Sorbonne Paris Cité. Paris, France. David Mannino, M.D.. Department of Preventive Medicine and Environmental Health. University of Kentucky College of ...
Editorials
own risk estimates, and it seems too early to transfer this knowledge into clinical practice. However, the present data may be useful in conducting stratified management of comorbidities in patients with COPD: combining results of this set of biomarkers with usual risk factors (age, smoking, systemic hypertension, cholesterol levels, etc.) may prove a useful approach to select a COPD subgroup that may benefit from a systematic diagnostic assessment for major comorbidities, eventually followed by specific intervention. The clinical value of this approach and its cost effectiveness will have to be tested in adequate clinical trials. “Noncommunicable” diseases (e.g., COPD, cardiovascular and metabolic disease, depression, and cancer) represent a major challenge in medicine (13), and are often associated with each other (14). In the general population, the realization that high levels of cholesterol and hypertension were strongly associated with subsequent cardiovascular morbidity and mortality led to early detection and intervention programs and a reduction in events (15). In the COPD population, the early identification of patients at risk for major comorbidities may lead to more aggressive diagnostic evaluation and appropriate preventive therapies that may ultimately reduce comorbidity-related events and mortality. As suggested by the present study and another recent study (12), heterogeneity in systemic inflammation, as reflected by variable results of biomarker combinations, may be a useful contribution to assess the risk of selected comorbidities in patients with COPD. This heterogeneity suggests that not all “inflammatory” events are the same, and individuals with multiple measures of inflammation may be phenotypically different from those with fewer measures and may require more aggressive intervention. One size no longer fits all! Author disclosures are available with the text of this article at www.atsjournals.org.
Pierre-Régis Burgel, M.D., Ph.D. Department of Respiratory Medicine Hôpital Cochin, AP-HP Paris, France and Université Paris Descartes Sorbonne Paris Cité Paris, France David Mannino, M.D. Department of Preventive Medicine and Environmental Health University of Kentucky College of Public Health Lexington, Kentucky References 1. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med (In press)
937 2. Agusti 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. 3. Han MK, Agusti 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. 4. Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V, Zulueta J, Cabrera C, Zagaceta J, Hunninghake G, et al.; BODE Collaborative Group. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:155–161. 5. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962–969. 6. Burgel PR, Paillasseur JL, Caillaud D, Tillie-Leblond I, Chanez P, Escamilla R, Court-Fortune I, Perez T, Carre P, Roche N. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur Respir J 2010;36:531–539. 7. Rutten FH, Cramer MJM, Grobbee DE, Sachs APE, Kirkels JH, Lammers JWJ, Hoes AW. Unrecognized heart failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J 2005;26:1887–1894. 8. Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59:574–580. 9. Barnes PJ, Celli BR. Comorbidities in COPD. Eur Respir J 2009;33: 1165–1185. 10. Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:982–988. 11. Agusti A, Sobradillo P, Celli B. Addressing the complexity of chronic obstructive pulmonary disease from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine. Am J Respir Crit Care Med 2011;183:1129–1137. 12. Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PMA, Wouters E, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012;7:e37483. 13. Daar AS, Singer PA, Persad DL, Pramming SK, Matthews DR, Beaglehole R, Bernstein A, Borysiewicz LK, Colagiuri S, Ganguly N, et al. Grand challenges in chronic non-communicable diseases. Nature 2007;450:494–496. 14. Charlson M, Charlson RE, Briggs W, Hollenberg J. Can disease management target patients most likely to generate high costs? The impact of comorbidity. J Gen Intern Med 2007;22:464–469. 15. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, Giles WH, Capewell S. Explaining the decrease in US deaths from coronary disease, 1980–2000. N Engl J Med 2007;356:2388– 2398. Copyright ª 2012 by the American Thoracic Society DOI: 10.1164/rccm.201209-1634ED
Socioeconomic Barriers to Lung Transplantation Balancing Access and Equity The burden of human disease is unevenly distributed along social and economic gradients. Those with higher incomes, better jobs, and more years of schooling tend to be healthier, have better outcomes after the onset of illness, and simply live longer (1). Although the causal pathways are not completely worked out, lower socioeconomic status is linked to a number of factors that influence health status including environmental and neighborhood exposures, health behaviors, lifestyle factors, chronic stress, and access to healthcare (2).
