By David Fiore, MD

Professor of Family Medicine, University of Nevada, Reno

Dr. Fiore reports no financial relationships relevant to this field of study.

SYNOPSIS: The authors of this meta-analysis reviewed patient-level data on 6,708 patients from 26 randomized studies that examined procalcitonin-directed antibiotic therapy for acute respiratory tract infections. They found a 1% reduction in mortality and a 2.4-day reduction in antibiotic exposure for the procalcitonin-directed therapy groups. How procalcitonin can be incorporated into routine clinical practice, in what settings, and whether it is cost-effective are still unclear.

SOURCE: Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: A patient level meta-analysis. Lancet Infect Dis 2017 Oct 13. pii: S1473-3099(17)30592-3. doi: 10.1016/S1473-3099(17)30592-3. [Epub ahead of print].

Procalcitonin was first identified by Leonard J. Deftos and Bernard A. Roos in the 1970s. It is composed of 116 amino acids and is produced by parafollicular cells (C cells) of the thyroid and by the neuroendocrine cells of the lung and the intestine.1 In the 1990s, investigators started examining the relationship of procalcitonin to bacterial infection.2 In the 2000s, investigators began testing procalcitonin as a marker for bacterial infection and its use in clinical decision-making.3,4 In 2017, the FDA approved the use of procalcitonin for guiding antibiotic therapy in acute respiratory infections. These authors, who reported funding from Thermo Fisher (makers of the procalcitonin lab test), published this review in October 2017 both as a meta-analysis in Lancet Infectious Diseases and as a Cochrane Review. They reviewed patient-level data for 6,708 patients from 26 trials in 12 countries. Two trials were outpatient-based and looked at upper respiritory infections (URIs) (n = 1,008), 11 were from EDs and medical wards (n = 3,253), and 13 were from ICUs (n = 2,447). Each study used its own protocol and algorithm to determine how procalcitonin should direct therapy. Compliance with the algorithms ranged from 44-100%. The baseline characteristics of the patients in the two groups were similar, with most patients recruited from the ED or ICU.

The primary endpoints were 30-day mortality and treatment failure (defined by each study). Schuetz et al reported a statistically significant reduction in mortality in the procalcitonin group, which demonstrated a mortality of 9%, compared to 10% in the control group, resulting in a number to test and treat to save one life of 100 and a relative risk reduction of 10%.

These results are slightly better if the outpatient (URI) studies are excluded; the absolute risk reduction of mortality increases to 1.4% (number needed to test and treat = 71, relative risk reduction of 13%).

The authors also reported a reduction of antibiotic duration of 2.4 days in the procalcitonin-guided treatment groups and a reduction in antibiotic-related side effects (16% vs. 12%).

COMMENTARY

Although these results are very promising and are consistent with prior studies and a 2012 Cochrane Review (conducted by some of the same authors),5 there still are some important questions that must be answered before we can feel confident using procalcitonin to guide our clinical practice.

The first concern is that different cutoffs and algorithms were used to direct therapy. As clinicians, we will need to see prospective confirmation of previously developed algorithms using a preset cutoff before we can be confident in using procalcitonin in our own practices. Furthermore, the issue of variability between different methods of assessing procalcitonin must be addressed. In addition to the technical issues mentioned above, the “human” factor in ordering procalcitonin may limit its cost-effectiveness and its utility.

If physicians start ordering procalcitonin on patients with a very low risk of bacterial infection (as we’ve seen with D-dimer for venous thromboembolism), the false-positive rate will overwhelm the true positive rate and the utility of the test.

In my estimation, the bottom line still is somewhat mixed. It seems that ordering and carefully using a procalcitonin level as part of your clinical reasoning likely is useful, especially in those patients about whom you are unsure as to whether they have a bacterial infection. But widespread use should wait until we see more studies that are not funded by the makers of the test and should use consistent cutoff levels and algorithms.

REFERENCES

  1. Deftos LJ, Roos BA, Parthemore JG. Calcium and skeletal metabolism. West J Med 1975;123:447-458.
  2. Dandona P, Nix D, Wilson MF, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab 1994;79:1605-1608.
  3. Daubin C, Parienti JJ, Fradin S, et al. Procalcitonin levels and bacterial aetiology among COPD patients admitted to the ICU with severe pneumonia: A prospective cohort study. BMC Infect Dis 2009;9:157.
  4. Guven H, Altintop L, Baydin A, et al. Diagnostic value of procalcitonin levels as an early indicator of sepsis. Am J Emerg Med 2002;20:202-206.
  5. Schuetz P, Müller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2012 Sep 12;(9):CD007498. doi: 10.1002/14651858.CD007498.pub2.