Comparison of the computed tomography (CT) results focused on morphological changes, indicative of emphysematous and obstructive changes. Subsequent statistical analysis revealed significant changes in airway thickness (Table 2). Air trapping could be shown in 3 of 6 CTs of obstructive pattern and in 17 of 39 nonobstructive patients (not significant).
Patients with an obstructive pattern developed BOS significantly often and earlier (9/17 vs. 14/105, P=0.0001; see Fig. 3). No differences in mortality could be detected (2/17 vs. 12/104, P=0.41). In total, 14 patients died during follow-up surveillance. Seven died as a result of BOS, three patients died because of complications of acute renal failure, two died because of posttransplantation lymphoma disease, and two because of sepsis.
Based on our findings, the presence of an early spirometric obstructive pattern in lung transplant recipients is associated with both increased incidence and an earlier onset of BOS. Possible reasons for obstructive airway disorders after LTx include upper airway abnormalities, anastomic complications, AR, infection, secretion, and BOS. Rejection and infection were ruled out in the patients presented here by an intense surveillance program including bronchoalveolar lavage (BAL) and transbronchial biopsy (TBB) in all recipients. A correlation between PGD and the development of BOS was described by Christie et al. (7). Even this risk factor was not increased in the obstructive patients.
BOS is the commonest posttransplantation airway complication. It affects the small airways and correlates histological with an obliterative bronchiolitis. There are different types of BOS, which differ in the time of the FEV1 decline (8). In the early postoperative period, BOS is unlikely (9). Airway neutrophilia is a marker to detect early BOS as it often accompanies BOS-related progressive bronchoconstriction (10). In obstructive and nonobstructive pattern patients, who developed BOS, there were only three in total presenting a neutrophilia (>15% in BAL) after 3 months. Median percentage of neutrophils in BAL (both groups) decreased after the third month (probably due to mucosal healing and fibrin reduction) and increased again. There were no increased neutrophilis in BAL of obstructive patients. Although BOS can occur in the absence of neutrophilia (fibroproliferative BOS) (8), this form is usually seen late after transplantation (11). Although, these findings do not exclude BOS as reason for FEV1 decline, chart analysis suggested a donor-related etiology.
The early obstructive pattern was associated with donor organs displaying reduced oxygenation before harvesting and longer donor smoking history. A possible explanation may be that these organs had subclinical structural damage before transplantation, although not all donor lungs in these recipients fulfilled extended donor criteria (12).
According to current guidelines, the criteria for COPD including reduced FEV1:C ratio, expiratory flow limitations and elevated hyperinflation were fulfilled in obstructive pattern patients (13). However, for obvious proof of mild donor COPD detailed spirometric history (of the donor) was not available. As data before transplantation of donor history were rare, we used CT studies after transplantation to search for structural abnormalities. On imaging studies, obstructive pattern patients show an increased airway thickening as one indicator for structural changes (14). Airway thickness correlates closely with airway inflammation and smoking history in asthma and COPD patients (15). Other structural changes, for example, emphysema or bronchiolitis were not seen in our imaging studies. The highest correlation between emphysema and CT findings was described for values lower than −910 HU (16). This failed to be significant and was discordant to TLC findings that pointed to hyperinflation. Imaging studies for correct determination of air trapping were available in six patients with obstructive pattern. Prospective studies were needed to further evaluate this aspect (planned in our center, clinical trails, NCT00774449).
Another indicator for an underlying irreversible structural change in obstructive patients was the occurrence of pathologic pulmonary function (FEV1:VC ratio and TLC) from the first lung function on. Interestingly, recipients with an early obstructive pattern demonstrated an earlier peak FEV1 after the transplantation. Usually, a late peak in FEV1 occurs around 12 months posttransplantation as a result of full lung expansion, healing, improved physical fitness, and increasing chest mobility.
An alternative hypothesis would be that obstructive patterns could result from donor and recipient size mismatch. Eberlein et al. (17) reported of supranormal expiratory airflow as a predictor of improved survival and suggested a size mismatch and increased elastic recoil as causative. Unfortunately hyperinflation in that study was not measured but calculated from recipient's weight and height. In contrast to previous studies, we found no significant differences in size mismatch between our obstructive pattern and nonobstructive pattern groups. Interestingly, in the article by Eberleins et al., the control group was more frequently affected by obstructive airway disorders with a median FEV1:FVC of 0.62.
Extended criteria donor lungs were more frequently used in patients who ultimately developed obstructive pattern after transplantation. It was previously shown that recipients who received extended donor lungs and lower PO2/FIO2 ratio within the first 6 hours posttransplantation had significantly longer mechanical ventilation time and decreased long-term survival (18, 19). Measurement of PO2:FIO2 ratio 48 hr after LTx revealed no significant differences.
