Procalcitonin guidance for reduction of antibiotic use in patients hospitalized with severe acute exacerbations of asthma: a randomized controlled study with 12-month follow-up

Asthma is a problem worldwide, with an estimated incidence of 300 million affected individuals and 250,000 annual deaths from asthma [1]. Acute exacerbations of asthma account for nearly 2 million emergency department (ED) visits and 500,000 admissions each year in the United States, frequently ranking as a major cause of absence from work and decreased productivity and incurring the greatest health-care costs [2],[3]. Severe exacerbations of asthma are potentially life-threatening and often put patients at increased risk of ED admission and hospitalization.

Because most exacerbations of asthma are associated with viral respiratory tract infection (RTI) and bacterial infection seems to play only a minor role, global asthma management guidelines do not recommend routine use of antibiotics [4]. However, in countries with high prescription rates for antibiotics, many asthma patients with exacerbations are treated with antibiotics, leading to antibiotic overuse and bacterial resistance [5]-[7]. In the United States, approximately 22% of acute asthma patients in the ED receive an antibiotic unnecessarily [7]. In England, a high antibiotic prescription rate (57%) was observed in asthma patients [6]. In our previous study in China, about 70% of patients with mild to moderate acute exacerbation of asthma received antibiotics [5].

As many as 75% of all antibiotic doses are prescribed for RTIs, such as acute bronchitis, community-acquired pneumonia (CAP), acute exacerbations of asthma or chronic obstructive pulmonary disease (COPD), despite their mainly viral cause [8]. This inappropriate use of antibiotics is believed to be a main cause of the spread of bacterial resistance [9]. There is a need to reduce unnecessary antibiotic use during treatment of RTI, and much effort has been put into the search for sensitive and specific tools to guide antibiotic therapy in RTI patients. Clinical trials that have used procalcitonin (PCT) to guide antibiotic therapy for patients with RTI have shown that a biomarker-driven algorithm can cut antibiotic prescribing significantly and that this can be achieved without any increase in adverse events or treatment failures [5],[10]-[17]. PCT-guided antibiotic stewardship reduced initial antibiotic prescription rates by 40% to 50% in patients with LRTI (lower respiratory tract infection) presenting to the ED [13] and by 70% to 80% in ambulatory patients presenting to their general physicians [15] and reduced total antibiotic exposure in CAP by 40% to 50% [10].

In our previous study, we demonstrated that PCT can be used accurately and effectively to determine whether acute asthma patients have bacterial infections and to guide the use of antibiotics in the treatment of acute exacerbation of mild to moderate asthma [5]. However, we included few severe asthma patients in the study, and the study had only a 6-week follow-up period. We therefore undertook a randomized controlled study to assess the usefulness of PCT guidance for antibiotic use in hospitalized patients with severe acute exacerbation of asthma, and this time included a 12-month follow-up period.

We observed a significant reduction in antibiotic use in patients hospitalized with severe acute exacerbations of asthma for whom a decision could be made on the basis of an algorithm of PCT measurements. Importantly, withholding antibiotic treatment did not cause apparent harm according to clinical and laboratory outcomes at discharge and during the 12-month follow-up period.

Exacerbation of asthma is often precipitated by a viral respiratory infection, and atypical bacteria such as Mycoplasma pneumoniae and Chlamydophila pneumoniae may play a role in its pathogenesis [23]-[25]. Antibiotic use during treatment of asthma exacerbation remains controversial, and few patients are estimated to benefit from this type of antibiotic treatment. In the TELICAST study [26], a total of 278 adults with acute exacerbation of asthma were randomly assigned to receive 10 days of treatment with oral telithromycin or placebo in addition to usual care. Patients in the telithromycin group had a significantly greater improvement in asthma symptoms, but they did not show an improvement in peak expiratory flow rates measured in the morning at home. However, routine use of antibiotics for exacerbations of asthma is of no benefit and may cause unwanted effects, so the empirical use of antibiotics is not recommended. In a randomized double-blind study [27], Graham and colleagues assessed the value of amoxicillin in 60 adults admitted to the hospital with acute exacerbations of asthma, with 37 exacerbations treated with amoxicillin and 34 with placebo. Response to treatment was closely monitored, but no significant differences between groups were demonstrated with regard to improvement measured by length of hospital stay, time until 50% improvement in symptoms, patient self-assessment and respiratory function, and symptoms and respiratory function at discharge. More recently, in the AZISAST study [28], 55 patients were randomly assigned to receive azithromycin and 54 were to receive placebo. Add-on treatment with azithromycin did not decrease the frequency of severe exacerbations of asthma and LRTI requiring antibiotics.

