help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on January 18, 2007, doi:10.1164/rccm.200609-1301OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200609-1301OCv1
175/7/731    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Van Muylem, A.
Right arrow Articles by Estenne, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Van Muylem, A.
Right arrow Articles by Estenne, M.
American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 731-736, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200609-1301OC

Original Article

Early Detection of Chronic Pulmonary Allograft Dysfunction by Exhaled Biomarkers

Alain Van Muylem1, Christiane Knoop1 and Marc Estenne1

1 Department of Chest Medicine, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium

Correspondence and requests for reprints should be addressed to Marc Estenne, M.D., Chest Service, Erasme University Hospital, 808, Route de Lennik, B-1070 Brussels, Belgium. E-mail: mestenne{at}ulb.ac.be


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Early detection of bronchiolitis obliterans syndrome (BOS) is important because therapies are more likely to be effective if employed early in the disease process.

Objectives: To compare the performance of exhaled NO and CO (which reflect airway inflammation) and the slope of the alveolar plateau for helium (which reflects heterogeneity of ventilation distribution) for detection of BOS stages 0-p and 1.

Methods: Recipients of bilateral (n = 64) and single (n = 1) lung grafts were prospectively monitored for 1,249 days; the helium slope was derived from single-breath washouts and exhaled NO and CO were measured by chemiluminescence on 933 occasions.

Measurements and Main Results: At the end of follow-up, 9 patients were in stage 0-p and 16 patients were in BOS stage 1 or higher; 21 patients had at least one measurement made in BOS stage 0-p. All markers increased in BOS stage 0-p, but only the helium slope increased in BOS stage 1. The helium slope had better sensitivity for detection of stages 0-p and 1 than either exhaled NO or CO, but considering exhaled NO and CO together improved their sensitivity; the best sensitivity was found with the three markers in combination. The biomarkers had high negative predictive values, but low specificity and positive predictive values.

Conclusions: After lung transplantation, (1) the helium slope and exhaled NO, but also exhaled CO, increase in BOS stage 0-p, (2) the helium slope has better sensitivity than exhaled NO and CO for the detection of BOS stages 0-p and 1, and (3) exhaled biomarkers have high negative predictive values, but low specificity and positive predictive values.

Key Words: lung transplantation • graft rejection • distribution of ventilation • exhaled gases



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
The slope of the alveolar plateau for helium increases several months before post-transplantation bronchiolitis obliterans syndrome (BOS) develops.

What This Study Adds to the Field
Exhaled biomarkers, including helium slope and exhaled NO and CO, have high negative predictive values, but low specificity and positive predictive values in the detection of bronchiolitis obliterans syndrome.

 
Bronchiolitis obliterans is the leading cause limiting long-term survival after lung transplantation (1). Bronchiolitis obliterans, and its clinical correlate bronchiolitis obliterans syndrome (BOS) (2), affect up to 50 to 60% of patients who survive 5 years after transplantation and account for about 30% of all deaths occurring after the third postoperative year (3). For many years, the treatment of BOS was disappointing; but more recently several promising therapeutic approaches have been proposed. For example, oral azithromycin (4–6) and total lymphoid irradiation (7) were reported to improve or stabilize lung function in many patients with established BOS, and it was suggested that the incidence and progression of BOS could be reduced by administration of statins (8) and inhaled cyclosporine (9).

Early detection of functional changes is important because these therapies are more likely to be effective in improving or stabilizing lung function, and in preserving the majority of lung function, if employed early in the disease process. Accordingly, in an attempt to detect dysfunction of the small airways before established BOS is present, a new stage, called the potential BOS (BOS 0-p) stage, was added in 2002 to the BOS scoring system (2).

