Procalcitonin testing for diagnosing and monitoring sepsis (ADVIA Centaur BRAHMS PCT assay, BRAHMS PCT Sensitive Kryptor assay, Elecsys BRAHMS PCT assay, LIAISON BRAHMS PCT assay and VIDAS BRAHMS PCT assay)

There were 8 randomised controlled trials that provided data on the effectiveness of using procalcitonin testing with standard clinical practice to guide antibiotic therapy in intensive care unit settings. All studies were done in adult populations. No studies done in paediatric intensive care unit settings met the inclusion criteria for the review.

There were 4 studies done in adults with confirmed or highly suspected sepsis, in whom antibiotic therapy was indicated. One study included adults being treated in an intensive care unit for suspected bacterial infection, or who developed sepsis during their stay. Two studies included adults being treated in intensive care unit settings who were considered to be at increased risk of developing sepsis (1 study in adults with acute pancreatitis and 1 study in adults with ventilator‑associated pneumonia). The final study included adults who were being treated for suspected bacterial infections in intensive care unit settings.

There was 1 study that assessed the effectiveness of using procalcitonin testing with standard clinical practice to guide the start of antibiotic treatment. All other studies assessed the effectiveness of using procalcitonin testing with standard clinical practice to decide when to stop antibiotic treatment.

There were 4 studies that reported data to allow the calculation of mean difference in the duration of antibiotic therapy between study arms. Two of these studies were done in patients with suspected or confirmed sepsis, 1 was done in patients with acute pancreatitis and 1 was done in patients with suspected bacterial infection and those who developed sepsis while in the intensive care unit. Three of these studies found that the addition of procalcitonin testing to standard clinical practice resulted in a statistically significant reduction in the mean duration of antibiotic therapy (Bouadma et al. 2010; Liu et al. 2013; Qu et al. 2012). The fourth study found that the addition of procalcitonin testing to standard clinical practice was associated with a trend towards reduction in the duration of antibiotic therapy, which was not statistically significant (Nobre et al. 2008). The summary effect estimate showed that the use of procalcitonin testing in addition to standard clinical practice was associated with a statistically significant reduction in the duration of antibiotic therapy (weighted mean difference –3.19 days; 95% confidence interval [CI] −5.44 to −0.95). However, between‑study heterogeneity was high.

When the meta‑analysis was restricted to the 2 studies done in populations with suspected or confirmed sepsis (Liu et al. 2013; Nobre et al. 2008), the summary effect estimate still showed that the addition of procalcitonin testing to standard clinical practice was associated with a statistically significant reduction in the duration of antibiotic therapy (weighted mean difference −1.20 days; 95% CI −1.33 to −1.07).

There were 3 further studies that reported median duration of antibiotic therapy. Two of these studies were done in people with suspected or confirmed sepsis, and found that the addition of procalcitonin testing to standard clinical practice had no statistically significant effect on the duration of antibiotic treatment (Annane et al. 2013; Deliberato et al. 2013). The third study was done in adults with ventilator‑associated pneumonia and found that the addition of procalcitonin testing to standard clinical practice was associated with a statistically significant reduction in the median duration of antibiotic therapy from 15 days to 10 days (Stolz et al. 2009).

There were 7 studies that reported lengths of hospital stay ranging from 11 to 27 days in the intervention groups (procalcitonin testing plus standard clinical practice) and from 11 to 33 days in the control groups (standard clinical practice alone). Four of these studies reported data to allow the calculation of mean difference in the duration of hospital stay between study arms. Two of these studies found that the addition of procalcitonin testing to standard clinical practice resulted in a statistically significant reduction in the mean duration of hospital stay (Liu et al. 2013; Qu et al. 2012). One study found that the addition of procalcitonin testing to standard clinical practice was associated with a trend towards reduction in the duration of hospital stay, which was not statistically significant (Nobre et al. 2008). The fourth study found that the addition of procalcitonin testing to standard clinical practice did not reduce the duration of hospital stay (Bouadma et al. 2010). The summary effect estimate showed that the use of procalcitonin testing with standard clinical practice was associated with a statistically significant reduction in the duration of hospital stay (weighted mean difference −3.85 days; 95% CI −6.78 to −0.92). However, between‑study heterogeneity was high.

