Our findings indicate that guidance with the measurement of procalcitonin levels reduces the exposure of patients to antibiotics after presentation to the emergency department for exacerbations of COPD. This initial difference in antibiotic exposure is not followed by increased antimicrobial usage after hospitalization for up to 6 months. Thereby, the clinical outcome, including exacerbation rate and time to the next exacerbation, was not compromised.
The absolute risk reduction of 31.5% in antibiotic exposure implies that for one in every four patients who were admitted to the hospital due to an ECOPD, one course of antibiotic therapy can be prevented (number-needed-to-treat, 3.2; 95% CI, 2.3 to 5.3).
Given the prevalence of COPD and the duration of illness, a reduction in antibiotic prescriptions for the treatment of exacerbations could have a tremendous impact on the overall economic burden of the disease under current budget constraints. In addition, the controlled prescription of antibiotics decreases selective pressure for the emergence of bacterial resistance.
A metaanalysis of placebo-controlled trials concluded that there was a small but significant benefit from the treatment of exacerbations of COPD with antibiotics in terms of overall recovery. A more recent extensive review of the literature suggested that antibiotic therapy significantly decreased mortality and lack of response to treatment in patients experiencing exacerbations of COPD. Moreover, it has been proposed that antibiotic therapy may reduce further antibiotic prescriptions following the presenting exacerbation and may increase the time until the next exacerbation in a selected population of patients. Several characteristics have been suggested to identify patients who are at a greater risk for severe exacerbation, including the presence or severity of underlying obstructive disease, comor-bid conditions, frequency of exacerbation, and severity of symptoms at presentation. Most of these proposed criteria have been analyzed in different retrospective study designs. However, none has been validated by a prospective randomized trial.
Similarly, a wide variety of surrogate markers of the inflammatory process have been measured in patients in the stable state and during and ECOPD. Most of them provide laboratory confirmation supporting the diagnosis of exacerbation. Unfortunately, their role in patient management is far from certain, as prospective studies under longterm follow-up are not available.
In this prospective, interventional study, we randomized unselected, consecutive COPD patients to receive antibiotics based on serum procalcitonin levels at hospital admission. The vast majority of admitted patients took part in the study, assuring the applicability of the proposed approach under “real-life” conditions. The acquisition of data from family physicians provided unbiased long-term follow-up information.
From November 2003 to March 2005, 288 patients with suspected COPD exacerbations were admitted to the emergency department (Fig 1). Of the 226 randomly assigned patients, 18 were removed because they failed to meet spirometric criteria for the presence of COPD. No patient dropped out thereafter, and no patient was lost to follow-up.
Baseline characteristics of the patients in both groups were much the same (Table 1). Current use of antibiotic therapy for exacerbations of COPD was reported by 45 patients (22%), with equal distribution in both groups (p = 0.753).
Overall, cultures from sputum yielded pathogenic bacteria in 37 and 40 patients (36% and 38%, respectively; p = 0.886). Gram-negative bacteria accounted for 69% of all microorganisms recovered (53 organisms), and Gram-positive organisms accounted for 31% of all microorganisms recovered (24 organisms). The most frequently isolated organisms were Enterobacteriaceae spp (18 organisms) and Streptococcus pneumoniae (14 organisms).
The following medications were prescribed for the treatment of the exacerbation: enteral and/or parenteral steroids (88%; procalcitonin group, 89%; stan-dard-therapy group, 93%; p = 0.196); inhaled steroids (91%; procalcitonin group, 93%; standard-therapy group, 89%; p = 0.325); (32-agonist and/or anticholinergic agents (100%; procalcitonin group, 100%; standard-therapy group, 100%; p = 1); and theophylline (5%; procalcitonin group, 6%; standard-therapy group, 4%; p = 0.437).
On hospital admission, the median procalcitonin level was 0.096 ng/mL (interquartile range [IQR], 0.070 to 0.200). Figure 2 shows the procalcitonin values measured at admission to the emergency department. Procalcitonin values were 0.25 ng/mL in 41 patients (20%). Procalcitonin levels in patients pretreated with antibiotics were 0.097 ng/mL (IQR, 0.063 to 0.180) compared to 0.096 ng/mL (IQR, 0.070 to 0.21) in antibiotic-naive patients (p = 0.601).
At the index exacerbation, procalcitonin guidance significantly reduced antibiotic prescriptions (40% vs 72%, respectively; p < 0.0001) and antibiotic exposure (RR, 0.56; 95% CI, 0.43 to 0.73; p < 0.0001), compared to standard therapy (Fig 3). The reduction in RR of antibiotic exposure for patients in the procalcitonin group was 44% (95% Cl, 0.27 to 0.57; p < 0.0001), and the absolute risk reduction was 31.5% (95% CI, 18.7 to 44.3%; p < 0.0001). Subsequent antibiotic use for the treatment of exacerbations of COPD within 6 months did not differ between the two groups (46 vs 43 courses, respectively; p = 0.290). Accordingly, procalcitonin-guided antibiotic therapy at the index exacerbation allowed a significant sustained reduction in total antibiotic exposure for up to 6 months (RR, 0.76; 95% CI, 0.64 to 0.92; p = 0.004). There was no difference in the mean (± SD) time to the next exacerbation treated with antibiotics in the procalcitonin and standard-therapy groups (76.7 ± 49.6 vs 76.1 ± 50.9 days, respectively; p = 0.819).
