Upper respiratory tract infections (URTI) are predominantly of viral origin, sometimes of bacterial and only rarely of other aetiologies. Overall, URTI cause millions of medical consultations and are amongst the most common reason for antibiotic therapy in primary care. To date, there is no validated diagnostic test that allows identifying the viral and/or bacterial microorganism causing the infection with high sensitivity. The diagnostic work-up and treatment decisions are therefore mainly based on ambiguous clinical criteria. As a consequence, despite the mainly viral aetiology, in Europe and the United States (US) over 50% of URTI are treated with antibiotics , , , . While early initiation of antibiotic therapy is – without doubt – highly effective to reduce morbidity caused by bacterial infections , , overuse of antibiotics in outpatients with viral infections , typically URTI, increases antimicrobial resistance and is associated with enormous costs and adverse drug reactions , . A safe, rational and effective reduction of antibiotic overuse in the URTI outpatient population is therefore a public health priority.
In addition to repeated educational efforts, circulating markers of inflammation and infection have been found helpful in estimating the risk of bacterial infections and thus the need for antibiotic treatment. Particularly, the biomarker procalcitonin (PCT) – a precursor protein of calcitonin – has been proofed several times to be useful. PCT levels increase to much higher levels in severe bacterial infections, and remain relatively low in viral infections , . Furthermore, PCT reveals prognostic information in patients with respiratory infections , .
Recent randomised-controlled trials (RCTs) have demonstrated that PCT guided clinical decision making for the initiation and discontinuation of antibiotic therapy results in lower antibiotic exposure without negatively affecting outcome , , , , , , , , , , , , , . Indeed a favourable effect of PCT guided antibiotic therapy has been documented for community-acquired pneumonia  and sepsis . Although most trials focused on sepsis and patients with lower respiratory tract infections, two trials also included URTI in the primary care setting. Herein, we assessed safety and efficacy of using PCT guided antibiotic therapy within different URTI subpopulations in primary care by pooling data in an individual patient data meta-analysis.
Materials and methods
Data collection and patients
This analysis includes all patients with URTI from a previous individual patient data meta-analysis , where a comprehensive search of the literature was conducted using PubMed (MEDLINE) and Cochrane Library to identify relevant studies. We also performed a search update in September 2016, but no additional studies were retrieved. This report adheres to the PRISMA-IPD Statement  and the trial PRISMA flow diagram is presented in the appendix (see Supplemental Figure 1). We focused on two trials involving URTI patients. Both included studies were randomised, multicentre, non-inferiority trials approved by the Local Ethic Committees (University Hospital Basel, Switzerland; Hanover Medical School, Germany). (Trial Registration: isrctn.org, Identifier: ISRCTN73182671; and ClinicalTrials.gov [trial numbers NCT00827060 and NCT00688610]).
Inclusion criteria were age ≥18 years with symptoms of a respiratory tract infection based on a clinical judgement. URTI diagnoses included acute pharyngitis, acute tonsillitis, acute otitis media, acute laryngitis/tracheitis, acute sinusitis and the common cold (Table 1).
The initial meta-analysis was pre-specified in collaboration with the Cochrane database of systematic reviews . Briefly, the aim of the meta-analysis was to assess the safety and efficacy of a PCT algorithm to guide initiation and duration of antibiotic treatment in patients with acute respiratory tract infections (ARI) assigned to routine PCT measurement or standard of care without PCT measurement. This approach was performed over a large range of patients with varying severities in different clinical settings. Patients with a clinical diagnosis of either upper or lower ARI from 14 randomised or quasi-randomised trials were included. Trials focusing exclusively on paediatric patients or on another purpose than initiation and duration of antibiotic therapy were not eligible. Further details about identifying suitable trials were published previously . No ethical approval was needed for this meta-analysis. Written informed consent was obtained from all participants within the initial trials, including consent to participate in further analyses.
