Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034063 (pulmonary edema)
 10,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive immunotherapy with interleukin-2 (IL-2) is associated with a generalized vascular leak syndrome. Pulmonary edema is a common occurrence and is rarely responsible for acute respiratory failure requiring assisted ventilation. The authors have performed a retrospective review of chest radiographs in 19 patients undergoing the priming course of high-dose IL-2 therapy for metastatic melanoma and renal cell carcinoma. This study was primarily designed to evaluate the prevalence and patterns of pulmonary edema and pleural effusions. During the first 5 days of therapy, alveolar edema was identified in 21% (n = 4) and signs of interstitial edema in 53% (n = 10) of patients. Pleural effusions were seen in 42% (n = 8). No patient in this series required assisted ventilation during this period. However, two patients subsequently developed fatal, drug-related myocardial injury. IL-2 toxicity is a well established cause of self-limited, increased-permeability pulmonary edema.
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PMID:Vascular leak syndrome associated with interleukin-2: chest radiographic manifestations. 235 90

To evaluate the radiographic manifestations of the response of intrathoracic metastases to and the toxicity of interleukin-2 (IL-2) therapy, the chest radiographs and computed tomographic scans of 43 patients receiving 103 cycles of IL-2 treatment and lymphokine-activated killer cells for advanced renal cell carcinoma were reviewed. Among these 43 patients, 31 could be assessed for response of metastatic disease: Complete response was seen in one (3%), partial response in 11 (36%), mixed response in nine (29%), progressive disease in five (16%), and stable disease in five (16%). In 103 treatment cycles radiographic evidence of toxicity included pleural effusions (45.6%), pulmonary edema (21.4%), increased cardiothoracic ratio (16.5%), increased azygos vein diameter (9.7%), pericardial effusion (5.8%), and hilar lymphadenopathy (1.0%). These toxic effects could be distinguished from metastatic disease by a temporal relationship to treatment cycles. A favorable response to IL-2 therapy was significantly correlated (P less than .001) with the presence of pleural effusions.
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PMID:Interleukin-2 therapy for advanced renal cell carcinoma: radiographic evaluation of response and complications. 239 11

The administration of interleukin-2 (IL-2) and lymphokine activated killer (LAK) cells to patients with advanced metastatic cancer has yielded encouraging results. The purported ability of LAK cells to be discriminatively tumoricidal, thus sparing normal host tissue, represents a major advance over conventional chemotherapy. However, IL-2 adoptive immunotherapy results in dose-limiting toxicity characterized by weight gain, dyspnea, ascites, and peripheral-pulmonary edema suggestive of a vascular leak syndrome. It is unclear whether the observed toxicity is directly related to IL-2 and/or LAK cells. The authors examined the cytolytic nature of human LAK cells against human endothelial, epithelial, and fibroblast cell lines. Bovine endothelial cells also were studied. Using a 51Cr release assay, the cytolytic potential, time course, and effect of reactive oxygen intermediate inhibitors were studied. LAK cells were uniformly toxic against all cell lines, in contrast to high dose rIL-2 and excipient. Significant cytolysis was observed within 30 minutes and increased over the first 2 hours of LAK cells coming in contact with target cells. Reactive oxygen intermediate inhibitors did not reduce cytolytic activity. The authors thus found human LAK cells to be rapidly cytolytic against a variety of human and bovine cell lines. This cytolysis was independent of reactive oxygen intermediates.
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PMID:Nonspecific cytotoxicity of recombinant interleukin-2 activated lymphocytes. 266 84

