TRANSATLANTIC AIRWAY CONFERENCE Biomarkers that Predict and Guide Therapy for Exacerbations of Chronic Obstructive Pulmonary Disease C. E. Brightling Institute for Lung Health, Department of Infection, Immunity and Inflammation, The University of Leicester, United Kingdom
Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. COPD exacerbations have a major impact on morbidity and mortality. The etiology of COPD exacerbations is largely due to viral and bacterial infections in combination with underlying inflammation that is typically neutrophilic, although it is eosinophilic in 10 to 25% of cases. We review the recent studies that have defined novel biological clusters at exacerbation events and consequently identified important biomarkers to direct
therapy. These biomarkers include C-reactive protein, procalcitonin, and peripheral blood eosinophil count, which are readily available. We are therefore at a point of making personalized antibiotic and corticosteroid therapy in COPD exacerbations a reality. Integration of the wealth of emerging data to further define the complexity of exacerbations also promises to identify new targets and biomarkers to treat COPD exacerbations. Keywords: COPD; biomarkers; neutrophils; eosinophils; CRP
(Received in original form February 1, 2013; accepted in final form February 25, 2013 ) Correspondence and requests for reprints should be addressed to C. E. Brightling, Ph.D., Institute for Lung Health, Clinical Sciences Wing, University Hospitals of Leicester, Leicester LE3 9QP, UK. E-mail:
[email protected] Ann Am Thorac Soc Vol 10, Supplement, pp S214–S219, Dec 2013 Copyright © 2013 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201302-023AW Internet address: www.atsjournals.org
Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality. Exacerbations (i.e., the worsening of the patient’s symptoms beyond normal day-to-day variations) are particularly important because they are associated with high economic costs and accelerated lung function decline and have a negative impact on quality of life and mortality (1–3). Guidelines for treatment of stable COPD recommend a stratified approach as determined by disease severity, with step-by-step increases in treatment as the disease progresses (1, 2). Current guidelines recommend treatment of exacerbations with corticosteroids, together with antibiotics in the presence of increased sputum production and purulence. There is an increasing recognition that COPD is a heterogeneous condition in terms of clinical presentation; inflammation, which is typically neutrophilic but in 10 to 25% of cases is eosinophilic (4–6); small airway obliteration; and emphysema and bacterial colonization (7). This heterogeneity in S214
disease is associated with variable response to therapies. Indeed, although therapy improves symptoms and exercise capacity and reduces exacerbation frequency, the magnitude of benefit is small and restricted to subgroups of patients, and none of the current therapies affects disease progression. We therefore need to improve our understanding of the gene–environment interactions that underlie the interplay between pollutants, host susceptibility to damage and infection, and remodeling that increases the risk of exacerbations and contributes to their onset. We also need to identify biomarkers to direct current therapies and develop future therapies toward personalized medicine.
Phenotyping COPD Exacerbations Patients with COPD have considerable dayto-day variability in their disease as a consequence of interactions between their
underlying disease and exposure to pollutants and bacterial colonization. The most likely cause of COPD exacerbations is airway infection with viruses and bacteria, although the association between acquisition of a new pathogen versus persistent infection and the interplay with airway inflammation, lung function, and symptoms is poorly understood (8). However, an exacerbation might alternatively reflect further destabilization of the intrinsically unstable or homeokinetic state of the disease in the absence of measurable inflammation or demonstrable evidence of acquisition of a new pathogen (Figure 1). Indeed, the strongest predictor of a COPD exacerbation is a previous history of an exacerbation, which has led to the concept of frequent versus infrequent exacerbators (9). This distinction may reflect patients with different susceptibility to infection or identify those with increased variability of their underlying disease, perhaps due to inflammation or autoimmune processes or
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Figure 1. Chronic obstructive pulmonary disease (COPD) is a variable disease with day-to-day and within day instability. COPD exacerbations represent further instability often in response to a trigger. Treatment can be targeted to reduce risk and prevent events or to modify their resolution directed by predictors or biomarkers.