Only 2 of the 4 studies were done in populations with suspected or confirmed sepsis (Liu et al. 2013; Nobre et al. 2008). When the meta‑analysis was restricted to the 2 studies, the summary effect estimate showed that the addition of procalcitonin testing to standard clinical practice was associated with a greater reduction in duration of hospital stay (weighted mean difference –4.32 days; 95% CI –6.50 to –2.14).

There were 3 further studies that reported median duration of hospital stay. Of these, 2 were done in people with suspected or confirmed sepsis and 1 was done in people with ventilator‑associated pneumonia. All found that the addition of a procalcitonin algorithm had no statistically significant effect on the duration of hospital stay (Annane et al. 2013; Deliberato et al. 2013; Stolz et al. 2009).

There were 6 studies that reported lengths of intensive care unit stay ranging from 3.5 to 22 days in the intervention groups (procalcitonin testing plus standard clinical practice) and from 3 to 23 days in the control groups (standard clinical practice alone). Four of these studies reported data to allow the calculation of mean difference in the duration of intensive care unit stay between study arms. Two of these studies found that the addition of procalcitonin testing to standard clinical practice resulted in a statistically significant reduction in the mean duration of intensive care unit stay (Liu et al. 2013; Qu et al. 2012). One study found that the addition of procalcitonin testing to standard clinical practice was associated with a trend towards reduction in the duration of intensive care unit stay, which was not statistically significant (Nobre et al. 2008). The fourth study found that the addition of procalcitonin testing to standard clinical practice did not reduce the duration of intensive care unit stay (Bouadma et al. 2010). The summary effect estimate showed that the addition of procalcitonin testing to standard clinical practice was associated with a trend towards decreased duration of intensive care unit stay, which did not reach statistical significance (weighted mean difference –2.03 days; 95% CI –4.19 to 0.13). However, between‑study heterogeneity was high.

As with previous outcomes, only 2 of the 4 studies were done in populations with suspected or confirmed sepsis (Liu et al. 2013; Nobre et al. 2008). When the meta‑analysis was restricted to the 2 studies, the summary effect estimate showed that the addition of procalcitonin testing to standard clinical practice was associated with a statistically significant reduction in the duration of intensive care unit stay (weighted mean difference –2.31 days; 95% CI –3.97 to –0.65).

There were 2 further studies that reported median duration of intensive care unit stay. Both of these studies were done in people with suspected or confirmed sepsis and both found that the addition of procalcitonin testing to standard clinical practice had no statistically significant effect on the duration of intensive care unit stay (Annane et al. 2013; Deliberato et al. 2013).

There were 5 studies that reported 28‑day all‑cause mortality (Bouadma et al. 2010; Liu et al. 2013; Nobre et al. 2008; Qu et al. 2012; Stolz et al. 2009). All found no statistically significant difference in mortality rates between patients in the intervention group (procalcitonin testing plus standard clinical practice) and those in the control group (standard clinical practice alone). The summary relative risk was 0.98 (95% CI 0.76 to 1.27). This finding was consistent when the meta‑analysis was restricted to studies done in people with suspected or confirmed sepsis (relative risk 1.07; 95% CI 0.54 to 2.12).

There was 1 study that reported mortality at 60 days and found no statistically significant difference between the intervention and control groups (relative risk 1.15; 95% CI 0.89 to 1.48; Bouadma et al. 2010). One further study reported mortality at 5 days and found no statistically significant difference between the intervention and control groups (relative risk 1.0; 95% CI 0.25 to 4.04; Annane et al. 2013).

There were 3 studies that reported intensive care unit mortality. All found no statistically significant difference in the intensive care unit mortality rate between the intervention and control groups (Annane et al. 2013; Deliberato et al. 2013; Layios et al. 2012). The summary relative risk was 0.87 (95% CI 0.55 to 1.37). This finding was consistent when the meta‑analysis was restricted to studies done in people with suspected or confirmed sepsis (relative risk 0.59; 95% CI 0.27 to 1.28).

There were 4 studies that reported rates of infection relapse or recurrence. All found no statistically significant difference in the infection relapse or recurrence rate between the intervention and control groups (Bouadma et al. 2010; Deliberato et al. 2013; Liu et al. 2013; Nobre et al. 2008). The summary relative risk was 1.37 (95% CI 0.77 to 2.44). This finding was consistent when the meta‑analysis was restricted to the 3 studies done in people with suspected or confirmed sepsis (relative risk 1.89; 95% CI 0.47 to 7.59).

