A 45-year-old man underwent allogeneic HSCT for acute myeloid leukemia 18 months ago. He now presents with progressive dyspnea on exertion and dry cough. Pulmonary function testing shows FEV1/FVC ratio of 0.68, FEV1 at 68% predicted (decline of 12% from pretransplant baseline), and RV/TLC ratio of 125%. Expiratory HRCT demonstrates mosaic attenuation with air trapping in small airways. Microbiologic workup including BAL is negative for infection. The condition marked **B** in the diagram is suspected. Which of the following best describes the pathophysiologic mechanism underlying this pulmonary complication?
A. Opportunistic fungal infection of distal alveoli with granulomatous inflammation and cavitation
B. Chemotherapy-induced direct epithelial toxicity affecting alveolar type II pneumocytes with subsequent fibrosis
C. Acute inflammatory infiltration of large airways with mucus plugging and reversible bronchospasm
D. Donor T-cell–mediated alloimmune attack on terminal bronchiole epithelium with concentric fibroproliferation causing irreversible airflow obstruction
Explanation
Why option 1 is correct
Bronchiolitis obliterans syndrome (BOS), the condition marked B, is the predominant late noninfectious pulmonary complication after allogeneic HSCT and is now classified as the pulmonary manifestation of chronic graft-versus-host disease (cGVHD). The pathophysiology is characterized by donor T-cells mounting an alloimmune attack specifically on the epithelium of terminal bronchioles, leading to concentric fibroproliferation (constrictive bronchiolitis) and irreversible airflow obstruction. This mechanism directly explains the patient's PFT findings (FEV1/FVC <0.7, FEV1 decline >10%) and imaging findings (mosaic attenuation and air trapping on expiratory HRCT), which reflect small airway obstruction while larger airways remain spared. The NIH 2014/2020 consensus criteria require demonstration of this pathophysiology through PFT and imaging findings in the absence of infection.
Why each distractor is wrong
Option 2 (acute inflammatory infiltration of large airways): This describes asthma exacerbation or acute bronchitis, not BOS. BOS specifically affects terminal bronchioles (small airways), not large airways, and the obstruction is irreversible fibroproliferation, not reversible bronchospasm. Large airways are characteristically spared in BOS, which is why chest imaging may appear misleadingly mild.
Option 3 (opportunistic fungal infection): This describes an infectious pulmonary complication, not BOS. The clinical vignette explicitly states that microbiologic workup including BAL is negative for infection, which is a mandatory criterion for BOS diagnosis. Fungal infections would present with cavitary lesions and granulomatous inflammation, not the mosaic attenuation pattern of small airway obstruction.
Option 4 (chemotherapy-induced epithelial toxicity): While chemotherapy can cause pulmonary toxicity, this mechanism does not explain BOS. BOS is specifically a manifestation of cGVHD driven by donor T-cell alloimmunity against recipient tissues, not direct drug toxicity. The timing (18 months post-HSCT) and clinical presentation (insidious dyspnea with normal auscultation) are classic for BOS, not acute chemotherapy toxicity.
High-YieldNEET PG
BOS is cGVHD of the lungs—donor T-cells attack terminal bronchioles (not large airways), causing irreversible constrictive bronchiolitis; diagnosis requires PFT evidence of airflow obstruction, imaging proof of small airway disease, and exclusion of infection. Symptoms appear late; routine PFT surveillance every 3 months post-HSCT is essential for early detection.
NIH cGVHD Consensus 2020; Blood 2018
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