- Email: [email protected]
Detection of bronchiolitis obliterans syndrome (BOS) in single lung transplant recipients
The Journal of Heart and Lung Transplantation Volume 22, Number 7
of disease progression, given the heterogeneous nature of cystic fibrosis (CF) lung disease involvement. We observed that substantial disparity in ventilation/perfusion abnormalities identified a group of CF patients at risk for dying on the transplant list. In addition, we confirmed earlier reports that an elevated PCO2 is associated with greater risk of mortality while waiting. Although not directly measured in every patient at the time of transplant evaluation, pulmonary arterial pressure estimates via echocardiogram (right ventricular systolic pressure) were not significantly different between the study groups. Trends toward higher dead space ventilation (VDS/VT), VE/VCO2 and lower maximal oxygen uptake during exercise were observed in the group of patients who died while on the lung transplant waiting list, suggesting greater exerciseinduced impairment of pulmonary vascular reserve. However, these differences were not statistically significant. A subsequent analysis comparing the observed estimate of pulmonary arterial pressure to disparity in both ventilation and perfusion between lungs revealed no substantial correlation (mean R2 ⫽ 0.05). One possible explanation is that heterogeneous abnormalities seen on ventilation/perfusion scans may not always accompany an important change in PA pressure, considered a global estimate of the entire pulmonary vascular bed. Variability of pulmonary vascular reserve among different lung regions may lead to relatively normal mean values through compensatory dilation of the normal vascular beds. Nonetheless, we do not dispute that, if significant pulmonary hypertension is identified, then it represents an independent risk factor for early death while waiting for a lung transplant. Michael L. Stanchina, MD Kelan G. Tantisera, MD Suzanne L. Aquino, MD John C. Wain, MD Leo C. Ginns, MD
DETECTION OF BRONCHIOLITIS OBLITERANS SYNDROME (BOS) IN SINGLE LUNG TRANSPLANT RECIPIENTS To the Editor: Lung transplantation has become an acceptable treatment option for end-stage lung disease.1 Single lung transplantation can be used for patients with chronic obstructive pulmonary disease (COPD) and doi:10.1016/S1053-2498(02)00637-X
829
idiopathic pulmonary fibrosis (IPF).1 Long-term survival is limited because of the development of bronchiolitis obliterans (BO), which is thought to represent chronic lung allograft rejection. Bronchiolitis obliterans syndrome (BOS) is a surrogate marker of BO and uses forced expiratory volume in 1 second (FEV1) to quantify the degree of allograft dysfunction.2,3 FEV1 does not have the ability to differentiate the relative contribution to pulmonary function of each lung in single lung transplant recipients. In patients with COPD the native lung is probably characterized by relatively low flow in the early part of expiration, but more preserved lung volume, as is common in obstructive lung disease. Therefore, the relative contribution of the native lung to the FEV1 is small and the allograft determines the value of the FEV1 to a significant degree. In contrast, patients with IPF have restriction in their native lung. The lung volume is decreased, but most of it empties in the early part of expiration. Although its contribution to the FEV1 is small compared with the allograft, it is likely more significant than that of an equivalent native lung with COPD. As a result, FEV1 might be a more sensitive marker for allograft pathology in single lung transplant recipients with COPD than IPF. In a recent article, Haider et al4 observed that single lung transplant recipients with COPD have better survival after development of BOS compared with single lung transplant recipients with IPF, despite having a lower FEV1 at the time of BOS development. The investigators noted that the use of FEV1 as a marker of allograft dysfunction and chronic rejection might not be equally applicable to patients with COPD and IPF. Their data appear to support this observation: If one assumes that each native lung contributes approximately half of the FEV1 prior to transplantation, then each native lung has an FEV1 of 0.27 liter in COPD and 0.70 liter in IPF, according to the data provided for the patients in their study. These values are 15% (0.27liter/1.84 liters) in COPD patients and 30% (0.70liter/2.36liters) in IPF patients of the total FEV1 after transplantation. Our letter provides another possible explanation for the poor prognosis of single lung transplant recipients with IPF and BOS compared to recipients with COPD and BOS. Patients with IPF and BOS are detected later in their disease because of the use of FEV1 as a surrogate marker for chronic rejection. This might contribute to their high mortality following development of BOS. Use of other parameters, like DLCO, FVC or
