EDITORIALS
Screening for Lung Cancer Improving Outcomes with Better Patient Selection In 2013, based largely on the findings from the NLST (National Lung Cancer Screening Trial) (1), the US Preventive Services Task Force revised its lung cancer screening guideline and recommended annual screening with low-dose computed tomography (LDCT) in adults aged 55–80 years who have a 30 pack-year history and currently smoke or have quit within 15 years (2). This change has been largely endorsed by other major medical societies and patient advocacy groups in the United States, although there are lingering concerns regarding the balance of benefits and harms from screening. The revised recommendation was largely driven by the observed reduction in lung cancer-specific mortality from 1.66 to 1.33% with annual LDCT, or three fewer deaths from lung cancer per 1,000 individuals. This represents a 20% relative reduction in mortality from lung cancer (1). The large number of false positives identified by screening also raises the concern for harm, resulting in uncertainly regarding the true benefit of LDCT screening and in the ability to translate the findings of the NLST into clinical practice. Although the NLST is the largest of several randomized lung cancer screening trials, several other smaller trials have reported results or are still ongoing (3–7). Given the concerns regarding the generalizability of NLST results, the outcomes from these studies has been greatly anticipated. Earlier this year, the Italian DANTE (Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays) trial reported long-term follow-up results and failed to show a mortality benefit with LDCT among 2,472 male smokers with a minimum smoking history of 20 pack-years (5). In this issue of the Journal, Wille and colleagues (pp. 542–551) report the long-term results from another European study, the DLCST (Danish Lung Cancer Screening Trial) (8). This trial enrolled 4,104 men and women aged 50–70 years with at least a 20 pack-year history (former smokers should have quit after age 50 years and within 10 years of enrollment). Eligible participants were randomized to either five annual rounds of LDCT screening or no screening, with outcomes collected up to 5 years after the last round of scans. DLCST was a well-conducted trial performed at two specialized lung cancer centers in Denmark. Screening adherence rates were high, there was very limited contamination of the control group, few patients were lost to follow-up, and outcome ascertainment was aided by the use of national registries. The study found no difference in lung cancer-specific or allcause mortality between the two groups, which confirms an earlier mortality analysis from this trial published in 2012 (7). Although this study had limited statistical power to identify a benefit, the nearly identical mortality rates in the two groups do not provide any hint of an effect (8). In subgroup analysis, the authors demonstrate higher lung cancer mortality among older patients with both greater smoking exposure (.35 pack-years) and concomitant chronic obstructive pulmonary disease (COPD). How do we now interpret the results of randomized screening trials that have evaluated use of LDCT? Should the lack of a mortality benefit from DLCST, as well as DANTE, affect our interpretation of results from the larger NLST? To address these questions, we must consider important differences, beyond just sample size, between the NLST and these smaller studies that might further explain the observed differences in outcomes. DLCST 478
