Abstract
Obliterative bronchiolitis (OB) is the first cause of death of long-term survivors of lung transplantation. The diagnosis is based on pathology and/or on an irreversible decrease in forced expiratory volume in 1 s (FEV1) below 80% of the best postoperative value. We tested whether indexes of ventilation distribution may provide evidence of OB before conventional pulmonary function tests (PFTs). Fifty-seven patients with heart-lung (n = 47) or double-lung (n = 10) transplantation were monitored with conventional PFTs and measurements of the slope of the alveolar plateau for He (SHe), SF6 (SSF6), and N2 (SN2) obtained during single-breath washouts. The date at which a functional variable showed an irreversible change outside the 97.5% confidence interval was compared with the date at which a greater than 20% fall in FEV1 was observed. A total of 1,929 tests (median, 30 tests per patient) were performed during the 1,215 d (range, 164–2,829 d) of follow-up. Eighteen patients showed an irreversible and greater than 20% fall in FEV1 during the course of the study. This alteration was preceded by a rise in SHe in 17 patients and by a rise in SN2 in 16 patients, which indicated a more heterogeneous ventilation. The median time interval between the change in SHe and SN2 and the 20% decrease in FEV1 was 356 and 168 d, respectively, with seven patients showing an interval of 18 mo or more. Conventional PFTs, including midexpiratory flow rates, deteriorated after indexes of ventilation distribution. Thirty-nine patients did not show any significant and irreversible alteration in conventional PFTs over the study period; only seven of these patients developed significant alterations in ventilation distribution. We conclude that measurements of ventilation distribution detect posttransplant OB much earlier than conventional PFTs.
Because the branching pattern of the bronchial tree results in an increasingly large number of small airways in peripheral generations, these airways contribute little to total pulmonary resistance. So, a large proportion of small airways may be damaged or obliterated without impairing any of the conventional tests of pulmonary function (1). More than 20 yr ago, Buist and Ross (2) and Cosio and colleagues (3) showed that the single-breath nitrogen washout, which tests the evenness of ventilation, allows early detection of obstruction of peripheral airways in smokers without functional signs of chronic airflow obstruction. Since these studies, considerable theoretical and experimental work has been done using single- and multiple-breath washouts of one or more inert gases (4, 5), but tests of ventilation distribution have not emerged so far as a valuable tool to improve patient diagnosis and management in clinical practice.
In the present studies we have investigated whether indexes of ventilation distribution may provide early evidence of chronic allograft dysfunction after lung transplantation. Obliterative bronchiolitis (OB), which is considered to be a manifestation of chronic rejection and leads to obliteration of terminal bronchioles in up to 50 to 70% in long-term survivors (6-8), makes ventilation more heterogeneous and alters inert gas single-breath washout (9). In this longitudinal study, we have analyzed physiologic data collected over more than 3 yr in 57 lung transplant recipients; 18 of these eventually developed OB whereas 39 were free of the complication at the end of the study. We found that tests of ventilation distribution invariably deteriorated well before conventional pulmonary function tests. Therefore, adding these tests to patient follow-up may allow early detection of OB and indicate the need for increased immunosuppression before irreversible changes occur in the airways.
Between August 1983 and December 1998, 81 heart–lung transplantations (HLTs) and 16 double-lung transplantations (DLTs) were performed in 97 patients at our institution (Erasme University Hospital, Brussels, Belgium). Thirteen patients died and 2 patients developed OB before measurements of ventilation distribution were available in our laboratory (June 1991), 21 patients had a follow-up of less than 6 mo (16 deaths within the first 6 postoperative months and 5 patients operated after June 1998), 2 patients had asthma, and 2 patients were too young to perform the measurements satisfactorily, leaving 57 patients (34 males) eligible for study. These patients gave verbal informed consent to the procedures as approved by the ethics committee of our institution and were studied prospectively from June 1991 or from transplantation to December 1998 or death. At the time of transplantation (HLT in 47 patients and DLT in 10 patients), the patients were (mean ± SD) 35.3 ± 12.3 yr of age. Preoperative diagnosis was cystic fibrosis in 25 patients, primary pulmonary hypertension in 15 patients, bronchiectasis in 5 patients, Eisenmenger syndrome in 4 patients, emphysema in 3 patients, idiopathic pulmonary fibrosis in 2 patients, sarcoidosis in 1 patient, coal-miner pneumoconiosis in 1 patient, and histiocytosis X in 1 patient. Induction immunosuppressive therapy consisted of antithymocyte globulin, cyclosporine, azathioprine or mycophenolate mofetyl, and methylprednisolone. Maintenance immunosuppression was based on cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and methylprednisolone. Augmented immunosuppression for allograft rejection included additional courses of antithymocyte globulin and/or increased corticosteroid dosage. In the early phase of the transplant program fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBB) was performed in postoperative months 1, 3, 6, and 12 and annually thereafter, and when clinically indicated. From 1995 onward, surveillance biopsies were no more performed after the first postoperative year.
