Procalcitonin in Sepsis: A Guide to Antibiotic Stewardship
Procalcitonin: A Biomarker For Sepsis
Procalcitonin is a highly specific biomarker for the diagnosis of sepsis. The word sepsis is derived from the Greek word "sepo" which means "I rot". The first mention of the word sepsis occurs in the poems of Homer. Although the mortality in sepsis has reduced from 50%-75% to a range of 30%-50% the incidence of sepsis has increased annually in the past forty years. This reduction in mortality is largely attributable to the discovery and use of antibiotics in the past hundred years of medicine. The total deaths sepsis causes is statistically similar to myocardial infarction.
Population: 2.4 to 3% incidence in general population.
ICU: 10-14% incidence in ICU patients.
ICU: 16% incidence in general population.
Brun-Buisson et al. JAMA 1995
S Todi et al. Crit Care 2007
Sands et al. JAMA 1997
Systemic Inflammatory Response Syndrome (SIRS): Not The Same As Sepsis
Systemic inflammatory response syndrome (SIRS) may occur in the absence of infection.
Two or more of the SIRS criteria are needed to document it-
- Temperature more than 380C (100.40F) or less than 360C (96.80F).
- Heart rate more than 90 beats/minute.
- Respiratory rate more than 20 /min or PaCO2 < 32 mmHg.
- White Blood Cell Count(WBC ) more than 12,000 cells/mm3 or 4,000 cells/mm3, or more than 10% immature (band) form of white blood cells.
So What Is Sepsis?
Systemic response to infection – It is confirmed or suspected infection plus 2 SIRS criteria.
Severe Sepsis –
Sepsis associated with organ dysfunction, hypo perfusion, or hypo tension.
Septic Shock –
Severe Sepsis that cannot be resuscitated or stabilized with IV fluids alone.
So if you have fever, a fast heart rate, fast breathing and increased white blood cells you do not necessarily have sepsis because these can occur in the presence of systemic inflammatory response syndrome. For sepsis the presence of infection (either suspected or confirmed by microbial techniques) is necessary. So medical conditions like pancreatitis, burns, trauma may present with fever, tachycardia, tachypnea and increased white cell count either due to SIRS or Sepsis and there is no objective way to differentiate one from another.
Biomarkers For Sepsis
What Is An Ideal Bio Marker?
A bio marker may be simply defined as a laboratory measurement that reflects the activity of a disease process. An ideal bio marker should not only help in the early diagnosis of a disease but also provide information regarding its severity and prognosis. Serial measurements of an ideal bio marker before and after the therapy should show decline to indicate the effectiveness of therapy. Erythrocyte Sedimentation Rate (ESR) is the oldest bio marker and is in use from the past ninety years. Other common bio marker is C reactive protein (CRP) which in use since the past 30 years.
Mortality In Sepsis
Why Do We Need A Bio Marker Like Procalcitonin?
A bio marker like procalcitonin may help differentiate SIRS from sepsis. This differentiation is of paramount importance because infection or sepsis would require antibiotics whereas inflammatory conditions do not require antibiotic treatment. A misdiagnosis may result in either cost escalation of treatment if antibiotics are administered to a person not suffering from sepsis whereas if antibiotics are delayed or denied in a patient of sepsis it will cause increased mortality or morbidity. So the best case scenario will be a bio marker which will objectively differentiate a infective cause of illness from a not infective one to guide the clinical decisions regarding antibiotic administration, thereby taking the guesswork out of the equation.
Procalcitonin (PCT) : A Prohormone
It is a protein composed of a chain of 116 aminoacids. It is a pro-hormone of calcitonin and is secreted from all parenchymal tissues in response to bacterial infection. Calcitonin on the other hand is secreted by the C cells of the thyroid only. The regulation of procalcitonin is by the CALC-1 gene located on chromosome 11. A bacterial infection increases the CALC-1 gene expression and stimulates the release of procalcitonin. The normal serum procalcitonin level is less than 0.05 ng/ml.
Procalcitonin Normal Range
The level of procalcitonin in normal individuals is <0.5ng/ml. It can increase to very high values up to 1000 ng/ml. A PCT value of >2ng/ml is highly suggestive of an infectious process but the levels between 0.5-2 ng/ml lie within an equivocal range which neither confirm nor deny an infectious process. This group may include post surgical patients, polytrauma patients, newborn infants, patients with extensive burns, patients with viral infections or local infections or autoimmune diseases and neoplastic disease.
Procalcitonin Kinetics In Sepsis
Procalcitonin Kinetics in Sepsis
Procalcitonin levels start increasing within three hours of infection and levels peak in blood at six to twelve hours after infection. It has a half life of around twenty four hours after which levels start declining.
Role of Procalcitonin In Clinical Practice
Assist in the diagnosis of sepsis.
To monitor clinical course & therapy.
Predict prognosis of disease.
Prognostic Value Of Procalcitonin
The level of procalcitonin concentration in serum is higher in more severe infections but the decrease in concentration was more important for survival than the absolute values.
Karlsson et al. Critical Care 2010, 14:R205
Use Of Serum Procalcitonin Levels In Various Clinical Situations
Procalcitonin In Acute Respiratory Tract Infections
Procalcitonin guided therapy markedly reduced the use of antibiotics without affecting the patient outcome (Arch Intern Med. 2008; 168(18):2000-2007).
This has important clinical and epidemiological implications as antimicrobial drugs are often overused in self limiting respiratory infections.
Serum Procalcitonin Measurement For The Early Diagnosis Of Candidemia In Critically Ill Patients
Intensive Care Med (2006) 32:1577–1583
Procalcitonin levels do not increase in fungal infections. High procalcitonin level in a patient with clinical sepsis will unlikely be due to fungal infections. So if a critically ill patient has low serum PCT but clinically apparent sepsis patient should be further assessed and investigated for fungal infections.
Procalcitonin In HIV Infections (AIDS)
The level of procalcitonin does not increase even in advanced disease in HIV positive patients. It is only in the presence of sepsis that procalcitonin induction is observed. Infections like tuberculosis, cerebral toxoplasmosis, pneumocystis carinii pneumonia, viral and local bacterial and fungal infections do not increase the level of procalcitonin in HIV patients.
Procalcitonin In New Born Infants
Procalcitonin concentration peaks between 24 to 36 hours after birth and during this period markedly increased concentration can be observed even in the absence of relevant bacterial infection.
Clinical Chemistry 44, No. 6, 1998
Limitations of Procalcitonin As Biomarker
Procalcitonin may increase without sepsis
Procalcitonin may be normal in sepsis
New born less than 48 hours of birth
Bacterial Infection (If localized)
Early phase of sepsis
Medullary C-cell cancers of the thyroid
Pulmonary Small-Cell Carcinoma
Advantages of procalcitonin over C Reactive Protein
Secretion begins after infection
Response to treatment
Effect of steroid & Non steriodal anti inflammatory drugs (NSAID’s)
To monitor clinical course & therapy
Significant reduction in antibiotic use
number of prescriptions and
duration of use
No impact on mortality, length of hospital stay
Arch Intern Med (2011); Clin Infect Dis (2011); Crit Care Med (2010); Infection (2009)
Systematic review and meta-analysis of procalcitonin guided antibiotic therapy
Good Antibiotic Stewardship
So procalcitonin may be used to assist in the more judicious use of antibiotics both inside and outside Intensive Care Units. A good antibiotic stewardship will prevent the emergence of multi drug resistance bacteria and help reduce the burden of sepsis.