In addition, several groups of investigators assessed the usefulness of other biomarkers. We (10) and others (11) showed that in patients with bilateral grafts, the slope of the alveolar plateau for nitrogen or helium obtained during a single-breath washout test increased several months before BOS developed, which reflected an early increase in the heterogeneity of ventilation distribution in peripheral airways (12). A pilot study suggested that the use of this technique may be extended to patients with emphysema with single-lung grafts (13). Other potential noninvasive early markers include exhaled nitric oxide (eNO) and carbon monoxide (eCO). Exhaled NO is a well-recognized biomarker of airway inflammation. In stable lung transplant recipients and patients with BOS, eNO reflects the expression of bronchial epithelial inducible nitric oxide synthase and positively correlates with airway neutrophilia, which is a prominent feature of BOS (14–16). Carbon monoxide is produced endogenously from the stress protein heme oxygenase (HO)-1, which is increased in a variety of oxidant/inflammatory-mediated injuries (17, 18). HO-1 degrades heme with the production of iron, biliverdin, and CO. In bronchiolitis obliterans lesions, HO-1 staining correlates with myeloperoxidase expression (reflecting oxidant load) and with neutrophilic infiltration of the bronchiolar wall (19). Therefore, both eNO and eCO may reflect increased airway neutrophilia, and hence be used as surrogate markers of bronchiolitis obliterans.

Four studies have shown that eNO is increased in patients with BOS compared with patients without BOS (15, 20–22). However, the contribution of serial eNO measurements to the early detection of BOS is difficult to assess from these studies because of one or more of the following factors: the cross-sectional design, the small number of patients and measurements, the short follow-up time, and the absence of longitudinal analysis of individual patients. In addition, the BOS 0-p stage was not always included in the analysis and no comparison with other surrogate markers was provided.

Exhaled CO has been studied in asthma and chronic obstructive pulmonary disease (18), but, to the best of our knowledge, it has not been studied so far in the context of lung transplantation.

The aims of the present study were to compare the performance of eNO, eCO, and single-breath washout–derived helium slope for the detection of chronic allograft dysfunction (diagnosed as BOS 0-p and BOS 1) in a cohort of 65 lung transplant recipients who were monitored longitudinally over a 5-year period. We hypothesized that exhaled gases and helium slope may have complementary roles for the early detection of BOS, with eNO and eCO reflecting primarily the degree of airway inflammation and helium slope being more sensitive to changes in small airway caliber. Some of the results of these studies have been previously reported in the form of an abstract (23).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The study included 27 patients who had undergone transplantation before the start of the study and were in BOS stage 0, and 38 patients who had undergone transplantation between September 2000 and December 2005. Patients had bilateral (n = 50), heart–lung (n = 14), or single-lung (n = 1; with a contralateral pneumonectomy) grafts. The control group consisted of 20 healthy subjects matched for sex and age with the patients. All subjects gave verbal informed consent to the procedures as approved by the ethics committee of our institution (Erasme University Hospital, Brussels, Belgium).

Methods
Spirometry was measured according to standard techniques (24). Distribution of ventilation was measured by a single-breath washout test (10, 12, 13, 25, 26). After connection to a double bag-in-box system, the subjects 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/second. The slope of the alveolar plateau for He (SHe) was obtained by linear regression analysis; an increase in SHe indicated more heterogeneous ventilation. Measurements of eNO and eCO were obtained with a chemiluminescence analyzer (Logan Research Ltd, Rochester, UK) (27). Subjects performed a slow expiratory VC against a fixed expiratory resistance to create a constant flow of 200 ml/second. eNO and CO levels were measured at the end of expiration.

Data Analysis
BOS stages were defined according to published criteria (2); the baseline for midexpiratory flow rate (FEF25–75) was computed from values obtained at the time of the two highest FEV1 measurements, as proposed by Hachem and coworkers (28).

The lowest values of eNO, eCO, and SHe obtained in each patient in BOS 0 were compared with the last value obtained in BOS 0, and with the highest value obtained in BOS 0-p and BOS 1. We then determined the significant value for a change (29) from the confidence interval (CI), which was calculated on the basis of three or four separate measurements obtained in 10 stable lung transplant recipients. Individual coefficients of variation were computed for eNO, eCO, and SHe, and the 97.5% CI was obtained by multiplying the mean coefficient of variation by 1.96. For each patient the CI for eNO, eCO, and SHe was then calculated using the average of the two lowest measurements obtained in BOS 0.

