The objectives of this randomized controlled, open intervention trial are to evaluate whether a PCT guided diagnostic and therapeutic strategy in patients with LRTI lead to similar patient relevant outcomes, reduced total antibiotic use as well as length of hospitalization as compared to a management without PCT testing but based on the enforced implementation of current guidelines. The primary study hypothesis is that a PCT guided LRTI management is non-inferior to standard care based on implemented guidelines. The primary endpoint is disease specific failure within 30 days following index hospital admission and we assume non-inferiority if the combined disease specific failure rate is less than 7.5%.
Patients from six hospitals in Switzerland are being included. Full ethical approval for this trial which is in compliance with the Helsinki Declaration has been obtained from all local ethical committees. All responsible heads of the medical departments of the participating study hospitals have approved and signed the study protocol and all participating patients must give written informed consent.
This trial is supervised by an independent safety monitoring board which is not involved in the design and the conduct of the trial. The board consists of a pneumologist, an infectious disease specialist and an intensive care specialist.
We recruit the patients in six secondary and tertiary care clinics in northern and central Switzerland. The characterisation of the study clinics is presented in table . The 6 public hospitals are variable in size, patient care capacity and employment of medical and nursing staff, but have a comparable length of hospital stay per patient (mean hospital stay 8.3 +/- 0.57 days)[15
Baseline characteristics of the six participating study hospitals in the northern and central part of Switzerland .
Local investigators and their staff received a structured seminar to become familiar with the details of the protocol, the rationale and the design of the trial, the study website for patients inclusion and randomisation and all study forms.
In December 2006, all participating hospitals started to consecutively screen all adult patients admitted to the emergency department with suspected LRTI.
Inclusion criteria for patients are written informed consent, age ≥ 18 years and admittance from the community or a nursing home with the main diagnosis of acute LRTI (i.e., less than 28 days). LRTI is defined by at least one respiratory symptom (cough, sputum production, dyspnea, tachypnea pleuritic pain) plus one auscultatory finding or sign of infection (core body temperature >38.0°C, shivers, leucocyte count >10 G/L or <4 G/L cells) independent of antibiotic pre-treatment. The LRTI conditions are defined as follows: CAP is defined as a new or increased infiltrate on chest radiograph [16
]. COPD is defined by post-bronchodilator spirometric criteria according to the GOLD-guidelines as a FEV1/FVC ratio below 70% and the severity categorized according to GOLD criteria [18
]. Acute bronchitis is defined as LRTI in the absence of an underlying lung disease or focal chest signs or infiltrates on chest X-ray, respectively [20
]. Exclusion criteria are the inability to give written informed consent, insufficient German language skills, active intravenous drug users, severe immunosuppression, accompanying chronic infection or endocarditis or very severe medical co-morbidity where death is imminent.
Clinicians in the emergency departments of participating clinics are advised to access a web based study algorithm and enter baseline data of all eligible patients with LRTI on admission and to check all inclusion and exclusion criteria prior to randomisation (figure ). Randomization of patients to PCT guidance or guideline enforced antibiotic therapy is based on a pre-specified computer generated randomization list and concealed by using a centralized password-secured website [21
]. This website provides all study-related information including guidelines and patient flow. The randomization is stratified by the participating clinic and the type of LRTI (acute bronchitis, AECOPD, CAP).
Figure 1 All consecutive patients with lower respiratory tract infection are potentially eligible for this trial. If all inclusion criteria are fulfilled and no exclusion criteria are present, the physician has to explain to the patient the trial, ask for participation (more ...)
We summarized guidelines on the management of CAP, acute bronchitis and AECOPD based on the most recent guidelines by the European Respiratory Society (ERS) and the American Thoracic Society (ATS) supplemented by evidence from recent guidelines and published current concepts [16
]. These guidelines have been adapted by a panel of local internists, emergency physicians, pneumologists, infectious disease experts and clinical epidemiologists and have been successfully used in the clinical setting. To optimize the implementation of these guidelines for all patients the treating physician is enforced to follow web-based guideline algorithms, controlled by email alerts released for every patient screened and recruited, respectively. If the algorithm for PCT guidance or the guidelines for antibiotic therapy are overruled, the study centre has to be informed as soon as possible.
PCT is measured using a rapid sensitive immunoassay with a functional assay sensitivity of 0.06 ug/L (Kryptor PCT, Brahms, Hennigsdorf, Germany). The coefficient of variation of the assay at 0.1 ug/L, 0.25 ug/L, 0.5 ug/L and 10 ug/L were 16%, 7%, 5% and 3%, respectively. The test is performed at the central lab of each participating hospital. The assay time for PCT measurements require less than 20 minutes and PCT results are routinely available within one hour upon ordering.
PCT levels are communicated by the password secured website to the treating physician together with a treatment recommendation for antibiotics based on the PCT algorithm exclusively for patients randomized to the PCT intervention arm. Similarly, for the patients in the guideline-enforced group treatment recommendation based on guidelines are displayed. All participating physicians received detailed information about the use of PCT cut off ranges and the algorithm as presented in figure is published in the investigators brochure and on the internet platform.
Figure 2 Antibiotic stewardship based on procalcitonin (PCT) cut-off ranges. Re-evaluation of the clinical status and measurement of serum PCT levels is mandatory after 6–24 h in all persistently sick and hospitalized patients in who antibiotic are withheld. (more ...)
In both groups, hospitalized patients are clinically reassessed and blood is sampled on days 3, 5, 7, and on the day of discharge to assess the resolution of the presumed infection. In both groups, a switch of antibiotics from intravenous to oral is advised if patients show stable or improving vital signs, resolution of the predominant clinical sign or if oral intake is possible (adequate consciousness and reflexes to swallow fluids and tablets, no malabsorption) [16
]. In hospitalized patients with an acute bronchitis, a chest X-ray after 3–5 days is routinely performed to confirm the diagnosis and exclude pneumonia.
