A 42-year-old woman comes to the office with a nonproductive cough and worsening shortness of breath with exertion. The patient has a history of primary pulmonary hypertension and underwent lung transplantation 8 months ago. She states that she has not missed any doses of her transplant medications. A chest x-ray reveals surgical evidence of her transplant but clear lung fields. Pulmonary function testing demonstrates a forced expiratory volume in 1 second (FEV₁), 67% of her best posttransplant FEV₁. Her forced vital capacity remains largely unchanged. A lung biopsy shows areas of total fibrotic obstruction in the terminal bronchioles. This patient's condition is most likely caused by which of the following?

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This patient with cough, dyspnea, obstructive findings on spirometry, and fibrotic destruction of the small airways likely has chronic transplant rejection. Lung transplantation may be complicated by both acute and chronic rejection. Chronic rejection is a major cause of morbidity and mortality and occurs in almost half of all patients within 5 years of transplantation. These patients commonly present with dyspnea and a dry cough. Spirometry shows an airflow limitation with a drop in both the forced expiratory volume in 1 second (FEV₁) and the FEV₁ to forced vital capacity (FVC) ratio. Chronic rejection affects the small bronchioli producing the obstructive lung disease known as bronchiolitis obliterans. Initially, histopathology shows lymphocytic inflammation and destruction of the epithelium of the small airways. Subsequently, fibrinopurulent exudate and granulation tissue are found in the lumen of the bronchioli, which ultimately results in fibrosis, scarring, and the progressive obliteration of small airways. (Choice A) Acute rejection usually occurs within the first 6 months. It is frequently asymptomatic and commonly discovered on surveillance biopsies. Histopathology demonstrates perivascular and interstitial mononuclear cell infiltrates. (Choices B and F) Underlying lung disease, such as pulmonary hypertension or chronic obstructive pulmonary disease (COPD), may recur in the lung allograft. However, the obstructive pattern on spirometry and the histopathology findings are better explained by chronic rejection than by pulmonary hypertension or COPD, the latter of which would also show increased goblet cells and mucus gland hyperplasia. (Choice D) Ischemia-reperfusion injury is a form of noncardiogenic pulmonary edema that occurs in the allograft due to surgical trauma or organ ischemia. It is seen during the first few days following transplantation. (Choice E) Infection is a leading cause of death in lung transplant recipients. Cytomegalovirus causes the most significant opportunistic infection in transplant recipients. Infected cells have a characteristic intranuclear inclusion surrounded by a clear halo (owl's eye inclusion). Educational objective: Chronic rejection is a major problem in lung transplant recipients; it affects small airways, causing bronchiolitis obliterans. It is characterized by lymphocytic inflammation, fibrosis, and, ultimately, destruction of the bronchioles. __________ References: A review of bronchiolitis obliterans syndrome and therapeutic strategies. (http://www.ncbi.nlm.nih.gov/pubmed/21767391) Lung transplantation: chronic allograft dysfunction and establishing immune tolerance. (http://www.ncbi.nlm.nih.gov/pubmed/24979671)

A 42-Year-Old Woman Comes to the Office with a Nonproductive