Spirometric Obstructive Lung Function Pattern Early After Lung Transplantation

Suhling, Hendrik1,4; Dettmer, Sabine2; Rademacher, Jessica1; Greer, Mark1; Shin, Hoen-Oh2; Tudorache, Igor3; Kühn, Christian3; Haverich, Axel3; Welte, Tobias1; Warnecke, Gregor3; Gottlieb, Jens1


In the January 27, 2012 issue of Transplantation in the article by Suhling et al, “Spirometric Obstructive Lung Function Pattern Early After Lung Transplantation”, an author's name was printed incorrectly. “Greer Mark” should have appeared as “Mark Greer.” This has been corrected in the online version of the article.

Transplantation. 93(8):e37, April 27, 2012.

doi: 10.1097/TP.0b013e31823dd670
Clinical and Translational Research

Background. An obstructive pattern in pulmonary function test is common after lung transplantation (LTx) and may be caused by multiple disorders. In this study, the impact and outcome of an obstructive spirometric pattern identified in transplant recipients early posttransplantation were investigated.

Methods. Analyzing all patients undergoing double LTx between September 1, 2007, and October 1, 2009, we separated patients with an obstructive (forced expiratory volume in 1 sec [FEV1]: vital capacity [VC] <0.7) and a nonobstructive pattern (FEV1:VC ≥0.7) in pulmonary function tests 3 months after transplantation. Pulmonary function measurement, bronchoscopy, laboratory parameter, computed tomography morphology, mortality, and bronchiolitis obliterans syndrome (BOS)-free survival were analyzed up to 36 months after transplantation. In addition, information about donor lungs were collected (age, smoking history, and blood gas before lung harvesting).

Results. From 122 recipients included, 17 (14%) exhibited an obstructive pattern. Recipients with an early obstructive pattern were older at transplantation, had significantly decreased FEV1, increased total lung capacity, and donor organ with lower pO2 when ventilated with 100% oxygen before retrieval. Obstructive patients developed their best FEV1 earlier after LTx and demonstrated a significant increase in BOS development (47% vs. 14%).

Conclusions. An obstructive lung function pattern early after LTx was associated with earlier development of BOS and may have negative impact on outcome after double LTx. Early obstructive pattern after transplantation might be an indication of structural donor lung injury.

1Department of Pulmonary Medicine, Hannover Medical School, Hannover, Germany.

2Department of Radiology, Hannover Medical School, Hannover, Germany.

3Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

The authors declare no funding or conflict of interest.

Address correspondence to: Hendrik Suhling, M.D., Department of Respiratory Medicine, Hannover Medical School, OE6870, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: suhling.hendrik@mh-hannover.de

H.S. participated in research design, data analysis, writing of the manuscript; S.D. participated in writing of the manuscript and analyzed CT scans; J.R., H.-o.S., I.T., C.K., A.H., T.W., and G.W. participated in writing of the manuscript; M.G. participated in writing of the manuscript and corrections in English language; and J.G. participated in research design, data analysis, and writing of the manuscript.

Received 18 July 2011. Revision requested 16 August 2011.

Accepted 18 October 2011.

Article Outline

Within the past 2 decades, lung transplantation (LTx) has gained increasing acceptance as a viable treatment option for various end-stage lung diseases (1). Regular pulmonary function tests are an essential part of standard posttransplantation monitoring. Early after transplantation, airway complications and acute rejection (AR) are encountered most frequently as a cause of an obstructive pattern. Late after transplantation, bronchiolitis obliterans syndrome (BOS) as the underlying disease becomes more frequent and affects 50% recipients after 5 years (1). Donor-transmitted respiratory diseases (most commonly asthma) are much rarer reasons for an obstructive pattern (2). Chronic obstructive pulmonary disease (COPD), as the most common respiratory disease in developed countries (3), affecting 13% of the general population older than 40 years (4) could cause this airway pattern. Acceptance of extended donors even increased in last years (5) amplifies the risk of structural damaged donors. Acceptable short-term results with a slight increase in primary graft dysfunction (PGD) were shown for organs exhibiting low pO2 (<300 mm Hg) or a history of tobacco exposure or active infection (5, 6). Even with optimal on-site investigation during organ retrieval, earlier stages of structural lung disease may be missed among potential organ donors. In this study, we analyzed the outcome of lung transplant recipients with a persistent obstructive pattern.

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From the 198 adult patients who underwent LTx between September 1, 2007 and October 1, 2009, 76 did not fulfill the inclusion criteria: 29 due to bronchial stenosis, 14 due to single LTx, and 33 loss of regular follow-up (died or were still in hospital and no lung function was available 3 months after LTx). In total 122 patients were included, of whom 17 (14%) exhibited a forced expiratory volume in 1 sec (FEV1): vital capacity [VC] ratio less than 70%, defined as an obstructive pattern. From 122 patients, 6 were still in hospital after 3 months (no significant difference between the groups).

The specifications of donor parameters are illustrated in Table 1: donors from obstructive pattern patients had an increased smoking history with more pack years indicating a higher rate of heavy smoker donors. Donor lungs in this group had a significantly decreased pO2:FiO2 ratio (<350 mm Hg pO2 with 100% oxygen, 7 of 17). No obstructive pattern patient received a lung with a pO2 more than 500 mm Hg when ventilated with 100% oxygen.

Differences in FEV1:VC ratios (tiffenau index) in the two groups over the time were illustrated in Figure 1. In Figure 2, maximal expiratory flow 25–75, FEV1, forced vital capacity (FVC), and total lung capacity (TLC) differences between the groups were shown. No significant differences for other parameters analyzed could be found. PGD grade 0 to 3 was analyzed and showed no significant differences (Table 1). Twelve patients underwent size reduction of the donor lung (three obstructive patterns and nine nonobstructive patterns, not significant). A size mismatch more than 10 cm was found in a single patient.

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).

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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.

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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.

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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.

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Study Design

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.

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Donor Variables

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.

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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).

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Primary Graft Dysfunction

For classification of PGD, we used criteria defined by Christie et al. (7), 48 hr after LTx.

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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).

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Imaging Studies

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).

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We studied BOS-free survival as a primary outcome parameter. We analyzed patient and graft survival as secondary parameters.

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Statistical Analysis

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.

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The authors thank Anja Boemke and Jan Fuge, both from the Department of Respiratory Medicine, Hannover Medical School, for data acquisition.

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Lung transplantation; Bronchiolitis obliterans; Airway obstruction; COPD; Obstructive lung function (max 5)

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