Bronchoalveolar Lavage MICB is Associated with Severe Primary Graft Dysfunction, Prolonged Mechanical Ventilation, and Low Post-Transplant FEV1 in Lung Transplant Recipients

Abstract

<h3>Purpose</h3> Primary graft dysfunction (PGD) is associated with increased morbidity and mortality after lung transplant. Natural killer (NK) cells may potentiate PGD following recognition of stress molecules that are increased during lung injury. Here, we hypothesized that the bronchoalveolar lavage (BAL) stress molecule MICB would be associated with PGD, early morbidity, and post-transplant lung function. <h3>Methods</h3> BAL was collected from 74 lung transplant recipients at two centers on post-operative day (POD) 1. MICB was measured by ELISA. PGD was categorized by ISHLT criteria as severe (grade 2/3) or none (grade 0/1) on POD 2 or 3. Peak lung function was defined as the mean of the best 2 post-transplant FEV₁ values. Differences in MICB protein and FEV₁ among PGD groups were assessed using the Mann Whitney U test. The association between MICB and time to extubation was determined by adjusted Cox proportional hazards models. <h3>Results</h3> BAL MICB was increased in subjects with severe PGD (<b>Fig. 1A</b>, 59 interquartile range (IQR) 30-142 pg/mL, p = 0.001) compared to those without PGD (27 IQR 15-55 pg/mL). Relative to subjects without PGD, those with PGD and greater than median BAL MICB (PGD⁺MICB^hi, <b>Fig. 1B</b>, Hazard Ratio [HR] 5.9, Confidence Interval [CI] 2.9 - 12.5, p <0.00001) and subjects with PGD and lower than median BAL MICB (PGD⁺MICB^low, HR 3.1, CI 1.6-5.) had increased post-transplant mechanical ventilation time. Peak post-transplant FEV₁ was reduced for PGD⁺MICB^hi (<b>Fig. 1C</b>, 2 IQR 1.6-2.7 L, p = 0.004) and PGD⁺MICB^low (1.9 IQR 1.5-2.3 L, p = 0.03) subjects compared to those without PGD (2.9 IQR 2.2-3.6 L). <h3>Conclusion</h3> BAL MICB protein was increased in subjects with severe PGD and was associated with prolonged mechanical ventilation. Recipients with elevated BAL MICB and severe PGD also had lower peak lung function. BAL MICB may be a useful biomarker of PGD severity, is mechanistically linked to NK cell activation, and is a potential therapeutic target.