Exploring Chronic Lung Transplant (LTx) Allograft Dysfunction (CLAD): The Potential Clinical Prognostic Relevance of Single Bite Transbronchial Biopsy (TBB) Microarray

Purpose TBB histologic assessment of CLAD status, particularly late post-LTx, is typically clinically unhelpful. Microarray analyses using the Molecular Microscope Diagnostic System (MMDx) in kidney & heart recipients are proving useful in providing mechanistic targets that inform therapeutic interventions, and could show similar promise in LTx. Methods LTx recipients with clinical instability- typically a falling FEV 1 and symptoms- had bronchoscopic lavage with microbiologic & cytologic analyses and TBB [4-6 bites analyzed via histology, I TBB bite by MMDx microarray (Alberta Transplant Applied Genomic Center, Edmonton)]. The MMDx uses weighted equations to reflect probabilities of 4 idealized archetypes [Normal, T-cell rejection (TCMR), antibody-mediated rejection (ABMR), Injury]. One month post-TBB a clinical diagnosis was determined, & subsequent change in FEV 1 was reassessed 6 months post-TBB. Clinicians were blinded to MMDx scores. Results 48 of 50 LTx who underwent TBB assessment at 1463±1296d post-LTx, (FEV 1 32-118% predicted), had an assessable TBB for MMDx. Clinical diagnoses at 1 month post-TBB were CLAD n=21, infection n=17, ABMR n=5, TCMR n=4 & effusion n=1. TBB ISHLT grade was A0 n=46, A1 n=1, B0 n=11, B1 n=1; all others Ax and/or Bx. At 6 months post-TBB, using the highest of the 4 MMDx archetype scores, 1/12 (8%) Normal, 7/14 (50%) TCMR, 5/19 (26%) ABMR & 0/3 (0%) Injury recipients, had rapidly progressive CLAD. 15 patients had DSA>500, 9/15 were in ABMR group- 4 with rapidly progressive CLAD. In 31 patients without a clinical diagnosis of infection at 1 month, 11% Normal, 58% TCMR, 60% ABMR & 0% Injury group recipients went on to have rapidly progressive CLAD. Longer term follow-up (mean of 450±168d) in the TCMR arm and ABMR arm noted there were n=4 & 3 and n=2 & 1 deaths/re-LTx respectively, with 1 other re-LTx in the Normal group: all were CLAD related. Conclusion The MMDx score on single bite TBB specimens provided potentially useful mechanistic, therapeutic & prognostic detail in LTx recipients with clinical instability, whilst TBB histology was not clinically helpful in this cohort. The apparent association or confounding of infection, DSA and a predominant ABMR phenotype is notable. A prospective trial of MMDx directed therapy may be indicated.