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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

sufficient in itself to cause the structural features of COPD. The current study is unable to answer these questions; however, murine models of autoimmunity have provided some interesting insights into these issues. A study by Brandsma and colleagues (12) found no association between induced autoimmunity and lung disease, irrespective of the presence of acute cigarette smoke exposure. Contrary to this, Motz and coworkers (20) described the induction of COPD-like inflammation and pathology when T cells from cigarette smoke–exposed wild-type mice were transferred into Rag 22/2 mice. In this study, pulmonary inflammation and emphysema occurred irrespective of smoke exposure, suggesting that the transferred T cells were capable of causing features of COPD. However, the results should be interpreted with caution: the inflammation and structural changes seen in the Rag22/2 mice were far greater than in the smoke-exposed wildtype mice from whom the T cells were isolated. Thus it is possible that the Rag 22/2 mice were unable to regulate T cell responses and subsequent inflammation, leading to heightened lung destruction. Interestingly, dysregulation of adaptive immunity may be a feature of human COPD, where fewer regulatory T cells and less FOXP3 RNA has been noted in lung tissue (8). So, what does the current study add to our understanding of autoimmunity in COPD? It certainly provides some interesting insights, suggesting that autoantibodies are important only in a subset of patients, although which subset remains unclear, and raising the issue of sensitivity and specificity of conventional tests in this patient group. However, many questions remain. The use of healthy control subjects fails to differentiate whether AT-autoimmunity is a feature of all chronic inflammatory conditions, is caused by chronic inflammation, or is specific to COPD. There is also no clear evidence of causation and little understanding of the functional consequence of ANA and AT antibodies. This should be investigated further, as it may offer a new therapeutic paradigm for this important disease. Author Disclosure: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Elizabeth Sapey, M.B.Ch.B., Ph.D. Alice M. Wood, M.B.Ch.B., Ph.D. School of Clinical and Experimental Medicine University of Birmingham Birmingham, United Kingdom References 1. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, Cherniack RM, Rogers RM, Sciurba FC, et al. The nature of smallairway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653. 2. Rutgers SR, Postma DS, ten Hecken NH, Kauffman HF, van der Mark TW, Koeter GH, Timens W. Ongoing airway inflammation in patients with COPD who do not smoke. Thorax 2000;55:12–18. 3. Nu´n˜ez B, Sauleda J, Anto´ JM, Julia` MR, Orozco M, Monso´ E, Noguera A, Go´mez FP, Garcia-Aymerich J, Agustı´ A; PAC-COPD Investigators. Anti-tissue antibodies are related to lung function in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011;183:1025–1031. 4. Bonarius HPJ, Brandsma CA, Kerstjens HA, Koerts JA, Kerkhof M, Nizankowska-Mogilnicka E, Roozendaal C, Postma D, Timens W.

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Antinuclear autoantibodies are more prevalent in COPD in association with low body mass index but not with smoking history. Thorax 2011;66:101–107. Tan EM, Feltkamp TEW, Smolen JS, Butcher B, Dawkns R, Fritzler MJ, Gordon T, Hardin JA, Kalden JR, Lahita RG, et al. Range of anti-nuclear antibodies in healthy individuals. Arthritis Rheum 1997; 40:1601–1611. Mathews JD, Whittingham S, Hooper BM, Mackay IR, Stenhouse NS. Association of autoantibodies with smoking, cardiovascular morbidity and death in the Busselton population. Lancet 1973;302:754–758. Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun 2010;34: J258–J265. Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, Green L, Hacken-Bitar J, Huh J, Bakaeen F, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med 2007;13:567–569. Ma S, Lin YY, Turino GM. Measurements of desmosine and isodesmosine by mass spectrometry in COPD. Chest 2007;131:1363–1371. Greene CM, Low TB, O’Neill SJ, McElvaney NG. Anti-proline-glycineproline or antielastin autoantibodies are not evident in chronic inflammatory lung disease. Am J Respir Crit Care Med 2010;181:31–35. Goswami S, Barranco W, Lee SH, Grudo A, Corry DB, Kheradmand F. An autoimmune basis in the disease pathogenesis of COPD/emphysema. J Immunol 2007;178:130–141. Brandsma CA, Timens W, Geerlings M, Jekel H, Postma DS, Hylkema MN, Kerstjens HA. Induction of autoantibodies against lung matrix proteins and smoke-induced inflammation in mice. BMC Pulm Med 2010;10:64. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW, Csizmadia E, Zhang Y, Sciurba FC, Duncan SR. Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:156–163. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Moore M, Sullivan A, Nicolls MR, Fontenot AP, Tuder RM, Voelkel N. An animal model of autoimmune emphysema. Am J Respir Crit Care Med 2005; 171:734–742. Birring SS, Brightling CE, Bradding P, Entwisle JJ, Vara DD, Grigg J, Wardlaw AJ, Pavord ID. Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study. Am J Respir Crit Care Med 2002;166:1078–1083. van der Strate BW, Postma DS, Brandsma CA, Melgert BN, Luinge MA, Geerlings M, Hylkema MN, van den Berg A, Timens W, Kerstjens HA. Cigarette smoke induced emphysema: a role for the B cell? Am J Respir Crit Care Med 2006;173:751–758. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2008;360:2445–2454. Sullivan AK, Simonian PL, Falta MT, Cosgrove GP, Brown KK, Kotzin BL, Voelkel NF, Fontenot AP. Oligoclonal CD41 T cells in the lungs of patients with severe emphysema. Am J Respir Crit Care Med 2005; 172:590–596. Polverino F, Baraldo S, Bazzan E, Agostini S, Turato G, Lunardi F, Balestro E, Damin M, Papi A, Maestrelli P, et al. A novel insight into adaptive immunity in chronic obstructive pulmonary disease: B cell activating factor belonging to the tumor necrosis factor family. Am J Respir Crit Care Med 2010;182:1011–1019. Motz GT, Eppert BL, Scott C, Wesselkamper SC, Flury JL, Borchers MT. Chronic cigarette smoke exposure generates pathogenic T cells capable of driving COPD-like disease in Rag22/2 mice. Am J Respir Crit Care Med 2010;181:1223–1233.

