D103-01 Luspatercept-Associated Intrapulmonary Shunting: A Novel Cause of Unexplained Hypoxemia in a Patient With Myelodysplastic Syndrome

Introduction Platypnea-orthodeoxia syndrome (POS) is caused by intra or extracardiac right to left shunting exacerbated by positional changes. In the absence of identified cardiac anatomic abnormalities, the differential diagnosis includes pulmonary vascular causes. Diffuse intrapulmonary micro-arteriovenous malformations (AVMs) can be due to hereditary hemorrhagic telangiectasia, hepatopulmonary syndrome, pulmonary hypertension, ARDS, and autoimmune or inflammatory conditions. In this case we report a suspected novel medication-associated cause of diffuse pulmonary micro-AVMs. Case A 72-year-old woman presented to urgent care with subacute dyspnea and new hypoxemia, with SpO2 88% on ambient air. Oxygen therapy up to 15 liters per minute (L/min) was initiated with improvement in her SpO2 to 95%. She denied chest pain, fever, or prior lung disease. Her past medical history included myelodysplastic syndrome (MDS), rheumatoid arthritis, GERD, osteoarthritis, hypertension, and diabetes mellitus. Exam revealed orthodeoxia. Chest radiograph and CT pulmonary angiography were unremarkable. Pulmonary function testing was normal. Right-heart catheterization revealed normal pressures. Transesophageal echocardiography with agitated saline showed delayed passage of bubbles into the left atrium from the superior pulmonary vein, suggestive of an intrapulmonary shunt. Technetium-99m macroaggregated albumin (Tc-99m MAA) scan demonstrated a 17% shunt fraction. Pulmonary angiography showed no discrete macroscopic arteriovenous malformations but did show early filling of lower-lobe pulmonary vein. PaO2 significantly improved during balloon occlusion testing, consistent with diffuse microvascular shunting. Luspatercept was considered as a likely culprit due to the temporal association with symptom onset and new cutaneous telangiectasia formation. Following discontinuation, the patient’s oxygen requirement decreased from 6-10 L/min to 2-3 L/min at rest. She was discharged on home oxygen. Discussion Luspatercept is an activin receptor ligand trap used to treat MDS through modulation of transforming growth factor-β (TGF-β) signaling, which regulates vascular remodeling and augments endothelial proliferation. There are no prior reported cases that associate its use with pulmonary AVMs. However, sotatercept (an analog) is known to induce telangiectasias and vascular remodeling in pulmonary arterial hypertension. This suggests that changes in endothelial homeostasis could in theory promote capillary dilation or microvascular changes, potentially leading to micro-AVMs and the development of intrapulmonary shunting. The temporal relationship between luspatercept use, development of symptoms and improvement after drug discontinuation supports a possible medication-related effect. While causality cannot be confirmed, this case underscores the importance of considering drug-induced right-to-left shunting. To our knowledge, this represents the first reported case of suspected luspatercept-associated diffuse intrapulmonary micro-AVMs and POS.