ProACT: Procalcitonin-Guided Treatment of Lower Respiratory Tract Infections
Huang DT, Yealy DM, Filbin MR, et al.; ProACT Investigators.
Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection.
N Engl J Med. 2018 Jul 19;379(3):236-249. [Full text]
The synthesis of procalcitonin, the precursor of calcitonin that regulates homeostasis, can be increased by some endotoxins and cytokines, especially those released in response to bacterial infection. For this reason it has been purported that procalcitonin may aid in distinguishing between bacterial and viral infections and could be a tool to improve antibiotic stewardship.
The Procalcitonin Antibiotic Consensus Trial (ProACT) authors note that European trials using procalcitonin for suspected lower respiratory tract infections (LRTIs) have shown decreased antibiotic use without harm. They rightly note that prescribing patterns in the US may vary from Europe and that in those trials protocol variation (use or not of antibiotics) was strictly regulated and perhaps not reflective of real world practice. They therefore designed ProACT to determine whether a procalcitonin antibiotic prescribing guideline that recommended but not mandated antibiotic treatment (a more pragmatic, real world implementation) would result in less exposure to antibiotics without higher rate of adverse events.
Patient population and Design
A total of 14 hospitals in the US recruited patients, none of which used procalcitonin in routine care prior to the study.
Adult patients (≥18 yo) presenting to the ED with an an initial diagnosis of acute LRTI (<28 d in duration) but had not yet decided to give antibiotics, with uncertainty regarding the need for antibiotics, Not all patients ended up with a final diagnosis of a LRTI, many had COPD, asthma, or bronchitis, to name a few.
Patients were excluded for conditions in which physicians were unlikely to withhold antibiotics
(prior antibiotics, vasopressor use, mechanical ventilation via ET tube, severe
immuno-suppression, accompanying non-respiratory infection, known lung abscess/empyema), if they had conditions that could elevate procalcitonin without a bacterial infection (chronic dialysis, metastatic cancer, recent surgery <7d), or had limited ability to follow-up (i.e. prisoners, homeless).
Intervention
Procalcitonin was measured in the ED, and if the patient was hospitalized, 6 to 24 hours later and on days 3, 5, and 7, if still hospitalized and receiving antibiotics. Patients were randomized 1:1 in a usual group and a procalcitonin group. In the usual-care group, a procalcitonin was drawn but the results were clinically unavailable. The procalcitonin group was given guidelines for prescribing antibiotics based on level, as follows:
| Procalcitonin (μg/L) | Antibiotic Use Guideline |
| <0.1 | Strongly discouraged |
| 0.1 to 0.25 | Discouraged |
| >0.25 to 0.5 | Recommended |
| 0.5 | Strongly recommended |
Outcomes
The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment.
The primary safety outcome was a composite of adverse outcomes within 30 days that could be attributable to withholding antibiotics (hospitalization, ICU admission, death).
Secondary outcomes included prescription of antibiotics in the ED, antibiotic receipt by day 30, antibiotic-days during the hospital stay (among those admitted), ICU admission, recurrent ED visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.
The authors estimated that with 1514 patients, the trial would have at least 80% power to both detect a between-group difference of 1 antibiotic-day and to declare non inferiority with an assumed 11% rate of adverse outcomes in the usual-care group. Recruitment was increased to a goal of 1664 patients given their rate of loss to follow-up (18%).
Results
A total of 1664 patients were enrolled and underwent randomization. but only 1345 (81.2%) completed 30-day follow-up. Baseline characteristics were similar between groups.
The final diagnoses, available for 1645 patients, included asthma exacerbation (39.3%), COPD exacerbation (31.9%), acute bronchitis (24.2%), and community-acquired pneumonia (19.9%). For most patients the initial procalcitonin level was < 0.1 μg/L (77.4%). The minority had a procalcitonin of 0.1 to 0.25 μg/L (14.4%), 0.25 to 0.5 μg/L (3.1%), or >0.5 μg/L (5%). A total of 782 patients (47.2%) were hospitalized. Clinicians adhered to the procalcitonin guideline recommendation for 577 of 792 patients (72.9%).
