Discipline - Clinical chemistry
First added in 2019
Changed in 2020
To guide antibiotic therapy or its discontinuation in sepsis and lower respiratory tract infections; (For use only in tertiary care facilities and above)
Venous whole blood, Capillary whole blood, Plasma
Summary of evidence evaluation
Key supporting evidence was contained in a Cochrane review of randomized clinical trials (RCTs) of procalcitonin test strategies used to initiate or discontinue antibiotics in acute respiratory infections (8). The review comprised 32 RCTs with analysis of data on individual participants in 26 and a total of 6708 participants. The main benefits were a 2.4-day reduction in exposure to antibiotics (5.7 versus 8.1 days, 95% CI –2.71 ; –2.15, P < 0.001) and a lower risk for antibiotic-related side-effects (16.3% versus 22.1%, adjusted odds ratio 0.68, 95% CI 0.57 ; 0.82, P < 0.001). No difference in mortality was noted in 11 trials in emergency departments (76/1892 versus 79/1913) (RR=0.97 (0.70, 1.36), no heterogeneity), but a reduction in mortality was evident in 16 trials in intensive care units (530/2617 versus 586/2616) (RR=0.88 (0.77, 1.00), no heterogeneity). No significant difference was found in treatment failure (procalcitonin test 23.0%, control group 24.9%). The length of stay in hospital and in intensive care units was similar. Data were presented only for mortality and treatment failure; however, additional data to support the conclusion on antibiotic use and side- effects were provided to the SAGE IVD by the authors of the review. A second Cochrane review of RCTs of procalcitonin test strategies used in adults with sepsis, severe sepsis or septic shock (9) comprised 10 RCTs published up to 2015, with a total of 1215 participants. The mean time to receiving antimicrobial therapy in the intervention groups was reduced by 1.28 days with procalcitonin testing (95% CI: –1.95 ; –0.61). The mortality rate was reduced at the longest follow‐up (RR=0.81 (0.65–1.01)) and at 28 days (RR 0.89, (0.61–1.31)) but not at discharge from intensive care (RR 1.03 (0.5– 2.11)) or hospital (RR 0.98 (0.75–1.27)). None of the primary studies had included an analysis of a change in antimicrobial regimen from a broad to a narrower spectrum. The authors considered that the inevitable lack of blinding in test-treatment trials incurred a risk of bias, which was not considered a concern by SAGE IVD.
Summary of SAGE IVD deliberations
The evidence that the procalcitonin test could reduce the use of antibiotics appears to be strong and justifies its use in diagnosis and during treatment to contribute to a decision on starting and discontinuing antibiotics. While data on reductions in mortality rates varied by setting and condition, showing either a reduction or no effect, there was no evidence that reducing antibiotic use put patients at risk of harm. Although the accuracy of diagnosis of sepsis was not high and while a single measurement could predict progression to severe sepsis but not mortality, the test-treatment trials provide convincing evidence that use of the test benefits patients and reduces antibiotic use. No comparison has been reported of procalcitonin with other, cheaper biomarkers, such as C-reactive protein, which can be used for the same purpose.
SAGE IVD recommendation
SAGE IVD recommended inclusion on the EDL of the test for procalcitonin levels in serum and plasma, noting the strong evidence for its quality and performance and the flexible assay formats and levels. SAGE IVD considered that guidelines or an algorithm are required for its use, although the complexity and variability of sepsis might make this difficult. The test should therefore be used only in tertiary care facilities where physicians are available to modify or override decision thresholds where required in view of clinical presentation and patient characteristics.
Details of submission from 2020
Disease condition and impact on patients: According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis is a life- threatening organ dysfunction caused by dysregulated host-response to systemic infection. Mortality due to severe sepsis is 28–50% or more, even in developed countries, despite significant investments in critical care resources. Does the test meet a medical need? The procalcitonin test has several potential uses in sepsis, and the results are useful, with other factors, for deciding when to start and when to discontinue antibiotic treatment. How the test is used: The currently approved intended uses are to: a. assess the risk of critically ill patients with infections on admission to an intensive care unit for progression to severe sepsis and septic shock; b. decide to discontinue antibiotic therapy as early as possible; and c. assess the cumulative 28-day risk for all-cause mortality of patients with severe sepsis or septic shock in an intensive care unit or in emergency or other medical wards. Other proposed intended uses are in deciding on antibiotic therapy for inpatients or outpatients with suspected or confirmed lower respiratory tract infections, community-acquired pneumonia, acute bronchitis or acute exacerbation of chronic obstructive pulmonary disease and in deciding to discontinue antibiotic therapy in these patients (1).
Public health relevance
Prevalence: Sepsis arises when the body’s response to an infection injures its own tissues and organs, potentially leading to death or significant morbidity. The burden of sepsis is probably highest in LMICs; however, the available data are from studies in high-income countries. An estimated 30 million people are affected worldwide every year, potentially leading to 6 million deaths; 3 million newborns and 1.2 million children globally per year have sepsis. One in ten deaths associated with pregnancy and childbirth is due to maternal sepsis, and over 95% of deaths due to maternal sepsis occur in LMICs. Socioeconomic impact: In an analysis of billings in the US health care system in 2013, sepsis cost nearly US$ 24 billion annually and is thus the most expensive condition treated in the entire system. The mean expense per hospital stay was > US$ 18 000, which was 70% more expensive than the average stay. The cost of care for sepsis rose by 19% between 2011 and 2013 (2).