enrolled patients at a lower risk for lung cancer when compared with NLST: participants were younger (age 50–70 vs. 55–74 yr in NLST) and had less smoking exposure (.20 vs. 30 pack-years in NLST). This resulted in lung cancer detection rates of 5.1 and 2.7 per 1,000 person-years in the screened and control groups, respectively, which is considerably lower than rates of lung cancer observed in NLST, which yielded 6.5 and 5.7 cases per 1,000 in the screened and control groups, respectively (1, 8). Secondary analyses from NLST have shown that patients at the highest risk for lung cancer were more likely to benefit from screening, and that patients in the lowest-risk quintile, as defined by age and smoking history, had almost no mortality advantage with LDCT (9, 10). DLCST similarly demonstrates fewer lung cancer deaths among lower-risk patients: only 10 (13%) of 77 lung cancer deaths occurred in patients without COPD and less than 35 pack-years of smoking, although this group represented one-third of the study population. The recognition of COPD as an important factor in identifying those at highest risk of developing lung cancer in DLCST confirms the findings seen from several other recent analyses (11–13). Another factor that may have affected the mortality results in DLCST is the algorithm used for management of suspicious lung nodules. Scans were considered positive if a nodule larger than 5 mm was present. Participants with nodules between 5 and 15 mm underwent repeat imaging at 3 months, and only nodules larger than 15 mm or rapidly growing nodules (.25% increase in volume) were referred for further diagnostic evaluation. Although this resulted in a lower false-positive rate when compared with NLST, this could have negatively affected the overall stage distribution of cancers identified; 54% of lung cancers identified with screening were either stage I or II compared with 63% in the NLST (14). Although there were significantly more early-stage cancers identified with LDCT, there was no significant difference in the rate of stage IV disease. The lack of a decrease in the rate of metastatic disease likely contributed to the overall lack of mortality benefit. In addition, the current report does not describe the diagnostic or treatment interventions employed, nor does it provide any information on surgical mortality, which could have contributed to the lack of an overall benefit (15). The lung cancer screening landscape now includes one large trial demonstrating a mortality benefit, and two smaller trials without benefit. Whether the lack of benefit in DLCST and DANTE are largely driven by small sample size or by other important differences in patient selection, diagnostic algorithm employed, and outcomes and complications of treatment employed, is difficult to determine. It is likely that a combination of these factors resulted in a lack of benefit. This places even greater emphasis on the NELSON (NederlandsLeuven Longkanker Screenings Network) trial, a collaborative Dutch–Belgian study that has randomized 15,822 participants to LDCT screening versus no screening (4). The DLCST was originally designed to allow for pooling of data with the much larger NELSON trial; however, the latter study has undergone several important revisions in its study design that may preclude the ability to perform formal meta-analyses. NELSON’s unique features include the use of volume doubling time to assess nodule growth, and prolonged screening intervals for later rounds of screening.
American Journal of Respiratory and Critical Care Medicine Volume 193 Number 5 | March 1 2016
EDITORIALS With the recent decision by the Centers for Medicare & Medicaid Services and other payers to cover the costs of lung cancer screening, the implementation in the United States is marching forward. European authorities, in contrast, have largely chosen to await the results of the NELSON trial. In centers where screening is performed, the results of the DLCST should be used as an opportunity to recognize the importance of strategies that result in careful patient selection to minimize any potential harms. The DLCST investigators are to be congratulated for including pulmonary function in their trial, which confirms the importance of COPD in identifying those at greatest risk for lung cancer. Although more work is needed to identify the best methods for identifying populations that will benefit from screening, one recent advance is the development of PLCOm2012, a logistic model incorporating four smoking variables and seven other variables, including COPD, to estimate lung cancer risk (16). A 6-year risk greater than 0.015% using this model identifies patients most likely to benefit from screening and, importantly, was more efficient than the currently recommended NLST criteria using only age and smoking history. Better selection of patients for screening, using model based tools such as PLCOm2012, will likely result in greater benefits and fewer harms from screening and warrants further evaluation. n