DOI: 10.1164/rccm.201012-2002ED

Dying from, and with, Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) recently surpassed cerebrovascular disease to become the third leading cause of death in the United States (1), and it remains the only leading cause of death that is increasing in prevalence (2). Even though

COPD is a major cause of death, ostensibly many more people die from other causes after living with COPD and its numerous comorbid conditions. The presence and risk of comorbidity play such a prominent role in COPD that some experts have

Editorials

advocated that COPD be incorporated into the ‘‘chronic systemic inflammatory syndrome’’ (3). This approach asserts that COPD and several of its comorbid conditions, including coronary artery disease, are unified by chronic systemic inflammation (3), and that comorbid conditions themselves place a significant burden on those living with COPD (4). In this issue of the Journal, Ekstro¨m and colleagues (pp. 1032– 1036) provide information regarding cause-specific mortality for a national population of patients treated with long-term oxygen therapy (LTOT) for severe COPD (5). In a prospective study, they evaluated 7,628 patients who started on LTOT after January 1, 1987 and obtained baseline data on lung function, smoking status, arterial gas tension of oxygen (PaO2) and carbon dioxide (PaCO2) when breathing air and during oxygen therapy. The study showed an increase in crude overall mortality of 1.6% per year (95% confidence interval [CI], 0.9–2.2). The absolute risk of death increased for circulatory disease (increase of 2.8% per year; 95% CI, 1.3– 4.3) and for digestive organ disease (increase of 7.8% per year; 95% CI, 1.9–14.0), but decreased for respiratory disease (decrease of 2.7% per year; 95% CI, 2.0–3.3) and lung cancer (decrease of 3.4% per year; 95% CI, 1.1–5.7). These results indicate that while strides have been made in reducing deaths from respiratory disease for individuals living with COPD, comorbid conditions continue to confer a significant burden. At face value these findings may seem mundane. After all, one could state that if death due to one set of causes (respiratory diseases) is reduced, it would follow logically that, given natural limitations in lifespan, deaths due to other causes (cardiovascular and gastrointestinal diseases) would increase. In addition, studies that use death certificates to determine cause of death have the potential for bias due to changes in diagnostic methods and classification by physicians over time. Digging deeper, however, the findings of this study are strikingly important. The study prospectively follows a national cohort over nearly two decades with virtually no losses to follow-up—a remarkably complete data set. It therefore enriches, using the less biased population-based study design, the body of data regarding causes of death obtained in recent international COPD clinical trials (6, 7). Perhaps more importantly, this study presents us with a difficult question: why have patients with COPD not had the same reduction in cardiovascular deaths as the general population? In the current report by Ekstro¨m and colleagues, the excess mortality (simply defined as the ratio of mortality due to a specific cause in the COPD LTOT cohort over that of general population standardized for age, sex, and calendar year to produce a standardized mortality ratio [SMR]) for cardiovascular disease in patients with COPD prescribed LTOT was remarkably high, with an annual increase in SMR of 7.3. This can be interpreted to mean that advances in cardiovascular disease treatment have translated into benefits for the general population, but not individuals living with COPD. The overlap between risk factors for the development of COPD and atherosclerosis are clearly established, and risk of cardiovascular morbidity and mortality is well documented in patients with COPD as well as in individuals with reduced lung function (8–11). To translate the benefits seen in cardiovascular mortality in the general population to patients with COPD will require evaluating whether patients with COPD respond similarly to the general population to interventions that are known to prevent cardiovascular events. In addition, an assessment of whether individuals living with COPD are evaluated with the same detailed attention to cardiovascular risk reduction as people who do not have COPD is warranted. One could assert that the diagnosis of COPD in and of itself is a major risk factor for cardiovascular disease, and aggressive preventive strategies against cardiovascular events, both pharmacologic and behavioral,

