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Moraxella catarrhalis is an important respiratory tract pathogen, causing otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease (COPD). Adults with COPD make antibody responses to M. catarrhalis following infection, but little is known about the identity of the antigens to which these antibodies are directed. In this study, 12 serum samples obtained from adults with COPD who had cleared M. catarrhalis from the respiratory tract following infection and who had developed new serum immunoglobulin G (IgG) to their infecting strain were subjected to a series of assays to identify the antigens to which potentially protective antibodies were directed. Sera were adsorbed with intact bacterial cells, and antibodies were eluted from the surfaces of the bacteria. Analysis by flow cytometry established that adsorption and elution effectively detected antibodies specifically directed to surface-exposed epitopes. Immunoblot assays of adsorbed and eluted serum fractions were performed with purified outer membranes and purified lipooligosaccharide of homologous infecting strains and with a series of mutants deficient in expression of individual outer membrane proteins (OMPs). While heterogeneity in antibody responses among individuals was observed, five major OMPs, UspA1, UspA2, Hag, TbpB, and OMP CD, were identified as targets of antibodies to surface epitopes in the majority of adults with COPD who cleared the organism. These results have important implications in understanding human immune responses to M. catarrhalis and in elucidating the elements of a protective immune response.

BACKGROUND: Screening of progenitor cell grafts (marrow, peripheral blood, and cord blood) for microbial contamination is required by the standards of AABB. Clinical sequelae from infusion of these contaminated grafts, however, is uncommon. STUDY DESIGN AND METHODS: A retrospective analysis of 735 consecutive marrow and peripheral blood progenitor cell harvests between 1998 and 2003 was performed. Analysis included incidence, clinical outcome, and cost outcomes of positive blood cultures and antibiotic therapy. RESULTS: Thirty-three of 735 (4.5%) harvests were contaminated. The incidence of microbial contamination varied with the source of the graft (4 of 26 [15%] were cord blood, 8 of 177 [4.5%] were marrow, and 21 of 532 [3.9%] were peripheral blood). Coagulase-negative Staphylococcus (n = 22) and Propionibacterium acnes (n = 8) were most frequently isolated. Potentially pathogenic organisms were isolated in 6 of 735 (0.81%) grafts (methicillin-sensitive Staphylococcus aureus, 4; methicillin-resistant S. aureus, 1; and Enterobacter cloacae, 1). The estimated total cost of surveillance was approximately $81,585. The cost of vancomycin therapy in 4 patients who received prophylactic antibiotic therapy was approximately $10,000. No adverse sequelae followed infusion of contaminated grafts. CONCLUSION: Clinical sequelae following infusion of microbially contaminated progenitor cells is extremely rare. Prophylactic empiric antibiotics may be unnecessary. Routine microbial surveillance of progenitor cell grafts is a low-yield procedure.

Interactions of nontypeable Haemophilus influenzae (NTHI) with human macrophages contribute to the pathogenesis of NTHI-induced infection in humans. However, the immunologic mechanisms that initiate and perpetuate NTHI-mediated macrophage responses have not been well explored. Outer membrane protein (OMP) P6 is a conserved lipoprotein expressed by NTHI in vivo that possesses a Pam 3 Cys terminal motif, characteristic of immunoactive bacterial lipoproteins associated with Toll-like receptor signaling. We theorized that OMP P6 is a potent immunomodulator of human macrophages. To test this hypothesis, we purified OMP P6 as well as OMP P2, the predominant NTHI outer membrane protein, and lipooligosaccharide (LOS), the specific endotoxin of NTHI, from NTHI strain 1479. Human blood monocyte-derived macrophages, purified from healthy donors, were incubated with each outer membrane constituent, and cytokine production of macrophage supernatants interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), IL-10, IL-12, and IL-8 was measured. OMP P6 selectively upregulated IL-10, TNF-α, and IL-8. While OMP P6 (0.1 μg/ml for 8 h) elicited slightly greater concentrations of IL-10, it resulted in over ninefold greater concentrations of TNF-α and over fourfold greater concentrations of IL-8 than did OMP P2. OMP P6 at doses as low as 10 pg/ml was still effective at induction of macrophage IL-8, while OMP P2 and LOS were not. OMP P6 of NTHI is a specific trigger of bacteria-induced human macrophage inflammatory events, with IL-8 and TNF-α as key effectors of P6-induced macrophage responses.

Evidence is mounting that nontypeable Haemophilus influenzae grows as a biofilm in the middle ear of children with otitis media and the airways of adults with chronic obstructive pulmonary disease. To begin to assess antigens expressed by H. influenzae in biofilms, cell envelopes of bacteria grown as a biofilm were compared to those grown planktonically. A approximately 30kDa peroxiredoxin-glutaredoxin was present in greater abundance during growth in biofilms. Mutants deficient in expression of peroxiredoxin-glutaredoxin were constructed by homologous recombination in four clinical isolates. The mutants showed a 25-50% reduction in biofilm formation compared to the corresponding parent strains. To study in vivo expression of peroxiredoxin-glutaredoxin during human respiratory tract infection, paired pre- and post-exacerbation serum from adults with chronic obstructive pulmonary disease and H. influenzae in sputum were assayed using an enzyme-linked immunosorbent assay and purified recombinant peroxiredoxin-glutaredoxin. Eight from 18 (44.4%) paired serum samples showed a significant increase in antibody to peroxiredoxin-glutaredoxin from pre- to post-infection. These results indicate that (1) peroxiredoxin-glutaredoxin is present in greater abundance in H. influenzae biofilms compared to planktonically grown bacteria; (2) peroxiredoxin-glutaredoxin is involved in biofilm formation by H. influenzae and the degree of involvement varies among strains; and (3) peroxiredoxin-glutaredoxin is expressed by H. influenzae during infection of the human respiratory tract and is recognized by the human immune system.

Exacerbations are a characteristic feature of chronic obstructive pulmonary disease and contribute significantly to associated morbidity and mortality. Renewed interest in this common clinical problem and research using new investigative tools has enhanced substantially the understanding of the pathogenesis of exacerbations. Results of recent clinical trials and observational studies have allowed refinements in treatment of exacerbations that should im-prove patient outcomes. This article discusses a rational, stratified approach to the use of antibiotics for this condition based on these recent studies.

In an increasingly cost-conscious clinical environment, practitioners may be reluctant to prescribe erythropoietic agents for patients with mild anemia unless reimbursement guidelines are changed. In our institution, reimbursement requirements force us to wait for hemoglobin levels to fall to < 10 g/dL before initiating treatment with this mainstay of anemia therapy. These requirements often result in delayed treatment, which is clearly unacceptable, particularly when compared with reimbursement regulations in neighboring states. This article addresses the appropriate timing of intervention with erythropoietic therapy, the optimization of schedule and dose, and their impact on overall quality of life.