The Journal of Heart and Lung Transplantation July 2003
830
FEV1/FVC might be more appropriate for earlier detection of allograft dysfunction in single lung transplant recipients with IPF. Our hypothesis needs to be validated in prospective studies. Techniques that could assess the relative importance of each lung in pulmonary function measurements need to be developed and validated. Denis Hadjiliadis, MD, MHS, FRCP(C) and Michael A. Hutcheon, MD Division of Respirology University of Toronto 200 Elizabeth Street, 10-EN-N-240 Toronto General Hospital Toronto, Ontario M5G 2C4, Canada REFERENCES 1. Arcasoy SM, Kotloff RM. Medical progress: lung transplantation. N Engl J Med 1999;340:1081–91. 2. Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation: a review. Chest 1998;114: 1411–26. 3. Cooper J, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts: International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12:713–6. 4. Haider Y, Yonan N, Mogulkoc N, Carroll KB, Egan JJ. Bronchiolitis obliterans syndrome in single lung transplant recipients—patients with emphysema versus patients with idiopathic pulmonary fibrosis. J Heart Lung Transplant 2002; 21:327–33.
AUTHOR’S RESPONSE To the Editor: Our data have demonstrated that, despite a significant reduction in forced expiratory volume in 1 second (FEV1), emphysema patients with (bronchiolitis obliterans syndrome) (BOS) have prolonged survival in-amanner similar to the survival seen in emphysema patients prior to transplantation.1,2 This suggested that the native lung could provide ventilatory support after the onset of BOS, therefore influencing survival. Hadjiliadias et al speculated that the reason for the poor survival in the comparison group of IPF patients, despite relatively well-preserved FEV1, was due to a late diagnosis of BOS being achieved. It is widely accepted that FEV1 has limitations as a surrogate for graft dysfunction, particularly in the early phase of disease. Consequently, the recent update on the diagnostic criteria for BOS has focused on the importance PII: S1053-2498(02)00636-8
of a potential BOS stage (BOS-P),3 which is defined as a fall in FEV1 to 81% to 90% of baseline and/or a fall in forced expiratory flow in the mid-expiratory phase (FEF25%–75%) to ⬍75% of baseline. Despite this recent publication, it has been well recognized in clinical practice that a change in small airway indices should prompt investigation into diagnosing or excluding BOS.4 Indeed, this practice was applied during our data collection period and therefore it is unlikely that a late diagnosis of BOS in IPF patients occurred. The suggestion that DLCO may be more appropriate for the detection of allograft dysfunction in IPF patients is not unreasonable. However, our data show that the average DLCO post-transplant for IPF patients is 48% of predicted. Change in DLCO is notoriously difficult to standardize. With a starting point of 48%, there is little capacity for withinpatient change from that value, particularly if one considers that a change of at least ⬎10% is required for statistical significance. Hadjiliadias et al speculated that the proportional ventilation of the native lung is 15% in COPD patients, compared with 30% of IPF patients in IPF. This pattern of ventilation was described previously by Chacon et al utilizing differential ventilation perfusion scanning.5 They demonstrated that the native lung receives 20% ventilation in emphysema patients, compared with 35% in IPF patients5; however, this was found in clinically stable patients at 6 months post-transplant. It is our contention that, immediately after the onset of BOS, there is a shift of ventilatory dependence to the native lung. The ventilatory dependence on the native lung then reflects the survival patterns seen prior to transplant, with emphysema patients showing a favorable survival pattern compared with IPF patients.2 Ultimately, the prospective collection of physiologic data from ongoing multi-center therapeutic studies and utilization of the updated BOS classification will be useful for further improving our understanding of the natural history of BOS. Jim Egan, MD Irish National Lung Transplant Program Mater Misericordiae Hospital University College Dublin Dublin, Ireland REFERENCES 1. Haider Y, Mogulkoc N, Carroll KB, Yonan N, Egan JJ. The survival of patients with emphysema following the development of BOS. J Heart Lung Transplant 2002;21:327–33. 2. Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick
