A 55-Year-Old Man With Cough and Hematochezia.

CASE PRESENTATION: A 55-year-old man presented to the ED with a 3-week history of worsening cough and shortness of breath. He had blood-tinged sputum, fever, night sweats, and a 2.7 kg weight loss within the same period. For the past few days, he had taken amoxicillin-clavulanate for presumed sinusitis. Despite this, his symptoms persisted, prompting him to seek further evaluation. His medical history was significant for ulcerative colitis and he had some bloody diarrhea for the past few weeks. Medications included aspirin, mesalamine, multivitamins, folic acid, and herbal supplements including gingko biloba, ginseng, and turmeric-ginger. He never smoked and drank alcohol occasionally. Family history was notable for stroke and myocardial infarction.

Acute Respiratory Obstruction due to Accidental Inhalation of Perlite: A Novel Mechanism for Upper Airway Occlusion with Cast Formation.

A 56-year-old man died following a fall resulting in complete submersion into a deep pit containing insulation material, expanded perlite. The most striking finding at autopsy was of impacted, moist pale yellow perlite that extended from the epiglottis into the main bronchi resulting in complete obstruction of the larger and smaller airways with cast formation. Perlite inhalation differs from inhalation of inert materials such as sand and wheat due to its hygroscopic properties and ability to expand forming an occlusive cast. Subsequent analyses of perlite from the worksite and within the airways indicated that hydration of perlite and adsorption of organic molecules into the perlite glass flakes had formed an interlocking, three-dimensional structure that was likely responsible for triggering a coagulation-flocculation process causing strong cohesion between the aggregates of glass flakes. This unique mechanism was likely responsible for the formation of the plug of perlite that obstructed the upper airway.

Intratracheal bleomycin causes airway remodeling and airflow obstruction in mice.

In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. The authors quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, the authors evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL (terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling) assay, and immunohistochemistry for transforming growth factor ß1 (TGFß1), TGFß2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post bleomycin. IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin-treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high-dose bleomycin. Increased TUNEL(+) bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFß1 and TGFß2 and accumulation of S100A4(+) fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, profibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling.

L-arginine attenuates acute lung injury after smoke inhalation and burn injury in sheep.

Thermal injury results in reduced plasma levels of arginine (Arg). With reduced Arg availability, NOS produces superoxide instead of NO. We hypothesized that Arg supplementation after burn and smoke inhalation (B + S) injury would attenuate the acute insult to the lungs and, thus, protect pulmonary function. Seventeen Suffolk ewes (n = 17) were randomly divided into three groups: (1) sham injury group (n = 6), (2) B + S injury plus saline treatment (n = 6), and (3) B + S injury plus L-ARG infusion at 57 mg.kg(-1).h(-1) (n = 5). Burn and smoke inhalation injury was induced by standardized procedures, including a 40% area full thickness flame burn combined with 48 breaths of smoke from burning cottons. All animals were immediately resuscitated by Ringer solution and supported by mechanical ventilation for 48 h, during which various variables of pulmonary function were monitored. The results demonstrated that Arg treatment attenuated the decline of plasma Arg concentration after B + S injury. A higher plasma Arg concentration was associated with a less decline in Pao2/Fio2 ratio and a reduced extent of airway obstruction after B + S injury. Histopathological examinations also indicated a remarkably reduced histopathological scores associated with B + S injury. Nitrotyrosine stain in lung tissue was positive after B + S injury, but was significantly reduced in the group with Arg. Therefore, L-Arg supplementation improved gas exchange and pulmonary function in ovine after B + S injury via its, at least in part, effect on reduction of oxidative stress through the peroxynitrite pathway.

The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model.

Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling. The cysteinyl leukotrienes (LTC(4), D(4) and E(4)) are known to play important roles in the pathobiology of asthma. To evaluate the effect of low dose montelukast (MK) on the development of airway remodeling using a chronic murine model of allergic airway inflammation with subepithelial fibrosis, BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on days 0 and 14, received intranasal OVA periodically on days 14-75. MK treated mice received montelukast sodium intraperitoneally on days 26-75. The OVA sensitized/challenged mice developed an extensive eosinophil cell inflammatory response, goblet cell hyperplasia, mucus occlusion, and smooth muscle hypertrophy of the airways. In addition, in OVA sensitized/challenged mice, dense collagen deposition/fibrosis was seen throughout the lung interstitium surrounding the airways, blood vessels, and alveolar septae. The cysteinyl leukotriene 1 (CysLT1) receptor antagonist, MK significantly reduced the airway eosinophil infiltration, goblet cell hyperplasia, mucus occlusion, and lung fibrosis except airway smooth muscle hypertrophy in the OVA sensitized/challenged mice. The OVA sensitized/challenged mice had significantly increased epithelial desquamation compared with control mice. MK markedly reduced epithelial desquamation of airways in OVA/MK treated animals compared with OVA sensitized/challenged mice. MK treatment did not affect the levels of CysLT in lung tissue. Our results show that the important role of cysteinyl leukotrienes in the pathogenesis of asthma. Lower dose of CysLT1 receptor antagonism has a significant anti-inflammatory effect on allergen-induced lung inflammation and fibrosis but not airway smooth muscle hypertrophy in an animal model of asthma.

Use of studded Polyflex stents in patients with neoplastic obstructions of the central airways.