A variety of other general and disease‑specific adverse clinical outcomes were reported by 1 or more studies. These included multi‑drug‑resistant infection, sepsis‑related mortality, multiple organ dysfunction syndrome, ventilator‑associated pneumonia‑related clinical deterioration, duration of mechanical ventilation, and Sequential Organ Failure Assessment score at various time points. No study reported a statistically significant difference between the intervention and control groups for any adverse clinical outcome assessed. None of the studies reported antibiotic‑related adverse events.

There were 10 randomised controlled trials that provided data on the effectiveness of using procalcitonin testing with standard clinical practice to guide antibiotic therapy in emergency department settings. Two studies were done in children and the rest in adults. Most studies were done in people with respiratory presentations.

Of the adult studies, 2 were done in people with lower respiratory tract infection, 3 were done in people with community‑acquired pneumonia, 1 included people with chronic obstructive pulmonary disease exacerbations, 1 included people with suspected asthma exacerbations, and 1 was done in people with urinary tract infection. Of studies done in children, 1 included children with lower respiratory tract infection and 1 included children with community‑acquired pneumonia.

There were 7 studies, done in adults, which assessed the effectiveness of using procalcitonin testing with standard clinical practice to guide the start of antibiotic treatment. All of these studies found that the addition of procalcitonin testing to standard clinical practice was associated with a reduction in antibiotic use (relative risk 0.77; 95% CI 0.68 to 0.87; Christ‑Crain et al. 2004; Christ‑Crain et al. 2006; Roh et al. 2010; Roh et al. 2013; Schuetz et al. 2009; Stolz et al. 2007; Tang et al. 2013).

There were 2 studies done in children that reported contradictory results for the proportion of patients in the intervention and control groups who had antibiotic treatment. The study done in children with community‑acquired pneumonia found that the addition of procalcitonin testing to standard clinical practice to decide whether to start antibiotic treatment was associated with a statistically significant reduction in antibiotic use (relative risk 0.85; 95% CI 0.79 to 0.91; Esposito et al. 2011). Subgroup analyses showed that procalcitonin testing was associated with a greater reduction in antibiotic use for children with mild community‑acquired pneumonia (relative risk 0.69; 95% CI 0.59 to 0.80) than for children with severe community‑acquired pneumonia (relative risk 0.96; 95% CI 0.92 to 1.01).

The study done in children with lower respiratory tract infection (including community‑acquired pneumonia and non‑community‑acquired pneumonia) reported a trend towards increased antibiotic use when procalcitonin test results were added to standard clinical practice (relative risk 1.12; 95% CI 0.94 to 1.35; Baer et al. 2013). Subgroup analyses showed that for children presenting with non‑community‑acquired pneumonia, the addition of procalcitonin testing to standard clinical practice was associated with a statistically significant increase in antibiotic use (relative risk 2.71; 95% CI 1.46 to 5.01). But for children presenting with community‑acquired pneumonia the addition of procalcitonin testing was associated with a trend towards reduction in antibiotic use (relative risk 0.92; 95% CI 0.79 to 1.08). When data from the 2 studies on children presenting with community‑acquired pneumonia were combined the summary relative risk was 0.86 (95% CI 0.80 to 0.93).

There were 2 studies done in adults that reported data to allow the calculation of mean difference in the duration of antibiotic therapy between study arms. Both of these studies found that the addition of procalcitonin testing to standard clinical practice resulted in a statistically significant reduction in the mean duration of antibiotic therapy (Christ‑Crain et al. 2004; Christ‑Crain et al. 2006). The summary effect estimate showed that the addition of procalcitonin testing to standard clinical practice was associated with reduction in the duration of antibiotic therapy, which did not reach statistical significance (weighted mean difference –4.49 days; 95% CI –9.59 to 0.61). However, these studies included patients who did not have antibiotics in their estimates of mean duration. Therefore an additional meta‑analysis was done, excluding patients who did not have antibiotic treatment. The summary effect estimate for patients who had antibiotic treatment (that is, weighted mean difference conditional on having antibiotics) was 1.48 days (95% CI –13.64 to 16.59).

