Purpose

Lung transplant is the only definitive treatment in patients with end-stage lung disease. Chronic allograft rejection is the major cause of long-term morbidity and mortality in lung transplant recipients. The traditionally described chronic rejection, bronchiolitis obliterans syndrome (BOS), manifests as a persistent fall in forced expiratory volume in one second (FEV1) and associated ventilatory defects. However, recently a restrictive form of chronic rejection has been described that does not fit the traditional definition of BOS. The term chronic lung allograft dysfunction (CLAD) has been introduced to include all forms of graft dysfunction. Pulmonary function tests (PFT) provide global information about the native and transplanted lung. FEV1 and forced vital capacity (FVC) are reproducible, but neither are sensitive nor specific. Computed tomography (CT) provides structural information but often shows few or even no changes, despite clinical deterioration of the patient’s condition. With hyperpolarized helium-3 (HP 3He) MR imaging, individual lung function can be assessed; the regional ventilation can be depicted without onizing radiation and thus scanning can be repeated in the same subject without significant risk. HP 3He-MRI has been shown to be a sensitive method to detect ventilatory defects in lung transplant recipients (1,2). Hence, the purpose of this study was to determine if the changes in lung ventilation using HP 3He-MRI can provide in vivo pulmonary physiology highly relevant in defining CLAD phenotypes among lung transplant patients, phenotypes which otherwise are undetectable by the usual PFT parameters such as FEV1.

Methods

Thirteen lung transplant recipients [55.1 ±7.1 yrs (range 43, 68 yrs)] were included in the study under a protocol approved by our institutional review board. Informed consent was signed by the patients. Indications for transplant were: 7 patients with COPD, 1 with Langerhans Cell Histiocytosis, 1 pulmonary hypertension, 1 alpha antitrypsin deficiency, 2 idiopathic pulmonary fibrosis and 1 with cystic fibrosis. Eleven patients had undergone unilateral lung transplant (7 right, 4 left) and two patients had undergone bilateral lung transplant. Time from transplant to inclusion in the study was 2.5 ±2.5 yrs (range 0.25- 9.9 yrs). MR imaging was performed using a commercial 1.5-T whole-body scanner (Vision[ 1] , Siemens Medical Solutions, Malvern, PA) modified to operate at the 3He resonant frequency of 48 MHz by the addition of a broadband radiofrequency amplifier and a flexible 3He chest radiofrequency coil (IGC Medical Advances, Milwaukee, WI). Contiguous axial MR images covering the entire lung (FLASH; TR/TE, 7/3 ms; flip angle, 10°; matrix, 80x128; FOV, 26 x 42 cm; section thickness, 10 mm; interslice gap, none) were collected during a 15-20 sec breath hold immediately following inhalation of approximately 300 mL H3He gas mixed with approximately 700 mL of nitrogen. For each scan, the ventilated lung volume (%VD) on 3He-MRI was manually segmented by two independent blinded readers. Spirometry was performed in all patients at the time of the MRI exam and was compared to the baseline spirometry performed at the time of the transplant (%FEV1 change = %FEV1 at baseline - %FEV1 at the time of the study). % FEV1 change was annualized by dividing it by the number of years since the transplant. Spearman correlation between the ventilated volume of the transplanted lung and %FEV1 change (both absolute and annualized %FEV1 change) was calculated.

Results

Absolute %FEV1 change was -19.8±26.6% (range -64, +13). Annualized %FEV1 was -8.9±18.1% (range -42.7, +13). %VD in the transplanted lung was: 1) reader 1: 90.8%±12.8% (range 99.94-64.8), 2) reader 2: 87.8±14.01% (range 99.85-59.7), 3) average: 89.3±13.3 % (range 99.83-65.8). There was significant correlation between the absolute %FEV1 reduction and %VD (r=0.8364, p=0.0022, Fig 1a) as well as between annualized %FEV1 reduction and %VD (r=0.6925, p=0.0215, Fig 1b). Of note, 3He-MRI identified highly interesting CLAD phenotypes. While %VD was reduced in 4 subjects (solid red circles) with matching drop in %FEV1 and %VD, four other subjects (solid black circles) had divergent %FEV1 and %VD, dropping %FEV1 but normal %VD. These divergent patterns of the %FEV1 and %VD were highly suggestive of restrictive CLAD found in the four subjects (solid black circle) instead of classic BOS noted in the other four subjects (solid red circles).

Discussion

Declined lung function after lung transplant correlated well with decreased ventilated lung volume in the transplanted lung found with HP 3He-MRI. The discrepancy found in patients which showed %FEV1 reduction without impaired ventilation on HP 3He-MRI may indicate that the transplanted lung is experiencing both obstructive and restrictive disease, and therefore this imaging technique has the potential to provide new insights into the pathologic changes of chronic transplant rejection, currently termed CLAD.

Acknowledgements

No acknowledgement found.

References

[1] McAdams HP, et al. AJR Am J Roentgenol 1999 173:955–959. [2] Gast KK, et al. J Magn Reson Imaging. 2002 Mar;15(3):268-74