We report here our experience of secondary pulmonary alveolar proteinosis (PAP) in patients with hematologic malignancies. The diagnosis of PAP was made by bronchoalveolar lavage (BAL) and based on the identification of periodic acid-Schiff-positive proteinaceous material with the characteristic ultrastructural pattern. Ten patients with leukemia and secondary PAP are described. Three patients had received bone marrow transplants. Data obtained from sequential BAL have shown that at least four of them--all of them achieving complete remission or recovery from neutropenia after bone marrow transplantation--had reversible PAP, and we emphasize this potential reversibility. Furthermore, in order to estimate the frequency of PAP in hematologic patients, we retrospectively studied 113 episodes of pneumonia occurring in our department over a 2-yr period. The incidence of secondary PAP in patients with pulmonary symptoms was so estimated at 5.3% among all the hematologic population, and to 10% in patients with myeloid disorders. This report (1) confirms that BAL is an accurate way to diagnose PAP in immunocompromised hosts, (2) emphasizes that PAP is not an unusual cause of respiratory failure in this population and that it is strongly associated with myeloid disorders, and (3) shows that secondary PAP is potentially reversible, especially if complete remission of the underlying disease is achieved.

To establish the diagnosis of alveolar hemorrhage (AH) in cells recovered by bronchoalveolar lavage (BAL), Golde and colleagues created a score based on the hemosiderin content of alveolar macrophages stained with Prussian blue. We used an easier method, calculating the percentage of siderophages among the total alveolar macrophages recovered by BAL. We have retrospectively studied this method in 240 BALs performed in 194 immunocompromised patients. Prussian blue staining was performed on each BAL sample, and the Golde score was calculated for 47 samples chosen at random. The methods were compared for diagnosing AH. The percentage of siderophages correlated well with the Golde score. AH was defined by at least 20% siderophages. This definition was validated by comparison with the method of Kahn and coworkers. AH was present in 87 (36%) of the samples and was significantly associated with four parameters: thrombocytopenia (< 50,000/mm3), other abnormal coagulation parameters, renal failure (creatinine > or = 2.5 mg/dl), and a history of heavy smoking. The diagnosis of AH did not correlate with either the cause or the outcome of pneumonia. AH was seen more frequently in cardiac transplant patients (75%). In our experience, (1) a percentage of siderophages > or = 20% is sufficient and is an easier determinant of the diagnosis of AH than the Golde score; and (2) AH is rarely the sole cause of lung injury and is usually associated with other causes of pneumonia. AH may be considered more as a sign than as a distinct disease in this population.

p53 gene mutations are strongly associated with a poor risk of both objective and major responses to chemotherapy. Contact mutations are associated with the lowest risk of major response to chemotherapy.

Endoplasmic Reticulum (ER) stress of alveolar epithelial cells (AECs) is recognized as a key event of cell dysfunction in pulmonary fibrosis (PF). However, the mechanisms leading to AECs ER stress and ensuing unfolded protein response (UPR) pathways in idiopathic PF (IPF) remain unclear. We hypothesized that alveolar hypoxic microenvironment would generate ER stress and AECs apoptosis through the hypoxia-inducible factor-1α (HIF-1α). Combining ex vivo, in vivo and in vitro experiments, we investigated the effects of hypoxia on the UPR pathways and ER stress-mediated apoptosis, and consecutively the mechanisms linking hypoxia, HIF-1α, UPR and apoptosis. HIF-1α and the pro-apoptotic ER stress marker C/EBP homologous protein (CHOP) were co-expressed in hyperplastic AECs from bleomycin-treated mice and IPF lungs, not in controls. Hypoxic exposure of rat lungs or primary rat AECs induced HIF-1α, CHOP and apoptosis markers expression. In primary AECs, hypoxia activated UPR pathways. Pharmacological ER stress inhibitors and pharmacological inhibition or silencing of HIF-1α both prevented hypoxia-induced upregulation of CHOP and apoptosis. Interestingly, overexpression of HIF-1α in normoxic AECs increased UPR pathways transcription factors activities, and CHOP expression. These results indicate that hypoxia and HIF-1α can trigger ER stress and CHOP-mediated apoptosis in AECs, suggesting their potential contribution to the development of IPF.