Measurements of functional residual capacity (FRC), total lung capacity (TLC), residual volume (RV), inspiratory vital capacity (VC), and airway resistance (Raw) were obtained with the patient seated in a constant-volume body plethysmograph, and measurements of forced VC (FVC), midexpiratory flow rates (FEF25–75), forced expiratory volume in 1 s (FEV1), and carbon monoxide diffusing capacity (Dl CO) and transfer factor (Tl CO) were made using a Sensormedics (Anaheim, CA) 2400 unit, following the guidelines of the American Thoracic Society (10). For the study of ventilation distribution, we used a single-breath washout test, as described in our previous studies (9, 11, 12). The subjects were connected to a double bag-in-box system through a nonrebreathing valve with a 20-ml instrumental dead space. They inhaled a gas mixture containing 5% He, 5% SF6, and 90% O2 from FRC to 1 L above FRC, and then expired at a constant flow of 0.4 L/s. The slope of the alveolar plateau for N2, SF6, and He (SN2, SSF6, SHe) was obtained from a linear regression analysis performed between 35 and 80% of the expired volume. The downgoing He and SF6 slopes were treated as positive, as were upgoing N2 slopes; thus, an increase in SN2, SSF6, or SHe indicates a more heterogeneous ventilation. Single-breath washouts were always performed in duplicate by the same investigator and slope values were calculated as the average of two measurements. All signals were sampled at 50 Hz and stored in an Olivetti PC for subsequent analysis. Measurements of standard pulmonary function and distribution of ventilation were obtained on the same day once a week during the first three postoperative months, twice a month between postoperative months 4 and 6, once a month between postoperative months 7 and 12, and every 2 mo after the first postoperative year, and when clinically indicated. Eight patients were transplanted before June 1991 and entered the study at this date; the other patients were prospectively monitored from transplantation.
We determined the significant value for a change (13, 14) from the confidence interval (CI) that was calculated for each variable (VC, FVC, FEV1, FEV1/VC, RV, FRC, TLC, FEF25–75, Raw, Dl CO, Tl CO, SHe, SN2, SSF6, and the difference between SSF6 and SHe [9, 10]), using three or four consecutive measurements obtained in 10 stable lung transplant recipients. The first measurement was obtained between 90 and 1,013 (median, 146) d after surgery and the last measurement was obtained between 174 and 2,160 (median, 475) d after surgery. At the time of these tests the patients were in clinically stable condition with no respiratory symptoms, and they had normal pulmonary function (FEV1 = 94.6% of best postoperative value); in addition, a BAL and TBB obtained within 2 d of the tests showed no sign of infection or rejection. Individual coefficients of variation (CVs) were computed for each variable and the 97.5% CI was obtained by multiplying the mean CV by 1.96. For each patient in the study, we then calculated for each variable the average of the two highest postoperative measurements and the corresponding CI, and we determined whether the variable showed an irreversible change outside the CI (Figure 1). If it did, the date of this change was compared with the date at which the FEV1 showed an irreversible fall that exceeded 20% of the average of the two highest postoperative measurements obtained 3 to 6 wk apart; this is the spirometric criterion proposed by the International Society for Heart and Lung Transplantation (ISHLT) for the diagnosis of bronchiolitis obliterans syndrome (BOS) (15). It should be emphasized that our analysis considered only functional changes that did not recover over time, i.e., when the variable tested returned within the CI or when the FEV1 increased above 80% of baseline after a transient deterioration—due, for example, to an episode of acute rejection or infection (9, 10), these changes were discarded. Predicted values for lung volumes were derived from the European Coal and Steel Community (ECSC) Working Party (16) on the basis of the anthropometric characteristics of the recipients. Because these were similar to the characteristics of the donors, predicted values for the recipients and the donors were not significantly different.