In this issue of the Journal, Quon and colleagues (pp. 1008–1013) examine the influence of socioeconomic status on access to lung transplantation in the United States (3). Using data on 2,167 adults with cystic fibrosis enrolled in the Cystic Fibrosis Foundation Patient Registry, the authors found that Medicaid beneficiaries, those without a high school education, and those living in neighborhoods with a median household income below 200% of the federal poverty line (corresponding to about $34,000 per year for a family of four) (4) were less likely to be accepted into
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a lung transplant program even after accounting for differences in demographics, measures of disease severity, and potential contraindications. These findings are novel and build upon previous studies that have established low socioeconomic status as a barrier to accessing kidney transplantation services (5, 6). Many will react to this finding with outrage, calling it, as the authors have, a disparity. The word “disparity” has more than one definition. The federal government defines a disparity as any population-specific difference in disease incidence, health outcome, or access to care (7). An Institute of Medicine report defined disparities as “racial or ethnic differences in the quality of healthcare that are not due to access-related factors or clinical needs, preferences, and appropriateness of intervention” (8). Although these definitions may be suitable for certain purposes, both seem to be missing a central notion: the term “disparity” implies the presence of an inequity (or injustice) underlying the observed inequality between groups (9). Disparities might therefore be better defined as “differences in health that are not only unnecessary and avoidable, but in addition, are considered unfair and unjust,” a definition accepted by the World Health Organization (10). Did Quon and coworkers identify a disparity in this sense? An unavoidable and just difference is one due to natural biological variation (women have higher rates of breast cancer than men) or to freely chosen behaviors (football players have a higher incidence of head trauma) (10). On the other hand, differences that result from limited access to healthcare, harmful work or environmental exposures, or behaviors that are not freely chosen (but are instead dictated by social, financial, and other external pressures) are avoidable and unjust—and therefore should be considered disparities (10). Externally imposed constraints that restrict access to healthcare and limit the freedom to choose healthy lifestyles, behaviors, and environments are the central determinants of low socioeconomic status (10). It would therefore seem that Quon and colleagues have indeed uncovered a disparity in access to lung transplantation for those of low socioeconomic status. Yet, in the special case of transplantation, these findings should be considered in the context of an additional issue of equity. Transplant programs are charged with the equitable allocation of deceased donor organs, a scarce resource. We frequently deny transplantation to high-risk candidates to avoid performing a “futile” transplant (one in which life is not prolonged by transplantation) that could deprive another candidate of a chance for life. In the study by Quon and colleagues, could it be that transplant programs were simply making clinically appropriate decisions in light of a greater burden of high-risk features among those of low socioeconomic status? The authors tried to account for differences in high-risk features in their analysis, but, as they acknowledge, their crude measures of social support (presence of a partner) and nonadherence (fewer than four outpatient visits per year) cannot possibly capture the detail and nuance of a formal assessment by a trained and often highly experienced social worker. It is quite likely that unmeasured and poorly measured factors that predict a higher risk of death after transplantation, such as dysfunctional social support systems (11) and prior patterns of nonadherence (12), explain why candidates of low socioeconomic status were more likely to be denied lung transplantation. In this light, the findings of Quon and coworkers now appear appropriate and consistent with established selection guidelines for lung transplantation (13). How do we reconcile the somewhat contradictory notion of a disparity in access to transplant care that seems to be appropriate in light of the need to equitably allocate scarce donor organs? One might react by imposing a policy that requires high-risk candidates of low socioeconomic status to be exempt
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from certain established selection criteria. Although this might alleviate the disparity, it would likely be more than counterbalanced by the resulting inequity in lung allocation. Instead, we should take responsibility for the disparity and begin exploring ways to improve the candidacy of low-income patients with advanced lung disease even before the need for transplantation arises. Together, we can promote health equity and access to transplantation by increasing home care services for those with inadequate social support, enhancing transportation services for those without a car, protecting job security for those who fear missing days of work, and lowering out-of-pocket drug costs for those without adequate insurance coverage. In this era of increased provider accountability, it now becomes imperative that policymakers and leaders in pulmonary and transplant medicine work together to remedy these “barriers to candidacy.” A few limitations of the study should be mentioned. First, the authors’ study is cross-sectional in nature (individual follow-up times and rates of referral, acceptance, listing, and transplantation were not available) and relies on each cystic fibrosis center’s report of whether or not a patient was “accepted” at a transplant center—an unstandardized designation. Second, the authors opted to present odds ratios. Odds ratios are difficult to interpret and, in this case, where 38% of participants were not accepted for transplantation, will overestimate the true risk (or prevalence) ratio. For example, the odds ratio of 1.37 for the fully adjusted association between Medicaid insurance and not being accepted for transplantation might translate into only a 15 to 20% relative increase in the risk of not being accepted for transplantation. The magnitude of “harm” of Medicaid, if such harm exists, is probably small, corresponding to an absolute increase in risk of only about 5 to 8%. The study by Quon and colleagues highlights an unjust disadvantage among lung transplant candidates of low socioeconomic status. Add to this the unsettling finding of a net transfer of lungs from low-income donors to high-income recipients in the United States (14), and the status quo begins to seem untenable. A dialogue about access and equity in lung transplantation has commenced. There is much work now to be done. Author disclosures are available with the text of this article at www.atsjournals.org.