Extended criteria donor lungs lead to a higher incidence of PGD, but medium-term functional outcome including BOS was not adversely affected (20). Hennessy et al. described as donor risk factors for the development of BOS older age and current tobacco consumption. Recipients who received lungs from younger donors or those without current tobacco use had longer BOS-free survival (21). In line with these studies, we demonstrate the FEV1:VC ratio less than 70% as a good prognostic indicator after LTx for early development of BOS. Even there was no difference mortality.
Limitations of this study include the lack of a comprehensive donor history and limited long-term follow-up. Our results may be positively biased, given that only patients progressing into the outpatients follow-up program were included (22). The origin of obstructive changes in recipients in younger donor remains unclear. Reversibility of obstruction was seen only in a minority.
We demonstrated that early obstructive lung function may be a risk factor for BOS development after LTx. Potential risk factors for this airway pattern seem to be donor related (structural changes). The pathologic tiffenau index should be further evaluated in follow-up after LTx as a clinical tool to detect high-risk patients for chronic lung allograft dysfunction.
MATERIALS AND METHODS
A retrospective cohort study was performed in a single-transplantation center (Hannover Medical School, Germany). Adult patients (>18 years at time of transplantation) undergoing double LTx between September 1, 2007 and October 1, 2009 were included. The study excluded patients receiving single LTx (n=14) and those experiencing obstructive airway complications (e.g., bronchus stenosis, n=29), and patients had no follow-up data (no lung function 3 month after LTx, n=33). From 122 patients, 6 were in hospital after 3 months but lung function was available, all other patients entered our follow-up clinic before. Ongoing follow-up was performed until November 1, 2010.
Donor smoking history was reviewed, with donor lungs being subclassified according to pack years (0, <20, and >20) (12). In 22 patients, the donor smoking status was unknown. Donor height, weight, and gender were reviewed, along with arterial pO2 under ventilation with 100% oxygen.
The donor and recipient physical characteristics were compared, and size mismatch was defined as a size difference greater than 10 cm. Size reduction was performed as atypical resection (stapling) in three cases. Anatomical (typical resection) was performed in nine cases. In all cases, size reduction was indicated because of size mismatch usually in cystic fibrosis patients with small stature or small chest cavities in lung fibrosis patients.
Pulmonary Function Tests
At 1, 3, 6, 12, 18, 24, and 36 months after transplantation, lung function (body plethysmography or spirometry) and blood gas analysis were performed. Spirometry, consisting of forced expiratory volume in 1 sec (FEV1) and FVC, was performed according to American Thoracic Society/European Respiratory Society guidelines (23). The FEV1:VC ratio at the third month posttransplantation was used to define an obstructive pattern (13). All patients exhibiting a quotient less than 70% were marked as patients with obstructive pattern. Patients with FEV1:VC ratio more than or equal to 70% were allocated into the group of normal airway pattern. BOS was defined as irreversible FEV1 decline under 80% from baseline FEV1 (9).
Primary Graft Dysfunction
For classification of PGD, we used criteria defined by Christie et al. (7), 48 hr after LTx.
Surveillance TBBs were performed 1, 3, 6, and 12 months after transplantation. Additional TBBs were performed in cases of unexplained deterioration of graft function as required. All available biopsy specimens were analyzed, and a cumulative score for A and B grade rejection was calculated. Definitions of AR and BOS were made according to The International Society for Heart and Lung Transplantation guidelines (24, 25). Bronchoscopic findings for each patient were reviewed. The bronchoscopies after mucosal healing (>3 months) were screened, and the airway secretion was quantified. Airway colonization was defined as repeated isolation of identical bacterial pathogens on two consecutive lower respiratory tract samples at least 4 weeks apart (26).
We analyzed CT scans (in a period of 3–6 months after transplantation) of 13 patients with obstructive pattern and of 39 patients with nonobstructive pattern. Multidetector CT scans were performed in several institutions with varying scan protocols (slice thicknesses between 1 and 5 mm). This analysis was performed by a single, blinded radiologist (S.D.) unaware of the pulmonary function tests classification. Bronchiectasis, lung volume, mean transparency, areas with less than −910 and −950 HU (%), and increased bronchial wall thickness were used as indicators for emphysema (27). Air trapping was analyzed in CT scans with extra expiratory scans (6 obstructive pattern CTs and 39 nonobstructive pattern CTs).
We studied BOS-free survival as a primary outcome parameter. We analyzed patient and graft survival as secondary parameters.
Numeric data were reported as median and interquartile ranges (25% and 75%). Group comparisons were performed using either the Mann-Whithey U test or the student's t test. All reported P values are two sided unless otherwise indicated. For all analyses, P values less than 0.05 were considered statistically significant. In the case that there were less than 10 patients in one group at a given time point, no statistical analysis for that time point was performed. Categorical variables were analyzed using chi-square tests. Overall and BOS-free survival were assessed by the Kaplan–Meier method and ground compared by log-rank test. One patient was excluded as BOS onset was within 3 months after transplantation. For Figures 2 and 3, mean values and standard error of the mean were used.