due to biomechanical properties of the airways. The relative contributions of these mechanisms in the onset of an exacerbation warrants further study. Attempts have been made to phenotype the biological profiles of COPD exacerbations. Hurst and colleagues (10) studied 36 plasma biomarkers in 90 patients with COPD looking at paired baseline and exacerbation samples. C-reactive protein (CRP), a nonspecific marker of infection, inflammation, and injury, was the most selective but was not sufficient alone to confirm exacerbation diagnosis. When combined with one major symptom (increasing dyspnea, sputum volume, or purulence), CRP > 8 mg/ml performed better (95% specific and 57% sensitive for exacerbation diagnosis). None of the systemic biomarkers examined in this study was useful to predict exacerbation severity. After a proteomic analysis of serum from patients with an exacerbation of COPD, serum amyloid protein (SAA) was identified as a putative biomarker (11). SAA, like CRP, is increased at exacerbation onset compared with stable state, but it is more sensitive than CRP alone. The SAA serum concentration was also related to the severity of the COPD exacerbation but was poorly related to etiology, suggesting that it has limited value to directing therapy. Whether serum SAA has utility in predicting future risk of severity and poor outcomes requires further study. These studies compared stable state with exacerbations but did not fully classify the exacerbation event based on its potential
etiology. Bafadhel and colleagues recruited 145 patients into an observational study with biomarkers from blood and serum assessed at stable state and during exacerbations for 1 year (12) to define biomarkers to identify bacterial, viral, or eosinophilic-associated exacerbations. In their study, 55% of the exacerbations were associated with bacteria, 29% with virus, and 28% with sputum eosinophilia. From a comprehensive biomarker panel of over 30 mediators, differential cell counts in blood and sputum, and clinical variables, the biomarkers that best identified these clinical phenotypes were sputum IL-1b, serum CXCL10, and percentage peripheral blood eosinophils, respectively. The observation that CXCL10 was the best biomarker for identifying viral exacerbations (sensitivity, 80%; specificity, 60%) is consistent with previous findings that CXCL10 increases between baseline and exacerbation in COPD exacerbations due to human rhinovirus (13). Using unbiased cluster analysis, four biological exacerbation clusters were identified, and these validated the a priori etiological groups: “proinflammatory” bacterialpredominant, “Th1” viral-predominant, “Th2” eosinophilic-predominant, and a fourth group termed “pauciinflammatory” because this was associated with limited changes in the inflammatory profile (Figure 2). Disease severity according to GOLD criteria was not different between these biological clusters, and the biomarkers were associated with their respective potential etiologies independent of disease severity.
Brightling: Biomarkers that Predict and Guide Therapy for COPD Exacerbations
These findings support the concept of different “exacerbation phenotypes.” The eosinophilic and bacterial-associated phenotypes were also observed in stable disease and predicted the future exacerbation phenotype. Patients experienced more bacterial exacerbations if their stable sputum samples contained bacteria (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4–9.9) and more eosinophilic exacerbations if eosinophilic inflammation was present in the stable state (OR, 2.7; 95% CI, 1.3–5.7), suggesting that these biomarkers, in addition to directing therapy during the exacerbation event, might identify subgroups to target therapy with the aim of reducing future risk.
Phenotype-Specific Management of COPD Exacerbations The current evidence for the use of systemic corticosteroids and antibiotics in COPD exacerbations underscores the limited benefit of these therapies and their potential risks in an already vulnerable population. Several reviews have examined the role of antibiotics in the treatment of acute exacerbations of COPD. Vollenweider and colleagues (14) examined 2,068 participants in 16 randomized controlled trials of antibiotic versus placebo. Antibiotics for COPD exacerbations showed large and consistent benefits in patients admitted to intensive care, but for outpatients and inpatients the results were inconsistent. The risk for treatment failure was significantly reduced in inpatients and outpatients when all trials were included but not when the analysis for outpatients was restricted to currently used antibiotics. Antibiotics did not demonstrate significant benefit for mortality and length of hospital stay in inpatients. Rothberg and colleagues (15) compared outcomes for hospitalized patients receiving early antibiotic treatment for acute exacerbations of COPD versus late or no antibiotic treatment. In this retrospective analysis of almost 85,000 patients, those treated with antibiotics were less likely to be ventilated and had lower inpatient mortality rates and lower readmission rates. Adverse effects of antibiotics were again highlighted, notably an increase in the rate of Clostridium difficile infection in the antibiotic-treated group. A review by Puhan and colleagues S215
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Figure 2. Proportional representation of biological COPD clusters in three-dimensional ellipsoids with Th1, Th2, proinflammatory, and pauci-inflammatory clusters. The size of each ellipsoid is reflective of the proportion of patients in each group (adapted from Ref. 12).