There was no significant difference in antibiotic exposure during the first 30 days between the procalcitonin group and the usual-care group (mean antibiotic-days, 4.2 vs 4.3 days, P=0.87) or any subgroup.
By 30 days, 96 patients in the procalcitonin group (11.7%) and 109 patients in the usual-care group (13.1%) had incurred a safety outcome event, a difference which was not significant.
There were no difference in key secondary outcomes including, patients receiving any antibiotics within 30 days (57.0% and 61.8%, risk difference, −4.8%; 99.86% CI, −12.7 to 3.0), those receiving an antibiotic prescription in the ED (34.1% and 38.7%; risk difference, −4.6%; 99.86% CI, −12.2 to 3.0), or mean hospital antibiotic-days among hospitalized patients (2.6 and 2.7 days; risk difference −0.1; 99.86% CI, −0.8 to 0.6).
In post-hoc analysis of the usual-care arm, clinicians were prescribing antibiotics at a similar rate in the lowest procalcitonin tier (PCT <0.1) without the knowledge of that procalcitonin level.
Discussion
In this trial that implemented a procalcitonin antibiotic prescribing guide in 14 US hospitals that had not previously routinely used procalcitonin, the exposure to antibiotics was similar for patients presenting to the ED with suspected LRTI, regardless if procalcitonin was checked.
That clinicians prescribing pattern was similar in patients with the lowest procalcitonin (PCT < 0.1) whether or not that procalcitonin level was available to the treating clinician suggests the procalcitonin does not add to the medical decision making in these patients.
So how is one to use procalcitonin clinically for respiratory tract infections, if at all? A 2017 Cochrane review noted that procalcitonin “lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic‐related side effects” in patients with acute respiratory tract infections [1]. On the other hand, a 2020 systematic review and meta-analysis found that in patients with pneumonia, procalcitonin only had a sensitivity of 0.55 (95% CI, 0.37–0.71; I2 = 95.5%) and specificity of 0.76 (95% CI, 0.62–0.86; I2 = 94.1%) to distinguish bacterial from viral pneumonia [2].
The key difference between these are the populations in question: acute respiratory complaints versus confirmed pneumonia. The 2019 ATS and IDSA guidelines, which deals with confirmed pneumonia, states that procalcitonin is “not recommended to determine need for initial antibacterial therapy” [3]. In this setting, procalcitonin has poor sensitivity to distinguish viral from bacterial etiology. For delineating between various acute respiratory complaints it may have a role, though ProACT’s findings argue it does not change clinical practice.
Finally, some work has suggested procalcitonin has a role in cessation of antibiotics. This is another question altogether not addressed in ProACT. Suffice it to say that ATS/IDSA only recommend tredning procalcitonin “in settings where the average length of stay for patients with CAP exceeds normal practice (e.g., 5–7 d)” [3], a duration which is uncommon in the US.
| F: Follow up | Yes to 30 d |
| R: Randomization | Yes |
| I: Intention to treat | Yes |
| S: Similar at baseline | Yes |
| B: Blinding | Not of treating clinicians |
| E: Equal treatment | Yes |
| S: Source (funding) | National Institute of General Medical Sciences |
- Schuetz P, Wirz Y, Sager R, et al.B. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017 Oct 12;10(10):CD007498.
- Kamat IS, Ramachandran V, Eswaran H, et al. Procalcitonin to Distinguish Viral From Bacterial Pneumonia: A Systematic Review and Meta-analysis. Clin Infect Dis. 2020 Jan 16;70(3):538-542.
- Metlay JP, Waterer GW, Long AC, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019 Oct 1;200(7):e45-e67.
- Wilson KC, Schoenberg NC, Cohn DL, et al. Community-acquired Pneumonia Guideline Recommendations-Impact of a Consensus-based Process versus Systematic Reviews. Clin Infect Dis. 2021 Oct 5;73(7):e1467-e1475.