Objective : To demonstrate that 5 days of treatment with a new fluoroquinolone, gemifloxacin, is at least as effective as 7 days of treatment with levofloxacin in adult patients with acute exacerbation of chronic bronchitis (AECB). Design : Randomized, double-blind, double dummy, multicentre, parallel group study Setting : Sixty different medical centers in US, UK and Germany. Material and methods : A total of 360 adults (>40years of age) with AECB were randomly assigned to receive gemifloxacin 320mg once daily for 5 days or levofloxacin 500mg once daily for 7 days. The primary efficacy parameter was a clinical response at follow-up (Days 14–21). Results : In total, 335/360 patients completed the study (93.1%). Seven patients receiving gemifloxacin withdrew from the study compared to 18 patients receiving levofloxacin; this difference was statistically significant (Fisher's exact test: p =0.02). In the intent-to-treat (ITT) population, the clinical success rate at follow-up (Days 14–21) was 85.2% (155/182) with gemifloxacin and 78.1% (139/178) with levofloxacin. Clinical success rate in the per-protocol (PP) population was 88.2% (134/152) with gemifloxacin and 85.1% (126/148) with levofloxacin. At long-term follow-up (Days 28–35), the clinical success rates in the PP population were 83.7% (123/147) with gemifloxacin and 78.4% (109/139) with levofloxacin. The difference in success rates was 5.26% (95% CI: −3.83, 14.34). Conclusion : The clinical efficacy of gemifloxacin 320mg once daily for 5 days in AECB was at least as good as levofloxacin 500mg once daily for 7 days. Fewer withdrawals and superior clinical efficacy at long-term follow-up were also seen with gemifloxacin.

PURPOSE OF REVIEW Acute exacerbations of chronic obstructive pulmonary disease were a poorly defined and understood entity. The application of better study designs and new research methodologies has shed considerable light on the pathogenesis of this common clinical syndrome. RECENT FINDINGS Inflammation is an important component of the pathogenesis of chronic obstructive pulmonary disease, and exacerbations probably represent acute increases in airway inflammation brought about by one or more etiological agents. Environmental particulate and gaseous pollutants have been linked in epidemiological studies with increased respiratory symptoms and mortality in chronic obstructive pulmonary disease. Bacterial, viral and atypical pathogens, either alone or in concert, induce the majority of acute exacerbations. SUMMARY A bacterial cause of a substantial proportion of exacerbations is now firmly established by the results of bronchoscopy, molecular epidemiology, immunology and airway inflammation studies. Future research should focus on pathogenic mechanisms and host defence against the microbial pathogens associated with acute exacerbations of chronic obstructive pulmonary disease, in order to develop better treatment and prevention strategies.

Previous studies of immune response to Haemophilus influenzae after exacerbations of chronic obstructive pulmonary disease (COPD) have yielded contradictory results. Using homologous (infecting) strains and immunoassays to surface-exposed epitopes, we tested the hypothesis that adults with COPD make new antibodies to strain-specific, surface-exposed epitopes on H. influenzae after exacerbations. We collected clinical information, sputum, and serum monthly and during exacerbations from 81 patients with COPD over 56 months. Serum antibodies to H. influenzae after exacerbations associated with H. influenzae in sputum were detected with whole bacterial cell ELISA and bactericidal assays. An immune response to homologous H. influenzae occurred after 22 of 36 (61.1%) exacerbations with newly acquired strains compared with 7 of 33 (21.2%) exacerbations with preexisting strains (odds ratio [OR] = 4.4; 95%, 1.8 to 10.8; p = 0.001). An absence of an immune response was strongly associated with complement sensitivity (OR = 0.03; 95% confidence interval, 0.003 to 0.22; p = 0.001). New bactericidal antibodies developed after exacerbations were highly strain specific, showing bactericidal activity for only 11 of 90 (12.2%) heterologous strains. Development of an immune response to H. influenzae supports its role in causing exacerbations. The strain specificity of the immune response likely represents a mechanism of recurrent exacerbations.

Our understanding of the pathogenesis and consequences of acute exacerbations of chronic obstructive pulmonary disease (COPD) has increased considerably in the past decade. Several new lines of evidence support bacterial causation of about half the exacerbations. Contrary to previous data, recent studies with improved methodology have demonstrated that exacerbations do contribute to the loss of lung function in COPD. Another interesting new observation is that colonization by bacterial pathogens may not be innocuous, and in fact may lead to airway inflammation and contribute to pathogenesis of COPD. Evidence that bacteria cause exacerbations, that exacerbations contribute to loss of lung function, and that chronic colonization by bacteria may be harmful, has emphasized the potential importance of appropriate antibiotics in the treatment of exacerbations. An unfortunate paucity of data does not allow evidence-based recommendations to be made for optimal choice of antibiotics for exacerbations of COPD. Emerging data that antibiotics differ in unconventional measures of efficacy such as time to next exacerbation, improvement in health-related quality of life, and bacteriologic eradication will help us make concrete recommendations in the future.

Chronic obstructive pulmonary disease (COPD) is characterized by periodic exacerbations, some of which are caused by nontypeable Haemophilus influenzae (NTHI). P6 is an outer membrane lipoprotein that is highly conserved among strains of NTHI. We hypothesized that lymphocytes from patients with COPD who have exacerbations due to NTHI have a decreased ability to recognize P6. The in vitro lymphocyte proliferative response to P6 in 36 patients with COPD and 12 healthy control subjects was studied. Ten patients who had exacerbations due to NTHI in the previous 12 months showed statistically significant lower proliferation to P6 (stimulation index, log transformed mean +/- standard error 0.82 +/- 0.17) compared with 26 patients who had no exacerbations due to NTHI in the previous 12 months (1.42 +/- 0.13) and to 12 healthy control subjects (1.61 +/- 0.16). These three groups had no significant difference in the lymphocyte proliferative response to tetanus toxoid. There was no difference in serum antibody levels to P6 in the two groups with COPD. These results indicate that decreased proliferation of T cells to P6 is associated with exacerbations of COPD and suggest that the ability of T cells to recognize P6 is associated with relative protection from exacerbations due to NTHI.