included 13 placebo-controlled trials including 1,557 patients (16). Significant heterogeneity across trials was noted due to exacerbation severity. In this systematic review, antibiotics did not reduce treatment failure in outpatient mild to moderate exacerbations. However, in patients with severe exacerbations, there were significant benefits of antibiotics in terms of reducing treatment failure (number needed to treat = 4) and mortality (number needed to treat = 14). In a randomized study, 233 subjects at the onset of a COPD exacerbation received doxycycline for 1 week versus placebo, with systemic corticosteroids given to all subjects. Outcome at 30 days was similar, but at Day 10 those receiving doxycycline had greater improvements in clinical and microbiological outcomes, with good response associated with a CRP . 50 mg/L (17). A Cochrane review (18) collated data for 1,051 patients within 10 double-blinded randomized controlled trials and compared systemic corticosteroids with placebo on the outcomes of acute exacerbations of COPD. Systemic corticosteroids reduced the risk of treatment failure compared with placebo (OR, 0.5; 95% CI, 0.36–0.69), but S216
there was no significant reduction in mortality (OR, 0.87; 95% CI, 0.45–1.66). There was an early improvement in lung function (FEV1 increased by 140 ml) in the corticosteroid group, with later outcomes less convincingly favoring corticosteroids, and there was a reduction in hospital stay by 1.22 days in this group. Of concern was the significant increase in adverse events observed in the corticosteroid arm (OR, 2.33; 95% CI, 1.6–3.4). The number needed to harm or for one adverse event to occur was 6, with adverse events including hyperglycemia, weight gain, and insomnia. Thus, to maximize the benefit of corticosteroids and antibiotics in COPD exacerbations, it would be valuable to have biomarkers to identify phenotypes that respond to therapy and those for which there is the greatest risk of harm. Targeted Antibiotic Therapy for COPD
It is desirable to be able to reliably identify bacterial exacerbations and target antibiotics to this subgroup of patients. Procalcitonin (PCT) is a peptide produced in response to endotoxin and other mediators released in bacterial infections. It has been extensively
evaluated as a “bacterial infection” biomarker in many systemic infections, including lower respiratory tract infections and acute exacerbations of COPD (19, 20). Current evidence suggests a role in identification of bacterial acute exacerbations of COPD and in guiding the duration of antibiotic treatment. Schuetz and colleagues performed a noninferiority trial that included 1,359 patients with severe lower respiratory tract infections (21). Patients were randomized to antibiotics based on a PCT algorithm or standard clinical treatment. Overall adverse events were similar in both groups but with shorter courses of antibiotics in the PCT group (5.7 vs. 8.7 d). This reduction in treatment duration was also seen in patients with acute exacerbations of COPD (PCT group [2.5 d] vs. control group [5.1 d]) (21). These results and those from other studies suggest that PCT has a role as a biomarker for bacterial acute exacerbations of COPD and that it can be safely used to reduce inappropriate antibiotics in acute exacerbations of COPD. We and others have demonstrated that CRP is a similarly sensitive and specific biomarker to distinguish subjects who require antibiotics and may be a reliable, widely available alternative to PCT (20). Targeted Corticosteroid Therapy for COPD
In asthma and COPD, the presence of a sputum eosinophilia is associated with a good response to corticosteroids (6, 22, 23). More importantly, targeted corticosteroid therapy aimed at normalizing the sputum eosinophil count reduced exacerbations and hospital admissions in asthma and COPD (24, 25). Siva and colleagues randomized 82 patients with COPD to standard clinical care (in accordance with British Thoracic Society Treatment guidelines) or targeted sputum management. The sputum management group had less severe exacerbations (mean reduction of 62% per patient per year), with no difference in the number of mild and moderate exacerbations or between the average oral or inhaled corticosteroid doses in both groups (25). Whether evidence of an eosinophilic COPD phenotype identifies patients that will benefit from specific antieosinophil therapy such as anti-IL5 needs to be addressed and presents a tremendous opportunity after the success of this strategy in severe asthma (26, 27).