The operating characteristics of each biomarker were computed according to the following definitions: true positive, patient with abnormal test and in BOS > 0 at end of follow-up; false positive, patient with abnormal test and in BOS 0 at end of follow-up; true negative, patient with normal test and in BOS 0 at end of follow-up; false negative, patient with normal test and in BOS > 0 at end of follow-up. We considered eNO, eCO, and SHe as abnormal whenever two or more measurements obtained 3 weeks or more apart showed values above the CI; we selected a 3-week period because this is the duration during which a spirometric criterion must be met to establish a BOS stage (2).

Statistical analyses included unpaired and paired t tests, and the Mann-Whitney test, when appropriate. The level of significance was taken as p < 0.05.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The median follow-up was 1,249 days (range, 92–1,947 d), during which the patients performed a total of 933 measurements (median, 15 per patient; range, 3–27 per patient). Thirteen patients died during the course of the study, with death being associated with BOS in 8 patients. At the end of follow-up, 40 patients were in BOS 0, 9 were in BOS 0-p, and 16 were in BOS 1 or greater (5 in BOS 1, 2 in BOS 2, and 9 in BOS 3). Four patients increased directly from BOS 0 to BOS 1, but 21 patients had at least one measurement made in BOS 0-p; 12 of these then further deteriorated to BOS 1 or greater (see the online supplement for details about the patients who were still in BOS 0-p at the end of follow-up). The diagnosis of BOS 0-p was made on the basis of the FEV1 criterion in 10 patients, on the FEF25–75 criterion in 3 patients, and on both criteria in 8 patients. For the 25 patients who were in BOS > 0 at the end of follow-up, the median delay between transplantation and the diagnosis of BOS > 0 was 702 days (range, 306–2,940 d). For the 9 patients who were in BOS 0-p at the end of follow-up, the median time spent in this stage was 240 days (range, 63–1,120 d); for the 12 patients who changed from BOS 0-p to BOS >= 1, the median time spent in BOS 0-p was 193 days (range, 42–714 d).

For the 65 patients studied, the FEV1 at the end of study averaged 79.5 ± 24.4% of the best postoperative value and 80.7 ± 29.7% of predicted; corresponding values for the 25 patients in BOS > 0 were 57.3 ± 26.2 and 60.3 ± 31.7%, respectively.

For the 20 healthy control subjects, eNO, eCO, and SHe averaged 6.4 ± 3.3 ppb, 3.0 ± 1.4 ppm, and 1.5 ± 0.9% · L–1, respectively. In the 10 stable lung transplant recipients who were studied on three or four separate occasions to compute the confidence intervals of the three biomarkers, the first and last measurements were obtained at a median of 127 and 305 days after surgery. In these patients, mean coefficients of variation were 39% for eNO, 20% for eCO, and 47% for SHe, and mean values for FEV1, eNO, eCO, and SHe were 97 ± 7% of the best postoperative value, 5.9 ± 2.5 ppb, 3.8 ± 2.0 ppm, and 4.7 ± 4.0% · L–1, respectively. On average, values of eNO and eCO were similar in the control subjects and the patients, but values of SHe were significantly greater in the latter (p < 0.001).

Figure 1 shows typical changes in eNO, eCO, and SHe over time in one representative patient who went on from BOS 0 to BOS 0-p and to BOS 1. eNO and eCO showed abrupt changes on consecutive measurements, and tended to increase on going from BOS 0 to BOS 0-p but not from BOS 0-p to BOS 1; in contrast, SHe increased progressively with BOS stages. Figure 2 shows for the three biomarkers the lowest and last values obtained in each patient in BOS 0, and the highest values obtained in BOS 0-p and in BOS 1. Changes in eNO and eCO between BOS stages were variable between patients and relatively small in magnitude. For example, mean values for eNO were 3.5 ± 2.1 ppb in BOS 0, 8.2 ± 5.6 ppb in BOS 0-p, and 6.9 ± 5.4 ppb in BOS 1; corresponding values for eCO were 2.8 ± 1.6, 5.8 ± 4.1, and 5.4 ± 5.4 ppm, respectively. On average, values in BOS 0-p were significantly greater than lowest and last values in BOS 0, but there was no significant difference between BOS 1 and BOS 0 or BOS 0-p. Data for SHe were much more consistent; in a majority of patients, the last value in BOS 0 was greater than the lowest value in BOS 0, and most patients showed an increase in SHe on going from BOS 0 to BOS 0-p and from BOS 0-p to BOS 1; average values in the three stages were 1.8 ± 0.9, 6.7 ± 3.8, and 10.3 ± 5.1% · L–1, respectively.