To characterize the immune response to Moraxella catarrhalis after exacerbations of chronic obstructive pulmonary disease (COPD), pre- and postexacerbation serum and sputum supernatant samples obtained during 21 exacerbations in 18 patients were studied, using the homologous infecting isolates. New serum immunoglobulin G (IgG) detected by whole-cell enzyme-linked immunosorbent assay developed after 12 (57.1%) of 21 exacerbations. Analysis of serum samples with flow cytometry, which detects antibodies that are exclusive to epitopes on the bacterial surface, revealed that 5 (23.8%) of the 21 exacerbations were associated with the development of new serum IgG to surface epitopes. Three of these serum samples and 2 other serum samples contained new IgG directed at lipooligosaccharide. Flow cytometry revealed that new mucosal IgA to surface-exposed epitopes of the infecting isolate developed in sputum supernatants after 42% of exacerbations. Therefore, adults with COPD develop variable humoral immune responses to M. catarrhalis after exacerbations, including new serum IgG and new mucosal IgA to epitopes on the bacterial surface.

OBJECTIVES/SPECIFIC AIMS: To create a new semantically correct high-throughput phenotyping (HTP) platform. To demonstrate the utility of the HTP platform for observational research and can allow clinical investigators to perform studies in 5 minutes. To demonstrate the improved accuracy of observational research using this platform when compared with traditional observational research methods. To demonstrate that patients who have Roseacea are at increased risk of having obstructive sleep apnea (OSA). METHODS/STUDY POPULATION: This population is a set of 212,343 patients in the outpatient setting cared for in the Buffalo area over a 6-year period. All records for these patients were included in the study. Structured data was imported into an OMOP (OHDSI) database and all of the notes and reports were parsed by our HTP system which produces SNOMED CT codes. Each code is designated as a positive, negative or uncertain assertion and compositional expressions are automatically generated. We store the codified data 750,000,000 codes in Berkley DB, a NOSQL database, and we keep the compositional graphs in both Neo4J and in GraphDB (a triple store). Labs are coded in LOINC and drugs using RxNorm. We have developed a Web interface in .Net named BMI Search, which allows real-time query by subject matter experts. We analyzed the accuracy of structured Versus unstructured data by identifiying NVAF cases with ICD9 codes and then looked for any additional cases based on the SNOMED CT encodings of the clinical record. This was validated by 2 clinical human review of a set of 300 randomly selected cases. Separately we ran a study to determine the relative risk of OSA with and without Rosacea using the data set described above. We compared the rates using a Pearson χ2 test. RESULTS/ANTICIPATED RESULTS: We are able to parse 7,000,000 records in an hour and a half on 1 node with 4 CPUs. This yielded 750,000,000 SNOMED CT codes. The HTP data set yielded 1849 cases using ICD9 codes and another 873 using the HTP-NLU data, leading to a final data set of 2722 cases from our population of 212,343 patients. In total, 580 patients had Rosacea;5443 patients had OSA without Rosacea and 51 patients had OSA with Rosacea. Patients with Rosaca had an 8.8% risk of OSA whereas patients without Rosacia only had a 2.6% risk of OSA. This was highly statistically significant with a p2 test). The number needed to test was only 12. DISCUSSION/SIGNIFICANCE OF IMPACT: HTP can change how we do observational research and can lead to more accurate and more prolific investigation. This rapid turn around is part of what is necessary for both precision medicine and to create a learning health system. Patients with Rosacea are at increased risk of and should be screened for OSA.

The healthy lung has previously been considered to be a sterile organ because standard microbiological culture techniques consistently yield negative results. However, culture-independent techniques report that large numbers of microorganisms coexist in the lung. There are many unknown aspects in the field, but available reports show that the lower respiratory tract microbiota: 1) is similar in healthy subjects to the oropharyngeal microbiota and dominated by members of the Firmicutes, Bacteroidetes and Proteobacteria phyla; 2) shows changes in smokers and well-defined differences in chronic respiratory diseases, although the temporal and spatial kinetics of these changes are only partially known; and 3) shows relatively abundant non-cultivable bacteria in chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and bronchiectasis, with specific patterns for each disease. In all of these diseases, a loss of diversity, paralleled by an over-representation of Proteobacteria (dysbiosis), has been related to disease severity and exacerbations. However, it is unknown whether dysbiosis is a cause or a consequence of the damage to bronchoalveolar surfaces.Finally, little is known about bacterial functionality and the interactions between viruses, fungi and bacteria. It is expected that future research in bacterial gene expressions, metagenomics longitudinal analysis and host–microbiome animal models will help to move towards targeted microbiome interventions in respiratory diseases.

Background Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT – Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms. Methods This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset. Results In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman’s rho; p

Background Chronic obstructive pulmonary disease (COPD) is characterized by mucus hypersecretion that contributes to disease related morbidity and is associated with increased mortality. The Lung Flute® is a new respiratory device that produces a low frequency acoustic wave with moderately vigorous exhalation to increase mucus clearance. We hypothesized that the Lung Flute, used on a twice daily basis will provide clinical benefit to patients with COPD with chronic bronchitis. Methods We performed a 26 week randomized, non‐intervention controlled, single center, open label trial in 69 patients with COPD and Chronic Bronchitis. The primary endpoint was change in respiratory symptoms measured with the Chronic COPD Questionnaire (CCQ). Secondary endpoints included health status, assessed by the St. George Respiratory questionnaire (SGRQ), BODE (Body‐Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity) index score and exacerbation frequency. Results While the control patients did not demonstrate any significant changes in the primary endpoint (CCQ change at 26 weeks of +0.01, p = 0.8), a trend (p = 0.08) to decrease (improvement) in the CCQ (‐0.23 at 26 weeks) was seen with the Lung Flute. Furthermore, a significant improvement in the symptom domain of the CCQ was seen only with the lung flute (‐0.42, p = 0.004). Health status (SGRQ) improvement, was also only seen with the Lung Flute (‐3.23, p = 0.03). The BODE score increased in the control group (3.31 at baseline, 4.14 at 26 weeks), however it remained stable in the Lung Flute arm (3.16 at baseline and 26 weeks), with the changes from baseline being significantly different between the 2 arms (p = 0.01). There was a trend for less exacerbations in the Lung Flute group (p = 0.07). Adverse effects were minor, with only 1 patient discontinuing treatment because of lack of efficacy. Serious adverse effects seen were all determined to be unrelated to the device use. Conclusions The Lung Flute is a safe and effective treatment in COPD with chronic bronchitis, providing a wide array of benefits. ClinicalTrials.gov Identifier NCT01186822

Many chronic pulmonary diseases, including those that are not primarily infectious in etiology, have some aspects of their pathogenesis that are influenced by infectious organisms. Microorganisms may contribute to chronic lung diseases, either directly (i.e., overt infection) or indirectly, via the amplification of inflammatory pathways that are critical to host defense. As techniques for detecting and characterizing microorganisms have advanced, investigations of both infecting and colonizing organisms have yielded new insights into mechanisms of pulmonary disease. In addition, changes in patterns of infection and microbial resistance have important implications for treatment. Examples of these infectious–pulmonary associations, including Haemophilus influenzae infection and chronic obstructive pulmonary disease, nontuberculous mycobacteria and bronchiectasis, and human immunodeficiency virus and obstructive lung disease, are reviewed.

