Development Of Lung Toxicity Research Articles

Azacitidine induced lung injury: report and contemporary discussion on diagnosis and management.

Azacitidine, a hypomethylating agent, has caused a paradigm shift in the outcomes of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) who are not eligible for stem cell transplantation, particularly in combination with BCL2 and IDH inhibitors. Azacitidine and Azacitidine-based combinations have been widely considered a safe low-intensity therapy when compared to traditional conventional treatments. The development of lung toxicity from azacitidine is not a well-characterized adverse event. However, if it happens, it can be fatal, especially if not recognized and treated promptly. In this review, we aim to familiarize the reader with the presentation of azacitidine-induced lung injury, provide our suggested approach to management based on our experience and the current understanding of its mechanism, and review the literature of 20 case reports available on this topic.

Use of technetium-99m HMPAO scintigraphy for the detection of amiodarone lung toxicity in a rabbit model.

Amiodarone (AD) is a very effective anti-arrhythmic drug, but its use is often associated with serious pulmonary complications such as pneumonitis and interstitial pulmonary disease. The aim of this study was to investigate the relationship between the amount of amiodarone intake (and the related development of lung toxicity) and the lung uptake of technetium-99m labelled D,L-hexamethylpropylene amine oxime (HMPAO). Eighteen white female New Zealand rabbits were divided into three groups and fed AD by gavage at doses of 10 (group A), 50 (group B) or 150 (group C) mg/kg daily. 99mTc-HMPAO scintigraphy was performed at baseline and after 1, 2, 3 and 4 weeks of drug intake. Anterior images of 1 min duration were acquired at 30 min after the injection of 37 MBq 99mTc-HMPAO. Regions of interest (ROIs) were drawn on the lungs (L) and the upper limb (B) as the background. L/B ratios were calculated using the mean counts. In groups A and B histopathological evaluation of the lungs of all rabbits was performed at the end of the 4 weeks of AD intake, while in group C it was performed at 2 weeks because of increased mortality. At baseline, mean L/B ratios for groups A, B and C were 2.8 +/- 0.3, 2.8 +/- 0.3 and 2.8 +/- 0.4, respectively. After 3 weeks of AD intake, L/B ratios increased to 4.1 +/- 0.6 and 4.8 +/- 0.6 in groups A and B, respectively. The L/B ratio was 3.6 +/- 0.2 after 1 week of AD intake in group C. The correlation coefficients between the lung uptake of 99mTc-HMPAO and AD doses for groups A, B and C were r = 0.51 (P = 0.037), r = 0.74 (P = 0.0002) and r = 0.96 (P = 0.0001), respectively. Histopathological findings related to AD lung toxicity, such as interstitial pneumonitis and foamy alveolar macrophages, were observed more frequently in groups B and C than in group A. According to our findings, 99mTc-HMPAO lung uptake is correlated with AD dose. 99mTc-HMPAO lung imaging can demonstrate AD-induced lung injury.

Mechanisms of lung injury after bone marrow transplantation.

