Late airway rejection (chronic rejection) is usually seen in late post-transplant patients (months to years) and is the most common cause of morbidity and mortality in long-term survivors, affecting 50% to 60% of patients surviving 5 years. Chronic rejection is characterized by obliterative bronchiolitis (OB), an inflammatory process of small airways (membranous and respiratory bronchioles) resulting in fibrosis and complete occlusion, a form of constrictive bronchiolitis (see Chapter 63). The clinical correlate is called bronchiolitis obliterans syndrome (BOS), a diagnosis based on clinical findings and not on histologic sampling of bronchioles, which may be difficult to obtain with transbronchial biopsy. BOS is based on decrease in FEV₁ and FEF_25-75% compared with baseline. Trichrome stains highlight the smooth muscle of obliterated bronchioles and are required for full interpretation of transbronchial biopsies in lung transplant patients to rule out chronic rejection. Risk factors for the development of chronic rejection include previous episodes of acute rejection (particularly high grade, persistent, or late onset); infection, especially viral (cytomegalovirus, respiratory syncytial virus, parainfluenza, etc.); and development of anti-HLA antibodies and aspiration in association with gastroesophageal reflux disease. In addition to OB or chronic airway rejection designated “C” in the Working Formulation, chronic rejection is associated with accelerated graft vascular sclerosis or chronic vascular rejection designated “D” in the Working Formulation (see Table 104.1). The latter is of considerably less known clinical significance than the former.