Figure 1
View larger version (19K):
[in this window]
[in a new window]

  		Figure 1. Changes in exhaled NO (eNO), exhaled CO (eCO), and helium slope (SHe) over time in one representative patient who developed bronchiolitis obliterans syndrome (BOS). The continuous lines represent the confidence interval of normal values for each marker in this patient. Note that eNO and eCO showed abrupt changes on consecutive measurements and did not increase progressively with BOS stages. On the other hand, SHe showed a continuous increase as BOS developed.

 

Figure 2
View larger version (15K):
[in this window]
[in a new window]

  		Figure 2. Individual values for eNO, eCO, and SHe according to BOS stage. From left to right: Lowest and last values obtained in BOS 0, and the highest values obtained in BOS 0-p and BOS 1. SHe increased on going from BOS 0 to BOS 0-p and from BOS 0-p to BOS 1; in contrast, eNO and eCO increased between BOS 0 and BOS 0-p, but not between BOS 0-p and BOS 1. See text for comments.

 
Table 1 gives the operating characteristics of eNO, eCO, and SHe for the detection of graft dysfunction, diagnosed as BOS 0-p and BOS 1. SHe had better sensitivity than either eNO or eCO for the detection of both stages, but combining eNO and eCO improved the sensitivity of the tests. The best sensitivity was found with the combination of the three markers. Specificity and positive predictive values were relatively low for all biomarkers, but negative predictive values were high.


View this table:
[in this window]
[in a new window]

  		TABLE 1. OPERATING CHARACTERISTICS OF EXHALED NITRIC OXIDE, EXHALED CARBON MONOXIDE, AND HELIUM SLOPE FOR DETECTION OF CHRONIC ALLOGRAFT DYSFUNCTION, DIAGNOSED AS BRONCHIOLITIS OBLITERANS SYNDROME STAGE 0-p AND STAGE 1

 
Figure 3 shows the time interval between the date at which a biomarker became abnormal and the date at which the diagnosis of BOS 0-p and BOS 1 was made (a negative sign indicates that the marker deteriorated before spirometry). On average, SHe, eNO, and eCO became abnormal 164 days (range, –932 to 537 d), 97 days (range, –763 to 947 d), and 69 days (–969 to 1,106 d) before the diagnosis of BOS 0-p; only the time interval for SHe was significantly different from zero. Corresponding values for BOS 1 were 260 days (range, –932 to 246 d) for SHe (p = 0.001), 111 days (range, –1,246 to 483 d) for eNO (NS), and 263 days (range, –1,304 to 422 d) for eCO (p = 0.018). The time interval between the date at which any of the three biomarkers became abnormal and the date at which the diagnosis of BOS was made was –338 days (range, –969 to 449 d) for stage 0-p (p < 0.001) and –342 days (range, –1,304 to 246 d) for stage 1 (p < 0.001).


Figure 3
View larger version (9K):
[in this window]
[in a new window]

  		Figure 3. Time interval between the date at which eNO, eCO, and SHe became abnormal and the date at which the criteria for BOS 0-p (A) and for BOS 1 (B) were met. Data are shown for patients who showed a significant change in the marker: Of 21 patients who were in BOS 0-p, 19 had an increase in SHe, 14 had an increase in eNO, and 15 had an increase in eCO; corresponding figures for the 16 patients who were in BOS 1 were 16 for SHe, 13 for eNO, and 13 for eCO. A negative sign indicates that the marker deteriorated before spirometry. SHe deteriorated significantly before BOS 0-p and both SHe and eCO deteriorated before BOS 1.

