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Ann Arbor, MI
Dr. Martinez is Professor of Internal Medicine, and Dr. Curtis is Professor of Internal Medicine and VA Section Chief, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, and Veterans Administration Healthcare System.
Correspondence to: Fernando J. Martinez, MD, MS, FCCP, The University of Michigan Health System, 1500 E Medical Center Dr, 3916 Taubman Center, Box 0360, Ann Arbor, MI 48109; e-mail: fmartine{at}umich.edu
Comprehensive, evidence-based reviews12 on the management of acute exacerbations of COPD (AECOPD) recommend a multifaceted approach. That this approach includes antibiotics should not be surprising, given compelling data that bacterial infection is the likely cause in approximately 50% of AECOPD.3 Yet, despite numerous published placebo-controlled trials,3 and systematic reviews1456 suggesting an overall treatment effect, the role of antimicrobials in AECOPD remains controversial.7 This topic is clearly ripe for a conceptual breakthrough.
How does the practitioner decide whether an antibiotic should be prescribed to an individual patient? The classic study of Anthonisen et al8 continues to provide guidance; these investigators randomized patients during AECOPD to an antibiotic, while stratifying results based on the number of symptoms at presentation. Patients with at least two cardinal symptoms (increased dyspnea, increased sputum production, and/or change in sputum color) experienced a greater benefit with antibiotics. Sputum purulence also appears relevant, as the presence of purulent sputum is associated with a greater likelihood of bacterial growth.910 A bronchoscopic study11 employing quantitative cultures of protected specimen brush samples confirmed that self-reported sputum purulence was associated with bacterial infection. Given these data, it is not surprising that many international specialty societies have recommended antimicrobial therapy in AECOPD associated with a change in sputum characteristics.12
Nevertheless, antibiotic use in AECOPD is undoubtedly still excessive, exposing patients to considerable cost and potential adverse effects, and driving antibiotic resistance. A rapid, specific test to identify bacterial lower respiratory infections would be a major advance. Serum C-reactive protein was examined for this purpose and found wanting in both sensitivity and specificity.13 A more recent approach that holds considerable promise is serum procalcitonin measurement.14 Procalcitonin is a small (13 kd) protein that is normally undetectable in plasma.15 Procalcitonin increases markedly in bacterial infections, especially those associated with sepsis, but is not increased by inflammation that is autoimmune or due solely to viral infection. There is already encouraging evidence from single-center, cluster-randomized, single-blinded studies161718 that procalcitonin-guided therapy can safely reduce antibiotic use in patients with lower respiratory infection at a low likelihood of bacterial infection.
The article by Stolz and colleagues19 in this issue of CHEST (see page 9) extends this technique. In a single-center, single-blinded study, they recruited 208 consecutive patients admitted to the hospital with AECOPD and randomized them to usual care in which management was based on standard criteria without access to procalcitonin levels or to a procalcitonin group for whom antibiotic use was based on the procalcitonin level at the time of hospital admission. In the latter group, a procalcitonin level < 0.1 µg/L was considered to be nonbacterial and antimicrobial use was discouraged. In those with a procalcitonin level > 0.25 µg/L, the AECOPD were believed to be bacterial and antimicrobial therapy was encouraged. For patients with procalcitonin levels between 0.1 µg/L and 0.25 µg/L, the use of antimicrobial agents was based on the "stability of the clinical condition." Patients were followed up during the hospitalization, at a short-term visit, and through 6 months. The primary end point, total antimicrobial use during the index hospitalization, was significantly lower in the procalcitonin-guided group (40% vs 72%). No difference was noted in clinical success rate during the index hospitalization, antimicrobial use during the subsequent months, or time to the next exacerbation. Interestingly, no difference in procalcitonin level was noted between patients with or without sputum purulence, or between Anthonisen classification levels. This study clearly demonstrates that procalcitonin levels can be used to decrease antimicrobial in hospitalized AECOPD patients without adverse outcome.
Two important questions remain before procalcitonin-guided therapy can be recommended as a worldwide standard approach to AECOPD antimicrobial management. First, do patients with low (< 0.1 ng/mL) serum procalcitonin levels derive any benefit from antimicrobials? As patients with low procalcitonin levels were not randomized to antimicrobial therapy or placebo, the current study could not answer this question. Second, can these results be replicated in a multicenter trial in centers less familiar with procalcitonin-guided decision making, and especially in the United States, using the Food and Drug Administration-approved luminescence immunoassay rather than time-resolved amplified crytate emission technology used by Stolz et al19? This is particularly important, as this investigative group has extensive published experience in the use of procalcitonin levels in therapy of lower respiratory tract infections,16 including community-acquired pneumonia.18 Nevertheless, the authors should be commended for using a novel biomarker to reduce unnecessary antimicrobial use without adverse outcome. Furthermore, they provide vital preliminary data for the conduct of multicenter trials using similar methodologies that may provide clear guidance on optimal use of antimicrobial agents in AECOPD.
Footnotes
The authors have no conflicts of interest to disclose.
References
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