Author disclosures are available with the text of this article at www.atsjournals.org. Anil Vachani, M.D., M.S. Department of Medicine Perelman School of Medicine Philadelphia, Pennsylvania and Department of Medicine Corporal Michael J. Crescenz Veterans Administration Medical Center Philadelphia, Pennsylvania James R. Jett, M.D. Department of Medicine National Jewish Health Denver, Colorado
References 1. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. 2. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330–338. 3. Becker N, Motsch E, Gross ML, Eigentopf A, Heussel CP, Dienemann H, Schnabel PA, Eichinger M, Optazaite DE, Puderbach M, et al. Randomized study on early detection of lung cancer with MSCT in
Germany: results of the first 3 years of follow-up after randomization. J Thorac Oncol 2015;10:890–896. 4. Horeweg N, Scholten ET, de Jong PA, van der Aalst CM, Weenink C, Lammers JW, Nackaerts K, Vliegenthart R, ten Haaf K, Yousaf-Khan UA, et al. Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. Lancet Oncol 2014;15:1342–1350. 5. Infante M, Cavuto S, Lutman FR, Passera E, Chiarenza M, Chiesa G, Brambilla G, Angeli E, Aranzulla G, Chiti A, et al.; DANTE Study Group. Long-term follow-up results of the DANTE Trial, a randomized study of lung cancer screening with spiral computed tomography. Am J Respir Crit Care Med 2015;191:1166–1175. 6. Pastorino U, Rossi M, Rosato V, Marchiano` A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012;21:308–315. 7. Saghir Z, Dirksen A, Ashraf H, Bach KS, Brodersen J, Clementsen PF, Døssing M, Hansen H, Kofoed KF, Larsen KR, et al. CT screening for lung cancer brings forward early disease: the randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax 2012;67:296–301. 8. Wille MM, Dirksen A, Ashraf H, Saghir Z, Bach KS, Brodersen J, Clementsen PF, Hansen H, Larsen KR, Mortensen J, et al. Results of the randomized Danish Lung Cancer Screening Trial with focus on high-risk profiling. Am J Respir Crit Care Med 2016;193:542–551. 9. Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, Silvestri GA, Chaturvedi AK, Katki HA. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013;369:245–254. 10. Tammemagi ¨ MC, Katki HA, Hocking WG, Church TR, Caporaso N, Kvale PA, Chaturvedi AK, Silvestri GA, Riley TL, Commins J, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368: 728–736. 11. de-Torres JP, Wilson DO, Sanchez-Salcedo P, Weissfeld JL, Berto J, Campo A, Alcaide AB, Garc´ıa-Granero M, Celli BR, Zulueta JJ. Lung cancer in patients with chronic obstructive pulmonary disease. Development and validation of the COPD Lung Cancer Screening Score. Am J Respir Crit Care Med 2015;191:285–291. 12. Sanchez-Salcedo P, Wilson DO, de-Torres JP, Weissfeld JL, Berto J, Campo A, Alcaide AB, Pueyo J, Bastarrika G, Seijo LM, et al. Improving selection criteria for lung cancer screening: the potential role of emphysema. Am J Respir Crit Care Med 2015;191:924–931. 13. Young RP, Duan F, Chiles C, Hopkins RJ, Gamble GD, Greco EM, Gatsonis C, Aberle D. Airflow limitation and histology shift in the National Lung Screening Trial: the NLST-ACRIN Cohort Substudy. Am J Respir Crit Care Med 2015;192:1060–1067. 14. Church TR, Black WC, Aberle DR, Berg CD, Clingan KL, Duan F, Fagerstrom RM, Gareen IF, Gierada DS, Jones GC, et al.; National Lung Screening Trial Research Team. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013;368:1980–1991. 15. Tanner NT, Silvestri GA. Screening for lung cancer using low-dose computed tomography: are we headed for DANTE’s paradise or inferno? Am J Respir Crit Care Med 2015;191:1100–1101. 16. Tammemagi ¨ MC, Church TR, Hocking WG, Silvestri GA, Kvale PA, Riley TL, Commins J, Berg CD. Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. PLoS Med 2014;11:e1001764.