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This prospective longitudinal study assessed the performance of eNO, eCO, and single-breath washout–derived SHe for the early detection of chronic allograft dysfunction, as assessed by BOS staging, in a cohort of lung transplant recipients. The results revealed that eCO, in addition to SHe and eNO, was increased in early BOS. SHe had better sensitivity than either eNO or eCO for the detection of BOS 0-p and BOS 1, but combining eNO and eCO increased their sensitivity; the best sensitivity for the detection of BOS 0-p or BOS 1 was found by combining the three markers. SHe, but not the other markers, became abnormal before the diagnosis of BOS 0-p was made; for BOS 1, both SHe and eCO became abnormal before spirometry. The negative predictive values of the markers were high, but their specificity and positive predictive values were low.

Values of eNO obtained in patients in BOS 0 were similar to those of healthy control subjects, which confirms previous reports (14, 15, 20). Values of eCO were also similar in the patients and the control subjects, but values of SHe were significantly increased in the former. In keeping with this observation, two cross-sectional studies in small numbers of recipients who were free of BOS (25, 30) reported small but significant increases in nitrogen slope. These modest alterations might reflect subtle structural or functional abnormalities in the small airways consequent to the transplantation procedure itself (e.g., sequel of ischemia–reperfusion injury, and lung denervation with loss of resting vagal bronchomotor tone).

In agreement with previous reports (10, 11), we found that the slope of the alveolar plateau had excellent sensitivity for the detection of BOS 1. The present study extends these observations by showing that SHe also had good sensitivity for the detection of BOS 0-p, deteriorated before the diagnosis of BOS 0-p was made, and increased consistently with BOS progression (Figures 1–3GoGo). These results thus further validate SHe as an early and sensitive marker of airway dysfunction after bilateral lung transplantation.

In contrast to SHe, eNO and eCO showed abrupt changes on consecutive measurements (Figure 1) and did not consistently increase with BOS stages (Figure 2), although average values were greater in BOS 0-p than in BOS 0. The observation that eNO was increased only in early or rapidly progressing BOS is in agreement with the studies by Fisher and coworkers (20), Verleden and coworkers (21), and Brugière and coworkers (22); it might reflect a gradual decrease in the inflammatory component of the airway lesions with BOS progression, either as part of the natural history of the disease or secondary to treatments given to stabilize lung function (e.g., shift from cyclosporine to tacrolimus [31] or inhaled corticosteroids [32]; see the online supplement for treatment details).

One of the novel findings of this study was that eCO was increased in BOS 0-p. Several studies have provided evidence for the presence of excessive oxidative stress in BOS resulting primarily from the generation of free radicals and reactive oxygen species, particularly by activated neutrophils (33–35). For example, patients with BOS showed decreased glutathione concentration (which is the most important antioxidant in the lung) and increased percentages of oxidized glutathione and methionine sulfoxide in the epithelial lining layer or bronchoalveolar lavage (BAL) fluid (33, 34). Oxidative stress is a potent stimulus for HO-1, which is viewed as a beneficial response because HO-1 has important cytoprotective properties (17). One study (19) showed that HO-1 expression is increased in the airways of lung transplant recipients with lesions of bronchiolitis obliterans; in another study (36), HO-1 expression was increased in the BAL fluid of patients with BOS compared with patients without BOS. We suggest that activation of HO-1 is responsible, via the degradation of heme, for the elevated eCO levels found in association with BOS in the present study.

The increase in both eNO and eCO is believed to reflect, at least in part, the increase in BAL and airway neutrophilia (as assessed by endobronchial biopsies). In patients with BOS, eNO increases with BAL neutrophilia (15), and HO-1 expression correlates with myeloperoxidase staining and neutrophilic infiltration of the bronchial wall (19). However, a detailed longitudinal study by Zheng and coworkers (16) demonstrated that a significant proportion of patients with early BOS had no increase in BAL and airway neutrophilia compared with stable recipients without BOS; so, neutrophilia showed substantial intersubject variability in patients with BOS and had poor predictive value. Furthermore, infiltration of the airways by macrophages and lymphocytes generally failed to increase substantially in BOS 0-p (37). These factors might thus explain why the sensitivity of eNO for the detection of BOS varied widely (from 69 to 92%) between studies (21, 22), and why eNO and eCO had relatively low sensitivity (50–69%) for the detection of BOS in the present study.

