VA Center for Clinical Management Research. Ann Arbor, Michigan. References. 1. Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch.
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patients on a Slow Burn trajectory, there is no single time point at which that difference should be measured—instead a clinical trial should seek to change the trajectory of decline. For patients on a Relapsing Recurrence trajectory, a clinical trial should seek to maximize the number of impairment-free months. These are fundamental differences in trial design that call for an empirical grounding rather than guesswork. The present work by Woon and colleagues is an important step in the right direction, as it emphasizes how many assumptions we have been making and how much more data we truly need. Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The author thanks Mark Mikkelsen, M.D., M.S.C.E., of the University of Pennsylvania for his comments.
Theodore J. Iwashyna, M.D., Ph.D. Department of Medicine University of Michigan Ann Arbor, Michigan Institute for Social Research Ann Arbor, Michigan and VA Center for Clinical Management Research Ann Arbor, Michigan
References 1. Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, Zawistowski C, Bemis-Dougherty A, Berney SC, Bienvenu OJ, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference. Crit Care Med 2012;40:502–509. 2. Davydow DS, Hough CL, Langa KM, Iwashyna TJ. Symptoms of depression in survivors of severe sepsis: a prospective cohort study of older Americans. Am J Geriatr Psychiatry (In press) 3. Iwashyna TJ, Netzer G, Langa KM, Cigolle C. Spurious inferences about long-term outcomes: the case of severe sepsis and geriatric conditions. Am J Respir Crit Care Med 2012;185:835–841.
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4. Woon FL, Dunn CB, Hopkins RO. Predicting cognitive sequelae in survivors of critical illness with cognitive screening tests. Am J Respir Crit Care Med 2012;186:333–340. 5. Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, Spears L, Miller M, Franczyk M, Deprizio D, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874–1882. 6. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:1293–1304. 7. Boyd CM, Landefeld CS, Counsell SR, Palmer RM, Fortinsky RH, Kresevic D, Burant C, Covinsky KE. Recovery of activities of daily living in older adults after hospitalization for acute medical illness. J Am Geriatr Soc 2008;56:2171–2179. 8. Boyd CM, Ricks M, Fried LP, Guralnik JM, Xue QL, Xia J, BandeenRoche K. Functional decline and recovery of activities of daily living in hospitalized, disabled older women: the Women’s Health and Aging Study I. J Am Geriatr Soc 2009;57:1757–1766. 9. Rubenfeld GD. Does the hospital make you older faster? Am J Respir Crit Care Med 2012;185:796–798. 10. Hardy SE, Gill TM. Recovery from disability among community-dwelling older persons. JAMA 2004;291:1596–1602. 11. Yende S, D’Angelo G, Kellum JA, Weissfeld LA, Fine J, Welch RD, Kon L, Carter M, Angus DC; GenIMS Investigators. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008;1771:1242–1247. 12. Yende S, D’Angelo G, Mayr F, Kellum JA, Weissfeld L, Kaynar AM, Young T, Irani K, Angus DC. Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths. PLoS ONE 2011;6:e22847. 13. Streit WJ, Mrak RE, Griffin WST. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004;1:14. 14. Brown CJ, Roth DL, Allman RM, Sawyer P, Ritchie CS, Roseman JM. Trajectories of life-space mobility after hospitalization. Ann Intern Med 2009;150:372–378.