WHO or other clinical guidelines relevant to the test
Report by the WHO Secretariat for the Seventieth World Health Assembly in 2017 (3) and resolution WHA70.7 on improving the prevention, diagnosis and clinical management of sepsis. Endorsed at a WHO meeting on sepsis in 2018 and recommended for discontinuation of antibiotics for lower respiratory tract infections by the Infectious Diseases Society of America, the Agency for Healthcare Research and Quality and the United Kingdom National Institute for health and Care Excellence. Recommended for discontinuation of antibiotics in sepsis only by the first two organizations.
Evidence for clinical usefulness and impact
Treatment of sepsis, “a life-threatening organ dysfunction caused by dysregulated host-response to systemic infection” (4), is based on treatment of the underlying infection. It involves a difficult balance between administration of antibiotics as soon as possible, as any delay increases the mortality rate by 2% per hour and stopping broad-spectrum antibiotics to prevent the emergence of AMR as soon as they are no longer required. Patients with sepsis are often treated with antimicrobials for 10–14 days, although evidence suggests that treatment could be reduced to 5–7 days without harm. As the clinical signs and symptoms are not specific to sepsis and sepsis may be caused by bacterial but also by viral infections, antibiotics are not always indicated. Furthermore, the results of blood cultures for bacterial infection and of antibiotic susceptibility testing can take at least 24 h and sometimes up to 72 h. Blood culture positivity rates are typically low. Early identification of sepsis cases due to bacterial infections is therefore critical. During the past decade, procalcitonin testing has become widely used to identify bacterial sepsis. The sensitivity and specificity of the test to differentiate infectious from non-infectious causes of systemic inflammation are higher than those of other markers of inflammation and infection, such as C-reactive protein and cytokines such as IL-6. Furthermore, procalcitonin is not strongly increased in viral infections without bacterial superinfections. Elevated procalcitonin levels appear to be correlated with increasing bacterial load, and low procalcitonin levels tend to be associated with a low likelihood of a positive blood culture. Although it has limitations, a significant advantage of procalcitonin as a marker of bacterial sepsis is its early response to increased infection and to resolution of infection. It is therefore a useful aid, with clinical judgement and recognition that a number of non-infectious causes increase procalcitonin, in deciding when to start and when to discontinue antibiotic treatment.
Evidence for economic impact and/or cost–effectiveness
Balk et al. (5) concluded from a study on the effect of procalcitonin testing on health care use and costs in the USA that testing on admission to an intensive care unit significantly decreased the length of stay in hospital and in intensive care and the total cost of care. Steuten & Mantjes (6) concluded from a study by Assink-de Jong et al. (7) that hundreds of euros per patient were saved by use of procalcitonin testing and also reduced mortality, suggested in some countries to have a monetary value of US$ 50 000–150 000 per life-year saved.
Ethical issues, equity and human rights issues
Consent is required to obtain a serum or plasma sample. If the test becomes available at a low price on modern point-of-care testing platforms, it should reduce inequity, especially in resource-limited settings, where inappropriate use of antibiotics is often more common than in high-income countries, by providing antibiotics in a timely manner to those who need them and to prevent their misuse.
1. Goldberg B. Clinical considerations for procalcitonin-guided evaluation and management of lower respiratory tract infections and sepsis. Silver Spring (MD): Food and Drug Administration; 2017 (https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/UCM529262. pdf). 2. Introduction to the HCUP national inpatient sample. Rockville (MD): Healthcare Cost and Utilization Project (HCUP) and the Agency for Healthcare Research and Quality; 2014 (https:// www.hcup-us.ahrq.gov/db/nation/nis/NISIntroduction2014.pdf, accessed April 2019). 3. Improving the prevention, diagnosis and clinical management of sepsis (A70/13). Geneva: World Health Organization; 2017 (https://www.who.int/servicedeliverysafety/areas/sepsis/en/, accessed April 2019). 4. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801–10. 5. Balk RA, Kadri SS, Cao Z, Robinson SB, Lipkin C, Bozzette SA. Effect of procalcitonin testing on health-care utilization and costs in critically ill patients in the United States. Chest. 2017;151(1):23–33. 6. Steuten L, Mantjes G. Economic value of procalcitonin guidance. Lancet Infect Dis. 2016;16(9):1000. 7. Assink-de Jong E, de Lange DW, van Oers JA, Nijsten MW, Twisk JW, Beishuizen A. Stop Antibiotics on guidance of Procalcitonin Study (SAPS): a randomised prospective multicenter investigator- initiated trial to analyse whether daily measurements of procalcitonin versus a standard-of-care approach can safely shorten antibiotic duration in intensive care unit patients – calculated sample size: 1816 patients. BMC Infect Dis. 2013;13:178–84. 8. Schuetz P, Wirz Y, Sager R, Christ‐Crain M, Stolz D, Tamm M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;(10):CD007498. 9. Andriolo BNG, Andriolo RB, Salomão R, Atallah ÁN. Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syste Rev. 2017;(1): CD010959.