Any increase in oxidative stress is expected to increase eCO, but at the same time to reduce eNO, because formation of peroxynitrite (38) and then nitrate will remove NO from the gaseous phase (18). Consistent with this phenomenon, values of eNO and eCO often changed in opposite directions (Figure 4) and the sensitivity for the detection of BOS 0-p and BOS 1 increased significantly when the two markers were considered together (Table 1). The best sensitivity for the detection of BOS 0-p or BOS 1 was found by combining the three markers, which supports the hypothesis that exhaled gases and SHe have complementary roles.


Figure 4
View larger version (9K):
[in this window]
[in a new window]

  		Figure 4. Individual values of eNO and eCO obtained in the 65 patients studied, independent of BOS stage. Note that changes in eNO and eCO were frequently in opposite directions, such that patients with elevated eNO values tended to have low eCO values, and vice versa. See text for comments. Same conventions as in Figure 1.

 
The three markers had low positive predictive values, reflecting a high false-positive rate (i.e., patients with abnormal biomarkers who were still in BOS 0 at the end of follow-up). This finding, however, should be interpreted with caution because the false positive rate is time dependent and expected to decrease with the duration of follow-up. The median time interval between the date at which eNO, eCO, and SHe became abnormal and the end of follow-up averaged 529, 570, and 852 days in the group of true positives and 272, 224, and 574 days in the group of false positives (p < 0.007 and p < 0.05 by Mann-Whitney test for eNO and SHe, respectively). Thus, had the follow-up been longer in the latter, some patients with abnormal markers may have eventually developed BOS. In addition, the positive predictive value of a test is inherently dependent on the prevalence of the complication in the population studied; in this study, BOS > 0 developed in only 38.5% and BOS 1 or greater in only 24.6% of the patients during the 3.4 years of follow-up.

Clinical Utility
The operating characteristics of the markers studied here suggest that they may be clinically useful. Their high negative predictive values should help detect conditions that may confound the diagnosis of BOS (2) because they suggest that, in the absence of a significant rise in exhaled markers, BOS is an unlikely explanation for any decline in spirometry. In addition, SHe and the combined measurement of eNO and eCO had good sensitivity for the diagnosis of chronic allograft dysfunction, which is clearly a key feature for screening markers aimed at providing early detection of this complication. Although we acknowledge that an increase in one or more of these markers does not imply that BOS will develop in the near future (see above), such a rise should be interpreted as a warning signal and prompt close monitoring of the patient's lung function and clinical condition. Because the measurements reported here are totally noninvasive, they can be repeated without causing any harm to the patient. The persistence of abnormal marker(s) levels, with or without a loss of lung function, may warrant quantification of BAL and/or airway neutrophilia and chemokine concentrations (6, 39). Additional studies are now required to determine the potential benefit of starting therapeutic interventions early on, for example, when patients show elevations of exhaled biomarkers without concomitant functional changes, or when they are in BOS 0-p.


   FOOTNOTES
 
Supported in part by a grant (1.5050.02F) from the Fonds National de la Recherche Scientifique (FNRS, Belgium).

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200609-1301OC on January 18, 2007

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form September 13, 2006; accepted in final form January 18, 2007