Eight patients underwent IV bolus therapy with recombinant interleukin-2 (Cetus Corporation, Emeryville, CA) for treatment of metastatic melanoma or renal cell carcinoma. The patients were randomized to receive interleukin-2 alone or interleukin-2 in combination with lymphokine-activated killer cells. Radiographs showed pulmonary edema in five of the eight patients. The changes ranged from mild interstitial edema (two patients) to frank pulmonary edema (three patients). The edema generally resolved within 4 days after the termination of therapy (four patients), however, one patient developed edema and arrhythmias approximately 7 days after interleukin-2 therapy ended. Seven of the eight patients had either cardiac arrythmias or angina. The mechanisms that contribute to the pathogenesis of these cardiac complications with interleukin-2 therapy remain unclear. The development of pulmonary edema is thought to be caused by capillary leakage and cardiac pulmonary edema due to cardiac toxicity of the drug. The radiologic appearances of these types of pulmonary edema were indistinguishable from one another and from other causes of pulmonary edema. Our study shows that interleukin-2 can cause pulmonary edema, cardiac arrhythmias, and unstable angina. The severity of these conditions is unrelated to dose.
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PMID:Pulmonary edema as a complication of interleukin-2 therapy. 278 57

Adoptive immunotherapy, the administration of interleukin-2 (IL-2) and interleukin-2 activated cells, leads to tumor regression in some patients with advanced cancer. Although this new therapeutic modality offers hope for the future, at present, a multitude of toxicities limit the total dose and duration of therapy. Among the toxic side effects a purported third space or vascular leak syndrome is the most serious. In this review, we detail the evidence for a third space syndrome (peripheral edema, ascites, oliguria, elevated serum creatinine levels) and cardiopulmonary dysfunction (hypotension, respiratory distress, pulmonary edema, hypoxemia) with adoptive immunotherapy in human and animal studies. We conclude that IL-2 administration is associated with increased pulmonary microvascular permeability, infiltration of the lung parenchyma with large esterase negative lymphoid cells, hypoxemia, systemic hypotension, positive fluid balance and, in animals, transient pulmonary hypertension. These abnormalities do not seem to be caused by IL-2 directly; the causes may be mediated by IL-2 activated lymphocytes or other IL-2 activated cellular mediators.
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PMID:Cardiopulmonary toxicity of adoptive immunotherapy. 306 15

A new approach to cancer treatment has been developed based on the adoptive transfer of activated lymphocytes into cancer patients. Lymphocytes harvested from patients by leukapheresis are converted into lymphokine-activated killer (LAK) cells by incubation with recombinant interleukin-2 (rIL-2). These LAK cells are then infused back into the patients in combination with intravenous IL-2. Among 25 patients treated with this form of adoptive immunotherapy there were 11 patients with measurable tumor reductions, including 1 complete responder. The majority of responses occurred in patients with metastatic renal cell carcinoma, melanoma and colorectal carcinoma. The toxicities of IL-2, including fluid retention and pulmonary edema, limit therapy, and laboratory investigation is now aimed toward understanding the mechanism of IL-2 toxicity. The use of LAK cells and IL-2 in cancer therapy is still in a developmental stage and needs to be refined before its role can be definitely established.
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PMID:Therapy of cancer using the adoptive transfer of activated killer cells and interleukin-2. 312 51

Human recombinant interleukin-2 (rIL-2) was administered to normal and tumor-bearing BDF mice for 1 to 3 weeks, and the hematologic, clinical chemistry, gross and histopathologic findings were evaluated. Vascular leak syndrome (pulmonary edema, pleural effusion, ascites), hepatocyte necrosis, elevated hepatic serum transaminases, hypoalbuminemia, tissue and peripheral eosinophilia, thrombocytopenia, and prerenal azotemia were the detrimental effects of rIL-2 treatment. Vascular leak syndrome and hepatocyte necrosis were causally associated with vascular-oriented lymphocytic infiltration of pulmonary and hepatic parenchyma. Pleural effusions contained up to 99,000 cells/mm3, most of which were large granular lymphocytes. Antiserum to the glycolipid asialo GM1 (ganglio-n-tetrosylceramide), given simultaneously with rIL-2, prevented overt toxicity of rIL-2 (mortality, vascular leak syndrome, and hepatic damage) and substantially reduced infiltration of pulmonary and hepatic vasculature by asialo GM1+ lymphocytes. Asialo GM1 antiserum did not inhibit lymphoid hyperplasia, tissue infiltration by Lyt 2+ lymphocytes, tissue and peripheral eosinophilia, or thrombocytopenia in rIL-2 treated mice. Additionally, asialo GM1 antisera prevented toxicity, but not anti-tumor efficacy, of high dose rIL-2 therapy in BDF mice bearing the colon 38 adenocarcinoma. These results suggest that, in BDF mice and with this tumor model, vascular leak syndrome and hepatocyte necrosis are mediated by an endogenous subset of rIL-2-stimulated lymphocytes which are asialo GM positive, that mechanisms of toxicity and efficacy associated with high dose rIL-2 therapy are not necessarily the same, and that these mechanisms can be therapeutically separated.
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PMID:Toxicity of human recombinant interleukin-2 in the mouse is mediated by interleukin-activated lymphocytes. Separation of efficacy and toxicity by selective lymphocyte subset depletion. 326 43