The antibiotics that were prescribed included aminopenicillins (62%), fluoroquinolones (16%), cephalosporins (11%), macrolides (8%), antipseudo-monal penicillins (2%) and other agents (1%). A single antibiotic was used in 94 patients (80%; procalcitonin group, 83%; standard-therapy group, 68%; p = 0.124), two antibiotic agents were used in 20 patients (17%; procalcitonin group, 15%; stan-dard-therapy group, 29%; p = 0.112), and three antibiotic agents were used in 3 patients (3%; procalcitonin group, 2%; standard-therapy group, 3%; p = 1).
Overall, pneumonia developed in 10 patients during the course of the index exacerbation; 5 patients had continued to receive antibiotic therapy since hospital admission (procalcitonin group, 2 patients; standard-therapy group, 3 patients; p = 1.0), and 5 patients had not received antibiotic therapy (procalcitonin group, 4 patients; standard-therapy group, 1 patient; p = 0.205). Two additional patients received antibiotic therapy due to clinical failure (procalcitonin group, one patient; standard-therapy group, one patient; p = 1.0). One patient in the standard-ther-apy group was treated with antibiotics by the family physician immediately after hospital discharge.
From November 2003 to March 2005, consecutive patients > 40 years of age who had been admitted to the emergency department of the University Hospital Basel (Basel, Switzerland) with an ECOPD and met post-bronchodilator therapy spiromet-ric criteria, according to the Global Initiative for Chronic Obstructive Lung Disease guidelines, within 48 h of emergency department admission were included in this study. An ECOPD was defined as “a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.” Patients in whom there was found to be an alternative explanation for the presenting signs and symptoms other than a worsening of the underlying COPD were not included in the study. Patients who were considered to be vulnerable study participants (ie, those with psychiatric comorbidities) were excluded from the study. Other exclusion criteria were immunosuppression, asthma, cystic fibrosis, and the presence of infiltrates on chest radiographs on hospital admission.
This single-center, randomized, controlled trial was approved by the institutional review board and was registered with the Current Controlled Trials Database. All participants gave written informed consent.
Baseline assessment included clinical data and routine blood tests. Procalcitonin levels were measured within 1 h after blood sampling using 20 to 50 μL of plasma or serum by a time-resolved amplified cryptate emission technology assay (Kryptor PCT; Brahms AG; Hennigsdorf, Germany). The assay has a functional assay sensitivity of 0.06 ^g/L, which is 3-fold to 10-fold above normal mean values.
Spontaneously expectorated sputum samples were obtained for Gram staining and culture. Bacterial isolation and identification was performed with the use of standard techniques described by the American Society for Microbiology.
Spirometry was performed by trained lung function technicians who were blinded to group assignment, according to American Thoracic Society guidelines. The patients’ functional status was assessed with the help of a visual analog scale, ranging from 0 (feeling extremely ill) to 100 (feeling completely healthy). Respiratory symptoms were quantified using a questionnaire for patients with respiratory illnesses (range, 0 to 95 [with higher scores indicating greater discomfort]).
Patients satisfying the entry criteria were randomly assigned to one of two groups at the time of admission to the emergency department. In the standard-therapy group, antibiotic therapy was started based on current guidelines, according to the decision of the attending physician, who was unaware of the patient’s procalcitonin levels. In the procalcitonin group, antibiotic use was based on the measurement of procalcitonin levels at hospital admission. A procalcitonin level of 0.25 was considered to suggest the presence of bacterial infection, and antibiotic treatment was encouraged.
Reevaluation of circulating procalcitonin levels and clinical status was recommended after 6 to 24 h if antibiotic therapy was withheld. Except for the prescription of antibiotics at the index exacerbation, the prescription of all other medications was left entirely to the discretion of the treating physicians throughout the study period in both groups.
In the United States, COPD affects approximately 16 million adults, and is one of the fastest growing causes of morbidity and mortality. Exacerbations of COPD are responsible for > 2.4% of all acute medical hospital admissions and constitute the most important direct health-care costs associated with COPDA In the United States, the mean cost of hospital admission for COPD in a cohort of patients with severe COPD was estimated to be $7,100 (in US dollars).
Exacerbations of COPD can be triggered by a variety of factors, such as viruses, bacteria, and common pollutants. Thus, corticosteroids, anti-oxidants, and antibiotics may all have beneficial effects in treating or preventing some episodes, Antibiotics have demonstrated a marginal efficacy in the treatment of exacerbations of COPD. Nevertheless, a recent survey including 69,820 patients who had been hospitalized for exacerbations of COPD in 360 hospitals throughout the United States showed that 85% of all patients were given antibiotics. Not all patients will equally experience benefit from antibiotics. Subgroups of patients selected by evidence of bacterial infection or by severity of illness are more likely to benefit than those patients who are less ill. Therefore, the definition of a biomarker, which potentially detects such episodes or is specific to one subtype of exacerbation would be of great interest.
Serum levels of procalcitonin increase rapidly in the presence of infection. The ubiquitous release of procalcitonin during infections is induced either directly by microbial toxins (eg, endotoxin) and/or indirectly by humoral factors or the cell-mediated host response.- This induction is rather attenuated by cytokines released during viral infec-tions. Therefore, circulating levels of procalcitonin are markedly elevated in patients with bacterial infections compared to those with viral infections or other inflammatory conditions.