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Figure 3. Symptom resolution after the onset of a COPD exacerbation in subjects randomized to targeted corticosteroid therapy or standard care dependent upon the peripheral blood eosinophil count. Resolution was worst in subjects without a peripheral blood eosinophilia treated with systemic corticosteroids, suggesting corticosteroids can impair recovery in this group (adapted from Ref. 28). VAS = visual analog scale of symptoms.
The role of targeting corticosteroid therapy in those with eosinophilic inflammation at the exacerbation event has recently been studied. Bafadhel and colleagues performed a double-blind randomized controlled trial using peripheral blood eosinophil count as a biomarker to guide oral corticosteroid treatment in outpatient acute exacerbations of COPD (28). The peripheral blood eosinophil count of 2% was used as the cut-off in this study was derived from the group’s earlier published receiver-operator characteristic curves for the best predictors of a sputum eosinophilia (12). In the biomarker-driven study, a safe reduction in inappropriate oral corticosteroid prescriptions was demonstrated. Subjects without an eosinophilia treated with systemic corticosteroids had more adverse events and a poorer rate of recovery, suggesting that this biomarker identifies a group that might benefit and another that is harmed by corticosteroid therapy (Figure 3). This is consistent with recent evidence from the MAESTRAL study, which reported an increased treatment failure rate to antibiotic therapy for a COPD exacerbation when prescribed with oral corticosteroids versus in the absence of oral corticosteroids (29). Although patients receiving oral corticosteroids had more severe disease based on disease duration and baseline FEV1, the severity of exacerbations between groups was similar, suggesting
that corticosteroids might impair the resolution of an exacerbation event and increase the risk of treatment failure in some subjects. These findings support an urgent need to replicate and validate the use of a peripheral blood eosinophil count in directing corticosteroids at an exacerbation event in large studies in primary and secondary care settings.
Multiscale Modeling: the Future of COPD Phenotyping Phenotypes need to consider information derived at different scales of disease (i.e., gene–cell, cell–tissue, tissue–organ, and organ–whole person). Most approaches to phenotyping consider disease at a single scale (e.g., focusing upon genetics, cellular profiles, imaging, physiology, or symptoms) and do not integrate information to provide multidimensional phenotypes. This approach to integrate the underlying biology of disease with clinical expression is critical to inform our understanding of disease and to help to provide subgroups to target therapies. Integration of these data with statistical modeling such as factor and cluster analysis can provide more insight into the complexity of COPD phenotypes (12, 30– 33). Cluster analysis is a technique for data exploration that groups subjects without an a priori hypothesis. It seeks to organize information so that heterogeneous groups
Brightling: Biomarkers that Predict and Guide Therapy for COPD Exacerbations
of variables can be classified into more homogeneous groups. These types of analysis have been increasingly used over recent years to phenotype stable COPD and exacerbations and add to our understanding of disease. There are several large COPD studies gathering data available from multiple scales in patients with COPD: COPDMAP (www.copdmap.org), Spiromics (www. cscc.unc.edu/spir/), ECLIPSE (34), COPDgene (35), EvA (36), and AirPROM (www.airprom.eu). High throughput technology is being used, which will improve the ability to screen, identify, and validate biomarkers and will allow analysis of many different biomarkers simultaneously. Validation of these phenotypes will require longitudinal data collection in carefully characterized patient populations, but ultimately these data may be used to develop statistical models of future risk of lung function decline, risk of future exacerbations, or the likely treatment response. In addition to using these approaches to guide therapies, the interventions will also affect the patients’ phenotype and changes in clinical practice; for example, the increased use of macrolide antibiotics to reduce future exacerbation risk (37) is likely to affect the role of bacteria and inflammation at the exacerbation events. Conclusions
Clinically relevant exacerbation phenotypes, such as “eosinophilic” and “bacterial” phenotypes, can be identified with biomarkers, including peripheral blood eosinophilia and CRP or procalcitonin. Further studies need to validate the use of these biomarkers to direct therapy for COPD exacerbations. The general accessibility and simplicity means we should move quickly to validate and translate these biomarkers into routine clinical care. In parallel, further studies exploring the complexity of the cause and dynamics of COPD exacerbations will begin to unravel the complexity of the disease. These approaches will inform our understanding of COPD exacerbations but most importantly will take us several steps closer to realizing personalized treatment. n Author disclosures are available with the text of this article at www.atsjournals.org.
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