Copyright © 2016 by the American Thoracic Society
A Critical Role for Airway Microvessels in Lung Transplantation Lung transplantation permits a lifesaving treatment for patients with terminal pulmonary vascular and parenchymal diseases. As blood vessels, lymphatics, and nerves are severed and incompletely restored at the time of transplantation, these Editorials
anatomic derangements may contribute to early- and late-arising pathologies. Experimental and clinical evidence is mounting that microvessel damage, in particular, is bad for solid organ allografts, such as lung transplants. 479
Screening for Lung Cancer Improving Outcomes with Better Patient Selection In 2013, based largely on the findings from the NLST (National Lung Cancer Screening Trial) (1), the US Preventive Services Task Force revised its lung cancer screening guideline and recommended annual screening with low-dose computed tomography (LDCT) in adults aged 55–80 years who have a 30 pack-year history and currently smoke or have quit within 15 years (2). This change has been largely endorsed by other major medical societies and patient advocacy groups in the United States, although there are lingering concerns regarding the balance of benefits and harms from screening. The revised recommendation was largely driven by the observed reduction in lung cancer-specific mortality from 1.66 to 1.33% with annual LDCT, or three fewer deaths from lung cancer per 1,000 individuals. This represents a 20% relative reduction in mortality from lung cancer (1). The large number of false positives identified by screening also raises the concern for harm, resulting in uncertainly regarding the true benefit of LDCT screening and in the ability to translate the findings of the NLST into clinical practice. Although the NLST is the largest of several randomized lung cancer screening trials, several other smaller trials have reported results or are still ongoing (3–7). Given the concerns regarding the generalizability of NLST results, the outcomes from these studies has been greatly anticipated. Earlier this year, the Italian DANTE (Detection and Screening of Early Lung Cancer by Novel Imaging Technology and Molecular Essays) trial reported long-term follow-up results and failed to show a mortality benefit with LDCT among 2,472 male smokers with a minimum smoking history of 20 pack-years (5). In this issue of the Journal, Wille and colleagues (pp. 542–551) report the long-term results from another European study, the DLCST (Danish Lung Cancer Screening Trial) (8). This trial enrolled 4,104 men and women aged 50–70 years with at least a 20 pack-year history (former smokers should have quit after age 50 years and within 10 years of enrollment). Eligible participants were randomized to either five annual rounds of LDCT screening or no screening, with outcomes collected up to 5 years after the last round of scans. DLCST was a well-conducted trial performed at two specialized lung cancer centers in Denmark. Screening adherence rates were high, there was very limited contamination of the control group, few patients were lost to follow-up, and outcome ascertainment was aided by the use of national registries. The study found no difference in lung cancer-specific or allcause mortality between the two groups, which confirms an earlier mortality analysis from this trial published in 2012 (7). Although this study had limited statistical power to identify a benefit, the nearly identical mortality rates in the two groups do not provide any hint of an effect (8). In subgroup analysis, the authors demonstrate higher lung cancer mortality among older patients with both greater smoking exposure (.35 pack-years) and concomitant chronic obstructive pulmonary disease (COPD). How do we now interpret the results of randomized screening trials that have evaluated use of LDCT? Should the lack of a mortality benefit from DLCST, as well as DANTE, affect our interpretation of results from the larger NLST? To address these questions, we must consider important differences, beyond just sample size, between the NLST and these smaller studies that might further explain the observed differences in outcomes. DLCST 478