Fig. 1. Changes in forced expiratory volume in 1 s (FEV1) and slope of the alveolar plateau of the He single-breath washout (SHe) over time in one heart–lung transplant recipient. (Top) Dashed line corresponds to 100% of the best postoperative value and the continuous line indicates a 20% decrease. (Bottom) Dashed line corresponds to the average of the two highest postoperative values and the continuous line is the upper limit of the 97.5% confidence interval computed from data obtained in 10 stable transplant patients. Note that a significant change in SHe is observed 20.7 mo before the 20 % drop in FEV1.
[More] [Minimize]The median time of follow-up was 1,215 d (range, 164–2,829 d), during which a total of 1,929 functional tests was performed (median, 30 tests per patient; range, 6–91). All patients had a favorable outcome after transplantation and achieved normal pulmonary function; of the 57 patients studied, the best postoperative FEV1 averaged (mean ± SD) 98.4 ± 15.9% of the predicted normal value. Eighteen patients, however, developed chronic allograft dysfunction and at the end of the study (median follow-up = 1,612 d) only 9 of these patients were still alive (Table 1); at the time of the last functional assessment, 8 patients were in BOS Stage 1 (FEV1 = 66 to 80% of baseline value), 3 patients were in BOS Stage 2 (FEV1 = 51 to 65% of baseline value), and 7 patients were in BOS Stage 3 (FEV1 = 50% or less than baseline value) (15). A histologic diagnosis of OB was made in 10 patients, using tissue samples obtained by TBB in 7 patients, by open-lung biopsy in 1 patient, and at autopsy in 2 patients. In the other patients, no pathologic evidence of OB was seen on TBB.
| Patient No. | Age (yr) | Sex | Indication for Tx | Date of Tx | Status at End of Study | Duration of Follow-up (d ) | No. of Tests | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 40 | M | PPH | 30.04.89 | BOS 1 | 2,810 | 43 | |||||||
| 2 | 19 | M | CF | 29.12.89 | BOS 3* | 1,581 | 61 | |||||||
| 3 | 43 | M | PPH | 14.10.90 | BOS 3* | 600 | 40 | |||||||
| 4 | 31 | F | PPH | 20.04.91 | BOS 1* | 469 | 35 | |||||||
| 5 | 33 | M | CF | 10.06.91 | BOS 1 | 2,829 | 79 | |||||||
| 6 | 27 | M | CF | 25.08.91 | BOS 3* | 308 | 63 | |||||||
| 7 | 30 | F | PPH | 27.08.91 | BOS 2* | 2,753 | 70 | |||||||
| 8 | 38 | M | Bronchiectasis | 30.10.91 | BOS 3* | 2,687 | 91 | |||||||
| 9 | 21 | F | CF | 20.03.92 | BOS 1* | 1,403 | 41 | |||||||
| 10 | 39 | F | PPH | 22.10.92 | BOS 2 | 2,751 | 57 | |||||||
| 11 | 33 | F | PPH | 10.07.93 | BOS 3* | 549 | 43 | |||||||
| 12 | 50 | F | PPH | 10.09.93 | BOS 3 | 2,006 | 50 | |||||||
| 13 | 18 | M | CF | 12.10.93 | BOS 1 | 1,974 | 61 | |||||||
| 14 | 29 | M | CF | 13.02.95 | BOS 1 | 1,485 | 45 | |||||||
| 15 | 57 | F | PPH | 15.03.95 | BOS 3* | 632 | 34 | |||||||
| 16 | 51 | F | PPH | 13.06.95 | BOS 2 | 1,367 | 45 | |||||||
| 17 | 49 | M | Bronchiectasis | 25.01.97 | BOS 1 | 773 | 18 | |||||||
| 18 | 36 | M | Emphysema | 24.09.89 | BOS 1 | 2,735 | 43 | |||||||
| Median | 34.5 | 1,533 | 45 |
Table 2 displays the seven variables that showed a significant and irreversible change outside the CI at a time when the FEV1 was still greater than 80% of the best postoperative value, and the median time interval between the significant change and the 20% drop in FEV1. Individual results for FEF25–75 and SHe are illustrated in Figure 2. Generally, indexes of ventilation distribution showed a significant alteration before the criterion for the diagnosis of BOS Stage 1 was reached; for example, all patients but one had an abnormal rise in SHe at a time when the FEV1 was still greater than 80% of the best postoperative value (Figures 1 and 2, and Table 2); in 13 patients this increase was detected when values of FEV1 were still within the confidence interval—in our study the lower limit of the confidence interval for FEV1 corresponded to a 12% decrease, which is identical to the value reported by Martinez and colleagues (14). Similarly, 16 of 18 patients had a rise in SN2 that preceded the 20% decrease in FEV1. The median time interval between the change in the slope of the alveolar plateau and the drop in FEV1 was greater for He (356 d) than for N2 (178 d), but this difference did not reach significance. The rise in SHe occurred 18 mo or more before the drop in FEV1 in seven patients; a similar delay was observed for SN2 in five patients. The FEF25–75 did not do as well as indexes of ventilation distribution. In 12 of 18 patients the change in FEF25–75 preceded the 20% drop in FEV1, but in 5 patients it occurred later (Table 2).