There were 4 studies, done in adults, which reported median duration of antibiotic therapy, or mean with no estimate of variance. The results of these studies were consistent with the 2 studies included in the meta‑analysis, showing that the addition of procalcitonin testing to standard clinical practice was associated with a reduction in the duration of antibiotic therapy (Drozdov et al. 2014; Roh et al. 2010; Roh et al. 2013; Schuetz et al. 2009).

There was 1 study, done in children, which reported data on the duration of antibiotic therapy. This study found the addition of procalcitonin testing to standard clinical practice was associated with a statistically significant reduction in the duration of antibiotic therapy (mean difference –1.8 days; 95% CI –3.1 to –0.5; Baer et al. 2013).

There were 6 included studies in adults that reported duration of hospital stay ranging from 8 to 12 days in the intervention groups (procalcitonin testing plus standard clinical practice) and from 8 to 16 days in the control groups (standard clinical practice alone). Two of these studies reported data to allow the calculation of mean difference in the duration of hospital stay between study arms. Neither study found a statistically significant difference between groups (Christ‑Crain et al. 2004; Christ‑Crain et al. 2006). The summary effect estimate showed that addition of procalcitonin testing to standard clinical practice was associated with a non‑significant trend towards reduction in the duration of hospital stay (weighted mean difference –0.80 days; 95% CI –2.37 to 0.78).

There were 4 studies done in adults that reported median duration of hospital stay, or mean with no estimate of variance. Two of these studies, both done in people with community‑acquired pneumonia, reported results showing that addition of procalcitonin testing to standard clinical practice was associated with a reduction in the duration of hospital stay (mean duration 9.2 days and 14.6 days [Roh et al. 2010]; mean duration 14.6 days and 16.0 days [Roh et al. 2013]). The remaining 2 studies, (1 done in people with lower respiratory tract infection and 1 done in people with chronic obstructive pulmonary disease exacerbations) found that use of a procalcitonin algorithm did not affect the median duration of hospital stay (Schuetz et al. 2009; Stolz et al. 2007).

Both studies done in children reported data to allow the calculation of mean difference in the duration of hospital stay between study arms. These studies reported lengths of hospital stay ranging from 2.5 to 5.0 days in the intervention groups (procalcitonin testing plus standard clinical practice) and from 2.3 to 5.9 days in the control groups (standard clinical practice alone). When data on children presenting with community‑acquired pneumonia were combined, the summary effect estimate showed that the addition of procalcitonin testing to standard clinical practice was associated with a small reduction in the duration of hospital stay (weighted mean difference –0.74 days; 95% CI –1.17 to –0.31; Baer et al. 2013; Esposito et al. 2011).

One study reported data on duration of intensive care unit stay. This study was done in adults with chronic obstructive pulmonary disease exacerbations. It reported no statistically significant difference in the mean duration of intensive care unit stay between the study groups (mean difference –0.40; 95% CI –1.06 to 0.26; Stolz et al. 2007).

There were 2 studies in adults that reported hospital re‑admission rates. One study was in people with acute asthma exacerbations and the other was in people with urinary tract infection. Both studies found no statistically significant difference in re‑admission rates between patients in the intervention group (decision to stop antibiotics based on procalcitonin test result plus clinical judgement) and those in the control group (decision to stop antibiotics based on clinical judgement alone; Drozdov et al. 2014; Tang et al. 2013).

There were 2 studies (1 in adults with acute asthma exacerbations and 1 in adults with chronic obstructive pulmonary disease exacerbations) that reported the rate of second emergency department visits. Both found no statistically significant difference between the intervention and control groups (Stolz et al. 2007; Tang et al. 2013).

There were 6 studies done in adults that reported all‑cause mortality at various time points, ranging from 14 days to 6 months (Christ‑Crain et al. 2004; Christ‑Crain et al. 2006; Drozdov et al. 2014; Roh et al. 2010; Roh et al. 2013; Schuetz et al. 2009; Stolz et al. 2007; Tang et al. 2013). All studies reported no statistically significant difference in mortality rates between the intervention and control groups. The summary relative risk was 0.95 (95% CI 0.71 to 1.27). This finding was consistent when the meta‑analysis was restricted to the 2 studies reporting mortality at 6 months (relative risk 0.85; 95% CI 0.46 to 1.59). Neither of the 2 studies done in children reported mortality data.

