The FLARE Four
- Procalcitonin synthesis is greatly upregulated in the presence of bacterial infection or certain cytokines; in contrast, it's believed to be inhibited during viral infection
- According to professional society guidelines, procalcitonin level should not be the sole criterion for administering antibiotics
- Observational studies have reported higher levels of procalcitonin in patients with more severe COVID-19, but it's unclear whether this is related to bacterial co-infection or the severity of the viral infection, or both
- As in other conditions, procalcitonin should be interpreted in the broader clinical context of respiratory failure related to COVID-19
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In isolation, elevations of procalcitonin are insufficiently specific to guide antibiotic therapy in COVID-19, according to Viral Shah, MD, PhD, a fellow in the Division of Pulmonary and Critical Care at Massachusetts General Hospital. He gives details in a fast literature update posted on April 9, 2020.
Background on Procalcitonin
Procalcitonin, a peptide synthesized by thyroid neuroendocrine cells, is normally cleaved to yield calcitonin, the calcium-regulating hormone. In healthy people, serum procalcitonin levels are undetectable by usual assays. However, in the presence of bacterial endotoxin or certain cytokines, including interleukin-6, procalcitonin synthesis is greatly upregulated in multiple tissues.
Uncertain Value as a Biomarker
The effect of viral infection on procalcitonin contrasts with that of bacterial infections. T helper cells produce interferon-gamma, which is believed to inhibit procalcitonin production.
Accordingly, serum procalcitonin has been proposed as a diagnostic biomarker to distinguish between bacterial and viral infections. However, procalcitonin can also be elevated in non-infectious states such as burns and trauma.
The evidence for using procalcitonin to guide antibiotic therapy is mixed. For patients with community-acquired pneumonia, joint recommendations of the American Thoracic Society and Infectious Diseases Society of America published before the COVID-19 pandemic strongly advise initiating antibiotics based on clinical judgment, regardless of procalcitonin level.
Procalcitonin and COVID-19
Several studies from China have reported elevated procalcitonin levels (>0.5 or >1.0 ng/mL) in 6% to 30% of patients with COVID-19. Two of those studies correlated the procalcitonin level with the severity of disease or risk of death.
Interpretation of these data is difficult, though, because procalcitonin levels were not obtained in all patients, disease severity varied between studies and it's unclear how many patients had bacterial co-infection.
There are three possible interpretations of elevated procalcitonin in COVID-19:
- Represents bacterial co-infection
- Marker of severity of acute respiratory distress syndrome
- Elevated because COVID-19–associated respiratory failure causes immune dysregulation that increases the production of cytokines, which increase procalcitonin synthesis
Because of the unclear cause of elevated procalcitonin in COVID-19, it's not advisable to use the procalcitonin level by itself to guide antibiotic therapy. Procalcitonin should be interpreted in the broader clinical context of COVID-19 associated respiratory failure.
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