| Variable | Before | After | Concomitant | Median (d ) | Range (d ) | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| SHe | 17 | 0 | 1 | −356 | −1,520 to 0 | |||||
| SSF6 | 15 | 2 | 1 | −351 | −913 to 74 | |||||
| SN2 | 16 | 1 | 1 | −178 | −836 to 7 | |||||
| FEF25–75 | 12 | 5 | 1 | −102 | −1,246 to 137 | |||||
| Raw | 11 | 5 | 2 | −92 | −2,104 to 646 | |||||
| dS | 10 | 7 | 1 | −40 | −1,866 to 308 | |||||
| RV | 7 | 9 | 2 | −6 | −909 to 741 |
Fig. 2. Individual values of time interval between an irreversible decrease in forced expiratory volume in 1 s (FEV1) below 80% of the best postoperative value and an irreversible increase in the slope of the alveolar plateau of the He single-breath washout (SHe) or an irreversible decrease in midexpiratory flow rates (FEF25–75) outside the 97.5% confidence interval in 18 patients who developed bronchiolitis obliterans syndrome; boxes represent medians and interquartile intervals. A negative sign indicates that the change in the variable occurred before the 20% decrease in FEV1 whereas a positive sign indicates that it occurred afterward. Both variables generally deteriorated before FEV1. The median time interval between the change in SHe and the drop in FEV1 was 356 d whereas the median time interval between the change in FEF25–75 and the drop in FEV1 was 102 d (p = 0.034, Wilcoxon paired test).
[More] [Minimize]The group of 39 patients who did not develop chronic allograft rejection had a median follow-up of 911 d (p = 0.015 by Mann–Whitney U test, BOS group versus non-BOS group). Six of these patients demonstrated a significant rise in SHe and seven patients demonstrated a significant rise in SN2. These alterations occurred 298 and 236 d before the end of the study, respectively. Conventional pulmonary function tests proved to be stable in all patients and did not show any significant and irreversible change outside the CI, except for FEF25–75, which decreased significantly in two patients. On average, static and dynamic lung volumes were all greater than 90% of predicted at the end of the study, and the mean SN2 value was 3.8%/L; this value is within the range found in our previous report on 22 healthy subjects (9).
Lung transplantation has become an important therapeutic option for a number of patients with end-stage cardiopulmonary diseases (6). However, long-term survival is threatened by OB. With a prevalence of 50 to 70% in long-term survivors (6-8), OB has emerged as the most significant long-term complication and the first cause of late death after lung transplantation (7, 8). The diagnosis of OB can be made by TBB, but because of the patchy distribution of the lesions within the lung, the sensitivity of this technique has been relatively low at most centers, with a tissue diagnosis being obtained in only a small proportion of patients and often late in the course of the disease (17-19); in the present study, TBB yielded the diagnosis of OB in only 7 of 18 patients. In addition, because bronchoscopy with TBB is an expensive and invasive procedure, it cannot be used as a screening test. For these reasons, the vast majority of centers have stopped performing surveillance biopsies after the first postoperative year and rely on a decrease in FEV1 for the diagnosis of chronic allograft dysfunction, as proposed by the ISHLT (15).
Although this criterion has proved useful to categorize patients among different programs, it has been suggested that FEF25–75 may be more sensitive than FEV1 for the detection of OB. Of the 22 patients with OB who were studied by Patterson and colleagues (20), 16 had a fall in FEF25–75 that preceded the fall in FEV1, and the mean time interval was 112 d. A similar observation was made in the present study (Table 2), but the most conspicuous of our findings was that changes in indexes of ventilation distribution occurred well before changes in FEF25–75. The observation that SHe showed the earliest alteration is in agreement with theoretical work suggesting that this index should be particularly sensitive to ventilation inhomogeneities arising in the zone of the terminal bronchioles, which is precisely where the inflammation and scarring of OB develop (21). Increases in the slope of the alveolar plateau for He, N2, and SF6 are also observed during episodes of acute infection and rejection, but under these conditions these changes recover with treatment (9, 12). So, an alteration in ventilation distribution is not specific of OB but this diagnosis should be strongly suspected whenever it develops in the absence of acute infection or rejection or whenever it persists after these complications have been adequately treated.
