Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med ...
1046
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
(although nonlinear) bivariate relation to the other LHE patterns. Even though the measuring units of Fahrenheit and Celsius differ, in theory the correlation between measuring temperatures in Fahrenheit and Celsius should be exactly 1. However, due to measuring error, the correlation is usually a little less (e.g., 0.95) in real life. Therefore, the strong interrelationship between the LHE patterns indicates that the intuitive interpretation of the patterns as equal to (or surrogates of) the visual patterns is misleading. Furthermore, the high correlation (r . 0.82) of the LHE patterns with the standard CT measure for quantification of emphysema (%LAA-950) leads to the alternative interpretation of the LHE patterns as being general measures of emphysema without any real information on visual patterns. Obviously, the units of the various LHE patterns differ (just like measuring temperatures in Fahrenheit and Celsius), and that has no influence on the high correlations between these measures. The alternative interpretation of the results is supported by regression models relating each LHE pattern to COPD-related measures of disease severity, which indicate that the LHE patterns constitute an ordered range of increasing severities of emphysema (i.e., NE , mild centrilobular , moderate centrilobular , severe centrilobular , PL). Also, the very close (although inverse) relation between the NE and PB emphysema patterns (r ¼ 20.94) shows that the PB pattern is just another measure of general emphysema with no specific relation to the visual paraseptal emphysema pattern. Thus, we may conclude, as the authors have, that “emphysema occurs in distinct pathological patterns, but it is technically challenging to efficiently extract information on these patterns from [CT] scans . . . Additional work remains to be done integrating information from data-driven emphysema quantification algorithms and expert-derived emphysema classification patterns,” and there still seems to be a long way to go before computer software can automatically detect distinct and intuitively meaningful phenotypes in COPD. Author disclosures are available with the text of this article at www.atsjournals.org.
Asger Dirksen, M.D. Department of Respiratory Medicine, Gentofte Hospital Copenhagen University Hellerup, Denmark William MacNee, M.D. UoE/MRC Centre for Inflammation Research Queen’s Medical Research Institute Edinburgh, United Kingdom
VOL 188
2013
References 1. Silverman EK, Vestbo J, Agusti A, Anderson W, Bakke PS, Barnes KC, Barr RG, Bleecker ER, Boezen HM, Burkart KM, et al. Opportunities and challenges in the genetics of COPD 2010: an International COPD Genetics Conference report. COPD 2011;8:121–135. 2. Han MK, Agustí A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010;182:598–604. 3. Agustí A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122. 4. Agustí A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012;7:e37483. 5. Han MK, Kazerooni EA, Lynch DA, Liu LX, Murray S, Curtis JL, Criner GJ, Kim V, Bowler RP, Hanania NA, et al.; COPDGene Investigators. Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology 2011;261:274–282. 6. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agustí A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, et al.; ECLIPSE Investigators. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011;365:1184–1192. 7. Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, et al.; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:1065–1072. 8. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: glossary of terms for thoracic imaging. Radiology 2008;246:697–722. 9. Castaldi PJ, Estépar RSJ, Mendoza CS, Hersh CP, Laird N, Crapo JD, Lynch DA, Silverman EK, Washko GR. Distinct quantitative CT emphysema patterns are associated with physiology and function in smokers. Am J Respir Crit Care Med 2013;188:1083–1090. 10. Barr RG, Berkowitz EA, Bigazzi F, Bode F, Bon J, Bowler RP, Chiles C, Crapo JD, Criner GJ, Curtis JL, et al.; COPDGene CT Workshop Group. A combined pulmonary-radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation. COPD 2012;9:151–159. Copyright ª 2013 by the American Thoracic Society DOI: 10.1164/rccm.201309-1649ED
AECOPD: Acute Exacerbations of Chronic Obstructive Cardiopulmonary Disease? Chronic obstructive pulmonary disease (COPD), airflow obstruction, and emphysema are increasingly recognized as risk factors for accelerated atherosclerosis and cardiovascular disease independent of well-established and shared risk factors such as cigarette smoking, age, and environmental pollution (1). The increased cardiovascular risk is most pronounced for incident coronary artery disease, and patients with COPD are 1.5 to 5 times more likely to be affected than those without airflow obstruction (1). Accelerated atherosclerosis has been demonstrated in COPD by increases in both carotid intima-media thickness and lipid-rich plaques, with the latter being especially important in causing major acute coronary events (2). The mechanisms underlying this accelerated vascular disease are not
completely understood, but sympathetic surge, a procoagulant state, oxidative stress, and systemic inflammation likely all contribute (2). The possibility of a pathophysiologic link between pulmonary inflammation and resultant systemic inflammation has been previously suggested (3), and it is plausible that the latter may drive plaque instability. This can result in major coronary events (4), including myocardial infarctions, that are temporally associated with severe exacerbations of COPD (5). It has also been noted that even subtle rises in markers of cardiac injury are associated with worse exacerbation outcomes (6), though the pathophysiology of these injuries remains unknown and it is unlikely that they are caused by plaque rupture.
