Table 1.

Emerging Phenotypes of Chronic Lung Allograft Dysfunction: Key Features^{66, 69, 72, 73}

Entity	Classic BOS	RAS
Pulmonary function testing	Obstructive	Restrictive
HRCT thoracic imaging	•Air trapping usually present •No/minimal infiltrates •± Bronchiectasis	•± Air trapping •Infiltrates usually present •± Bronchiectasis
Histopathology	•Obliterative bronchiolitis	•Parenchymal/pleural fibrosis •± Obliterative bronchiolitis
Clinical course	Typically progressive, but may stabilize; individuals may have coexistent chronic bacterial infection	Tends to be relentlessly progressive; may start as or coincide with BOS
Proposed mechanism	Cytotoxic/proinflammatory lymphocyte (increased CD8T, NKT-like, and NK cells in small airways)	Antibody-mediated rejection (increased levels of immunoglobulins and complement proteins)
Risk factors for development	•PGD •Acute cellular or antibody-mediated rejection •GERD •Infections •Autoimmunity, persistent neutrophil influx •Air pollution •Genetic factors	•Severe lymphocytic bronchiolitis •Late-onset DAD •BAL eosinophilia •Increased BAL protein levels of alarmins •Sarcoidosis/interstitial lung disease •CMV donor/recipient mismatch •Younger age •Female •Infections •Acute rejection •BAL neutrophilia
Potential therapies	•Azithromycin •Switching immunosuppressive therapies •Total lymphoid irradiation •Extracorporeal photopheresis •Methotrexate •Cyclophosphamide •Montelukast	•Pirfenidone •Alemtuzumab
Median survival after diagnosis, y	2.5	1.5

BOS = bronchiolitis obliterans syndrome; CD8T = cytotoxic t-cell; CMW = cytomegalovirus; DAD = diffuse alveolar damage; GERD = gastroesophageal reflux disease; HRCT = high-resolution CT; NK, natural killer cell; NKT, natural killer t-cell; PGD = primary graft dysfunction; RAS = restrictive allograft syndrome.

(Adapted with permission from Verleden et al.⁶⁶)