Under realistic clinical practice conditions, the challenge for physicians is to identify asthma patients with bacterial RTI for whom antimicrobial treatment is likely to be beneficial. Patients are often prescribed antibiotics despite clinical practice guideline recommendations against the empiric use of antibiotics in acute exacerbations of asthma [5]-[7]. Clinical signs and symptoms of acute asthma and bacterial RTI overlap, as do commonly used laboratory parameters such as C-reactive protein (CRP) and white blood cell (WBC) count, making it difficult for physicians to distinguish viral from bacterial infections in asthma patients [29],[30]. Patients with severe exacerbations are more often treated with antibiotics because of high morbidity and mortality. The routine use of standard laboratory tests such as CRP level and WBC count seems to be motivated more by their low cost, easy availability and historic practice rather than by their diagnostic accuracy. Moreover, the reliability of CRP level and/or WBC count for guiding antimicrobial therapy is limited by their late peak levels as well as their suboptimal specificity, especially in patients with systemic inflammation [31],[32].

Circulating levels of PCT are elevated in patients with systemic bacterial infections, but they remain relatively low in patients with viral infections or inflammatory diseases [33],[34]. Hence, PCT levels may be used to support clinical decision-making for the initiation and discontinuation of antibiotic therapy [35]. Since the first pilot study published in 2004 [10], PCT-guided strategies for antibiotic treatment decision have gained much attention. Overall, it has been shown that PCT might be feasible in guiding antibiotic treatment in patients with acute exacerbations of COPD [12] as well as in limiting treatment duration in patients with CAP [11] and severe infectious diseases in the intensive care unit [36]-[39]. The main effect has been achieved either by discouraging antibiotic initiation or by shortening the duration of antibiotic treatment without increased rates of adverse outcomes [10]-[14],[37]. The use of PCT also has prognostic implications, as falling values correlate with good outcomes and static or increasing values correlate with adverse outcomes, including mortality [40],[41]. More recently, a PCT strategy was evaluated in primary care in patients with symptoms of acute respiratory infections, with results supporting the potential for substantial reductions in antibiotic use in this patient population [13],[15].

Only a few asthma patients were included in two previous trials of PCT-guided therapy, [10],[13]. In our own previous study, only 34 patients with severe exacerbation asthma were included [5]. The presently reported trial is, to our knowledge, the first clinical study focused on evaluation of the PCT test in its effectiveness in guiding antibiotic treatment of severe acute exacerbations of asthma.

However, some limitations of the present study should be recognized. First, we excluded patients older than 65 years of age, which may limit the application of our findings to older patients. Second, we did not conduct a formal cost-benefit study. To evaluate if a PCT-based strategy is cost-efficient under real-life conditions, cost aspects should be carefully considered. Third, this study was performed in a single center with a high baseline use of antibiotics for the treatment of asthma. Reductions in antibiotic use by means of PCT therapy guidance will be less in centers that already use antibiotics for asthma less often. Fourth, because of its relatively small sample size, our study has limited power to prove the safety of the PCT strategy, and we cannot exclude a potential harm of reducing antibiotic therapy on the basis of PCT guidance. Taking into account the limited population size in the study, a multicenter trial that includes a large number of patients with severe exacerbation of asthma is desirable to validate our data. We emphasize that any infection is too complex to be reduced to a single cutoff of a surrogate marker, and biomarkers should complement rather than replace good clinical practice. Certainly, results from the use of biomarkers should be considered in light of the pretest probability of disease presence.

The results of our study support the concept that PCT guidance reduces antibiotic exposure in patients with severe acute exacerbation of asthma without apparent harm. Given the prevalence of asthma and the duration of illness, a reduction in antibiotic prescriptions for the treatment of exacerbations could result in fewer side effects, lower costs and, in the long term, lead to diminishing drug resistance, particularly in countries such as China, where patients are suffering from the overuse of antibiotics [42],[43].

Antibiotic overuse in China is normal, and patients with severe acute exacerbations of asthma often receive inappropriate antibiotic treatment.

The results of this single-center study show that a significant reduction in antibiotic use in patients hospitalized with severe acute exacerbations of asthma for whom a decision could be made on the basis of an algorithm of PCT measurements.

Withholding antibiotic treatment on the basis of PCT guidance did not cause apparent harm for up to 12 months.

Additional larger multicenter studies are needed to confirm the usefulness of PCT guidance during treatment of severe asthma exacerbation.