Aim and endpoints
The aim of the current analysis was to study the effect of PCT guidance on adverse clinical outcome (treatment failure, days with restricted activities) and antibiotic consumption. In line with the initial Cochrane meta-analysis protocol , the predefined primary combined endpoint was defined as treatment failure at 28 days and number of days with restricted activities within 14 days after randomization. Treatment failure was defined as occurrence of at least one of the following events: death, hospitalization, ARI-specific complications (e.g. empyema for lower ARI, meningitis for upper ARI), recurrent or worsening infection, and patients reporting any symptoms of an ongoing respiratory infection (e.g. fever, cough, dyspnoea) at 28-days follow-up. Restricted activities were defined as number of days within the first 14 days after admission with restricted work or recreation.
Secondary endpoints were initiation of antibiotic therapy, and total days of antibiotic exposure.
In both trials, PCT was measured using a rapid sensitive assay with a functional assay sensitivity of 0.06 μg/L (Kryptor PCT, Brahms, Hennigsdorf, Germany) and an assay time of less than 20 min. We used different a priori defined PCT cut-offs (0.1 μg/L, 0.25 μg/L), which corresponds to cut-offs used in previous antibiotic stewardship trials, and also in practice guidelines on the use of PCT.
We used descriptive statistics including median with interquartile range (IQR), mean with standard deviation, and frequencies to describe the study populations, as appropriate. Statistics based on an intention to treat analysis.
For the primary endpoints treatment failure at 28 days and restricted activities at day 14, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression , . Apart from the group variable indicating the use of a PCT algorithm we included important prognostic factors such as patient age as additional fixed effects; to account for within-and between-trial variability, we added trial to the model as a random effect. We fitted corresponding linear and logistic regression models for continuous and binary secondary endpoints, respectively.
If subgroups were too small, values were labelled as “not applicable”. Tests were carried out at 5% significance levels. Analyses were performed with STATA 12.1 (Stata Corp., College Station, TX, USA).
Of 1008 patients included in the initial two trials, 644 patients with a follow-up of 28 days had a final diagnosis of URTI and were thus included in this analysis (see Supplemental Figure 2). Both trials had a non-inferiority design and the outcome assessment was blinded. PCT algorithms were similar in concept and recommended initiation or initiation and continuation of antibiotic therapy based on PCT cut-off levels. However, there are some differences between the two trials: Burkhardt et al.  used only a single PCT measurement on admission to guide initiation of antibiotics, while Briel et al.  used repeated measurements for guiding initiation and duration of antibiotic treatment. Adherence to algorithms was 85% in the Briel study and 87% in Burkhardt’s study. Both trials had a near-complete follow-up for mortality (99%).
Of 644 patients 228 were included in Switzerland and 416 in Germany. Baseline characteristics were stratified by randomisation arm and trial (Table 1). While there were balanced groups in regard to the randomisation of patients, there were differences comparing between the two trials regarding distribution of URTI subpopulations (common cold, acute sinusitis, acute pharyngitis), PCT blood levels (median and mean) and antibiotic treatment.
Risk of PCT guidance and adverse outcome
For our safety analysis, we focused on days with restricted activities and treatment failure defined as symptoms of ongoing or relapsing infection at 28 days. Table 2 summarises the results in the two groups as well as the effects from logistic regression analysis. Overall, no difference in treatment failure defined as symptoms of ongoing or relapsing infection at 28 days was found between groups (33.1% vs. 34.0%, OR 1.0, 95% CI 0.7–1.4; p=0.896). These results were similar across the different types of URTI (see Supplemental Figure 3), although some subgroups were small with large confidence intervals. Similarly, days with restricted activities did not differ between groups (8 [IQR 5, 13] vs 8 [IQR 5, 14] days, regression coefficient 0.2 days (95% CI –0.4 to 0.9), p=0.465). Again, no difference was found in any of the subgroups (see Supplemental Figure 3).