Specific bacterial species are implicated in the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD). However, recent studies of clinically stable COPD patients have demonstrated a greater diversity of airway microbiota, whose role in acute exacerbations is unclear. In this study, temporal changes in the airway microbiome before, at the onset of, and after an acute exacerbation were examined in 60 sputum samples collected from subjects enrolled in a longitudinal study of bacterial infection in COPD. Microbiome composition and predicted functions were examined using 16S rRNA-based culture-independent profiling methods. Shifts in the abundance (≥2-fold, P < 0.05) of many taxa at exacerbation and after treatment were observed. Microbiota members that were increased at exacerbation were primarily of the Proteobacteria phylum, including nontypical COPD pathogens. Changes in the bacterial composition after treatment for an exacerbation differed significantly among the therapy regimens clinically prescribed (antibiotics only, oral corticosteroids only, or both). Treatment with antibiotics alone primarily decreased the abundance of Proteobacteria , with the prolonged suppression of some microbiota members being observed. In contrast, treatment with corticosteroids alone led to enrichment for Proteobacteria and members of other phyla. Predicted metagenomes of particular microbiota members involved in these compositional shifts indicated exacerbation-associated loss of functions involved in the synthesis of antimicrobial and anti-inflammatory products, alongside enrichment in functions related to pathogen-elicited inflammation. These trends reversed upon clinical recovery. Further larger studies will be necessary to determine whether specific compositional or functional changes detected in the airway microbiome could be useful indicators of exacerbation development or outcome.

Rationale: Previous studies from our laboratory have shown that peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD) prone to exacerbations with nontypeable Haemophilus influenzae have impaired responses to lipoprotein P6. We hypothesized that an underlying immunosuppressive network could be responsible for the defective antibacterial immunity observed in these patients. We evaluated T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSC), and exhausted T effector cells (programmed death 1 [PD-1]+) in patients with COPD, because these cells are known to play a pivotal role in suppressing immune responses. Objectives: We performed an in-depth characterization of Tregs, T effector cells, and MDSC in COPD and correlated their levels and function with disease severity. Methods: Treg, effector T cell, and MDSC frequency from patients with COPD and healthy subjects’ PBMCs were analyzed by flow cytometry. Treg immunosuppressive capacity was measured by in vitro suppression assay. The frequency of interferon-γ producing T cells and T-cell proliferation were measured after blocking CTLA-4 and PD-1. Plasma proinflammatory and immunosuppressive cytokine levels were measured. Measurements and Main Results: Significantly increased levels of Tregs, MDSC, and PD-1+ exhausted effector T cells were present in patients with COPD compared with healthy subjects. Tregs from patients with COPD suppressed P6-specific T-cell proliferation to a greater extent than Tregs from healthy subjects. Plasma levels of Treg-generated cytokines, IL-10, and transforming growth factor-β were elevated. Blockade of CTLA-4 resulted in significant augmentation of T-cell IFN-γ production in patients with COPD. Conclusions: Functionally suppressive Tregs, MDSCs, and exhausted PD-1+ T cells contribute to effector T-cell dysfunction in COPD.

Background Alveolar macrophages (AM) in COPD have fundamentally impaired responsiveness to Toll-like receptor 2 (TLR2) and TLR4 ligands of non-typeable Haemophilus influenzae (NTHI). However, the contribution of innate immune dysfunction to exacerbations of COPD is unexplored. We hypothesised that impaired innate AM responses in COPD extend beyond NTHI to other pathogens and are linked with COPD exacerbations and severity. Methods AMs, obtained by bronchoalveolar lavage from 88 volunteers with stable-to-moderate COPD, were incubated with respiratory pathogens (NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP) and TLR ligands lipopolysaccharide, Pam 3 Cys) and elicited IL-8 and TNF-α were measured by microsphere flow cytometry. NF-κB nuclear translocation was measured by colorimetric assay. AM TLR2 and TLR4 expression was determined by immunolabeling and quantitation of mean fluorescent indices. Participants were monitored prospectively for occurrence of COPD exacerbations for 1 year following bronchoscopy. Non--parametric analyses were used to compare exacerbation-prone and non-exacerbation-prone individuals. Results 29 subjects had at least one exacerbation in the follow-up period (exacerbation-prone) and 59 remained exacerbation-free (non-exacerbation-prone). AMs of exacerbation-prone COPD donors were more refractory to cytokine induction by NTHI (p=0.02), MC (p=0.045) and SP (p=0.046), and to TLR2 (p=0.07) and TLR4 (p=0.028) ligands, and had diminished NF-κB nuclear activation, compared with non-exacerbation-prone counterparts. AMs of exacerbation-prone subjects were more refractory to TLR2 upregulation by MC and SP (p=0.04 each). Conclusions Our results support a paradigm of impaired innate responses of COPD AMs to respiratory pathogens, mediated by impaired TLR responses, underlying a propensity for exacerbations in COPD.

Despite the increasing awareness of their pathogenesis and clinical consequences, research on and clinical management of acute exacerbations of chronic obstructive lung disease (AECOPDs) have been hindered by the lack of a consistent and reliable definition. Symptom-based definitions of exacerbations are sensitive to events and account for unreported exacerbations. Event (healthcare utilization)-based definitions are somewhat more definitive but miss unreported events. Objective quantification of symptoms in AECOPD is now possible with the development of the Exacerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT-PRO), a patient-reported outcome (PRO) measure.Several studies have revealed that unreported AECOPDs are more frequent than reported events and are associated with long-term adverse consequences. New antibiotic development for AECOPD has been hampered by the lack of validated measures for resolution of exacerbations. As a result of these observations, a unique collaborative effort between academia, industry and regulatory agencies resulted in the development of the EXACT-PRO. It consists of 14 questions that generate a score between 0 and 100, and it has been shown to have excellent reliability and validity.In the absence of a reliable biomarker, the definition and measurement of exacerbations has been subjective and imprecise. PRO measures such as EXACT can provide much needed objectivity in assessing symptom-defined exacerbations, which may translate into a uniform outcome measure in clinical trials. With further development and validation, it may have a role in clinical practice in the earlier detection of exacerbations, stratification of an exacerbation severity and the assessment of clinical response to treatment.