of disease progression, given the heterogeneous nature of cystic fibrosis (CF) lung disease involvement. We observed that substantial disparity in ventilation/perfusion abnormalities identified a group of CF patients at risk for dying on the transplant list. In addition, we confirmed earlier reports that an elevated PCO2 is associated with greater risk of mortality while waiting. Although not directly measured in every patient at the time of transplant evaluation, pulmonary arterial pressure estimates via echocardiogram (right ventricular systolic pressure) were not significantly different between the study groups. Trends toward higher dead space ventilation (VDS/VT), VE/VCO2 and lower maximal oxygen uptake during exercise were observed in the group of patients who died while on the lung transplant waiting list, suggesting greater exerciseinduced impairment of pulmonary vascular reserve. However, these differences were not statistically significant. A subsequent analysis comparing the observed estimate of pulmonary arterial pressure to disparity in both ventilation and perfusion between lungs revealed no substantial correlation (mean R2 ⫽ 0.05). One possible explanation is that heterogeneous abnormalities seen on ventilation/perfusion scans may not always accompany an important change in PA pressure, considered a global estimate of the entire pulmonary vascular bed. Variability of pulmonary vascular reserve among different lung regions may lead to relatively normal mean values through compensatory dilation of the normal vascular beds. Nonetheless, we do not dispute that, if significant pulmonary hypertension is identified, then it represents an independent risk factor for early death while waiting for a lung transplant. Michael L. Stanchina, MD Kelan G. Tantisera, MD Suzanne L. Aquino, MD John C. Wain, MD Leo C. Ginns, MD
DETECTION OF BRONCHIOLITIS OBLITERANS SYNDROME (BOS) IN SINGLE LUNG TRANSPLANT RECIPIENTS To the Editor: Lung transplantation has become an acceptable treatment option for end-stage lung disease.1 Single lung transplantation can be used for patients with chronic obstructive pulmonary disease (COPD) and doi:10.1016/S1053-2498(02)00637-X
829
idiopathic pulmonary fibrosis (IPF).1 Long-term survival is limited because of the development of bronchiolitis obliterans (BO), which is thought to represent chronic lung allograft rejection. Bronchiolitis obliterans syndrome (BOS) is a surrogate marker of BO and uses forced expiratory volume in 1 second (FEV1) to quantify the degree of allograft dysfunction.2,3 FEV1 does not have the ability to differentiate the relative contribution to pulmonary function of each lung in single lung transplant recipients. In patients with COPD the native lung is probably characterized by relatively low flow in the early part of expiration, but more preserved lung volume, as is common in obstructive lung disease. Therefore, the relative contribution of the native lung to the FEV1 is small and the allograft determines the value of the FEV1 to a significant degree. In contrast, patients with IPF have restriction in their native lung. The lung volume is decreased, but most of it empties in the early part of expiration. Although its contribution to the FEV1 is small compared with the allograft, it is likely more significant than that of an equivalent native lung with COPD. As a result, FEV1 might be a more sensitive marker for allograft pathology in single lung transplant recipients with COPD than IPF. In a recent article, Haider et al4 observed that single lung transplant recipients with COPD have better survival after development of BOS compared with single lung transplant recipients with IPF, despite having a lower FEV1 at the time of BOS development. The investigators noted that the use of FEV1 as a marker of allograft dysfunction and chronic rejection might not be equally applicable to patients with COPD and IPF. Their data appear to support this observation: If one assumes that each native lung contributes approximately half of the FEV1 prior to transplantation, then each native lung has an FEV1 of 0.27 liter in COPD and 0.70 liter in IPF, according to the data provided for the patients in their study. These values are 15% (0.27liter/1.84 liters) in COPD patients and 30% (0.70liter/2.36liters) in IPF patients of the total FEV1 after transplantation. Our letter provides another possible explanation for the poor prognosis of single lung transplant recipients with IPF and BOS compared to recipients with COPD and BOS. Patients with IPF and BOS are detected later in their disease because of the use of FEV1 as a surrogate marker for chronic rejection. This might contribute to their high mortality following development of BOS. Use of other parameters, like DLCO, FVC or