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002;166:440–444.[Free Full Text]
  2. Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, Mallory GB, Snell GI, Yousem S. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310.[CrossRef][Medline]
  3. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: Twenty-third Official Adult Lung and Heart–Lung Transplant Report—2006. J Heart Lung Transplant 2006;25:880–892.[CrossRef][Medline]
  4. Gerhardt SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168:121–125.[Abstract/Free Full Text]
  5. Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AJ, Lordan JL, Dark JH, Corris PA. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005;172:772–775.[Abstract/Free Full Text]
  6. Verleden GM, Vanaudenaerde BM, Dupont LJ, Van Raemdonck DE. Azithromycin reduces airway neutrophilia and IL-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2006;74:566–570.
  7. Fisher AJ, Rutherford RM, Bozzino J, Parry G, Dark JH, Corris PA. The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant 2005;5:537–543.[CrossRef][Medline]
  8. Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271–1278.[Abstract/Free Full Text]
  9. Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006;354:141–150.[Abstract/Free Full Text]
  10. Estenne M, Van Muylem A, Knoop C, Antoine M. Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution. Am J Respir Crit Care Med 2000;162:1047–1051.[Abstract/Free Full Text]
  11. Reynaud-Gaubert M, Thomas P, Badier M, Cau P, Giudicelli R, Fuentes P. Early detection of airway involvement in obliterative bronchiolitis after lung transplantation: functional and bronchoalveolar lavage cell findings. Am J Respir Crit Care Med 2000;161:1924–1929.[Abstract/Free Full Text]
  12. Van Muylem A, Verbanck S, Estenne M. Monitoring the lung periphery of transplanted lungs. Respir Physiol Neurobiol 2005;148:141–151.[CrossRef][Medline]
  13. Van Muylem A, Scillia P, Knoop C, Paiva M, Estenne M. Single-breath test in lateral decubitus reflects function of single lungs grafted for emphysema. J Appl Physiol 2006;100:834–838.[Abstract/Free Full Text]
  14. Gabbay E, Walters EA, Orsida B, Whitford H, Ward C, Kotsimbos TC, Snell GI, Williams TJ. In stable lung transplant recipients, exhaled nitric oxide levels positively correlate with airway neutrophilia and bronchial epithelial iNOS. Am J Respir Crit Care Med 1999;160:2093–2099.[Abstract/Free Full Text]
  15. Gabbay E, Walters EA, Orsida B, Whitford H, Ward C, Kotsimbos TC, Snell GI, Williams TJ. Post-lung transplant bronchiolitis obliterans syndrome (BOS) is characterized by increased exhaled nitric oxide levels and epithelial inducible nitric oxide synthase. Am J Respir Crit Care Med 2000;162:2182–2187.[Abstract/Free Full Text]
  16. Zheng L, Whitford HM, Orsida B, Levvey BJ, Bailey M, Walters EH, Williams TJ, Kotsimbos T, Snell GI. The dynamics and associations of airway neutrophilia post lung transplantation. Am J Transplant 2006;6:599–608.[CrossRef][Medline]
  17. Slebos DJ, Ryter SW, Choi AMK. Heme oxygenase-1 and carbon monoxide in pulmonary medicine. Respir Res 2003;4:7.[Medline]
  18. Barnes PJ, Chowdhury B, Kharitonov SA, Magnussen H, Page CP, Postma D, Saetta M. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;174:6–14.[Abstract/Free Full Text]
  19. Lu F, Zander DS, Visner GA. Increased expression of heme oxygenase-1 in human lung transplantation. J Heart Lung Transplant 2002;21:1120–1126.[CrossRef][Medline]
  20. Fisher AJ, Gabbay E, Small T, Doig S, Dark JH, Corris PA. Cross sectional study of exhaled nitric oxide levels following lung transplantation. Thorax 1998;53:454–458.[Abstract/Free Full Text]
  21. Verleden GM, Dupont LJ, Van Raemdonck DE, Vanhaecke J. Accuracy of exhaled nitric oxide measurements for the diagnosis of bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2004;78:730–733.[Medline]
  22. Brugière O, Thabut G, Mal H, Marceau A, Dauriat G, Marrash-Chahla R, Castier Y, Leseche G, Colombat M, Fournier M. Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome. Eur Respir J 2005;25:813–819.[Abstract/Free Full Text]
  23. Estenne M, Van Muylem A, Knoop C. Comparison of exhaled nitric oxide (eNO) and helium slope (SHe) for early detection of graft dysfunction after heart–lung (HLT) and bilateral lung (BLT) transplantation [abstract]. Proc Am Thorac Soc 2006;A829.
  24. American Thoracic Society. Standardization of spirometry: 1994 update. Am Rev Respir Dis 1995;152:1107–1136.
  25. Van Muylem A, Antoine M, Yernault JC, Paiva M, Estenne M. Inert gas single-breath washout after heart–lung transplantation. Am J Respir Crit Care Med 1995;152:947–952.[Abstract]
  26. 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. Thorax 1997;52:643–647.[Abstract]
  27. Kharitonov SA, Alving K, Barnes PJ; European Respiratory Society Task Force. Exhaled and nasal nitric oxide measurements: recommendations. Eur Respir J 1997;10:1683–1693.[CrossRef][Medline]
  28. Hachem RR, Chakinala MM, Yusen RD, Lynch JP, Aloush AA, Patterson GA, Trulock EP. The predictive value of bronchiolitis obliterans syndrome stage 0-p. Am J Respir Crit Care Med 2004;169:468–472.[Abstract/Free Full Text]
  29. Pennock BE, Rogers RM, McCaffree DR. Changes in measured spirometric indices: what is significant? Chest 1981;80:97–99.
  30. Arens R, McDonough JM, Zhao H, Blumenthal NP, Kotloff RM, Grunstein MM. Altered lung mechanics after double-lung transplantation. Am J Respir Crit Care Med 1998;158:1403–1409.[Abstract/Free Full Text]
  31. Verleden GM, Dupont LJ, Van Raemdonck D, Vanhaecke J. Effect of switching from cyclosporine to tacrolimus on exhaled nitric oxide and pulmonary function in patients with chronic rejection after lung transplantation. J Heart Lung Transplant 2003;22:908–913.[CrossRef][Medline]
  32. De Soyza A, Fisher AJ, Small T, Corris PA. Inhaled corticosteroids and the treatment of lymphocytic bronchiolitis following lung transplantation. Am J Respir Crit Care Med 2001;164:1209–1212.[Abstract/Free Full Text]
  33. Riise GC, Williams A, Kjellstrom C, Schersten H, Andersson BA, Kelly FJ. Bronchiolitis obliterans syndrome in lung transplant recipients is associated with increased neutrophil activity and decreased antioxidant status in the lung. Eur Respir J 1998;12:82–88.[Abstract]
  34. Behr J, Maier K, Braun B, Schwailblmair M, Vogelmeier C; Munich Lung Transplant Group. Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart–lung transplantation. Transplantation 2000;69:1856–1860.[CrossRef][Medline]
  35. Reid D, Snell G, Ward C, Raj K, Ward R, Zheng L, Williams T, Walters H. Iron overload and nitric oxide–derived oxidative stress following lung transplantation. J Heart Lung Transplant 2001;20:840–849.[CrossRef][Medline]
  36. Slebos DJ, Kauffman HF, Dijkhuizen B, Zonderland J, Koëter GH, van der Bij W, Postma DS. Heme oxygenase-1 expression in alveolar macrophages is elevated in patients with bronchiolitis obliterans syndrome after lung transplantation [letter]. J Heart Lung Transplant 2004;23:1213–1214.[CrossRef][Medline]
  37. Zheng L, Whitford HM, Orsida B, Levvey BJ, Bailey M, Walters EH, Williams TJ, Kotsimbos T, Snell GI. Longitudinal comparisons of lymphocytes and subtypes between airway wall and bronchoalveolar lavage after human lung transplantation. Transplantation 2005;80:185–192.[CrossRef][Medline]
  38. McDermott CD, Gavita SM, Shennib H, Giaid A. Immunohistochemical localization of nitric oxide synthase and the oxidant peroxynitrite in lung transplant recipients with obliterative bronchiolitis. Transplantation 1997;64:270–274.[CrossRef][Medline]
  39. Reynaud-Gaubert M, Marin V, Thirion X, Farnarier C, Thomas P, Badier M, Bongrand P, Giudicelli R, Fuentes P. Upregulation of chemokines in bronchoalveolar lavage fluid as a predictive marker of post-transplant airway obliteration. J Heart Lung Transplant 2002;21:721–730.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 Am. J. Respir. Crit. Care Med.Home page
P. A. Corris and J. D. Christie
Update in Transplantation 2007
Am. J. Respir. Crit. Care Med., May 15, 2008; 177(10): 1062 - 1067.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
A. Van Muylem, P. A. Gevenois, E. Kallinger, A. A. Bankier, C. Knoop, G. Verleden, and M. Estenne
Single-breath test in lateral decubitus reflects function of single lungs grafted for interstitial lung disease
J Appl Physiol, January 1, 2008; 104(1): 224 - 229.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200609-1301OCv1
175/7/731    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Van Muylem, A.
Right arrow Articles by Estenne, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Van Muylem, A.
Right arrow Articles by Estenne, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2007 American Thoracic Society