Background: Acute respiratory tract infections such as acute exacerbations of chronic bronchitis (AECB), acute otitis media (AOM), and acute bacterial rhinosinusitis (ABRS) account for ∼75% of antibiotic prescriptions written and are among the leading reasons for physician office visits in the United States. Resistance of the predominant pathogens in respiratory tract infections ( Streptococcus pneumoniae, Haemophilus influenzae , and Moraxella catarrhalis ) to available antibiotics has led clinicians to reevaluate the diagnosis and management of these infections. Objective: The purpose of this review is to provide primary care practitioners with an accessible combined resource for the management of AECB, AOM, and ABRS. Methods: This review was based on discussions from a roundtable meeting (sponsored by an educational grant from GlaxoSmithKline) that convened clinicians versed in the management of upper and lower respiratory tract infections. In addition, primary articles were identified by a MEDLINE search and through secondary sources. Results: To reduce the prevalence of resistance, judicious and appropriate use of antibiotics must be implemented in clinical practice. With accurate diagnosis of bacterial and nonbacterial conditions, and patient education on antibiotic use and misuse, the excessive use of antibiotics and ensuing resistance can be reduced. The incorporation of pharmacokinetic and pharmacodynamic data with minimum inhibitory concentration values can provide a more comprehensive assessment of antibiotic activity in vivo. Stratification of patients with AECB according to patient characteristics and frequency of exacerbation can be used to determine which patients will benefit from antibiotic treatment and to guide clinicians in their choice of antibiotic. The Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group has issued recommendations on the management of AOM based on prior antibiotic therapy, which is a risk factor for antimicrobial resistance. The Sinus and Allergy Health Partnership guidelines for the treatment of ABRS in adults and children are based on the predicted efficacy of various antibiotics as well as patient age, severity of disease, likelihood of bacterial infection, likelihood of spontaneous resolution, and in vitro susceptibility of the predominant pathogens based on pharmacokinetic and pharmacodynamic breakpoints. Conclusions: Guidelines for the management of AECB, AOM, and ABRS emphasize the importance of differentiating between bacterial and nonbacterial infections, choosing an antibiotic based on the likelihood of infection with resistant pathogens, and providing coverage against the predominant pathogens. The judicious use of antibiotics also has been identified as an instrumental part of controlling unnecessary antibiotic use and subsequent resistance.

Acute exacerbations of chronic bronchitis (AECB) are a major cause of morbidity and mortality. Bacterial pathogens are implicated in about half the episodes of AECB. Empirical antibacterials have a significant benefit in AECB; however, several recent developments have considerably complicated antibacterial choice for this condition. New fluoroquinolone antibacterials introduced in the last decade are theoretically well suited for the treatment of AECB, as the in vitro antimicrobial spectrum of these drugs includes all the major pathogens involved. The pharmacokinetic and pharmacodynamic properties of the new fluoroquinolones are superior to many other antibacterials used to treat AECB. In trials, clinical success with the new fluoroquinolones was equivalent and bacteriological success was occasionally superior to nonfluoroquinolone comparators. However, these clinical trials did not assess several potentially important end-points for which the theoretical superiority of the fluoroquinolones may translate into differences in outcome. Rare but serious adverse effects with some of the new fluoroquinolones have shaken the confidence of prescribing physicians in this class of drugs. Emergence of the resistance of Streptococcus pneumoniae to fluoroquinolones has raised concerns about indiscriminate and widespread use of the new agents for trivial infections. Patients with AECB are a heterogeneous population who should be stratified in order to appropriately choose empirical antibacterial therapy. Highly efficacious antibacterial therapy, such as the new fluoroquinolones, is appropriate as a first-line choice for patients who have risk factors for a poor outcome or are in intensive care units. Such selected use of the new fluoroquinolones balances individual benefit with societal concerns of the use of these agents for AECB.

Study objectives: The etiologic role of bacterial pathogens isolated from sputum culture in 40 to 50% of acute exacerbations of chronic bronchitis (AECB) is controversial. If bacterial pathogens cause these AECB, they should be associated with greater neutrophilic airway inflammation than pathogen-negative exacerbations. Design: This hypothesis was tested by comparing levels of interleukin (IL)-8, tumor necrosis factor (TNF)-a, and neutrophil elastase (NE) in 81 sputum samples obtained from 45 patients with AECB. Four groups were compared. In the first three groups, nontypeable Haemophilus influenzae (n 5 20), Haemophilus parainfluenzae (n 5 27), and Moraxella catarrhalis (n 5 14) were isolated as sole pathogens, respectively. In the fourth group, only normal flora was isolated (n 5 20). Paired samples, obtained from individual patients at different times, that differed in their culture results were also compared. Setting: An outpatient research clinic at a Veterans Affairs Medical Center. Patients: These patients were participating in a prospective, longitudinal study of the dynamics of bacterial infection in chronic bronchitis, for which they were seen in the study clinic on a monthly basis as well as when they were experiencing symptoms suggestive of AECB. Interventions: None. Measurements and results: H influenzae exacerbations were associated with significantly higher sputum IL-8, TNF-a, and NE. M catarrhalis exacerbations demonstrated significantly higher sputum TNF-a and NE when compared to pathogen-negative exacerbations. H parainfluenzaeassociated exacerbations had an inflammatory profile similar to pathogen-negative exacerbations. Sputum elastase level distinguished bacterial from nonbacterial AECB and correlated with clinical severity of the AECB. Conclusions: Increased airway inflammation associated with isolation of H influenzae and M catarrhalis supports an etiologic role of these pathogens in AECB. (CHEST 2000; 118:1557‐1565)

The role of infection in exacerbations of COPD remains controversial and incompletely understood. Although some investigators believe that bacteria are not important for patients with exacerbation, we disagree and believe that patients with at least two of the three cardinal symptoms of exacerbation should receive antibiotic therapy. With an open-minded view of the area, we review the data, showing that bacteriologic studies, pathologic investigations, and clinical trials all support roles for bacteria and antibiotic therapy in this disease. Still, many questions remain, and future studies will be needed to better define the mechanisms of bacterial invasion in the bronchitic patient and to develop effective vaccines to prevent exacerbations. In the meantime, we must rely on antibiotic therapy, and we will need prospective studies to corroborate preliminary findings showing that different patients may require different therapies; thus, patient subsetting may be vital in the selection of antibiotic therapy for exacerbations of COPD.