The authors thank Anja Boemke and Jan Fuge, both from the Department of Respiratory Medicine, Hannover Medical School, for data acquisition.
1. Christie JD, Edwards LB, Kucheryavaya AY, et al.. The Registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official adult lung and heart-lung transplant report–2010. J Heart Lung Transplant 2010; 29: 1104.
2. Corris PA, Dark JH. Aetiology of asthma: Lessons from lung transplantation. Lancet 1993; 341: 1369.
3. Halbert RJ, Isonaka S, George D, et al.. Interpreting COPD prevalence estimates: What is the true burden of disease? Chest 2003; 123: 1684.
4. Geldmacher H, Biller H, Herbst A, et al.. [The prevalence of chronic obstructive pulmonary disease (COPD) in Germany. Results of the BOLD study]. Dtsch Med Wochenschr 2008; 133: 2609.
5. Botha P, Fisher AJ, Dark JH. Marginal lung donors: A diminishing margin of safety? Transplantation 2006; 82: 1273.
6. Botha P, Trivedi D, Searl CP, et al.. Differential pulmonary vein gases predict primary graft dysfunction. Ann Thorac Surg 2006; 82: 1998.
7. Christie JD, Carby M, Bag R, et al.. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: Definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2005; 24: 1454.
8. Vanaudenaerde BM, Meyts I, Vos R, et al.. A dichotomy in bronchiolitis obliterans syndrome after lung transplantation revealed by azithromycin therapy. Eur Respir J 2008; 32: 832.
9. Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. Am J Respir Crit Care Med 2002; 166: 440.
10. Neurohr C, Huppmann P, Samweber B, et al.. Prognostic value of bronchoalveolar lavage neutrophilia in stable lung transplant recipients. J Heart Lung Transplant 2009; 28: 468.
11. Verleden GM, Vos R, De Vleeschauwer SI, et al.. Obliterative bronchiolitis following lung transplantation: From old to new concepts? Transpl Int 2009; 22: 771.
12. Reyes KG, Mason DP, Thuita L, et al.. Guidelines for donor lung selection: Time for revision? Ann Thorac Surg 2010; 89: 1756.
13. Rabe KF, Hurd S, Anzueto A, et al.. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007; 176: 532.
14. Arakawa H, Fujimoto K, Fukushima Y, et al.. Thin-section CT imaging that correlates with pulmonary function tests in obstructive airway disease. Eur J Radiol 2011; 80: e157.
15. Kosciuch J, Krenke R, Gorska K, et al.. Relationship between airway wall thickness assessed by high-resolution computed tomography and lung function in patients with asthma and chronic obstructive pulmonary disease. J Physiol Pharmacol 2009; 60(suppl 5): 71.
16. Thurlbeck WM, Muller NL. Emphysema: Definition, imaging, and quantification. AJR Am J Roentgenol 1994; 163: 1017.
17. Eberlein M, Permutt S, Brown RH, et al.. Supranormal expiratory airflow after bilateral lung transplantation is associated with improved survival. Am J Respir Crit Care Med 2011; 183: 79.
18. Oto T, Levvey BJ, Whitford H, et al.. Feasibility and utility of a lung donor score: Correlation with early post-transplant outcomes. Ann Thorac Surg 2007; 83: 257.
19. Thabut G, Christie JD, Kremers WK, et al.. Survival differences following lung transplantation among US transplant centers. JAMA 2010; 304: 53.
20. Botha P, Trivedi D, Weir CJ, et al.. Extended donor criteria in lung transplantation: Impact on organ allocation. J Thorac Cardiovasc Surg 2006; 131: 1154.
21. Hennessy SA, Hranjec T, Swenson BR, et al.. Donor factors are associated with bronchiolitis obliterans syndrome after lung transplantation. Ann Thorac Surg 2010; 89: 1555.
22. Burton CM, Carlsen J, Mortensen J, et al.. Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. J Heart Lung Transplant 2007; 26: 681.
23. Miller MR, Hankinson J, Brusasco V, et al.. Standardisation of spirometry. Eur Respir J 2005; 26: 319.
24. Lee JC, Christie JD. Primary graft dysfunction. Proc Am Thorac Soc 2009; 6: 39.
25. Oto T, Levvey BJ, Snell GI. Potential refinements of the International Society for Heart and Lung Transplantation primary graft dysfunction grading system. J Heart Lung Transplant 2007; 26: 431.
26. Gottlieb J, Mattner F, Weissbrodt H, et al.. Impact of graft colonization with gram-negative bacteria after lung transplantation on the development of bronchiolitis obliterans syndrome in recipients with cystic fibrosis. Respir Med 2009; 103: 743.
27. Litmanovich D, Boiselle PM, Bankier AA. CT of pulmonary emphysema—Current status, challenges, and future directions. Eur Radiol 2009; 19: 537.
Lung transplantation; Bronchiolitis obliterans; Airway obstruction; COPD; Obstructive lung function (max 5)© 2012 Lippincott Williams & Wilkins, Inc.