Eleven years on: A clinical update of key areas of the 1996 lung allograft rejection working formulation

More than 10 years have passed since the Working Formulation for the Classification of Pulmonary Allograft Rejection was revised. This review revisits this classification from a clinical perspective, to detail ongoing practical experience and new experimental data, aiming to ensure ongoing clinical relevance. The pulmonary council members of the International Society for Heart and Lung Transplantation (ISHLT) were canvassed regarding particular areas in the practical diagnosis and interpretation of lung rejection in need of review and revision. An international panel of lung transplant physicians and surgeons reviewed and summarized the available literature and current clinical practice to create a document as an update for other lung transplant clinicians. The "A" rejection grade has proved robust and reproducible. Grade A1 rejection shows promise of clinical utility. The "B" grade is confounded by infection and is poorly reproducible, but may correlate with long-term outcomes. The "C" grade is less relevant than the clinical classification of bronchiolitis obliterans syndrome (BOS). The "D" grade has not proved useful. Antibody-mediated (humoral) rejection requires more study, being currently difficult to diagnose, but possibly of great clinical importance. The demonstration of graft eosinophilia, bronchiolitis obliterans-organizing pneumonia (BOOP) or upper lobe fibrosis are all notable, but of controversial etiology and significance. No practical surrogate bronchoalveolar lavage marker of acute or chronic rejection has been detected to date. The 1996 Working Formulation for the Classification of Pulmonary Allograft Rejection has proved clinically practical and useful. Further studies are required to expand on the role of humoral rejection and the relevance of the sub-divisions of each grade. More than a decade has passed since the Working Formulation for the Classification of Pulmonary Allograft Rejection was revised.(1) Although the broad pillars of the Working Formulation continue to underpin clinical human lung transplantation (LTx), 11 additional years of practical experience and experimental data now need to be incorporated to maintain scientific accuracy and clinical relevance. After discussions with colleagues from pulmonary and pathology councils of the International Society for Heart and Lung Transplantation (ISHLT) and canvassing the general ISHLT membership, specific areas have been chosen on which to focus this update. Our review represents the deliberations and consensus of a group of LTx physicians and surgeons focusing on the clinical viewpoint.