Effect of PCT guidance on antibiotic exposure
In the overall URTI population, PCT guidance resulted in lower antibiotic prescription (17.8% vs. 51.0%, OR 0.2, 95% CI, 0.1–0.3; p<0.001) and in a 2.4 day (95% CI –2.9 to –1.9; p<0.001) shorter antibiotic exposure compared to control patients (Table 3). The effects were strong across all URTI diagnoses although not all subgroups showed significant results due to the small sample size. Figure 1 and Supplemental Figure 4 shows the antibiotic exposure in the overall URTI population and in different subgroups based on type of URTI. Again, results suggest a strong effect on antibiotic initiation across the spectrum of URTI.
Key findings of this individual patient data meta-analysis investigating the effects of PCT in URTI patients from two previous randomised trials in regard to antibiotic use and clinical outcomes are twofold: First, PCT guided antibiotic therapy strongly reduced the risk of initiation of antibiotic therapy from 51% to 18% in URTI resulting in a decrease of overall antibiotic exposure of 2.4 days. These effects were observed across the different URTI subgroups including patients with common cold, sinusitis, laryngitis/tracheitis, otitis, tonsillitis and pharyngitis. Second, we did not find any evidence that lower antibiotic exposure by use of PCT guidance would result in adverse clinical outcomes, namely in regard to number of days with restricted activity and treatment failure defined as reported symptoms of ongoing or relapsing infection at 28 days. This approach, thus, appeared to be safe. Again, results were similar in the overall population as well as in URTI subgroups including common cold, acute sinusitis, acute laryngitis/tracheitis, acute otitis media, acute tonsillitis and acute pharyngitis. Although we were able to pool patients from two rather large trials into this analysis, some of the subgroups have small number and future research is needed to study different URTI subpopulations in this regard.
These analyses expand results from previous trials looking at PCT guided antibiotic therapy in different types of infections including lower respiratory tract infections , , , sepsis , urinary tract infections , among others. Importantly, while PCT was mainly used to monitor patients and decide whether antibiotic treatment can be stopped in more severe infections, the main effect in this primary care patient population was on initial initiation of antibiotics . Reducing antibiotic treatment in primary care is of high relevance as antimicrobial resistance is one of the most urgent problems threatening healthcare systems, causing longer drug adverse events and costs . Therefore, judicious use of antibiotics – mainly in the primary care setting due to its enormous over-prescription – is highly important to preserve their effectiveness . Beside this, economic savings should be considered. A recent large US health system perspective estimated substantial savings associated with PCT protocols when used in patients with acute lower respiratory tract infections across common treatment settings mainly by reducing unnecessary antibiotic utilisation .
We recently found low PCT levels to be a strong predictor against treatment failure in patients with respiratory tract infections. This finding may help to “rule out” risk with a high negative predictive value and thus improve site-of-care decisions . The role of prognostication by validated risk scores is endorsed by respiratory infection guidelines mostly in the setting of pneumonia . Yet, these scores are validated only for lower respiratory tract infections but not URTI. Thus, there is a need for additional prognostic markers, which are objectively and rapidly available, as well as responsive to the clinical course. Based on this analysis, PCT is a promising candidate in this regard and helps to identify patients presenting with URTI with no need of antibiotic treatment.
Young et al. found in a meta-analysis of randomised trials that common clinical symptoms cannot reliably identify patients with rhino-sinusitis for whom antibacterial treatment is indicated. Based on the result of this meta-analysis, antibiotics were not justified even if patients report symptoms for longer than 7–10 days. The number needed to treat for antibiotics was high with 15 patients with rhinosinusitis-like complaints . This study shows the low diagnostic accuracy of clinical parameters thus the need for additional markers, such as PCT, to improve management in patients with URTI .