Dose-intensive chemotherapy combined with localized or total body irradiation (TBI) followed by autologous or allogeneic hematologic stem-cell transplantation is increasingly being used to treat a number of solid tissue and hematologic malignancies. In the case of some hematologic cancers (e.g., AML, ALL, CML, and CLL), which are refractory to conventional dose chemotherapy, several studies now report that allogeneic transplantation offers increased cure rates and increased long-term survival (1–3). Even patients with nonmalignant chronic conditions, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, sickle cell, and thalassemias (4–6), as well as those with autoimmune disorders (7, 8), are being considered for hematogenous stem-cell transplantation. At some centers, autologous stem-cell transplantation after high-dose chemotherapy is frequently performed for advanced stage and high-risk breast cancer (9). Despite the acclaim and promise of this emerging combined pharmacologic and immunologic technology, side effects remain one of the major limitations to its success. In some cases, those side effects can limit an individual’s future therapeutic options. In a majority of regimens, noninfectious forms of pulmonary toxicity ( see Table 1) (infectious pneumonias are not addressed in this perspective) all too often inflict unwanted complications, resulting in increased morbidity and mortality. The incidence of noninfectious pulmonary toxicity after bone marrow transplantation has been estimated to be 12 to 70%, and much depends on the specific patient population being analyzed, the details of their respective therapeutic regimen, and the criteria used to define lung toxicity. In 1991, the National Heart, Lung, and Blood Institute held a workshop to review clinical-pathologic features of idiopathic pneumonia syndrome (IPS), a severe form of lung toxicity seen in about 12% of allogeneic marrow transplant recipients (10). The diagnosis of IPS in this setting requires evidence of widespread alveolar injury, as well as an absence of an active lower respiratory tract infection. However, less severe forms of lung toxicity, not meeting this criteria, often occur after autologous transplant. For example, delayed pulmonary toxicity syndrome (DPTS) develops in up to 64% of patients who undergo high-dose chemotherapy and autologous bone marrow transplantation for advanced stage breast cancer, and DPTS is best diagnosed on the basis of reductions in serial D L CO measurements (11). What challenges a clinical investigator’s ability to dissect out important factors in the development of lung toxicity is the myriad of variables specifically assigned to an individual’s treatment regimen. Table 2 outlines a partial list of variables that are likely to play important roles in the pathogenesis of post–BMT lung toxicity (12, 13). Further limiting our understanding of the pathophysiology of lung toxicity has been the lack of animal models. Recently, however, several groups have begun characterizing mouse models of IPS that appear to mimic the human disease process. Shankar and colleagues (14) at the University of Kentucky have developed a mouse model of IPS that utilizes a semi-allogeneic parental → F1 transplant strategy after a conditioning regimen of TBI to induce a mild form of graft versus host disease (GVHD). Several features of this model appear particularly relevant to the human condition. First, these animals develop progressive lung injury over a 3to 12-wk period that is pathologically characterized by prominent perivascular and peribronchiolar inflammation with diffuse alveolar interstitial mononuclear cell inflammation. Second, the acute phase of this GVHD appears mediated by CD8 1 cells, whereas CD4 1 cells are associated with the chronic form of GVHD. Third, these animals develop mild, localized interstitial fibrosis at the later time points analyzed. What features are necessary for the development of lung disease in this model? Shankar and associates (15) begin to answer this question in this current issue, but in doing so, generate additional questions. First, the kinetics of pulmonary injury seen in this model are unique when compared with that of other tissues (including liver, ear, skin, colon, and tongue) in that the temporal progression develops relatively slowly over a 9to 25-wk time frame, whereas the other extrapulmonary target organs analyzed showed maximal GVHD within 3 wk posttransplant followed by resolution over the remaining time frame. Second, preconditioning irradiation was found to be necessary for the development of IPS on the basis of several observations. The degree of lung injury showed irradiation dose-dependency. Animals that were not pretreated with conditioning irradiation showed no lung injury, whereas ( Received in original form April 13, 1999 )

Bleomycin lung toxicity detected by technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy.

In this study we investigated bleomycin-induced pulmonary toxicity in patients with germ-cell tumour by means of technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy. Twenty untreated patients who had no clinical or radiological evidence of pulmonary disease received four courses of etoposide, cisplatin and bleomycin chemotherapy. Aerosol lung scintigraphy and pulmonary function tests were performed in all patients before bleomycin treatment and after administration of 180 and 360 mg bleomycin. On the basis of the scintigrams the percentage decline in activity per minute (Kep) was evaluated, which represented an accurate parameter of lung membrane permeability. Pretreatment Kep values (0.891 +/- 0.286) were significantly lower than those obtained following 180 and 360 mg bleomycin treatment (1.176 +/- 0.336 and 1.389 +/- 0.477, respectively; P < 0.0005). The Kep values obtained with 180 and 360 mg bleomycin treatments were also significantly different (P < 0.005). In contrast, no significant change was observed in the results of pulmonary function tests. Our results demonstrate that evaluation of the pulmonary clearance of 99mTc-DTPA represents a useful means of monitoring the functional status of the lung epithelial membrane during bleomycin treatment. Further prospective studies are needed to assess the relationship between increase in permeability and development of lung toxicity in order to decide which patients should discontinue bleomycin therapy.