In a study of 15 DLT recipients, Arens and colleagues (22) reported that 9 of 11 stable patients without BOS had a significant increase in SN2, which suggested the presence of small airway dysfunction. However, the cross-sectional design of this study did not allow the authors to determine what percentage of their patients eventually developed BOS. Only 7 of the 39 patients without BOS studied here demonstrated a significant and irreversible alteration in ventilation distribution. It is possible, although speculative at this stage, that this alteration will be followed by a gradual decline in FEV1.
It has been reported that the presence of OB may be suggested by increases in specific airway resistance (23), increased levels of neutrophils and interleukin 8 (IL-8) in BAL fluid (24), areas of air trapping on expiratory high-resolution computed tomography (CT) images (25), and increased levels of exhaled nitric oxide (26). Whether some of these changes may occur before alterations in ventilation distribution is unknown. It should be stressed, however, that the single-breath washout appears particularly well suited as a screening test because it takes only a few minutes to be measured, does not necessitate special operator expertise or patient aptitude, requires only simple equipment, and is totally noninvasive. On the other hand, this is not an appropriate test for patients with single-lung transplantation; for these patients, techniques that allow specific investigation of the function of the graft should be preferred (27).
On the whole, the treatment of OB has been unsuccessful, but a study by Bando and colleagues (28) has shown that resolution or stabilization with augmented immunosuppression occurs frequently if the diagnosis is made when patients are still in BOS Stage 0. Thus, by allowing detection and treatment of OB in a preclinical stage, prospective measurements of ventilation distribution might prevent irreversible lumenal occlusion and scarring of the airways. This possibility should now be evaluated by a prospective trial of intensified immunosuppression in patients with early alterations in ventilation distribution.
| 1. | Hogg J. C., Macklem P. T., Thurlbeck W. M.Site and nature of airway obstruction in obstructive lung disease. N. Engl. J. Med.278196813551360 |
| 2. | Buist A. S., Ross B. B.Quantitative analysis of the alveolar plateau in the diagnosis of early airway obstruction. Am. Rev. Respir. Dis.108197310781087 |
| 3. | Cosio M., Ghezzo H., Hogg J. C., Gorbin R., Loveland M., Dosman J., Macklem P. T.The relations between structural changes in small airways and pulmonary-function tests. N. Engl. J. Med.298197812771281 |
| 4. | Paiva M., Engel L. A.Theoretical studies of gas mixing and ventilation distribution in the lung. Physiol. Rev.671987750796 |
| 5. | Verbanck S., Schuermans A., Van Muylem A., Melot C., Noppen M., Vincken W., Paiva M.Conductive and acinar lung zone contribution to ventilation inhomogeneity in COPD. Am. J. Respir. Crit. Care Med.157199815731577 |
| 6. | Hosenpud J. D., Benett L. E., Keck B. M., Fiol B., Boucek M. M., Novick R. J.The Registry of the International Society for Heart and Lung Transplantation: fifteenth official report—1998. J. Heart Lung Transplant.171998656668 |
| 7. | Arcasoy S. M., Kotloff R. M.Review article: lung transplantation. N. Engl. J. Med.340199910811091 |
| 8. | Boehler A., Estenne M.Obliterative bronchiolitis after lung transplantation. Curr. Opin. Pulm. Med.62000133139 |
| 9. | Van Muylem A., Antoine M., Yernault J. C., Paiva M., Estenne M.Inert gas single-breath washout after heart–lung transplantation. Am. J. Respir. Crit. Care Med.1521995947952 |
| 10. | American Thoracic SocietyStandardization of spirometry: 1994 update. Am. Rev. Respir. Dis.152199511071136 |
| 11. | Van Muylem A., De Vuyst P., Yernault J. C., Paiva M.Inert gas single-breath washout and structural alteration of respiratory bronchioles. Am. Rev. Respir. Dis.146199211671172 |