Bacterial infection of the lower respiratory tract can impact on the etiology, pathogenesis, and the clinical course of COPD in several ways. Several recent cohort studies suggest that lung growth is impaired by childhood lower respiratory tract infection, making these individuals more vulnerable to developing COPD on exposure to additional injurious agents. Impairment of mucociliary clearance and local immune defense in smokers allows bacterial pathogens to gain a foothold in the lower respiratory tract. These pathogens and their products can cause further impairment of mucociliary clearance due to enhanced mucus secretion, disruption of normal ciliary activity, and airway epithelial injury, and thus persist in the lower respiratory tract. This chronic colonization of the lower respiratory tract by bacterial pathogens could induce a chronic inflammatory response with lung damage. Nontypeable Haemophilus influenzae, usually regarded as an extracellular mucosal pathogen, has been demonstrated to cause intracellular infections of the upper and lower respiratory tract respiratory tissue. Increased incidence of chronic Chlamydia pneumoniae infection of the respiratory tract has been associated with COPD. These chronic infections of respiratory tissues could contribute to the pathogenesis of COPD by altering the host response to cigarette smoke or by inducing a chronic inflammatory response. Application of newer molecular and immunologic research techniques is helping us define precisely the role of bacterial infection in COPD.

Infectious agents are a major cause of acute exacerbations of chronic bronchitis (AECB) and COPD. Several respiratory viruses are associated with 30% of exacerbations, with or without a superimposed bacterial infection. Atypical bacteria, mostly Chlamydia pneumoniae, have been implicated in < 10% of AECB. The role of bacterial pathogens when isolated from the respiratory tract during AECB has become better defined by application of several newer investigative techniques. Bacterial pathogens can be isolated in significant concentrations from distal airways in 50% of AECB. Specific immune responses to surface exposed antigens of the infecting pathogen have been shown to develop after an exacerbation. Emerging evidence from molecular epidemiology and measurement of airway inflammation further support the role of bacteria in AECB. When properly defined, 80% of AECB are likely to be infectious in origin.

A vicious circle of infection and inflammation in the airways in chronic obstructive pulmonary disease (COPD) could cause progressive lung damage and contribute to progressive loss of lung function characteristic of this disease. Bacteria and viruses cause a substantial proportion of exacerbations of COPD, which have now been clearly characterized as inflammatory events with adverse consequences in the course of COPD. Chronic infection by virus, bacteria, and other microbes is also prevalent in COPD, and human and experimental data are linking this chronic infection to COPD pathogenesis. COPD is heterogeneous; therefore it is likely infections have a varying degree of importance among patients with this disease.

Chronic bronchitis is an increasing cause of significant morbidity and mortality. Despite treatment, respiratory tract infection is the most common identifiable cause of death for patients with chronic obstructive pulmonary disease. Repeated infectious exacerbations may ultimately cause acute and chronic lung injury. The most common bacterial aetiologies of acute exacerbations of chronic bronchitis (AECB) include Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae.Pseudomonas aeruginosa is often a nosocomial pathogen and is becoming more prevalent in patients with severe underlying disease. Viruses are responsible for approximately one-third of acute exacerbations overall. Atypical pathogens are causative pathogens in 65 years) or have recurrent exacerbations. In patients who do not have these risk factors (i.e. those with simple chronic bronchitis), agents such as co-trimoxazole remain useful.

Although chronic obstructive pulmonary disease (COPD) was arbitrarily defined in the early 1960s as a single disease characterized by chronic airflow obstruction (1), it has long been recognized as a heterogeneous group of related disorders. In the 1950s, Dornhorst described two extreme phenotypes of patients with severe respiratory disease: pink puffers and blue bloaters (2). More recently, the heterogeneity of patients with COPD was elegantly demonstrated in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. The authors showed that for a given level of airflow limitation, there were major differences in dyspnea, exercise capacity, rates of exacerbations, and health status (3), reinforcing interest in understanding the determinants of heterogeneous clinical presentation. At that time, the concept of COPD phenotypes was defined by group of experts as “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)” (4). The goals of phenotyping are to help in the identification of specific biological pathways, to enrich clinical trials in patients at high risk for outcomes of interest, and to pave the way for provision of individualized care. Because multiple patient characteristics have been identified that might contribute to identifying potential phenotypes, novel mathematical methods (e.g., principal component and cluster analyses) have been introduced in the COPD field with the goal of analyzing large amounts of clinical, imaging, and biological data (5). In recent years, several studies have used these mathematical approaches to analyze cohorts of patients with COPD with the goal of identifying clinically relevant COPD phenotypes (reviewed in Reference 6). Some phenotypes appeared relatively reproducible across studies, including two severe phenotypes with poor prognosis: young patients with severe respiratory disease but few cardiovascular comorbidities and older patients with less severe respiratory disease but high rates of metabolic and cardiovascular comorbidities (5, 6). However, all previous cluster studies had limitations related to relatively small numbers of patients, lack of extensive data for patient characterization, and lack of prospective validation of phenotypes in some of the studies. In this month’s issue of AnnalsATS, Rennard and colleagues (pp. 303–312) sought to identify clinically relevant COPD phenotypes, using data generated by the ECLIPSE study (7). The strengths of their analysis include the relatively large number of patients; standardized collection of clinical, physiological, radiological, and biomarker data; and a 3-year standardized follow-up period to assess clinically relevant outcomes. However, the patients included in the ECLIPSE study were not consecutive patients with COPD in the community but, rather, a select group of patients at tertiary care centers willing and able to participate in a 3-year study. The majority of those patients were receiving COPD maintenance treatment, and the intensity and appropriateness of such treatment likely affected the various parameters used in the cluster analysis, as well as measured outcomes (e.g., symptoms, exacerbations). These potential confounders should be recognized when interpreting this study. Were the clusters derived from this analysis clinically meaningful? Cluster A, composed of patients with mild COPD who had excellent outcomes, and cluster D, composed of patients with severe airflow obstruction who fared poorly, confirm what we see in everyday clinical practice. Cluster C, the comorbid cluster, supports increasing awareness that comorbid conditions may be as important in determining COPD phenotypes as characteristics of the lung disease itself. These observations confirm the validity of clusters that have been identified in earlier studies (6). Cluster B was the smallest cluster but is intriguing in that it identified patients with mild to moderate emphysema who experienced rapid progression despite a rate of current smoking (31%) that was comparable to that of the other groups. The most dissatisfying cluster is Cluster E, the mixed group, which accounted for half of the patients. Essentially, this fifth cluster is composed of patients who could not be clustered otherwise. Cluster E represents the largest group, with variable outcomes. It is a reminder of the limitations of cluster analysis and the considerable heterogeneity of COPD. The authors of this study recognize that many of the variables included in the ECLIPSE study are not usually measured in the clinical setting, and the analytic method does not use well-defined cutoff values to

