Abstract Introduction Pulmonary alveolar proteinosis (PAP) is a rare interstitial lung disease characterized by the abnormal accumulation of surfactant within alveoli, leading to impaired gas exchange and progressive respiratory insufficiency. PAP may occur in congenital, autoimmune, or secondary forms, the latter often associated with hematologic malignancies, infections, or exposure to certain drugs. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor widely used in myeloproliferative neoplasms, has been associated with immunomodulatory effects that can predispose patients to opportunistic infections and rare pulmonary toxicities. We present a rare case of ruxolitinib-associated pulmonary alveolar proteinosis, highlighting the importance of early recognition of drug-induced PAP and its distinction from infection or disease progression. Case Presentation A 39-year-old man with B-cell acute lymphoblastic leukemia status post allogeneic matched-unrelated donor hematopoietic stem cell transplant complicated by chronic cutaneous graft-versus-host disease and restrictive lung disease presented with acute hypoxemic respiratory failure. He developed multifactorial shock requiring intubation and vasopressor support. Chest CT showed diffuse bilateral ground-glass opacities. Treatment with pulse-dose corticosteroids and broad-spectrum antibiotics led to improvement and extubation. Five days later, he developed recurrent respiratory failure requiring re-intubation. Workup revealed coronavirus and Stenotrophomonas maltophilia pneumonia, and transbronchial biopsy demonstrated pulmonary alveolar proteinosis (PAP). Given concern for ruxolitinib-induced pulmonary toxicity, the drug was discontinued. Despite tracheostomy placement and two therapeutic lobar lavages, his respiratory status continued to decline. He was not an ECMO candidate owing to profound cytopenias. Following multidisciplinary discussions, care was transitioned to comfort measures, and he passed away shortly thereafter. Discussion Ruxolitinib, a selective JAK1/2 inhibitor used in graft-versus-host disease and myeloproliferative disorders, modulates cytokine signaling and impairs macrophage activation. This immune dysregulation may predispose to pulmonary alveolar proteinosis (PAP) through defective surfactant clearance. Although PAP is classically autoimmune or secondary to hematologic malignancy, ruxolitinib-associated PAP is exceedingly rare, with only a few cases reported. Recognition is challenging due to overlapping infectious and inflammatory etiologies in immunocompromised patients. Prompt discontinuation of ruxolitinib and supportive interventions such as whole-lung lavage are key, though outcomes remain poor in severe or progressive cases. Conclusion This case highlights ruxolitinib as a potential cause of secondary pulmonary alveolar proteinosis, emphasizing the need for clinicians to maintain a high index of suspicion for drug-induced lung injury in immunocompromised patients. Early recognition and discontinuation of the offending agent are essential to optimize outcomes and guide appropriate management. This abstract is funded by: none
Chug et al. (Fri,) studied this question.