The Journal of Heart and Lung Transplantation July 2003
830
FEV1/FVC might be more appropriate for earlier detection of allograft dysfunction in single lung transplant recipients with IPF. Our hypothesis needs to be validated in prospective studies. Techniques that could assess the relative importance of each lung in pulmonary function measurements need to be developed and validated. Denis Hadjiliadis, MD, MHS, FRCP(C) and Michael A. Hutcheon, MD Division of Respirology University of Toronto 200 Elizabeth Street, 10-EN-N-240 Toronto General Hospital Toronto, Ontario M5G 2C4, Canada REFERENCES 1. Arcasoy SM, Kotloff RM. Medical progress: lung transplantation. N Engl J Med 1999;340:1081–91. 2. Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation: a review. Chest 1998;114: 1411–26. 3. Cooper J, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts: International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12:713–6. 4. Haider Y, Yonan N, Mogulkoc N, Carroll KB, Egan JJ. Bronchiolitis obliterans syndrome in single lung transplant recipients—patients with emphysema versus patients with idiopathic pulmonary fibrosis. J Heart Lung Transplant 2002; 21:327–33.
AUTHOR’S RESPONSE To the Editor: Our data have demonstrated that, despite a significant reduction in forced expiratory volume in 1 second (FEV1), emphysema patients with (bronchiolitis obliterans syndrome) (BOS) have prolonged survival in-amanner similar to the survival seen in emphysema patients prior to transplantation.1,2 This suggested that the native lung could provide ventilatory support after the onset of BOS, therefore influencing survival. Hadjiliadias et al speculated that the reason for the poor survival in the comparison group of IPF patients, despite relatively well-preserved FEV1, was due to a late diagnosis of BOS being achieved. It is widely accepted that FEV1 has limitations as a surrogate for graft dysfunction, particularly in the early phase of disease. Consequently, the recent update on the diagnostic criteria for BOS has focused on the importance PII: S1053-2498(02)00636-8
of a potential BOS stage (BOS-P),3 which is defined as a fall in FEV1 to 81% to 90% of baseline and/or a fall in forced expiratory flow in the mid-expiratory phase (FEF25%–75%) to ⬍75% of baseline. Despite this recent publication, it has been well recognized in clinical practice that a change in small airway indices should prompt investigation into diagnosing or excluding BOS.4 Indeed, this practice was applied during our data collection period and therefore it is unlikely that a late diagnosis of BOS in IPF patients occurred. The suggestion that DLCO may be more appropriate for the detection of allograft dysfunction in IPF patients is not unreasonable. However, our data show that the average DLCO post-transplant for IPF patients is 48% of predicted. Change in DLCO is notoriously difficult to standardize. With a starting point of 48%, there is little capacity for withinpatient change from that value, particularly if one considers that a change of at least ⬎10% is required for statistical significance. Hadjiliadias et al speculated that the proportional ventilation of the native lung is 15% in COPD patients, compared with 30% of IPF patients in IPF. This pattern of ventilation was described previously by Chacon et al utilizing differential ventilation perfusion scanning.5 They demonstrated that the native lung receives 20% ventilation in emphysema patients, compared with 35% in IPF patients5; however, this was found in clinically stable patients at 6 months post-transplant. It is our contention that, immediately after the onset of BOS, there is a shift of ventilatory dependence to the native lung. The ventilatory dependence on the native lung then reflects the survival patterns seen prior to transplant, with emphysema patients showing a favorable survival pattern compared with IPF patients.2 Ultimately, the prospective collection of physiologic data from ongoing multi-center therapeutic studies and utilization of the updated BOS classification will be useful for further improving our understanding of the natural history of BOS. Jim Egan, MD Irish National Lung Transplant Program Mater Misericordiae Hospital University College Dublin Dublin, Ireland REFERENCES 1. Haider Y, Mogulkoc N, Carroll KB, Yonan N, Egan JJ. The survival of patients with emphysema following the development of BOS. J Heart Lung Transplant 2002;21:327–33. 2. Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick