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(Chest. 2005;128:1379-1384.)
© 2005 American College of Chest Physicians

Iron Accumulation in Lung Allografts Is Associated With Acute Rejection But Not With Adverse Outcome*

Petra Sandmeier, MD; Rudolf Speich, MD, FCCP; Elzbieta Grebski, MD; Peter Vogt, MD; Erich W. Russi, MD, FCCP; Walter Weder, MD and Annette Boehler, MD, FCCP

* From the Medical Clinics (Drs. Sandmeier and Speich), Division of Pulmonary Medicine (Drs. Grebski, Russi, and Boehler), Department of Pathology (Dr. Vogt), and Division of Thoracic Surgery (Dr. Weder), University Hospital, Zurich. Switzerland.

Correspondence to: Rudolf Speich, MD, FCCP; Department of Internal Medicine; University Hospital Zurich; Raemistrasse 100; CH-8091 Zurich; Switzerland; e-mail: klinspr{at}usz.unizh.ch


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Iron content in lung allografts is increased after transplantation. It was hypothesized that this may lead to fibrosis and posttransplant bronchiolitis obliterans syndrome (BOS).

Methods: In a prospective study, we evaluated 399 BAL fluid (BALF) and transbronchial lung biopsy samples obtained concurrently from 72 consecutive lung transplant recipients.

Results: The hemosiderin scores (HSs) of the BALF samples increased steadily during the postoperative period (p < 0.001). Patients with at least one acute rejection episode (AR) grade ≥ A2 event had higher mean HSs, the difference being significant after the second (p < 0.008) and the sixth postoperative months (p < 0.05). The HS correlated with the number of ARs (p < 0.004), and it significantly increased after the first AR (p < 0.04). Except for oral anticoagulation, no other risk factors for elevated iron content were found. There was no correlation between HS or number of ARs and the development of BOS or survival, respectively.

Conclusions: Progressive iron accumulation in lung allografts seems to be caused mainly by an AR, possibly due to perivascular leakage of erythrocytes. Neither increased HS nor the frequency of ARs were risk factors for subsequent development of BOS. Early detection and treatment of ARs might uncouple their association with BOS.

Key Words: bronchiolitis obliterans syndrome • BAL • iron metabolism • lung transplantation • transbronchial lung biopsy


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Despite its undoubted success, the long-term results of lung transplantation are still hampered by the occurrence of bronchiolitis obliterans syndrome (BOS), which is characterized clinically by progressive airflow limitation mainly due to small airway obstruction.1 Histopathologic specimens reveal fibrous scarring of the bronchiolar wall with sometimes eccentric formation of a fibrous plaque and obliteration of the lumen by granulation tissue.2 Until recently, up to two thirds of all lung transplant recipients acquired BOS after a period of 5 years after lung transplantation.123 The disease has a variable course, but some patients experience a rapid loss of lung function with ensuing respiratory failure.

The best known risk factor for the development of BOS is the incidence of acute rejection episodes (ARs) occurring mainly during the first postoperative months,4567 particularly when recurrent, high grade,46 or persistent.4 Thus, the prevention or early detection and treatment of these ARs might be one of the most important measures to reduce the incidence of BOS. Since it has been shown that significant ARs can occur in up to one third of clinically and functionally stable transplant recipients,8910 it was hypothesized that surveillance transbronchial lung biopsies (TBBs) performed during the first 6 postoperative months might lead to the early detection and treatment of occult ARs and therefore decrease the incidence of BOS. This hypothesis, however, has remained unproven due to the lack of controlled prospective studies.

In a study of follow-up TBBs after treatment of ARs, Clelland and co-authors11 demonstrated that the amount of cellular perivascular infiltrates decreased, but at the same time hemosiderin appeared around the vessels, possibly as a result of previous vascular injury. The hemosiderin pigment tended to persist long after the cellular infiltrate had disappeared. In a subsequent study in 10 patients, Baz et al12 confirmed the increased iron accumulation in lung allografts 3 to 15 months after transplantation. They demonstrated the presence of iron by Prussian blue stain primarily within the alveolar macrophages of TBB specimens. Total iron concentration was significantly higher in the epithelial lining fluid of the allografts as compared to that of normal control subjects. BOS subsequently developed in four of these patients. These findings were emphasized by a study by Reid et al,13 who found increased hemosiderin scores (HSs) and ferritin levels in BAL fluid (BALF), in addition to elevated levels of nitrite in BALF in transplant recipients, and a weak relationship between BALF ferritin and nitrite concentrations in the patients with BOS. This suggested that the lung allograft may be subject to significant iron- and NO-derived free radical damage.

Based on the data of Trulock et al,8 we believed that early diagnosis and treatment of AR in asymptomatic lung transplant recipients might have a preventive impact on the development of BOS. Thus, from the beginning of our lung transplant program, we adopted a strategy of performing TBBs on a regular monthly basis for at least the first 6 postoperative months.9 In addition, we collected BALF samples for prospective hemosiderin staining in these patients, hypothesizing that increased iron accumulation may play a direct or indirect pathogenic role in the development of BOS.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Between November 1992 and April 2000, a total of 94 lung transplantations were performed. The present study included 72 patients (15 single and 57 bilateral lung transplants) who survived at least 90 days and underwent at least two postoperative surveillance bronchoscopies. Fourteen patients were not included into the study because they died early. In eight cases, routine surveillance bronchoscopies could not be performed due to a complicated postoperative course. Patients were followed up over a mean period of 3.3 years (95% confidence interval [CI], 2.9 to 3.8 years).

Clinical Management
Details on surgery, clinical management, and postoperative course have been described in detail elsewhere.1415 The immunosuppressive regimen consisted of cyclosporine, azathioprine, and prednisone. Antilymphocyte globulin was administered as an induction therapy. Seven patients undergoing transplantation most recently received basiliximab instead. From 1999, mycophenolate mofetil has been routinely used instead of azathioprine. ARs were treated with prednisone pulses.

Bronchoscopic Techniques and Definitions
Monthly surveillance BALs and TBBs were performed as reported previously.9 A cellular differential of BALF was obtained on cytospin May-Grünwald Giemsa slides (1,000 revolutions per minute for 5 min) by counting a minimum of 200 cells. In each case, a cytocentrifuge slide was stained for hemosiderin by the Prussian blue procedure. The slides were stored and then prospectively examined by a physician unaware of the clinical course of the patients (P.S.). The hemosiderin content of alveolar macrophages was estimated by examining 200 macrophages. Each cell was ranked for hemosiderin content using the following scale: 0, no color; 1, faint blue in a part or the whole cytoplasm without or with single deep blue granules; 2, medium color intensity throughout the cytoplasm without or with deep blue granules in minor (< 50%) portions of the cytoplasm; 3, deep blue granules in major (> 50%) portions of the cytoplasm; and 4, deep blue granules throughout the cell. The total score on 200 cells was divided by two to obtain a HS for the average of 100 macrophages.16 Thirty BALF specimens were evaluated for quality control in a blinded fashion by the present examiner (P.S.) and the first author (E.G.) of our previous article on the HS.16 The interobserver agreement for the HS in these 30 BALF specimens was excellent (Spearman r = 0.99; p < 0.001; data not shown).

TBBs were performed as reported in detail elsewhere.89 The severity of an AR was graded according to the criteria of the International Society for Heart and Lung Transplantation.17 The acute rejection score was calculated according to Girgis and co-authors.6

In order to compare lung parenchyma iron content with the HS of BALF, a pathologist blinded to the BALF results (P.V.) retrospectively analyzed 49 randomly selected TBB specimens stained for iron according to Clelland et al,11 using the following score: 1, single small foci of iron; 2, a few foci; and 3, multiple small or few large foci. The scores of all biopsy pieces of one TBB procedure were added and then divided by the number of pieces.

Primary graft dysfunction was defined as a otherwise unexplained PaO2/fraction of inspired oxygen ratio < 200 beyond 72 h postoperatively.18 Cytomegalovirus disease was defined as histologic evidence of pneumonia, colitis, or gastroenteritis, accompanied by a positive viral culture finding or detection of cytomegalovirus by polymerase chain reaction.19 BOS was defined according to The Working Formulation of the International Society for Heart and Lung Transplantation.20

Statistical Analysis
Results are expressed as mean with 95% (CIs). Statistical comparison between the groups was performed with the Mann-Whitney U test. The Friedman analysis of variance was used for related samples of continuous variables. Associations among the various measures were calculated via Spearman rank-order correlations. A p value ≤ 0.05 was considered to be significant. Standard life-table analysis and the Kaplan-Meier method were used to estimate the cumulative incidence of BOS and overall survival.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There were 399 concurrently obtained BALF and TBB specimens available for analysis. The mean HS steadily increased during the first 9 months after lung transplantation (Fig 1 ), from 31 ± 5 (95% CI, 22 to 39) at month 1 to 107 ± 27 (95% CI, 54 to 159) at month 9 (p < 0.001).



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  		Figure 1.. HSs in BALF samples (mean with 95% CIs) at different time points after lung transplantation. There is a significant increase in the score over time (Friedman analysis of variance, p < 0.001).

 
There were 53 AR grade ≥ A2 events in 33 of the 72 study patients (46%). Eight patients had two AR grade ≥ A2 events, four patients had three AR grades ≥ A2 events, and one patient had had five AR grade ≥ A2 events. Only 3 of the overall 53 ARs were graded as A3, and there were no grade A4 rejections. Only five of the ARs (9%) occurred in symptomatic patients. All others were detected by surveillance biopsy in stable asymptomatic lung transplant recipients with normal lung function.

As shown in Figure 2 , during the whole postoperative course the mean HS was higher in the BALF samples of patients with at least one AR grade ≥ A2 event. The difference was significant 2 months (p < 0.008) and 6 months (p < 0.05) after transplantation.



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  		Figure 2.. HSs in BALF samples (mean with 95% CIs) at different time points after lung transplantation in patients who had at least one AR grade ≥ A2 event (filled squares) and those who did not (filled circles). There is a significant difference at month 2 (p < 0.008) and at month 6 (p < 0.05). Only patients with ARs underwent more than eight procedures.

 
As shown in Figure 3 , mean HS was significantly higher in the BALF samples of patients with one AR grade ≥ A2 event (62; 95% CI, 53 to 71) compared to the BALF specimens of those without an AR during the postoperative course (44; 95% CI, 37 to 51; p < 0.001). Patients with two or more AR grade ≥ A2 events had significantly higher HSs (89; 95% CI, 74 to 103) than those with only one AR (p < 0.004) or no ARs (p < 0.001).



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  		Figure 3.. Comparison of HSs (mean with 95% CIs) in the BALF samples of patients who never had an AR grade ≥ A2 event with those who had one AR grade ≥ A2 event (p < 0.001) and those who had two and more AR grade ≥ A2 events (p < 0.001; p < 0.004 compared with those who had one AR grade ≥ A2 event only).

 
In patients with an AR grade ≥ A2 event, 1 month after the biopsy the mean HS had increased by 28 (95% CI, 10 to 46). This increase was significantly greater than the mean HS increase of 6 (95% CI, 2 to 15) between two bronchoscopies in the patients never having an AR (p < 0.04).

A subgroup analysis of the patients who had never had an AR grade ≥ A2 event revealed no difference in HS between patients with constant A0 biopsy results (44, 95% CI, 32 to 56) and those with at least one AR grade A1 event (52; 95% CI, 39 to 65; p = not significant [NS]; data not shown).

Patients with primary graft dysfunction (n = 11) had higher HSs during their subsequent posttransplant course (83; 95% CI, 49 to 117) than those who could be extubated after 72 h (58; 95% CI, 47 to 68; n = 61). The difference, however, was not statistically significant. There was no difference in HS between patients who had cytomegalovirus disease (55; 95% CI, 31 to 78; n = 10) and those who did not (63, 95% CI, 51 to 74; n = 62), as well as in patients having at least one episode of bacterial pneumonia (68; 95% CI, 51 to 84; n = 26) and those who did not (58; 95% CI, 44 to 72; n = 46). Only one patient had invasive aspergillosis after single lung transplantation; his mean HS was high (129), but the infection was present only in the native lung.

Six patients received oral anticoagulation. Their 36 BALF specimens had significantly higher HSs (94; 95% CI, 71 to 118) than those of patients without anticoagulation (56; 95% CI, 51 to 62; p < 0.003). The exclusion of these patients from the analysis, however, did not influence the overall results (data not shown). No patient smoked at least 1 year before transplantation. There was no correlation between the number of biopsy procedures per patient and mean HS (Spearman r = 0.11; p = 0.36; data not shown).

There were no correlations between any of the BALF cell counts and HS (data not shown). Neither BALF samples with lymphocytosis, nor those with neutrophilia, nor those with eosinophilia showed significantly higher HS than the specimens with normal respective findings (data not shown).

The lung parenchyma iron content of 49 randomly selected TBB specimens was compared in a blinded fashion with the HS of the BALF samples obtained during the same procedure. The mean iron score of the TBBs were moderately well correlated with the HS of the BALF specimens (Spearman r = 0.46; p = 0.001; data not shown).

Thirteen of the 72 patients (18%) acquired BOS after a mean follow-up time of 3.3 years (95% CI, 2.9 to 3.8 years). The cumulative percentage of BOS calculated by the Kaplan-Meier method in the study patients was 32% at 5 years (data not shown; the respective value was 28% if the eight patients, who were at risk but did not undergo biopsy, were included). There was no significant difference in HS between the patients with (44; 95% CI, 18 to 71) and without subsequent BOS (65, 95% CI, 54 to 77; p = NS).

There was no difference in the cumulative incidence of BOS between patients with two or more biopsy-proven AR grade ≥ A2 events, compared with those having fewer than two such episodes. The mean number of AR grade ≥ A2 events was 0.8 (95% CI, 0.0 to 1.6) in patients in whom BOS subsequently developed, compared to 0.7 (95% CI, 0.5 to 0.9) in those without BOS (p = NS). The mean acute rejection score was 2.92 (95% CI, 0.88 to 4.96) in patients in whom BOS subsequently developed, compared to 2.63 (95% CI, 2.01 to 3.25) in those without BOS (p = NS).

Nineteen of the 72 patients (26%) subsequently died. The cumulative percentage of surviving patients at 5 years was 71%. Mean HS was not different between the survivors (66; 95% CI, 54 to 77) and nonsurvivors (45, 95% CI, 27 to 62; p = NS).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study is to our knowledge the first to assess longitudinally the evolution of iron accumulation in the lung allografts after transplantation. The prospective and blinded examination of a large series of BALF samples for hemosiderin-laden macrophages showed a steady increase in mean HS over time (Fig 1). Our data suggest that AR grade ≥ A2 events may have been the main contributory factor in the increase in iron content of the lung allograft. First, mean HS was higher at all time points in patients with at least one AR grade ≥ A2 event (Fig 2), and the difference was statistically significant after the second and sixth postoperative months. Second, HS correlated significantly with the number of AR grade ≥ A2 events (Fig 3). Third, there was a larger increase in HS at 1 month after an AR grade ≥ A2 event than the mean increase in HS between two bronchoscopies in the patients never having an AR.

In the search for other factors that might have contributed to this progressive iron accumulation in the lung allograft, we found that neither primary graft dysfunction nor cytomegalovirus disease had an influence on HS. As described in immunocompetent16 and non-lung transplanted immunosuppressed patients,21 bacterial pneumonia was not a contributing factor with respect to the HS. Moreover, there were no correlations between HS and cell distributions of the BALF. Only oral anticoagulation in six patients resulted in higher HSs compared to patients not receiving anticoagulation. However, the exclusion of these cases from analysis did not change the overall findings.

Egan and coworkers22 have reported an increase in hemosiderin-laden macrophages late after heart transplantation and hypothesized that cyclosporin-induced vascular injury might have contributed to this phenomenon. However, we were unable to detect the characteristic arteriolar hyalinosis in any of the 399 TBBs obtained concurrently with the BALF samples.

One might argue that bleeding due to repeated biopsies could lead to the accumulation of hemosiderin-laden macrophages in the BALF. We think that this is implausible for several reasons: (1) as reported previously,9 < 7% of the biopsy procedures led to a significant hemorrhage of an estimated amount > 100 mL, and the blood was usually removed by suctioning before the end of the procedure; (2) after severe diffuse alveolar hemorrhage, hemosiderin-laden macrophages are cleared completely within 2 to 4 weeks23; (3) there was no correlation between the number of biopsies per patient and their mean HS; (4) even if there would be an accumulation due to repeated biopsies, from a kinetic point of view the HS then would not increase steadily but level off at some time point after transplantation; (5) in a series of immunosuppressed patients, frank hemoptysis was not a risk factor for elevated HS21; and (6) the differences between patients with and without ARs would not be explained.

Our hypothesis that an AR grade ≥ A2 event may be the main contributory factor for the progressive iron accumulation in the lung allograft is in accordance with the data of Clelland and co-authors,11 who described the appearance of perivascular hemosiderin in biopsy samples obtained from lung transplant recipients after a previous AR. The dynamic evolution of iron accumulation after an AR is further substantiated by our findings. Examining consecutive BALF samples during and at any time after an AR grade ≥ A2 event demonstrated a significantly greater increase in the HS in the BALF specimens after the AR compared with the average monthly increase in patients without an AR.