Nontypeable Haemophilus influenzae (NTHI) causes recurrent respiratory tract infections in patients with chronic bronchitis. To elucidate the human immune response to NTHI, sera from 2 patients with exacerbations of chronic bronchitis due to NTHI were characterized. Both patients developed new bactericidal antibodies following infection. Immunoblot assays with homologous strains revealed antibodies to many antigens, with minimal difference between pre- and postexacerbation sera. By contrast, whole cell radioimmunoprecipitation, which detects antibodies exclusively to epitopes exposed on the bacterial surface, revealed that both patients made new antibodies to a limited number of antigens following infection, including P2, the major outer membrane protein of NTHI. Adsorption experiments showed that strain-specific, surface-exposed epitopes on the P2 molecule are targets for bactericidal antibodies. These results indicate that new bactericidal antibodies following infection by NTHI recognize antigenically heterogeneous surface-exposed epitopes on P2 and other surface proteins of NTHI.

Outer membrane protein E (OMP E) is a 50-kDa major OMP of Branhamella catarrhalis. Polyclonal antisera and four monoclonal antibodies (MAbs) to OMP E were generated to study its antigenic structure. All antibodies recognized epitopes in all 19 B. catarrhalis strains tested by immunoblot assays. By flow cytometry, it was determined that MAbs 1B3 and 9G10d recognized epitopes which are expressed on the surface of the intact bacterium, while MAbs IC11 and 7C10 recognized epitopes which were buried within the outer membrane. A competitive enzyme-linked immunosorbent assay showed that MAbs 1B3 and 9G10d recognize the same or closely related epitopes. Proteinase K treatment of whole bacterial cells revealed that MAbs 1B3 and 9G10d recognize a surface-exposed epitope located in the 17-kDa region towards the amino terminus of OMP E. The human serum and mucosal antibody responses to OMP E in adults with chronic bronchitis were studied. A majority of these patients had immunoglobulin A to OMP E in sputum supernatants. None of ten adults who experienced lower respiratory tract infections due to B. catarrhalis demonstrated a clear-cut rise in antibody titer to OMP E in serum or sputum supernatant. This study has demonstrated that OMP E has at least one surface-exposed epitope which is highly conserved among strains of B. catarrhalis and which is located in the amino-terminal 184 amino acids of the molecule.

It is ironic that respiratory syncytial virus (RSV) infection in adults, though recognized for several decades, has been overlooked, at least in part, because of the importance of RSV in the pediatric population. The report by Falsey et al. in this issue of the Journal has placed the public health dimensions of RSV infection in adults in perspective.1 Though there are no immediate clinical implications of this study, it does have important repercussions for public health strategy and for the prioritization of the development of vaccines and antiviral agents. Several important features of the study design used by Falsey et . . .

Proteomic analysis of bronchoalveolar lavage fluid (BALF) in chronic obstructive pulmonary disease (COPD) patients may provide new biomarkers and deeper understanding of the disease mechanisms but remains challenging. Here we describe an ion-current-based strategy for comparative analysis of BALF proteomes from patients with moderate and stable COPD versus healthy controls. The strategy includes an efficient preparation procedure providing quantitative recovery and a nano-LC/MS analysis with a long, heated column. Under optimized conditions, high efficiency and reproducibility were achieved for each step, enabling a "20-plex" comparison of clinical subjects (n = 10/group). Without depletion/fractionation, a total of 423 unique protein groups were quantified under stringent criteria with at least two quantifiable peptides. Seventy-six proteins were determined as significantly altered in COPD, which represent a diversity of biological processes such as alcohol metabolic process, gluconeogenesis/glycolysis, inflammatory response, proteolysis, and oxidation reduction. Interestingly, altered alcohol metabolism responding to oxidant stress is a novel observation in COPD. The prominently elevated key enzymes involved in alcohol metabolism (e.g., ADH1B, ALDH2, and ALDH3A1) may provide a reasonable explanation for a bewildering observation in COPD patients known for decades: the underestimation of the blood alcohol concentrations through breath tests. These discoveries could provide new insights for identifying novel biomarkers and pathological mediators in clinical studies.

The paradigm of bacterial colonization of the lower airways in COPD contributing to progressive lung disease is supported by the association of bacterial colonization with advanced airway inflammation, increased frequency of exacerbations, and accelerated decline in lung function [1–3]. Once initiated, chronic inflammation and failure to clear bacteria of the lower airways may promote progression of COPD [4, 5]. Moreover, bacterial colonization of the airways is associated with increased risk of exacerbation of COPD [6]. Our previous studies identified a fundamental phagocytic defect of alveolar macrophages in COPD to 3 clinical strains of NTHI that is not attributable to active smoking [7]. However, macrophages derived from peripheral blood monocytes of COPD donors had no phagocytic impairment, suggesting a compartmentalized immunologic defect. Intracellular survival of NTHI in macrophages after phagocytosis has been theorized to play a role in bacterial persistence [8, 9]. However, we found no increase in intracellular viability of bacteria in COPD alveolar macrophages. Instead, failure to evoke a phagocytic response by alveolar macrophages in COPD may permit evasion of immune clearance by bacterial pathogens, providing a source for perpetuating inflammation. Our related findings of impaired cytokine responsiveness to outer membrane protein P6 and to lipooligosaccharide of NTHI further indicated that intrinsic alveolar macrophage impairment in COPD is not limited to a single intracellular signaling pathway [10]. Collectively, these studies support an immunologic basis for persistence of NTHI in the respiratory tract of adults with COPD. However, our previous investigation was limited to study of NTHI and did not determine if defective phagocytosis discriminated among respiratory targets [7]. Further, the impact of active smoking on alveolar macrophage dysfunction in COPD was not explored. Each bacterial species that causes infection in adults with COPD displays unique dynamics of colonization and immune interaction with human cells. Nontypeable Haemophilus influenzae (NTHI) and Moraxella catarrhalis are the 2 most prevalent bacteria associated with exacerbations of COPD [11, 12]. Host acquisition of new strains of NTHI and host lymphocyte and antibody responses to NTHI antigens are associated with exacerbations of COPD [13–15]. Host antibody responses to outer membrane antigens of M. catarrhalis are also associated with respiratory clearance [16]. Moreover, M. catarrhalis strains have conserved genes whose proteins are expressed during infection in COPD [17]. NTHI and M. catarrhalis are predominantly mucosal pathogens [15, 18]. Although Streptococcus pneumoniae is also a mucosal pathogen, it is a leading cause of community-acquired pneumonia in COPD [19, 20]. Each of these bacterial pathogens presents a unique set of potential immunologic triggers for different host pathways. Beyond this, the link between impaired alveolar macrophage innate defense and severity of COPD has only been explored to a limited degree. We hypothesized that the impaired immunologic responses of COPD alveolar macrophages to NTHI extend to other respiratory pathogens, and that responses to pathogen-associated molecular motifs of bacteria are different from responses to inert targets. We further theorized that dysfunctional alveolar macrophage phagocytosis in COPD, associated with failure to effectively clear respiratory pathogens, is associated with severity of disease in COPD and performed experiments to test these hypotheses.

