A 38-year-old woman with Hodgkin lymphoma presents 6 months after completing ABVD chemotherapy (which includes doxorubicin, bleomycin, vinblastine, and dacarbazine) with progressive dyspnea and a dry cough. Chest X-ray shows bilateral interstitial infiltrates. Which investigation is most specific for confirming alkylating agent–induced pulmonary toxicity?

Explanation

## Investigation of Alkylating Agent–Induced Pulmonary Toxicity ### Clinical Context: Bleomycin and Pulmonary Toxicity in ABVD **Important clarification:** In the ABVD regimen, **bleomycin** (not dacarbazine) is the primary agent responsible for pulmonary toxicity, presenting 3–12 months after therapy with progressive dyspnea, dry cough, and bilateral interstitial infiltrates. Dacarbazine is an alkylating agent in ABVD, but bleomycin-induced pulmonary toxicity is the dominant concern in this regimen. The question asks about confirming alkylating agent–induced pulmonary toxicity in general. ### Why DLCO (Pulmonary Function Tests) is the Answer **Key Point:** **Pulmonary function tests with DLCO measurement** is the most sensitive and functionally specific investigation for confirming and quantifying chemotherapy-induced pulmonary toxicity — it is the gold standard for *functional* confirmation and monitoring. 1. **Earliest functional marker**: DLCO (diffusing capacity of the lungs for carbon monoxide) declines before symptoms or radiographic changes become apparent, reflecting alveolar-capillary membrane injury. 2. **Quantifies severity**: A decline in DLCO >15% from baseline is a recognized criterion for grade ≥2 pulmonary toxicity (per CTCAE criteria) and guides decisions about continuing chemotherapy or initiating corticosteroids. 3. **Specificity for parenchymal involvement**: DLCO reflects alveolar-capillary membrane integrity, distinguishing interstitial/alveolar disease from other causes of dyspnea (cardiac, obstructive airway disease). 4. **Serial monitoring**: DLCO tracks disease progression and treatment response better than static imaging. **SME Note — Sensitivity vs. Specificity:** DLCO is correctly described as the most *sensitive* functional marker for early detection of chemotherapy-induced pulmonary toxicity. Among the listed options, it provides the most clinically actionable and specific functional confirmation of parenchymal injury from alkylating agents, making it the investigation of choice in this context. ### Comparison of Investigations | Investigation | Role | Limitation | |---|---|---| | **DLCO (PFT)** | Functional confirmation, severity grading, monitoring | Requires baseline for comparison; not etiologically specific | | HRCT chest | Morphologic pattern (fibrosis, GGO), extent | Cannot distinguish drug toxicity from infection/other ILD without clinical context | | BAL with differential | Excludes infection/malignancy; shows lymphocytosis or eosinophilia | Non-specific; not diagnostic of drug toxicity alone | | CXR | Initial screening | Low sensitivity; late finding; non-specific | **Clinical Pearl (Harrison's Principles of Internal Medicine):** In chemotherapy-induced pulmonary toxicity, DLCO is the most sensitive functional test and should be measured at baseline and serially during therapy. A >15% decline from baseline is actionable and warrants treatment interruption or dose modification. **High-Yield:** For NEET PG/INI-CET — DLCO is the investigation of choice for monitoring and confirming chemotherapy-induced pulmonary toxicity. BAL is useful to exclude infection or malignancy but is not diagnostic of drug toxicity. HRCT shows morphologic changes but cannot confirm etiology alone.