In addition to PCT, several studies have investigated the role of C-reactive protein (CRP) in patients with URTI , , . Similar to our study, CRP was helpful in reducing antibiotic treatment without negative effects in regard to patient outcomes. The study by Cals and colleagues found a combination of communication skills and CRP point-of-care testing to be most effectively because the interaction with the patient may be challenging if antibiotics have been used in this patient for many years to treat URTI . Also, in a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam, CRP point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients’ recovery. The advantages of CRP are the lower costs and the availability as a point of care device in primary care. Yet, studies found CRP to be less specific towards bacterial infection and have lower prognostic value compared to PCT , , . Thus, interventional research comparing these two markers in regard to their potential to direct antibiotic treatment are warranted , .
For some URTI subgroups, studies have compared PCT vs. CRP. One study compared CRP and PCT in a group A streptococcal acute tonsillitis population with the centor criteria defined as fever, tonsillar exudates, tender anterior cervical andenopathy and absence of cough plus rapid antigen detection test . Both markers, CRP and PCT, were inferior to these criteria when combined with rapid antigen detection testing in regard to both, sensitivity and specify. These results are in line with our findings where the effect of PCT in the group of patients with acute tonsillitis was weak. Importantly, we only had few patients in this subgroup making additional research necessary to understand the effects of PCT testing in tonsillitis patients.
The main strengths of our meta-analysis based on individual patient data are the large number of randomised primary care patients with URTI and the similarity of protocols making the pooling of data possible. Particularly, endpoints were similar in the two studies, as was recommendations regarding PCT use in the intervention group.
Nevertheless, we are aware of several limitations. First, we performed a post-hoc analysis of two pooled studies with some differences between populations. Second, the patient number of some URTIs subgroups, such as tonsillitis, laryngitis/tracheitis and otitis media was small. Herein, we only focussed on interventional trials as specified in the meta-analysis protocol and did not include any observational data which would potentially allow for larger sample sizes in the different subgroups and increase patients’ spectrum as in observational studies less rigorous exclusion criteria usually apply. Third, the numbers of adverse outcomes, especially severe complications, were low and thus we cannot make any conclusions regarding effects on mortality outcomes. Fourth, both studies, did not blind physician nor patients, which may bias the results.
PCT guided antibiotic therapy was strongly associated with reduced antibiotic exposure in URTI patients in the primary care setting without differences in outcomes. A broader use of PCT in the low acuity setting has the potential to lower antibiotic exposure and associated risk of multi-resistant bacteria.
We are grateful to the physicians, their staff and patients who participated in the data collection.
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The online version of this article (https://doi.org/10.1515/cclm-2017-0252) offers supplementary material, available to authorized users.
About the article
Published Online: 2017-06-29
Published in Print: 2017-11-27
Author contributions: Mr Odermatt, Ms Friedli, Mr Kutz and Mr. Schuetz had full access to all of the data in the study and take responsibility for the integrity of the data and performed the statistical work, and drafted the manuscript. All authors helped to interpret the findings, read and revised the manuscript critically for important intellectual content. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Availability of data and material: The datasets used and/or analysed during the current study is available from the corresponding author on reasonable request.
Research funding: This investigator-initiated PARTI trial was sponsored by a grant from the Swiss National Science Foundation (3300C0-107772) and by the Association for the Promotion of Science and Postgraduate Training of the University Hospital Basel. Brahms AG provided assay and kit material related to the study. Drs. Christ-Crain, Mueller, and Schuetz, received support from BRAHMS to attend meetings and fulfilled speaking engagements. Drs. Schuetz, Kutz, Christ-Crain and Mueller received support from bioMérieux to attend meetings and fulfilled speaking engagements. Heiner C. Bucher has received research support from BRAHMS. Dr. Schuetz and Dr. Christ-Crain were supported by funds of the Freiwillige Akademische Gesellschaft, the Department of Endocrinology, Diabetology and Clinical Nutrition, and the Department of Clinical Chemistry, all Basel, Switzerland.
Employment or leadership: Dr. Mueller has served as a consultant and received research support from BRAHMS and bioMérieux.
Honorarium: None declared.
Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.