enrolled patients at a lower risk for lung cancer when compared with NLST: participants were younger (age 50–70 vs. 55–74 yr in NLST) and had less smoking exposure (.20 vs. 30 pack-years in NLST). This resulted in lung cancer detection rates of 5.1 and 2.7 per 1,000 person-years in the screened and control groups, respectively, which is considerably lower than rates of lung cancer observed in NLST, which yielded 6.5 and 5.7 cases per 1,000 in the screened and control groups, respectively (1, 8). Secondary analyses from NLST have shown that patients at the highest risk for lung cancer were more likely to benefit from screening, and that patients in the lowest-risk quintile, as defined by age and smoking history, had almost no mortality advantage with LDCT (9, 10). DLCST similarly demonstrates fewer lung cancer deaths among lower-risk patients: only 10 (13%) of 77 lung cancer deaths occurred in patients without COPD and less than 35 pack-years of smoking, although this group represented one-third of the study population. The recognition of COPD as an important factor in identifying those at highest risk of developing lung cancer in DLCST confirms the findings seen from several other recent analyses (11–13). Another factor that may have affected the mortality results in DLCST is the algorithm used for management of suspicious lung nodules. Scans were considered positive if a nodule larger than 5 mm was present. Participants with nodules between 5 and 15 mm underwent repeat imaging at 3 months, and only nodules larger than 15 mm or rapidly growing nodules (.25% increase in volume) were referred for further diagnostic evaluation. Although this resulted in a lower false-positive rate when compared with NLST, this could have negatively affected the overall stage distribution of cancers identified; 54% of lung cancers identified with screening were either stage I or II compared with 63% in the NLST (14). Although there were significantly more early-stage cancers identified with LDCT, there was no significant difference in the rate of stage IV disease. The lack of a decrease in the rate of metastatic disease likely contributed to the overall lack of mortality benefit. In addition, the current report does not describe the diagnostic or treatment interventions employed, nor does it provide any information on surgical mortality, which could have contributed to the lack of an overall benefit (15). The lung cancer screening landscape now includes one large trial demonstrating a mortality benefit, and two smaller trials without benefit. Whether the lack of benefit in DLCST and DANTE are largely driven by small sample size or by other important differences in patient selection, diagnostic algorithm employed, and outcomes and complications of treatment employed, is difficult to determine. It is likely that a combination of these factors resulted in a lack of benefit. This places even greater emphasis on the NELSON (NederlandsLeuven Longkanker Screenings Network) trial, a collaborative Dutch–Belgian study that has randomized 15,822 participants to LDCT screening versus no screening (4). The DLCST was originally designed to allow for pooling of data with the much larger NELSON trial; however, the latter study has undergone several important revisions in its study design that may preclude the ability to perform formal meta-analyses. NELSON’s unique features include the use of volume doubling time to assess nodule growth, and prolonged screening intervals for later rounds of screening.
American Journal of Respiratory and Critical Care Medicine Volume 193 Number 5 | March 1 2016
EDITORIALS With the recent decision by the Centers for Medicare & Medicaid Services and other payers to cover the costs of lung cancer screening, the implementation in the United States is marching forward. European authorities, in contrast, have largely chosen to await the results of the NELSON trial. In centers where screening is performed, the results of the DLCST should be used as an opportunity to recognize the importance of strategies that result in careful patient selection to minimize any potential harms. The DLCST investigators are to be congratulated for including pulmonary function in their trial, which confirms the importance of COPD in identifying those at greatest risk for lung cancer. Although more work is needed to identify the best methods for identifying populations that will benefit from screening, one recent advance is the development of PLCOm2012, a logistic model incorporating four smoking variables and seven other variables, including COPD, to estimate lung cancer risk (16). A 6-year risk greater than 0.015% using this model identifies patients most likely to benefit from screening and, importantly, was more efficient than the currently recommended NLST criteria using only age and smoking history. Better selection of patients for screening, using model based tools such as PLCOm2012, will likely result in greater benefits and fewer harms from screening and warrants further evaluation. n