Published 2012 by the American Thoracic Society DOI: 10.1164/rccm.201206-1138ED
Making It Personal: Using Genomics to Predict Pulmonary Hypertension in Sickle Cell Disease In this issue of the Journal, Desai and colleagues (pp. 359–368) attempt to use genomic-based methods to enhance screening patients with sickle cell disease (SCD) for the presence of pulmonary hypertension (PH) (1). This work contributes significantly to this rapidly evolving field and may help provide insights into disease pathogenesis. Despite treatment advances over the past 20–30 years, patients with SCD have an average mortality in the fifth decade with pulmonary complications being the major cause of death (2). Much work has been done over the past decade to gain a greater understanding of the prevalence and natural history of PH in this population. Although not diagnostic of PH, an elevated tricuspid regurgitant jet velocity (TRV) by Dopplerechocardiography consistent with risk for PH occurs in approximately 30% of hemoglobin-SS and 10–25% of hemoglobin-SC adults and is an independent risk factor for mortality (3, 4). PH, diagnosed by right heart catheterization, occurs in 6–11% of hemoglobin-SS adults. Approximately 40–50% of patients with PH have pulmonary arterial hypertension (PAH), and the rest have pulmonary venous hypertension (PVH), primarily related to diastolic dysfunction (5–7). PH, regardless of etiology, is also an independent risk factor for mortality in SCD (7), supporting
the notion that echocardiographic screening is an effective screening tool. However, the high false-positive rate of echocardiography suggests that other noninvasive screening tests are needed to better risk stratify patients with SCD prior to right heart catheterization (6). The clinical heterogeneity observed in SCD despite the shared genetic hemoglobinopathy suggests that extra-erythrocytic factors play an important role in disease modulation. Over the past decade, a body of literature has emerged that supports the concept that other genetic modifiers of this disease exist. Large-scale genetic studies of patients with SCD have identified singlenucleotide polymorphisms (SNPs) in VCAM1, KL, and genes within the transforming growth factor (TGF)-b signaling pathway as being associated with different vascular complications of SCD, including an elevated TRV (8). Microarrays of peripheral blood mononuclear cells (PBMCs) from patients with SCD have demonstrated an antioxidant and proinflammatory phenotype when compared with normal volunteers, suggesting a dysregulation of each of these pathways in SCD (9). This is the first study to date that attempts to link SNP data with mRNA expression in circulating blood cells of patients with SCD with a specific clinical phenotype. In the present study, examination
Editorials
of PBMC mRNA expression from patients with SCD reveals that combining the expression patterns of 10 genes can predict the presence of an elevated TRV with 100% accuracy. The authors then applied this genetic “signature” to a validation set of 20 geographically distinct patients with SCD with or without right heart catheterization–defined PH and found a 90% positive predictive value for the presence of PH. SNP studies of these genes in 112 patients with SCD found five SNPs in GALNT13 and one in PRELP, 2 of the 10, to be associated with an elevated TRV. Although clearly not diagnostic of PH, an elevated TRV has been repeatedly associated with mortality risk in SCD, and epidemiologic studies demonstrate a link to other vascular complications, including leg ulcers, renal dysfunction, priapism, relative systemic hypertension (2), and a dysregulation of the arginine metabolome (2, 3, 10). This reflects the likely systemic vasculopathy of SCD and suggests that similar pathogenic mechanisms may occur across vascular beds. Circulating lymphocytes and monocytes are known to interact with the vascular endothelium in SCD and are thought to play a role in modulating endothelial dysfunction (11). Although it is unknown what role the observed changes in PBMC gene expression play in modulating vascular function, particularly within the pulmonary vasculature, similar expression changes in PBMCs from idiopathic PAH and PAH related to systemic sclerosis suggest that these cells may offer insights into PH pathogenesis (12, 13). The identification of genes linked to PH in other populations (ADORA2B and ADC) and the ability of the gene signature to predict PH with 90% sensitivity and specificity speaks to the overlap of an elevated TRV and PH in SCD. Although this study is clearly provocative, it has its limitations. Genetic studies are generally most useful when applied to large populations with well-defined phenotypes to minimize the issue of false-positive data as much as possible. The relative rarity of SCD, particularly in the United States, makes largescale genetics studies nearly impossible without the collaboration of multiple centers, and as such, smaller cohorts are often used. In the present study, the use of discovery and validation cohorts that are not only small but also phenotypically nonidentical because of the presence of both PH and renal dysfunction in one group, but not the other, raises serious concerns about the generalizability of the findings to the larger SCD population. Additionally, the inclusion of both patients with PAH and patients with PVH in the validation cohort is troubling as it implies a similar disease pathogenesis between them, which has, thus far, not been substantiated by the literature. It will be necessary to validate the findings of the present study in a much larger cohort before one can recommend this as a screening tool for PH. As the field of PH in SCD continues to evolve, much controversy has arisen among investigators in the field (14). Two of the primary areas of controversy surround the interrelationship between an elevated TRV and PH and the prevalence of group 1 PAH in this population. Although the results of this study are preliminary, the overlap of genes identified in cohorts of patients with an elevated TRV and PH suggests that these represent a clinically contiguous group of patients. It also stresses the importance of using echocardiographic screening for noninvasively identifying patients with SCD at risk for PH. Additionally, the identification of common genes in this study and other PAH populations supports a similar mechanism of vascular remodeling and plexiform lesions inherent to the group 1 classification (15). Although much work still needs to be done to better understand PAH in SCD both mechanistically and clinically, we believe that this study provides an interesting and provocative framework upon which to base future research.