There were 4 studies done in adults that reported data on rates of admission to the intensive care unit. All studies found no statistically significant difference in intensive care unit admissions between the intervention and control groups (summary relative risk 0.79; 95% CI 0.59 to 1.05; Stolz et al. 2007; Christ‑Crain et al. 2004; Christ‑Crain et al. 2006; Schuetz et al. 2009). Neither of the 2 studies done in children reported any information on intensive care unit admissions.

There were 2 studies, done in adults, which reported inconsistent results for rates of infection relapse or recurrence. One study, in adults with urinary tract infection, found no statistically significant difference in relapse or recurrence rates between the intervention and control groups (Drozdov et al. 2014). The second study, in adults with lower respiratory tract infection, found that the addition of procalcitonin testing to standard clinical practice was associated with a statistically significant reduction in infection relapse or recurrence rates (relative risk 0.57; 95% CI 0.36 to 0.92; Schuetz et al. 2009). One study, done in children with community‑acquired pneumonia, reported very low rates of infection relapse or recurrence and a non‑significant trend towards lower rates in the intervention group (relative risk 0.23; 95% CI 0.04 to 1.34; Esposito et al. 2011).

There was 1 study, done in adults with lower respiratory tract infection, which reported numbers of patients having antibiotic‑related adverse events. This study found that the addition of procalcitonin testing to standard clinical practice was associated with a reduction in antibiotic‑related adverse events (relative risk 0.71; 95% CI 0.58 to 0.86).

Both studies, done in children, reported the numbers having antibiotic‑related adverse events (Baer et al. 2013; Esposito et al. 2011). When data on children with community‑acquired pneumonia were combined, results showed that the addition of procalcitonin testing to standard clinical practice was associated with a non‑significant reduction in antibiotic‑related adverse events (relative risk 0.37; 95% CI 0.04 to 3.49). This finding was consistent when data for all children in both studies were included in the meta‑analysis (summary relative risk 0.40; 95% CI 0.06 to 2.78).

A variety of other general and disease‑specific adverse clinical outcomes were reported by 1 or more studies. These included composite adverse outcome measures, need for steroids, need for mechanical ventilation and complications from pneumonia. No study reported a statistically significant difference between the intervention and control groups for any adverse clinical outcome.

The External Assessment Group did a search to identify existing economic evaluations of people with sepsis or bacterial infection having care in emergency departments or intensive care units. Two studies were considered eligible for inclusion in the systematic review.

There was 1 study (Michaelidis et al. 2013) that considered procalcitonin testing in 2 scenarios. The first analysis was based on adults with an acute respiratory tract infection presenting to an outpatient clinic and judged by their physicians to need an antibiotic prescription. The second analysis was based on adults with an acute respiratory tract infection presenting to an outpatient clinic before any decision to start antibiotic therapy. Procalcitonin‑guided antibiotic therapy was both more costly and more effective than standard care alone. The incremental cost‑effectiveness ratios (ICERs) were $118,828 and $575,249 per quality‑adjusted life year (QALY) gained for the first and second analyses respectively.

The second study (Smith et al. 2013) considered the cost effectiveness of procalcitonin‑guided antibiotic therapy in adults with community‑acquired pneumonia in a hospital setting. Procalcitonin‑guided antibiotic therapy was both more costly and more effective compared with standard care alone. For patients with low‑risk community‑acquired pneumonia, procalcitonin‑guided antibiotic initiation is likely to be cost effective if the maximum acceptable ICER was $90,000 per QALY gained. For the same patients, procalcitonin‑guided antibiotic initiation and monitoring is likely to be cost effective if the maximum acceptable ICER was $40,000 per QALY gained. For patients with high‑risk community‑acquired pneumonia, procalcitonin‑guided antibiotic initiation and monitoring is likely to be cost effective if the maximum acceptable ICER was $170,000 per QALY gained.

The External Assessment Group developed a de novo economic model designed to assess the cost effectiveness of the addition of procalcitonin testing to standard clinical practice compared with standard clinical practice alone for:

• adults with confirmed or highly‑suspected sepsis in an intensive care unit setting

• adults with suspected bacterial infection presenting to the emergency department

• children with suspected bacterial infection presenting to the emergency department.

Children with confirmed or highly‑suspected sepsis in an intensive care unit setting were not considered because there was insufficient clinical evidence.