Jaime L. Hook, M.D. Department of Medicine Columbia University Medical Center New York, New York David J. Lederer, M.D., M.S. Departments of Medicine and Epidemiology Columbia University Medical Center New York, New York
References 1. Adler NE, Boyce T, Chesney MA, Cohen S, Folkman S, Kahn RL, Syme SL. Socioeconomic status and health: the challenge of the gradient. Am Psychol 1994;49:15–24. 2. Adler NE, Newman K. Socioeconomic disparities in health: pathways and policies. Health Aff (Millwood) 2002;21:60–76. 3. Quon BS, Psoter K, Mayer-Hamblett N, Aitken ML, Li CI, Goss CH. Disparities in access to lung transplantation for patients with cystic fibrosis by socioeconomic status. Am J Respir Crit Care Med 2012;186:1008–1013. 4. Department of Health and Human Services. Annual update of the HHS poverty guidelines. Fed Regist 2000;65:7555–7557. 5. Patzer RE, Perryman JP, Schrager JD, Pastan S, Amaral S, Gazmararian JA, Klein M, Kutner N, McClellan WM. The role of race and poverty on steps to kidney transplantation in the Southeastern United States. Am J Transplant 2012;12:358–368.
Editorials 6. Patzer RE, Amaral S, Wasse H, Volkova N, Kleinbaum D, McClellan WM. Neighborhood poverty and racial disparities in kidney transplant waitlisting. J Am Soc Nephrol 2009;20:1333–1340. 7. S. 1880–106th Congress: Minority Health and Health Disparities Research and Education Act of 2000. In: GovTrack.us [database of federal legislation]. Washington, DC: Civic Impulse [accessed 2012 Sep 25]. Available from: http://www.govtrack.us/congress/bills/106/s1880 8. Committee on Understanding Eliminating Racial and Ethnic Disparities in Health Care. Unequal treatment: confronting racial and ethnic disparities in health care. Washington, DC: The National Academies Press; 2003. 9. Hebert PL, Sisk JE, Howell EA. When does a difference become a disparity? Conceptualizing racial and ethnic disparities in health. Health Aff (Millwood) 2008;27:374–382. 10. Whitehead M. The concepts and principles of equity and health. Int J Health Serv 1992;22:429–445. 11. Dobbels F, Vanhaecke J, Dupont L, Nevens F, Verleden G, Pirenne J, De Geest S. Pretransplant predictors of posttransplant adherence and
939 clinical outcome: an evidence base for pretransplant psychosocial screening. Transplantation 2009;87:1497–1504. 12. Dew MA, Dimartini AF, De Vito Dabbs A, Zomak R, De Geest S, Dobbels F, Myaskovsky L, Switzer GE, Unruh M, Steel JL, et al. Adherence to the medical regimen during the first two years after lung transplantation. Transplantation 2008;85:193–202. 13. Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ, Egan T, Keshavjee S, Knoop C, Kotloff R, et al. International guidelines for the selection of lung transplant candidates: 2006 update–a consensus report from the pulmonary scientific council of the international society for heart and lung transplantation. J Heart Lung Transplant 2006; 25:745–755. 14. Sehgal AR. The net transfer of transplant organs across race, sex, age, and income. Am J Med 2004;117:670–675. Copyright ª 2012 by the American Thoracic Society DOI: 10.1164/rccm.201210-1776ED
Hermansky-Pudlak Syndrome Interstitial Pneumonia It’s the Epithelium, Stupid! Hermansky-Pudlak syndrome (HPS) is a rare inherited disease primarily affecting the intracellular biogenesis of lysosome-related organelles (1). The clinical spectrum of this disease includes oculocutaneous albinism, a bleeding diathesis, colitis, and lung fibrosis resembling idiopathic pulmonary fibrosis (IPF) in some. HPS interstitial pneumonia (HPSIP) shares the same aggressive course of lung fibrosis with IPF, resulting in progressive dyspnea, reduced exercise capacity, loss of life quality, and eventual death or need for lung transplantation (2, 3). HPSIP also shares the usual interstitial pneumonia histopathology with IPF, but, in contrast, it is characterized by giant lamellar body formation in alveolar epithelial cells type II (AECII), resulting in AECII swelling (2). Of note, lung fibrosis has only been observed in HPS-1, HPS-4 (4, 5), and HPS-2 (6) subtypes, which are associated with defects in the Biogenesis of Lysosome-Related Organelles Complex-3 or the Adaptor Protein-3 