| 12. | Van Muylem A., Melot C., Antoine M., Knoop C., Estenne M.Role of pulmonary function in the detection of allograft dysfunction after heart–lung transplantation. Thorax521997643647 |
| 13. | Pennock B. E., Rogers R. M., McCaffree D. R.Changes in measured spirometric indices: what is significant? Chest8019819799 |
| 14. | Martinez J. A. B., Paradis I. L., Dauber J. H., Grgurich W., Richards T., Yousem S. A., Ohori P., Williams P., Iacono A. T., Nunley D. R., Keenan R. J.Spirometric values in stable lung transplant recipients. Am. J. Respir. Crit. Care Med.1551997285290 |
| 15. | Cooper J. D., Billingham M., Egan T., Hertz M. I., Higenbottam T., Lynch J., Maurer J., Paradis I., Patterson G. A., Smith C., Trulock E. P., Vreim C., Yousem S.A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. J. Heart Lung Transplant.121993713716 |
| 16. | Quanjer, P., G. J. Tammeling, J. E. Cotes, O. F. Pedersen, R. Peslin, and J. C. Yernault. 1993. Lung volumes and forced ventilatory flows: report of the working party standardization of lung function tests. European Coal and Steel Community. Eur. Respir. J. 6(Suppl. 16):5–40. |
| 17. | Kramer M. R., Stoehr C., Whang J. L., Berry G. J., Sibley R., Marshall S. E., Patterson G. M., Starnes V. A., Theodore J.The diagnosis of obliterative bronchiolitis after heart–lung and lung transplantation: low yield of transbronchial lung biopsy. J. Heart Lung Transplant.121993675681 |
| 18. | Yousem S. A., Paradis I., Griffith B. P.Can transbronchial biopsy aid the diagnosis of bronchiolitis obliterans in lung transplant recipients? Transplantation571994151153 |
| 19. | Chamberlain R., Maurer J., Chaparro C., Idolor I.Evaluation of transbronchial lung biopsy specimens in the diagnosis of bronchiolitis obliterans after lung transplantation. J. Heart Lung Transplant.131994963971 |
| 20. | Patterson G. M., Wilson S., Whang J. L., Harvey J., Agacki K., Patel H., Theodore J.Physiologic definitions of obliterative bronchiolitis in heart–lung and double lung transplantation: a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second. J. Heart Lung Transplant.151996175181 |
| 21. | Abernathy E. C., Hruban R. H., Baumgartner W. A., Reitz R. A., Hutchins G. M.The two forms of bronchiolitis obliterans in heart–lung transplant recipients. Hum. Pathol.22199111021110 |
| 22. | Arens R., McDonough J. M., Zhao H., Blumenthal N. P., Kotloff R. M., Grunstein M. M.Altered lung mechanics after double-lung transplantation. Am. J. Respir. Crit. Care Med.158199814031409 |
| 23. | Bassiri A. G., Girgis R. E., Doyle R. L., Theodore J.Detection of small airway dysfunction using specific airway conductance. Chest111199715331535 |
| 24. | DiGiovine B., Lynch J. P., Martinez F. J., Flint A., Whyte R. I., Iannettoni M. D., Arenberg D. A., Burdick M. D., Glass M. C., Wilke C. A., Morris S. B., Kunkel S. L., Strieter R. M.Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J. Immunol.157199641944202 |
| 25. | Leung A. N., Fisher K., Valentine V., Girgis R. E., Berry G. J., Robbins R. C., Theodore J.Bronchiolitis obliterans after lung transplantation: detection using expiratory HRCT. Chest1131998365370 |
| 26. | Verleden G. M., Dupont L., Lamont J., Buyse B., Delcroix M., Van Raemdonck D., Lerut T., Vanhaecke J., Demedts M. G.Is there a role for measuring exhaled nitric oxide in lung transplant recipients with chronic rejection? J. Heart Lung Transplant.171998231232 |
| 27. | Ikonen T., Harjula A. L. J., Kinnula V. L., Savola J., Sovijärvi A.Assessment of forced expiratory volume in one second-fraction of the engrafted lung with 133-Xe radiospirometry improves the diagnosis of bronchiolitis obliterans syndrome in single lung transplant recipients. J. Heart Lung Transplant.141995244250 |
| 28. | Bando K., Paradis I. L., Similo S., Konishi H., Komatsu K., Zullo T. G., Yousem S. A., Close J. M., Zeevi A., Dusquenoy R. J., Manzetti J., Keenan R. J., Armitage J. M., Hardesty R. L., Griffith B. P.Obliterative bronchiolitis after lung and heart–lung transplantation. An analysis of risk factors and management. J. Thorac. Cardiovasc. Surg.1101995414 |