In all hospitalized patients hospital discharge should be considered if oral intake is feasible, vital signs are stable > 24 h (as defined above), and no evidence of acute serious co-morbidity that necessitates hospitalization is present and, if the patient has achieved pre-admission mobility state [16
]. At the day of discharge, all patients receive 2 leaflets providing general information for the patient and the general physician (GP) regarding this trial.
Outcomes and adverse events
The primary endpoint of this trial is the combined disease-specific failure rate within 30 days. The following events are considered as failures: (a) radiologically, microbiologically or clinically confirmed recurrence of infection in need of antibiotics, (b) local or systemic complications from LRTI including persistence or development of pneumonia (including nosocomial), parapneumonic effusions, lung abscess, empyema, any abscess (pharyngeal, parapharyngeal, sinusitis requiring sinus drainage, any remote abscess), acute respiratory distress syndrome (ARDS), (c) admission to the intensive care unit (ICU), (d) disease related hospital readmission and (e) death from any cause.
The secondary endpoints of this trial are (a
) antibiotic exposure for LRTIs (antibiotic prescription times duration of antibiotic therapy), (b
) side-effects from antibiotic treatment, (c
) time to clinical stability, (d
) length of hospital stay and (e
) quality of life according to EuroQol and LRTI-specific disease activity score[22
]. Five projects performed alongside to this trial (cost-effectiveness of PCT guided antibiotic therapy, impact of nursing and social factors for rate and duration of hospitalization, other biomarkers as diagnostic and prognostic tools in LRTI, free cortisol and copeptin levels to assess disease-related stress, microcalorimetry as a novel method for rapid diagnosis of bloodstream infections) synergize scientific efforts.
Outcomes are assessed during hospital stay at days 3, 5 and 7, and at hospital discharge and by structured phone interviews at days 30 and 180 (figure ) by medical students blinded to the treatment allocation of the patients. In case the patient is indicating the prescription of any new antibiotic or any unnamed drug following hospital discharge or is unable to give adequate information, or has been rehospitalised, the interviewer is obliged to contact the treating GP or the hospital and to receive notification of the prescription or a copy of the hospital transferral or demission letter.
Endpoints are reassessed by an independent endpoint committee of at least 2 clinicians blinded to patient allocation. Endpoint judgment is based on the case report form and, if necessary, on hard copies of the hospital chart that are made anonymous and blinded in regard to any information on PCT. In order to truly blind endpoint assessors all information on PCT will be discarded on relevant documents.
An adverse event in a subject is defined as any occurrence of unfavourable and unintended clinically relevant medical sign, symptom, or disease temporally associated with the study which does not necessarily have a causal relationship with the study procedure. If an adverse event occurs, the responsible clinician involved in the case is contacted by an unblinded member of the study team to verify all information and to complete a serious adverse event form. All adverse events within 180 days after study inclusion are monitored and continuously evaluated by the data safety and monitoring board. All adverse events must be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or the subject is lost to follow-up or has died.
Sample size and statistical considerations
The goal of this ongoing trial is to show non-inferiority of the PCT guided antibiotic management approach in comparison to enforced guidelines for the primary endpoint (i.e. the disease-specific failure rate within 30 days). To estimate the frequency of the primary endpoint, we used the data from our previous intervention trials [11
]. Based on these data, the risk of disease-specific failure in evaluable patients is assumed to be around 15% and, if losses to follow-up are treated as failures, the failure rate of all patients may increase to 20%. We assume non-inferiority if the disease specific failure for patients on procalcitonin-guided antibiotic therapy is less than 7.5% higher compared to those on guidelines-enforced management. Based on these estimates and assumptions, a minimal number of 1002 patients (501 patients per arm) are required. Table displays the power calculations for different assumed failure differences and non-inferiority boundaries with a one-sided type I error of 5% and a power of 80% to 90%. With 1002 patients, we have 80% power to exclude differences in failure rates of more than 9–12% in the respective LRTI subgroups and of ≥6% in death rates. In practice, a fixed recruitment period of 18 months is considered and all patients recruited in that period be randomized unless sample size after 18 months is below 1002 patients, which would lead to an extension of the recruitment period. The target size at each centre is 250 patients completed per protocol.
The primary analysis population is the full analysis set which includes all randomized patients following an intention-to-treat principle. For the primary analysis, losses to follow-up (on both arms) are regarded as treatment failures. A (two-sided) 90% confidence interval for the difference of the disease-specific failure rates will be calculated based on Cochran's test stratified by type of LRTI. If the confidence interval for the difference excludes 7.5% or more, the primary objective will be met. As a sensitivity analysis, the primary analysis will be repeated on the subset of patients with evaluable outcome only, i.e. drop-outs are excluded from this additional analysis, as well as the per-protocol population which excludes non-evaluable cases and major protocol violators.
In a second step, the primary endpoint will be explored for association with potential prognostic factors in a logistic regression. The factors that will be considered are: age, sex, LRTI subgroup, PSI and CURB65 score in CAP patients and GOLD criteria and Anthonisen type of exacerbation in COPD patients [18
]. Potential centre effects will be tested by including centre and physician as a random effect.
The trial data and sample base will be used for several pre-specified additional analyses. Theses projects include the development of clinical prediction rules for adverse medical outcomes in community-acquired LRTIs and to compare the diagnostic and prognostic accuracy of promising new biomarkers (e.g. proadrenomedullin (proADM), pro atrial natriuretic peptide (MR-proANP), copeptin, total and free cortisol) with traditional clinical signs and symptoms, the PSI and the CURB-65 score for patients with CAP and the Anthonisen criteria for patients with AECOPD [3