Complex. Interestingly, although HPS mono-mutant mice do not spontaneously develop lung fibrosis, HPS-1 and HPS-2 mice are highly susceptible to bleomycin-induced lung fibrosis (7), and mice with a combined HPS1 and HPS2 defect develop spontaneous pulmonary fibrosis (8, 9). AECII are highly active cells, as they secrete pulmonary surfactant, which is stored in lamellar bodies. Lamellar bodies are lysosome-related organelles in AECII. Thus, it is not surprising that murine and human HPSIP are associated with defective surfactant processing and transport, causing lysosomal and endoplasmic reticulum stress in AECII (8, 10). It is also known that alveolar macrophages are activated in patients with HPS-1 (11), HPS-1 and HPS-2 mono-mutant mice (12), and HPS1/2 double-mutant mice (13). In addition, the enhanced cytokine secretion by alveolar macrophages of patients with HPS-1 is down-regulated by pirfenidone (11). These data suggest a putative role for alveolar macrophages in driving lung fibrosis in patients with HPS-1. Despite these findings, evidence indicating a prominent role of AECII in the pathogenesis of HPSIP is mounting. It is reported that lung fibrosis in several mono- and double-mutant mice only occurred in mice with extensive AECII apoptosis (7, 8). Likewise, an association between the dysregulation of AECII and macrophage activation via S-nitrosylated surfactant protein D demonstrates that a secretory product of AECII can contribute to lung inflammation in HPSIP (14). In this issue of the Journal, Young and colleagues (pp. 1014– 1024) add further experimental evidence to the conceptional view
that the alveolar epithelium is centrally involved in the development of HPSIP (15). For this work, the authors focused on HPS-1 and HPS-2 murine models. Although they do not develop spontaneous pulmonary fibrosis, these murine models are highly susceptible to bleomycin-induced pulmonary fibrosis and, thus, are models for human HPS pulmonary fibrosis. Young and coworkers generated bone marrow chimeric mice and report that, in spite of transplanting HPS-1 and HPS-2 mutant mice with healthy wild-type bone marrow cells, these mice continued to develop a similarly severe lung fibrosis in response to bleomycin challenge. Furthermore, wild-type mice receiving bone marrow cells from HPS-1 or HPS-2 mutant mice did not show impressive fibrotic changes. However, epithelialspecific correction of the HPS2 defect largely prevented development of bleomycin-induced lung fibrosis, normalized cytokine concentrations, and corrected AECII lamellar body size. These observations are highly important as they show that AECII have a central role in the pathogenesis of HPSIP, and this publication adds to the growing body of literature that demonstrates the significant contribution of the alveolar epithelium to the initiation and development of pulmonary fibrosis. Another important event in HPS lung fibrosis addressed by Young and colleagues is AECII apoptosis, a persistent finding in human HPSIP, HPS1/2 double-mutant mice developing lung fibrosis (8), and other forms of fibrotic lung disease (16). Young and colleagues report early AECII apoptosis in HPS-2 mice in response to bleomycin challenge. When treated with a pancaspase inhibitor, these mice displayed decreased lung fibrosis and AECII apoptosis, which provides additional proof that epithelial apoptosis has a central role in HPSIP. Although no evidence of endoplasmic reticulum stress was found, the observed AECII apoptosis may be a result of lysosomal stress, which was not analyzed in this study. The study by Young and colleagues strengthens the pathomechanistic concept that, like in familial and sporadic IPF, dysfunction of AECII underlies the development of lung fibrosis in HPS (16–18). The comprehensive and provocative data presented in this publication raise several additional questions and open the door for novel therapeutic concepts. For example, would transgenic correction of the HPS1 epithelial defect in HPS-1 mice be associated with findings similar to those presented in this publication? Is correction of lamellar body morphology in these HPS-2 mice associated with normalization of defective surfactant