Author disclosures are available with the text of this article at www.atsjournals.org. Anil Vachani, M.D., M.S. Department of Medicine Perelman School of Medicine Philadelphia, Pennsylvania and Department of Medicine Corporal Michael J. Crescenz Veterans Administration Medical Center Philadelphia, Pennsylvania James R. Jett, M.D. Department of Medicine National Jewish Health Denver, Colorado
References 1. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM, Sicks JD; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. 2. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:330–338. 3. Becker N, Motsch E, Gross ML, Eigentopf A, Heussel CP, Dienemann H, Schnabel PA, Eichinger M, Optazaite DE, Puderbach M, et al. Randomized study on early detection of lung cancer with MSCT in
Germany: results of the first 3 years of follow-up after randomization. J Thorac Oncol 2015;10:890–896. 4. Horeweg N, Scholten ET, de Jong PA, van der Aalst CM, Weenink C, Lammers JW, Nackaerts K, Vliegenthart R, ten Haaf K, Yousaf-Khan UA, et al. Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. Lancet Oncol 2014;15:1342–1350. 5. Infante M, Cavuto S, Lutman FR, Passera E, Chiarenza M, Chiesa G, Brambilla G, Angeli E, Aranzulla G, Chiti A, et al.; DANTE Study Group. Long-term follow-up results of the DANTE Trial, a randomized study of lung cancer screening with spiral computed tomography. Am J Respir Crit Care Med 2015;191:1166–1175. 6. Pastorino U, Rossi M, Rosato V, Marchiano` A, Sverzellati N, Morosi C, Fabbri A, Galeone C, Negri E, Sozzi G, et al. Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 2012;21:308–315. 7. Saghir Z, Dirksen A, Ashraf H, Bach KS, Brodersen J, Clementsen PF, Døssing M, Hansen H, Kofoed KF, Larsen KR, et al. CT screening for lung cancer brings forward early disease: the randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax 2012;67:296–301. 8. Wille MM, Dirksen A, Ashraf H, Saghir Z, Bach KS, Brodersen J, Clementsen PF, Hansen H, Larsen KR, Mortensen J, et al. Results of the randomized Danish Lung Cancer Screening Trial with focus on high-risk profiling. Am J Respir Crit Care Med 2016;193:542–551. 9. Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, Silvestri GA, Chaturvedi AK, Katki HA. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med 2013;369:245–254. 10. Tammemagi ¨ MC, Katki HA, Hocking WG, Church TR, Caporaso N, Kvale PA, Chaturvedi AK, Silvestri GA, Riley TL, Commins J, et al. Selection criteria for lung-cancer screening. N Engl J Med 2013;368: 728–736. 11. de-Torres JP, Wilson DO, Sanchez-Salcedo P, Weissfeld JL, Berto J, Campo A, Alcaide AB, Garc´ıa-Granero M, Celli BR, Zulueta JJ. Lung cancer in patients with chronic obstructive pulmonary disease. Development and validation of the COPD Lung Cancer Screening Score. Am J Respir Crit Care Med 2015;191:285–291. 12. Sanchez-Salcedo P, Wilson DO, de-Torres JP, Weissfeld JL, Berto J, Campo A, Alcaide AB, Pueyo J, Bastarrika G, Seijo LM, et al. Improving selection criteria for lung cancer screening: the potential role of emphysema. Am J Respir Crit Care Med 2015;191:924–931. 13. Young RP, Duan F, Chiles C, Hopkins RJ, Gamble GD, Greco EM, Gatsonis C, Aberle D. Airflow limitation and histology shift in the National Lung Screening Trial: the NLST-ACRIN Cohort Substudy. Am J Respir Crit Care Med 2015;192:1060–1067. 14. Church TR, Black WC, Aberle DR, Berg CD, Clingan KL, Duan F, Fagerstrom RM, Gareen IF, Gierada DS, Jones GC, et al.; National Lung Screening Trial Research Team. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med 2013;368:1980–1991. 15. Tanner NT, Silvestri GA. Screening for lung cancer using low-dose computed tomography: are we headed for DANTE’s paradise or inferno? Am J Respir Crit Care Med 2015;191:1100–1101. 16. Tammemagi ¨ MC, Church TR, Hocking WG, Silvestri GA, Kvale PA, Riley TL, Commins J, Berg CD. Evaluation of the lung cancer risks at which to screen ever- and never-smokers: screening rules applied to the PLCO and NLST cohorts. PLoS Med 2014;11:e1001764.
Copyright © 2016 by the American Thoracic Society
A Critical Role for Airway Microvessels in Lung Transplantation Lung transplantation permits a lifesaving treatment for patients with terminal pulmonary vascular and parenchymal diseases. As blood vessels, lymphatics, and nerves are severed and incompletely restored at the time of transplantation, these Editorials
anatomic derangements may contribute to early- and late-arising pathologies. Experimental and clinical evidence is mounting that microvessel damage, in particular, is bad for solid organ allografts, such as lung transplants. 479