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should be tested for efficacy only on the basis of having COPD independent of other traditional cardiovascular risk factors. Notably, Ekstro¨m and colleagues report that more women than men are prescribed LTOT, which is consistent with shifting COPD demographics (12). In a prior report, the same authors found that women with oxygen-dependent COPD also have greater relative mortality than men (13). In addition, women with COPD report more dyspnea and worse health status compared with men after adjustment for lung function and smoking (14), and some speculate that there are differences in susceptibility to the adverse effects of cigarette smoke in women compared with men (15). It is not known if worsened health status in women compared with men with COPD is at least partially attributable to sex-related differences in comorbid conditions, particularly cardiovascular disease. A potential for higher prevalence of comorbid conditions among women may contribute to the associated increased relative mortality in women compared with men with severe oxygen-dependent COPD, and emphasizes the continued importance of evaluating sex differences in expression and outcome of patients with COPD (16). COPD is a complex systemic disease, and the outcome of those living with it depends on multiple factors. The finding by Ekstro¨m and colleagues that deaths from nonrespiratory causes are increasing concurrent with a reduction in respiratory causes of death magnify this complexity. Unraveling why patients with COPD may be more vulnerable to cardiovascular disease, and whether they benefit from cardiovascular prevention strategies, is of paramount importance. Understanding whether differential outcomes in women compared with men with COPD may be attributed to comorbidities is essential to providing specific therapies that improve outcomes. We look forward to future studies that define mechanisms for the epidemiologic findings reported by Ekstro¨m and colleagues, and improve the quality and duration of lives of people living with COPD. Author Disclosure: S.R.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.K. has received consultancy fees from Boehringer-Ingelheim (BI), Takeda Pharmaceuticals, AstraZeneca (AZ), Dey Pharmaceuticals, and Forest Laboratories; he has received lecture fees from AZ, GSK, BI, and Pfizer; and his institution has received grants from GSK.

Sharon R. Rosenberg, M.D., M.S. Ravi Kalhan, M.D., M.S. Asthma-COPD Program Northwestern University Feinberg School of Medicine Chicago, Illinois References 1. Minino AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. National Vital Statistics Reports. Hyattsville, MD: National Center for Health Statistics; 2010. 2. National Institute of Health/National Heart, Lung, and Blood Institute. Morbidity & Mortality: 2009 chart book on cardiovascular, lung, and blood diseases. 2009 Oct [accessed Jan 15, 2011]. Available at: http:// www.nhlbi.nih.gov/resources/docs/cht-book.htm. 3. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007;370:797–799. 4. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–212. 5. Ekstro¨m MP, Wagner P, Strom KE. Trends in cause-specific mortality in oxygen-dependent COPD. Am J Respir Crit Care Med 2011;183:1032– 1036. 6. McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA. Ascertainment of cause-specific mortality in COPD: operations of the torch clinical endpoint committee. Thorax 2007;62:411–415. 7. Celli B, Decramer M, Kesten S, Liu D, Mehra S, Tashkin DP; UPLIFT Study Investigators. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:948–955.

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8. 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. 9. Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127:1952–1959. 10. Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789. 11. Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:549–555. 12. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance–United States, 1971–2000. MMWR Surveill Summ 2002;51:1–16.