SummaryAcute exacerbations (AE) can be recurrent problems for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) increasing morbidity and mortality. Evidence suggests that ≥50% of acute exacerbations involve bacteria requiring treatment with an antibiotic which should have high activity against the causative pathogens. However, sputum analysis is not a pre-requisite for antibiotic prescription in outpatients as results are delayed and patients are likely to be colonised with bacteria in the stable state. Clinicians rely on the clinical symptoms, sputum appearance and the patient's medical history to decide if an AE-COPD should be treated with antibiotics. This article reviews the available data of antibiotic trials in AE-COPD. Management of frequent exacerbators is particularly challenging for physicians. This may include antibiotic prophylaxis, especially macrolides because of anti-inflammatory properties; though successful in reducing exacerbations, concerns about resistance development remain. Inhalation of antibiotics achieves high local concentrations and minimal systemic exposure; therefore, it may represent an attractive alternative for antibiotic prophylaxis in certain COPD patients. Inhaled antibiotic prophylaxis has been successfully used in other respiratory conditions such as non-cystic fibrosis bronchiectasis which itself might be present in COPD patients who have chronic bacterial infection, particularly with Pseudomonas aeruginosa.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMOnary disease (COPD) involve inflammatory events in the airway caused mostly by infection— bacterial, viral, or both. During the last 2 decades, the understanding of exacerbations has improved, and these exacerbations are now regarded as major contributors to cost of care, health status deterioration, loss of lung function, and mortality in COPD. However, treatment of exacerbations has not evolved significantly, and clinical failure rates (need for additional treatment or hospitalization) of 20% to 40% within 1 month are still prevalent. Prevention of exacerbations is at the forefront as a therapeutic goal in COPD. However, to apply preventive therapies effectively, identifying patients at risk for future exacerbations is critical but not simple. Chronic obstructive pulmonary disease is a heterogeneous disease with multiple phenotypes. Although the frequency of exacerbations is related to the severity of airflow obstruction, some patients with severe disabling lung disease never have exacerbations, whereas other patients with much less airflow obstruction have frequent exacerbations. Other clinical risk factors associated with frequent exacerbations include a history of previous exacerbations, poor diseasespecific health status, chronic bronchitis, and gastroesophageal reflux, with the strongest predictive factor being a history of previous exacerbations. If exacerbations worsen lung function and health status over time in patients with COPD, current predictive factors may simply rely on the consequences of prior exacerbations to predict future episodes. The current approach for identifying a high-risk patient to prevent exacerbations is likely “too little, too late.” Further refinement and earlier detection of exacerbation risk in COPD is clearly needed. In this issue of JAMA, Thomsen et al report findings from 2 large, population-based, prospective studies demonstrating that elevated levels of systemic inflammatory biomarkers (C-reactive protein, fibrinogen, and leukocyte count) were associated with future exacerbations of COPD. This association was observed after accounting for other variables important for determining the risk of exacerbations, especially lung function and history of exacerbations. (Chronic bronchitis and gastroesophageal reflux apparently were not included as potential risk factors.) The association had a stepwise pattern; elevations in levels of all 3 biomarkers had the highest utility in predicting exacerbations, whereas the predictive value was minimal to moderate if only 1 or 2 biomarkers were elevated. This study has several strengths, including a large number of patients (6574 with COPD and a total of 3083 exacerbations), prospective follow-up with no loss to follow-up, and reliable capture of exacerbations through a single central health care system database. The biomarkers studied are simple to measure, inexpensive, and readily available, and specific values are provided. Several aspects of experimental design need to be considered in interpreting the results. Chronic obstructive pulmonary disease was diagnosed if the ratio of forced expiratory volume in 1 second to forced vital capacity was less than 70%. Patients younger than age 40 years and those with selfreported asthma were excluded. Nevertheless, 1435 participants (22%) were life-long nonsmokers. Whether these patients truly had COPD or were elderly individuals with normal age-related reduction in lung elasticity is uncertain. The predictive value of the inflammatory biomarkers was attenuated in the nonsmoker subgroup. Because of the population-based rather than disease-targeted enrollment in this study, the proportion of patients with mild to moderate COPD is substantially larger than in other studies. Generalizability of their observations to more severe COPD may therefore be limited. The COPD severity distribution also likely explains the low exacerbation rate observed of 0.5 episodes per patient per year. Another factor that may have contributed to the low rate is the definition of exacerbation used, which included either a short course of corticosteroids (with or without antibiotics) or a hospital admission due to COPD. Many exacerbations, particularly in mild COPD, are diagnosed as acute bronchitis and treated with antibiotics only, and these episodes were not captured in this analysis. Another con

Acute exacerbations of COPD (AECOPD) are defined by clinical criteria, outlined in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [1]. These include an acute increase in one or more of the following cardinal symptoms, beyond day to day variability: dyspnea, increased frequency or severity of cough and increased volume or change in character of sputum, which represent an acute increase in airway inflammation. The role of infection in the pathogenesis of COPD, acute exacerbation and disease progression has been a clinical and research question for many years, and the pendulum has swung from infection as a major cause of acute exacerbation and COPD (British Hypothesis) [2], to infection as an unrelated epiphomenon in acute exacerbation [3–5], and back again to infection as integral in the development of AECOPD and likely an important contributor to COPD progression [6–19]. Upwards of 80 % of AECOPD are driven by infectious stimuli, with 40–50 % associated with bacterial infection and 30–50 % associated with acute viral infection, with some exacerbations having dual bacterial and viral causation [20]. Much of the advancement in our understanding of the role of infection is AECOPD is due to the advancement of clinical and research tools that have allowed researchers to accurately characterize the microbial pathogens, and better understand the host-pathogen interactions (Table 1).