Lipid-Laden Macrophages Are Not Diagnostic of Pulmonary Alveolar Proteinosis Syndrome and Can Indicate Lung Injury

To the Editor:

We read with interest the recent case report by Israel and colleagues that describes a young woman that presented with acute hypoxemia, bilateral pulmonary infiltrates, and a history of e-cigarette use (1). The authors concluded that this was a case of pulmonary alveolar proteinosis (PAP) secondary to vaping-associated lung injury on the basis of the radiological and cytological findings presented. The case presented is undoubtedly interesting, and the report raises several important topical issues, including the spectrum of e-cigarette– or vaping-associated lung injury (EVALI) and the utility of lipid-laden macrophages in BAL fluid. However, we have some remarks regarding this case and the suggested association between EVALI and PAP.

PAP is a rare syndrome characterized by progressive alveolar surfactant accumulation and hypoxemic respiratory failure and is categorized as primary, secondary, or congenital. Primary PAP accounts for the vast majority of cases and is caused by the disruption of GM-CSF (granulocyte–macrophage colony–stimulating factor) signaling, by GM-CSF autoantibodies (autoimmune PAP, accounting for 90% of cases), or by genetic mutations involving the GM-CSF receptor. Secondary PAP occurs in various conditions that cause altered function or a reduced number of alveolar macrophages resulting in abnormal surfactant clearance in the lung (2).

The case presented by Israel and colleagues is not entirely convincing for secondary PAP, and we believe it is more likely that either infection or EVALI was the principal issue for this patient. First, “crazy-paving” is not pathognomonic of PAP, and there are many other causes, including acute lung injury and lipoid pneumonia, both of which could be present as a result of EVALI in this case (3). Second, the presence of lipid-laden macrophages in BAL fluid is nonspecific, and although Oil-Red-O–positive cells are certainly a feature of PAP, they are present in many types of lung disease (4). Furthermore, the presence of periodic acid–Schiff–positive material again is not indicative of PAP alone and can be seen in a spectrum of pulmonary pathology (5). In this case, no biopsy was performed, and a label of secondary PAP was made on the basis of BAL and computed tomography findings. This is not the current best practice; indeed, all patients should have GM-CSF autoantibodies checked when PAP is suspected, and if there is no known secondary cause of PAP and GM-CSF signaling is intact, then a lung biopsy is needed to truly determine the presence of PAP syndrome (2). Finally, the rapid response to antibiotics and steroids, neither of which are effective therapies for primary or secondary PAP, go against this being a case of secondary PAP. Moreover, it would take several months for the alveolar macrophage pool to replenish/repair and export accumulated lipids, which is evidenced by the delayed response to inhaled GM-CSF seen in cases of autoimmune PAP (6). We conclude that this case more likely represents either infectious or inflammatory acute lung injury possibly related to EVALI, but the paucity of evidence cannot confirm secondary PAP.

Although we disagree that this is a case of secondary PAP, it highlights the importance of carefully interpreting the presence of lipid-laden macrophages in the lung. It has been demonstrated that in a mouse model of EVALI, there was altered surfactant phospholipid homeostasis and foamy macrophages but no evidence histologically of PAP lung disease (7). There have been numerous reports of Oil-Red-O macrophages in EVALI (8), but this likely represents lung injury resulting in abnormal surfactant production from type II pneumocytes or from altered macrophage function resulting in lipid accumulation. Hence, the interpretation of lipid-laden macrophages must be treated cautiously. With the increased recognition of EVALI as a novel pulmonary condition, there has been renewed focus on lipid-laden macrophages, but we conclude that foamy macrophages in EVALI likely indicate lung injury, and caution should be given to using this finding as a diagnostic marker (9).