecting
infections.
• Trásy et al. used delta-PCT (PCT level from preceding day
subtracted from PCT level on day of suspected infection) -
patients with an infection exhibited a significantly higher delta PCT
Procalcitonin in post op. period
J Immunol Res. 2016;2016:3530752
25. Guide Antibiotic Therapy in Respiratory
Infections
• PROCAP trial- Patients who presented to the emergency
department with suspected lower RTI, use of
procalcitonin to determine whether not to initiate
antibiotics
• Cutoff threshold of 0.25 g/L had a 47% reduced rate of
antibiotic exposure in the procalcitonin group with no
difference in laboratory or clinical outcomes.
26. • PROHOSP study - multicenter RCT
• Patients were randomized into either PCT based algorithm group-
antibiotics were strongly discouraged if procalcitonin was <0.1,
discouraged if 0.1-0.25, encouraged if 0.25-0.5, strongly
encouraged if >0.5.
• Antibiotic exposure and antibiotic associated adverse events were
significantly decreased in the PCT group while adverse outcomes
were similar in both groups.
• Clinical picture and radiology ?
Guide Antibiotic Therapy in Respiratory
Infections
27. Prognostication
• Several studies have looked at levels of PCT as
well as PCT clearance as prognostic markers and
found varying results
Procalcitonin in Renal Failure
• Basal PCT may be raised as half-life increases,
however kinetics is not altered and hence PCT
decline rates may be unaltered.
28. NEWER BIOMARKERS
• Several other biomarkers are investigated for sepsis.
Triggering receptor expressed on myeloid cells-1
(TREM-1)
Interleukin 27 (IL-27)
Presepsin
Cell free DNA
miRNA
29. • Biomarkers related to the symptoms of sepsis rather than
the mechanisms of inflammation have also been tested
CT-pro-AVP (C-terminal segment of pro-arginine
vasopressin
• A recent review and meta-analysis by Jiyong et al. showed
that elevated STREM-1, sampled and measured from the
location of infection, is highly predictive of bacterial
infection.
NEWER BIOMARKERS
Intensive Care Med. 2009;35:587-95
30. • A recent systematic review and meta-analysis which
compared diagnostic accuracy of presepsin and
procalcitonin for sepsis in critically ill adults concluded
that both were useful for early detection of sepsis and
lead to reduction of mortality in critically ill patients.
NEWER BIOMARKERS
J Intensive Care. 2019;7:22
31. • Cell-free plasma DNA (cfDNA) are fragments of
DNA that are released because of cell necrosis or
apoptosis.
Observational studies found that nonsurvivors of
sepsis and septic shock had higher levels of cfDNA
compared to survivors.
NEWER BIOMARKERS
32. • Sepsis - exaggerated proinflammatory state, but there
may be anti-inflammatory and immunosuppressive
component, especially in late sepsis or sepsis
occurring in elderly patients.
• New biomarkers ( degree of immunosuppression )
include circulating blood monocyte expression of HLA-
DR, programmed cell-death ligand-1 (PD-LI), and low
absolute lymphocyte counts - Immunostimulating or
immunomodulating therapy
NEWER BIOMARKERS