Editorials
In this regard, it is pertinent that arterial stiffness has been shown to be elevated in patients with stable COPD as compared with healthy controls (7, 8) and that this could again result from increased systemic inflammation (8, 9). Other noninflammatory mechanisms such as increased sympathetic tone and activation of the renin–angiotensin system may also contribute, and the latter might even have a blood pressure–independent effect (10). Arterial stiffness has been shown to be an independent risk factor for cardiovascular events (11) and could be a marker of atherosclerosis. However, increases in arterial stiffness may have important and direct hemodynamic consequences that cause subtle cardiac injury (12). Stiff central arteries influence blood pressure, causing a rise in systolic and a fall in diastolic blood pressure due to the faster reflection of pressure waves created by cardiac contraction at arterial branch points, thereby causing a wider pulse pressure (12). Increased systolic pressure and thus afterload can alter the tight balance between myocardial oxygen demand and myocardial capillary-to-fiber ratio, whereas a reduction in diastolic pressure can reduce coronary perfusion, resulting in myocardial ischemia (12). In a well-conducted observational cohort study reported in this issue of the Journal (pp. 1091–1099), Patel and colleagues compared markers of cardiac risk (arterial stiffness and C-reactive protein) and cardiac injury (troponin and brain natriuretic peptide) in patients with moderate-to-severe COPD with frequent exacerbations to those in patients with infrequent exacerbations, and also compared them between stable phase and acute exacerbation (13). This study adds important insights into pathophysiological relationships between acute exacerbations and cardiac injury. First, although severe exacerbations are known to be associated with myocardial ischemia (5), there is little published data to suggest that this occurs during mild-to-moderate episodes, and thus these findings are provocative. Though the rise in serum levels of troponin and brain natriuretic peptide might seem modest, and it is possible that some of the biomarker leak arises from the right ventricle, other studies have linked comparable rises in troponin to increases in the electrocardiogram-derived Cardiac Infarction Injury Score (CIIS), which has important short- and long-term prognostic implications for the prediction of coronary events (14). Second, although there were no incident major coronary events in the study during the follow-up year, the finding that arterial stiffness increases during exacerbations treated in an ambulatory setting and remains elevated for up to 8 weeks is a cause for concern, as these milder events are frequently not reported. As such, it is possible that recurring episodes of associated myocardial ischemia could be missed, which would prevent the recognition and appropriate management of critical comorbid cardiovascular disease. The fact that frequent exacerbators had greater arterial stiffness than infrequent exacerbators, and that exacerbations due to infections were associated with more significant elevations, also raises concern that repeated respiratory episodes could result in cumulative cardiac injury. Third, although the study is limited by a relatively small sample size, which might have precluded finding associations between arterial stiffness and some of its expected determinants such as heart rate and blood pressure, the study provides important evidence to support a mechanistic and temporal link between pulmonary exacerbation, systemic inflammation, and downstream arterial stiffness and cardiac injury. Frequent exacerbators are a distinct phenotype of COPD, and in addition to accelerated decline in FEV1, poorer quality of life, and poorer exercise capacity, they have increased mortality (15). Exacerbation-related cardiac injury might be a piece of the puzzle as to why this is the case. The current study adds to the
1047
urgency to test new and existing drugs that may modify inflammatory and noninflammatory pathways and in turn drive COPDrelated cardiovascular disease (16, 17). Although it is tempting to advocate the use of b-blockers and angiotensin pathway inhibitors (18), the answers might not be so simple (19), and more research is imperative. In the meantime, pulmonologists would be wise to remember that they are responsible not just for the physiologic complexities of the two lungs, but also for the simple pump in between. Author disclosures are available with the text of this article at www.atsjournals.org.