There are three possible reasons for the smaller but nevertheless significant increase in the HS over time in patients who never presented with an AR grade A2 event: (1) the rejection could have been missed due to a sampling error; (2) inapparent AR grade ≥ A2 event occurred between the two biopsy procedures; or (3) the vascular damage due to acute rejection graded as A1 was significant enough. The latter hypothesis seems unlikely, since there was no difference in HS in patients with at least one rejection grade A1 and those who always remained in grade A0. Thus, the possibility of a sampling error raises the question if more than the usual 9 to 12 biopsy samples should be taken during a procedure, or if more than a once-a-month schedule should be utilized. Both suggestions, however, seem to be impractical.

In the literature,1213 it is argued that elevated iron content in the lung allograft may cause metal-induced injury and fibrosis mediated by iron-generated oxidative stress. However, from our results we cannot confirm this apprehension. We did not find a correlation between cellular inflammatory parameters in the BALF, nor a higher mean iron content in patients who subsequently acquired BOS and those who died.

The fact that we were able to show a positive correlation between iron accumulation and AR, and that there was no correlation with respect to BOS contradicts the common opinion that AR is the main risk factor for BOS. Indeed, we could not find any association between AR grade ≥ A2 events and BOS. Thus, we hypothesize that in our patient population, early diagnosis and treatment of AR, detected in asymptomatic lung transplant recipients by surveillance TBB, might prevent the pulmonary allograft from serious injury. Thereby, the association between early AR and BOS might have been uncoupled. Similar results have been published by Swanson and colleagues,10who reported an incidence of nearly 50% in 209 surveillance procedures. In this study,10 the authors did not find any association between early AR and BOS or survival, respectively.

The notion that ARs were detected very early during our rigorous regular surveillance biopsy program is further substantiated by the comparison of BALF cell profiles in patients with and without ARs. BALF cell profiles were normal in 39% of patients during their AR grade ≥ A2 event, which was not significantly different from the percentage of the patients without a concurrent AR. This suggests that there were no significant inflammation processes going on at the time of AR. However, our finding of a lack of correlation of hemosiderin content and AR, respectively, with the subsequent development of BOS should be viewed with caution due to the small number of BOS cases in the present series.

In conclusion, the current study demonstrates that iron accumulates progressively in transplanted lungs during the first postoperative months. We found that AR grade ≥ A2 events are the main factor for iron increase.12,13 In contrast to the hypothesis of other authors, it does not seem that iron overload lead to airway damage manifested by BOS, but we should be cautious with this interpretation due to the small number of respective events. In addition, AR detected by surveillance biopsies were not a risk factor for the development of BOS. Thus, early detection and treatment of AR might uncouple their association with BOS.


   Footnotes
 
Abbreviations: AR = acute rejection episode; BALF = BAL fluid; BOS = bronchiolitis obliterans syndrome; CI = confidence interval; HS = hemosiderin score; NS = not significant; TBB = transbronchial lung biopsy

Received for publication October 20, 2004. Accepted for publication January 19, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Estenne, M, Hertz, MI (2002) Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 166,440-444[Free Full Text]
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  9. Boehler, A, Vogt, P, Zollinger, A, et al Prospective study of the value of transbronchial lung biopsy after lung transplantation. Eur Respir J 1996;9,658-662[Abstract]
  10. Swanson, SJ, Mentzer, SJ, Reilly, JJ, et al Surveillance transbronchial lung biopsies: implication for survival after lung transplantation. J Thorac Cardiovasc Surg 2000;119,27-37[Abstract/Free Full Text]
  11. Clelland, CA, Higenbottam, TW, Stewart, S, et al The histological changes in transbronchial biopsy after treatment of acute lung rejection in heart-lung transplants. J Pathol 1990;161,105-112[CrossRef][ISI][Medline]
  12. Baz, MA, Ghio, AJ, Roggli, VL, et al Iron accumulation in lung allografts after transplantation. Chest 1997;112,435-439[Abstract/Free Full Text]
  13. Reid, D, Snell, G, Ward, C, et al Iron overload and nitric oxide-derived oxidative stress following lung transplantation. J Heart Lung Transplant 2001;20,840-849[CrossRef][ISI][Medline]
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  17. Yousem, SA, Berry, GJ, Cagle, PT, et al Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant 1996;15,1-15[ISI][Medline]
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