Systemic administration of recombinant interleukin-2 (rIL-2) has been shown to be promising against certain metastatic cancers. However, major side effects, such as pulmonary edema, have limited its widespread use. Although this pulmonary edema has been attributed to a vascular leak syndrome, this hypothesis has not been verified in humans. The purpose of our study was to determine both the severity and mechanism of pulmonary edema in seven patients treated with rIL-2. The severity of edema was assessed by daily evaluation of chest radiographs, using a semiquantitative scale, as well as by repeated measurements of the alveolar-to-arterial oxygen gradient (A-aDO2) in each patient. To determine the mechanism of pulmonary edema, we serially measured in each patient the lung clearance of technetium 99m-diethylenetriamine pentaacetic acid (DTPA) 99mTc-DTPA), the plasma levels of Von Willebrand factor antigen, and the pulmonary capillary wedge pressure (PCWP). Our results show that there was a gradual increase in the chest radiography edema score that was paralleled by a significant increase in A-aDO2 over its baseline value. During rIL-2 treatment, 99mTc-DTPA clearance was augmented, and the plasma concentration of Von Willebrand factor antigen was elevated. PCWP climbed from 7 to 14 mm Hg and serum total protein fell from 66.1 to 42.1 gm/L. The results obtained indicate that although pulmonary edema associated with rIL-2 treatment is partially dependent on increased permeability of the lung, changes in hydrostatic and oncotic forces may be the principal determinants of edema development.
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PMID:Pulmonary edema during IL-2 therapy: combined effect of increased permeability and hydrostatic pressure. 759 42

Administration of interleukin-2 (IL-2) leads to pulmonary vascular leak. This form of pulmonary edema has previously been postulated to be due to the in vivo induction of tumor necrosis factor-alpha (TNF-alpha). To determine whether TNF-alpha plays a role in IL-2-induced pulmonary vascular leak, we performed in situ hybridization of lung sections and reverse transcriptase-polymerase chain reaction of bronchoalveolar lavage macrophages from IL-2-challenged mice. The results confirm an in situ upregulation of TNF-alpha mRNA expression in the lungs associated with vascular leak. In addition, a significant increase in TNF-alpha protein production was found in the lung following IL-2 administration, as measured by TNF-alpha-specific ELISA of lung supernatants (P = 0.028). Intravenous administration of a soluble TNF receptor significantly diminished IL-2-induced pulmonary vascular leak (P = 0.006). These findings confirm a central role for TNF-alpha in mediating the pulmonary vascular leak associated with IL-2 toxicity.
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PMID:Tumor necrosis factor-alpha plays a central role in interleukin-2-induced pulmonary vascular leak and lymphocyte accumulation. 803 44

Pulmonary edema and sepsis-like syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 minutes) at 10(6) U per rat (n = 4) elevated lung water content (37 +/- 6%, P < .05), myeloperoxidase activity (162 +/- 49%, P < .05), and serum thromboxane B2 (30 +/- 1 pg/100 microL, P < .01) and had no effect on serum tumor necrosis factor-alpha sCR-1 at 30 mg/kg (n = 5), but not at 10 mg/kg (n = 6), attenuated the elevation of lung water content (18 +/- 2%, P < .05) and myeloperoxidase activity (42 +/- 9%, P < .05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy.
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PMID:Interleukin-2-induced lung injury. The role of complement. 829 71


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