Surya P. Bhatt, M.D. UAB Lung Health Center University of Alabama at Birmingham Birmingham, Alabama Mark T. Dransfield, M.D. UAB Lung Health Center University of Alabama at Birmingham Birmingham, Alabama and Birmingham VA Medical Center Birmingham, Alabama
References 1. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2005;2:8–11. 2. Bhatt SP, Dransfield MT. Chronic obstructive pulmonary disease and cardiovascular disease. Transl Res 2013;162:237–251. 3. Barnes PJ. Future treatments for chronic obstructive pulmonary disease and its comorbidities. Proc Am Thorac Soc 2008;5:857–864. 4. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611–2618. 5. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010;137:1091–1097. 6. Chang CL, Robinson SC, Mills GD, Sullivan GD, Karalus NC, McLachlan JD, Hancox RJ. Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax 2011;66:764–768. 7. Mills NL, Miller JJ, Anand A, Robinson SD, Frazer GA, Anderson D, Breen L, Wilkinson IB, McEniery CM, Donaldson K, et al. Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk. Thorax 2008;63: 306–311. 8. Sabit R, Bolton CE, Edwards PH, Pettit RJ, Evans WD, McEniery CM, Wilkinson IB, Cockcroft JR, Shale DJ. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:1259–1265. 9. McAllister DA, Maclay JD, Mills NL, Mair G, Miller J, Anderson D, Newby DE, Murchison JT, Macnee W. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;176: 1208–1214. 10. Wilkinson IB, MacCallum H, Hupperetz PC, van Thoor CJ, Cockcroft JR, Webb DJ. Changes in the derived central pressure waveform and pulse pressure in response to angiotensin II and noradrenaline in man. J Physiol 2001;530:541–550. 11. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 2010;121:505–511. 12. Bai Y, Ye P, Luo L, Xiao W, Xu R, Wu H, Bai J. Arterial stiffness is associated with minimally elevated high-sensitivity cardiac, troponin T levels in a community-dwelling population. Atherosclerosis 2011;218: 493–498. 13. Patel ARC, Kowlessar BS, Donaldson GC, Mackay AJ, Singh R, George SN, Garcha DS, Wedzicha JA, Hurst JR. Cardiovascular risk, myocardial injury and exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1091–1099.
1048
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
14. Brekke PH, Omland T, Holmedal SH, Smith P, Søyseth V. Determinants of cardiac troponin T elevation in COPD exacerbation - a crosssectional study. BMC Pulm Med 2009;9:35. 15. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 2010;19:113–118. 16. Dransfield MT, Cockcroft JR, Townsend RR, Coxson HO, Sharma SS, Rubin DB, Emmett AH, Cicale MJ, Crater GD, Martinez FJ. Effect of fluticasone propionate/salmeterol on arterial stiffness in patients with COPD. Respir Med 2011;105:1322–1330. 17. Vivodtzev I, Minet C, Wuyam B, Borel JC, Vottero G, Monneret D, Baguet JP, Lévy P, Pépin JL. Significant improvement in arterial stiffness after endurance training in patients with COPD. Chest 2010;137:585–592.
