Procalcitonin

Procalcitonin is the 116 amino acid prohormone of calcitonin. In health it is made in thyroid C cells and converted to calcitonin, so serum levels are under 0.05 ng/mL. In systemic bacterial infection, cytokines (interleukin-1 beta, interleukin-6, tumour necrosis factor alpha) and endotoxin trigger widespread production in liver, lung, kidney, intestine and adipose tissue, and the prohormone is released without cleavage. Interferon gamma, produced in viral infection, suppresses this release, so levels are usually low in viral illness.

It is measured by immunoassay on serum or heparin or EDTA plasma and reported in ng/mL (equivalent to microg/L). Levels rise within 3 to 6 hours of the stimulus, peak at 12 to 24 hours and fall by about half each day when the infection is controlled (half life 20 to 24 hours).

Its main uses are the early identification of systemic bacterial infection and sepsis, direction of antibiotic initiation in lower respiratory tract infection, and shortening of antibiotic courses by serial measurement. It adds the most value in critically ill and respiratory patients, and little in localised infection.

Sepsis affects about 50 million people worldwide each year, with about 11 million deaths. Lower respiratory tract infection is the most common reason for antibiotic prescribing in hospital, and a large share of courses are unnecessary or too long.

Indications. Suspected sepsis, severe community acquired pneumonia, exacerbation of chronic obstructive pulmonary disease or asthma with suspected infection, fever in the neutropenic patient, neonatal sepsis, bacterial versus viral meningitis, post-operative infection, decision to stop antibiotics in the intensive care unit, and suspected medullary thyroid carcinoma or neuroendocrine tumour.

Specimen. Serum or heparin or EDTA plasma. Stable for 24 hours at 2 to 8 °C and longer when frozen. Results are available within an hour on automated analysers.

Reference range. Under 0.05 ng/mL in health. Under 0.1 ng/mL makes systemic bacterial infection very unlikely.

Interpretation bands.

• Under 0.1 ng/mL: bacterial infection very unlikely.
• 0.1 to 0.25 ng/mL: bacterial infection unlikely.
• 0.25 to 0.5 ng/mL: infection possible.
• 0.5 to 2 ng/mL: systemic infection likely, though other causes of inflammation are possible.
• 2 to 10 ng/mL: sepsis likely, with high risk of progression to severe sepsis.
• Over 10 ng/mL: severe sepsis or septic shock is likely.

Antibiotic decisions in lower respiratory tract infection. Under 0.1 ng/mL: antibiotics are discouraged. 0.1 to 0.25 ng/mL: discouraged. 0.25 to 0.5 ng/mL: encouraged. Over 0.5 ng/mL: strongly encouraged. These bands inform and do not replace clinical judgement, and they do not apply to a patient who is unstable, immunocompromised or has severe disease.

Stopping antibiotics. A fall of 80% or more from the peak, or a value under 0.5 ng/mL, supports stopping in a patient who has improved clinically. In intensive care this approach shortens antibiotic duration by 1 to 3 days without harm.

Sepsis prognosis. A value that fails to fall by at least 80% within 4 days, or that stays over 2 ng/mL, is associated with higher mortality.

Causes of raised procalcitonin without bacterial infection.

• Major trauma, burns, major surgery, cardiac arrest, cardiogenic shock, and prolonged ischaemia.
• Acute pancreatitis (especially necrotising), mesenteric ischaemia, heat stroke, rhabdomyolysis.
• Medullary thyroid carcinoma and small cell lung cancer or other neuroendocrine tumours.
• Severe kidney failure (modest rise, 0.5 to 2 ng/mL), though sepsis still produces a higher value.
• Cytokine release, CAR-T cell therapy, treatment with anti-thymocyte globulin and monoclonal antibodies, and transplant rejection.
• Neonates in the first 48 hours, with a physiological peak at 24 hours that can reach 20 ng/mL.
• Severe malaria, invasive fungal infection (moderate rise), and Kawasaki disease.

Causes of a falsely low value in infection.

• Localised infection (abscess, empyema, osteomyelitis, cystitis, infected prosthesis).
• Sampling in the first 6 hours.
• Subacute endocarditis, Mycoplasma, Chlamydia, Legionella (variable), tuberculosis, and some intracellular organisms.
• Immunosuppression with impaired cytokine response.

Critical values and findings needing immediate action.

• A value over 2 ng/mL with fever, hypotension or altered consciousness, which calls for urgent sepsis management.
• A value over 10 ng/mL.
• A rising value 48 hours into antibiotic therapy.
• A value over 0.5 ng/mL in a neonate beyond 48 hours of life.

Interferences and pitfalls.

• Procalcitonin is not an isolated decision tool, and the clinical picture comes first.
• A single low result in the first hours is repeated at 6 to 24 hours if suspicion remains.
• Non-bacterial causes of a high result (trauma, surgery, medullary carcinoma) must be excluded before concluding infection.
• Kidney failure delays clearance and shifts the bands upwards.
• Haemolysis, lipaemia and bilirubin have little effect, and heterophile antibodies can give false positives.
• Different assays have different detection limits, and local ranges apply.
• The test does not identify the organism or the source.

Special groups.

• Neonates: age specific limits are needed in the first 72 hours, and serial values are more informative than a single result.
• Children: useful to separate bacterial from viral illness in febrile infants and for bacterial meningitis (over 0.5 ng/mL favours bacteria).
• Pregnancy: no important change, and chorioamnionitis can raise it.
• Older adults: valuable when presentation is atypical.
• Immunosuppressed and neutropenic patients: useful when positive and less reliable when negative.
• Regions: severe malaria and typhoid raise values, so interpret with the local infection burden.

Follow up tests. Blood cultures before antibiotics, lactate, C-reactive protein, full blood count, urea and electrolytes, liver function tests, coagulation screen, urinalysis and culture, chest radiograph, respiratory pathogen PCR, cerebrospinal fluid analysis, imaging for source, calcitonin and RET testing when medullary carcinoma is suspected.