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13. Ekstrom M, Franklin KA, Strom KE. Increased relative mortality in women with severe oxygen-dependent COPD. Chest 2010;137:31–36. 14. de Torres JP, Casanova C, Hernandez C, Abreu J, Aguirre-Jaime A, Celli BR. Gender and COPD in patients attending a pulmonary clinic. Chest 2005;128:2012–2016. 15. Sin DD, Cohen SB, Day A, Coxson H, Pare PD. Understanding the biological differences in susceptibility to chronic obstructive pulmonary disease between men and women. Proc Am Thorac Soc 2007;4:671–674. 16. Han MK, Postma D, Mannino DM, Giardino ND, Buist S, Curtis JL, Martinez FJ. Gender and chronic obstructive pulmonary disease: why it matters. Am J Respir Crit Care Med 2007;176:1179–1184.

DOI: 10.1164/rccm.201101-0123ED

The Functional Costs of ICU Survivorship Collaborating to Improve Post-ICU Disability Survivorship is emerging as a major issue for critical care medicine. With an aging population, demand for critical care is increasing while ICU mortality is also improving (1–4). Consequently, there is a growing number of ICU survivors, creating a pressing need to address survivorship. In recent years, seminal studies have demonstrated the high prevalence of short- and long-term physical, cognitive, and mental health sequelae after critical illness (5–7). These sequelae can be profound and substantially impair survivors’ quality of life (8, 9). Two recent analyses of large cohorts of older adults have prospectively measured participants’ baseline status and demonstrated new, substantial, and persistent impairments in cognitive and physical function after critical illness (10, 11). In this issue of the Journal (pp. 1037–1042), Barnato and colleagues (12) add to this literature, focusing on changes in physical function after mechanical ventilation. Barnato and coworkers evaluated physical function in a population-based cohort of community-dwelling Medicare beneficiaries, aged 65 and older. The authors used prospectively collected interviews (1996–2003) from the Medicare Current Beneficiary Survey, a national longitudinal cohort study, and linked these data to Medicare inpatient claims files. Physical function was evaluated in two ways: (1) mobility status, measured using the Rosow-Breslau Functional Health Scale; and (2) activities of daily living (ADL), using the Katz scale. In the pre-post analysis, each beneficiary could contribute up to 3 person-years (PY) of observation, and a total of 48,030 personyears (PY) of data were analyzed. Participants were classified into 1 of 3 categories: no hospitalization (39,107 PY), hospitalization without mechanical ventilation (MV) (8,771 PY), and hospitalization with MV (152 PY). By comparing each beneficiary’s annual survey with data on subsequent hospitalization and MV episodes, the authors evaluated physical function before and after either hospitalization or MV, compared with a contemporary longitudinal control group of nonhospitalized patients. This study provides novel insights into the impact of critical illness. The 1-year mortality rate for these older adults receiving MV was remarkably high at 72.5%, emphasizing the importance of evaluating ICU patients’ outcomes beyond

Supported by funding from a Fellowship Award and the Bisby Prize, both from the Canadian Institutes of Health Research (to M.E.K.).

hospital discharge. Moreover, despite comparable baseline levels of physical function, MV patients had greater impairments in ADLs and mobility than hospitalized patients without MV. MV had a large incremental effect on ADL impairment. The crude increase in ADL impairment between MV survivors and hospitalized survivors without MV was similar to the incremental ADL impairment in hospitalized survivors without MV and the nonhospitalized control group. The mobility measure of physical function demonstrated a relatively smaller impairment for MV survivors compared with hospitalized patients without MV. This study also highlights important methodological issues in studying ICU survivors. Strengths of the study include a large, nationally representative sample; high survey response rates; and prospective, patient-reported baseline evaluations of physical function before MV. The latter point is especially important, since estimating baseline status using either proxy reports or population norms may be inaccurate (13). Hospitalization with MV occurred in less than 1% of the sample, demonstrating the large sample size required in studies prospectively measuring baseline status prior to the onset of critical illness. Even larger sample sizes will be required in younger populations who are at lower risk for critical illness. The generalizability of study findings to ICU patients less than 65 years old is uncertain because younger patients may experience less impairment (both in magnitude and duration) due to factors such as fewer co-morbidities and greater physiological reserve. However, as highlighted by the authors, the true magnitude of physical impairments may be even greater due to survivor bias (i.e., patients who died before the annual survey may have had even greater physical impairment than those who survived and responded). The factors leading to these physical impairments, including the contributing role of cognitive impairment and depression which have an especially important role in physical function for older populations, require further evaluation in future studies (Figure 1) (10, 14). Development, evaluation, and implementation of interventions for the prevention and treatment of post-ICU physical impairments represent major challenges for survivorship. Discharge from the ICU no longer marks the endpoint of critical illness. In addition to the ongoing impact on patients, post-ICU impairments are a major burden for families and for the healthcare system (especially Medicare), with high rates of