305 Author disclosures are available with the text of this article at www.atsjournals.org.
Elizabeth S. Klings, M.D. The Pulmonary Center Boston University School of Medicine Boston, Massachusetts Claudia R. Morris, M.D. Department of Emergency Medicine Children’s Hospital & Research Center Oakland Oakland, California
References 1. Desai AA, Zhou T, Ahmad H, Zhang W, Mu W, Trevino S, Wade MS, Raghavachari N, Kato GJ, Peters-Lawrence MH, et al. A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. Am J Respir Crit Care Med 2012;186:359–368. 2. Gladwin MT, Vichinsky E. Pulmonary complications of sickle cell disease. N Engl J Med 2008;359:2254–2265. 3. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 2004;350:886–895. 4. Klings ES, Anton BD, Rosenman D, Princeton S, Odhiambo A, Li G, Bernard SA, Steinberg MH, Farber HW. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression. Am J Hematol 2008;83:547–553. 5. Fonseca GH, Souza R, Salemi VC, Jardim CV, Gualandro SF. Pulmonary hypertension diagnosed by right heart catheterization in sickle cell disease. Eur Respir J 2012;39:112–118. 6. Parent F, Bachir D, Inamo J, Lionnet F, Driss F, Loko G, Habibi A, Bennani S, Savale L, Adnot S, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 2011;365:44–53. 7. Mehari A, Gladwin MT, Tian X, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 2012;307:1254–1256. 8. Steinberg MH. SNPing away at sickle cell pathophysiology. Blood 2008; 111:5420–5421. 9. Jison ML, Munson PJ, Barb JJ, Suffredini AF, Talwar S, Logun C, Raghavachari N, Beigel JH, Shelhamer JH, Danner RL, et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. Blood 2004; 104:270–280. 10. Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005;294:81–90. 11. Hebbel RP, Osarogiagbon R, Kaul D. The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy. Microcirculation 2004;11:129–151. 12. Grigoryev DN, Mathai SC, Fisher MR, Girgis RE, Zaiman AL, HoustenHarris T, Cheadle C, Gao L, Hummers LK, Champion HC, et al. Identification of candidate genes in scleroderma-related pulmonary arterial hypertension. Transl Res 2008;151:197–207. 13. Pendergrass SA, Hayes E, Farina G, Lemaire R, Farber HW, Whitfield ML, Lafyatis R. Limited systemic sclerosis patients with pulmonary arterial hypertension show biomarkers of inflammation and vascular injury. PLoS ONE 2010;5:e12106. 14. Bunn HF, Nathan DG, Dover GJ, Hebbel RP, Platt OS, Rosse WF, Ware RE. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 2010;116:687–692. 15. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. Circulation 2009;53:1573–1619. Copyright ª 2012 by the American Thoracic Society DOI: 10.1164/rccm.201206-1126ED