VOL 188
2013
18. Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006;47:2554–2560. 19. Ekström MP, Hermansson AB, Ström KE. Effects of cardiovascular drugs on mortality in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:715–720. Copyright ª 2013 by the American Thoracic Society DOI: 10.1164/rccm.201309-1651ED
b-Glucan Antigenemia Anticipates Diagnosis of Blood Culture–Negative Intraabdominal Candidiasis Necessity Is the Mother of Invention Invasive candidiasis has evolved into a problem of considerable significance in intensive care medicine, primarily because of the surge in the population at risk, incorporating patients with disease-related or iatrogenic immunosuppression and patients who are dependent on various types of supportive care. In the United States, there is a reported threefold increase of fungal sepsis during the years 1979 to 2000, with candidemia reported to be the third most common cause of nosocomial bloodstream infection in adult critical care patients with a 38% attributable mortality rate and a 30-day prolongation of hospital stay (1, 2). Recent figures from the United States suggest that from 2000 to 2005, the incidence of candidemia increased from 3.65 to 5.56 episodes per 100,000 people (3). In Europe the reported incidence of candidemia may be lower, with proportions ranging from 2 to 3% of bloodstream isolates (4). In a recent Danish national surveillance, which includes 2,820 cases of fungemia during the years 2004 to 2009, the incidence was reported as increasing from 7.7 to 8.6 per 100,000 (5). Despite the geographical differences, these data suggest an increasing incidence of candidemia in the past decade. Admittedly, although the rapid diagnosis of invasive candidiasis is crucial for appropriate management, with an increase in mortality associated with any delay of initiation of therapy (6), this currently eludes us. Our current diagnostic options are somewhat limited; although conventional microbiological, histological, and radiological techniques remain the cornerstone of diagnosis, they are insensitive and do not provide meaningful quantitative data (7). Monitoring the dynamic of Candida colonization in surgical patients and prediction rules based on combined risk factors are used with some effect to identify intensive care unit patients at high risk of invasive candidiasis susceptible to benefit from prophylaxis or preemptive antifungal treatment (8). Nevertheless, a specific marker for the prompt diagnosis of invasive fungal infection and/or the response to treatment will be most helpful. As a consequence, new non–culture-based laboratory techniques have been suggested that may be superior diagnostic tests for invasive candidiasis and allow for both the early diagnosis and tailoring the management of invasive candidiasis. Serologic [mannan, antimannan, and (1,3)-b-D-glucan (BG)] and molecular (polymerase chain reaction in blood and serum) tests have been proposed as possible invasive candidiasis biomarkers in high-risk patients (9, 10). However, although reasonably sensitive and specific, these techniques remain largely investigational, and their clinical usefulness remains to be established. With this in mind, the Fungal Infection Network of Switzerland (FUNGINOS) article in this issue of the Journal (pp. 1100– 1109) is judiciously timed (11).
BG is a cell wall polysaccharide found in most fungi, with the exception of the zygomycetes and Cryptococcus (12). Its presence in blood has previously been used for the detection of invasive fungal infection. The sensitivity and specificity of serum BG testing for diagnosing invasive candidiasis have ranged from 57 to 97% and 56 to 93%, respectively; in a recent metaanalysis, sensitivity was 75% (13). Tissot and colleagues identify a relevant clinical model, targeting a specific population in which blood culture has limited value in intraabdominal candidiasis diagnosis—patients with abdominal surgery already colonized with Candida (11). Although some of the uncertainties regarding BG detection are specificity and false positivity, this study suggests a superior diagnostic value of BG in the selected population of high-risk surgical patients compared with Candida score, colonization index, and corrected colonization index, with positive predictive value 72% and negative predictive value 80%. The practicality of BG as a diagnostic aide or a reflection of response to therapy may be in its negative predictive value to rule out invasive candidiasis and support discontinuation of either prophylactic or empiric antifungal therapy. Antimicrobial discontinuation as a consequence of biomarker analyses has been authenticated in intensive care unit patients with ventilatorassociated pneumonias without adversely affecting outcome (14). A noteworthy advantage of the BG assay is that the result can be obtained within 12 to 24 hours, in contrast to days for Candida microbiological assays—enhancing diagnosis and the initiation of antifungal therapy days prior to definite culture results might have significant impact on patient outcome and length of stay. In 57% of colonized patients, BG was more than or equal to 80 pg/ml, but two consecutive BG > 80 pg/ml values have better diagnostic value than Candida score, colonization index, or corrected colonization index. Although the FUNGINOS study does not suggest that clinical effectiveness can be accurately assessed by clearance of BG, poor outcome is associated with highly persistent (.400 pg/ml) levels of BG. Although the population cohort was small and specific in this study, patients with suspected but not proven intraabdominal candidiasis were excluded; therefore, the accuracy of BG diagnostic value may be overestimated. Nevertheless, this observational study provides valuable knowledge of BG use in the specific high-risk abdominal surgical setting. The limitations associated with the traditional culture techniques for the diagnosis of invasive fungal infections has propagated vigorous interest in newer non–culture-based diagnostics for invasive candidiasis. This search for the ideal diagnostic test for invasive candidiasis is a well-traveled road. BG is clearly