BACKGROUND: The Polyflex is a commercially available silastic airway stent with proven efficacy. Due to a smooth outer surface its anchorage in the airway wall is superficial which may lead to stent migration. OBJECTIVE: To study the performance of an newer version of the Polyflex stent with a studded outer surface, which should improve anchorage. METHODS: In a 5-centre international study the new stent was prospectively tested in symptomatic patients with neoplastic central airway stenosis of more that 50% of normal diameter. Insertion technique, efficacy of stent placement and stent-related complications were recorded before, 1 month and 3 months post stent placement. RESULTS: Under general anaesthesia and rigid bronchoscopy 27 stents were inserted in 26 patients, mean age: 62 years (range: 37-83), 16 men. Diagnoses were 18 bronchogenic carcinoma, 4 oesophageal carcinoma, 2 metastases, 1 tracheal carcinoma, and 1 schwannoma. The stents were inserted in the following locations: 10 right main bronchus, 8 left main bronchus, 7 trachea, and 2 tracheo-bronchial. There was significant improvement in all functional parameters assessed from before (A), to 1 month (B) and 3 months (C) after stent placement. The measured values (mean +/- SD) were for the WHO scale: A: 2.7 (0.8), B: 1.5 (0.9), C: 1.6 (1.0); for the Karnofsky scale: A: 44 (19), B: 72 (18), C: 71 (21); for the Dyspnoea Index: A: 3.3 (0.7), B: 1.5 (0.8), C: 1.9 (1.2); for FEV(1): A: 1.2 (0.5), B: 1.9 (0.6), C: 1.5 (0.5), and for FVC: A: 2.1 (0.7), B: 2.8 (0.7), C: 2.5 (1.0). Stent-related complications were 4 reversible stent obstructions by secretions, 1 migration. The observation period was mean 4.3 months (range 2 days to 23 months). CONCLUSION: The studded Polyflex showed excellent efficacy, was very well tolerated, and had a very low migration rate. It presents an improvement over the older smooth model and can be considered a true alternative to the most widely used silastic stent, the Dumon stent.

Sputum cytological atypia as a predictor of incident lung cancer in a cohort of heavy smokers with airflow obstruction.

Individuals with cytological atypia in sputum may be at increased risk for lung cancer. We conducted a longitudinal analysis of the association between lung cancer incidence and cytological atypia in sputum samples collected prospectively from an ongoing cohort of adults at high risk for lung cancer. Cohort members had a smoking history of > or = 30 pack-years and chronic obstructive pulmonary disease documented by pulmonary airflow testing. Sputum samples collected at baseline and periodically thereafter were examined by standard cytological methods. From the cohort of 2,006 people, there were 83 incident lung cancers over 4,469 person-years of observation. At baseline, the association between personal and behavioral characteristics, and sputum cytological atypia was assessed by multiple logistic regression. The association between sputum cytological atypia and incident lung cancer was then assessed by hazard ratios using proportional hazards regression analysis, adjusting for potential confounding factors. Cytological atypia graded as moderate or worse was associated with continuing cigarette smoking (adjusted odds ratio, 2.5; 95% confidence interval, 1.5-4.1), and with lower levels of intake of fruits and vegetables (P for trend = 0.04). Atypia was not associated with several other factors, including the degree of airflow obstruction, the use of vitamin supplements, nonsteroidal anti-inflammatory drugs, or metered-dose steroid inhalers. Incident lung cancer was increased among those with moderate or worse cytological atypia (adjusted hazards ratio, 2.8; 95% confidence interval, 1.4-5.5). This association was not confounded by other risk factors. We conclude that in this high-risk cohort, cytological atypia is associated with continuing smoking and low intake of fruits and vegetables, but that independent of these and other factors, the risk of incident lung cancer is increased among those with moderate or worse grades of cytological atypia in their sputum.

Lesion formation in radiofrequency surgery of the tongue base.

OBJECTIVES: Temperature controlled radiofrequency volumetric tissue reduction (RFVTR) of the tongue base is a minimally invasive technique for the treatment of obstructive sleep apnea. But despite its widespread use, little is yet known about in vivo effects in humans. Such knowledge would be essential for evidence-based criteria in the selection of energy application. METHODS: In a preparatory in vitro study, porcine tongues were preserved in growing medium. Lesions with different amounts of energy were applied, and maximum diameters were assessed. In the in vivo study, 11 patients were treated with RFVTR at the tongue base by employing different energy levels (800, 600, 400, or 200 J) on two application sites. Magnetic resonance imagery scans were performed 4 to 6, 8 to 10, and 24 hours after surgery. An inversion recovery technique was used to visualize the lesions. RESULTS: RFVTR created lesions at the porcine tongue from 50 J and higher. Maximum lesion sizes were achieved with 400 J. In vivo, all the lesions were clearly visible in the postoperative scans. Lesion size increased with the amount of energy applied. Maximum diameters were created from 600 J and higher. Higher amounts of energy only resulted in a slight increase in lesion length. CONCLUSIONS: The application of 600 J at 85 degrees C leads to optimal lesion sizes. Higher amounts of energy will not lead to a relevant increase in tissue necrosis. With regard to the time needed for application, 600 J appears to be the ideal adjustment for energy delivery in the treatment of the human tongue.

Therapy-related café coronary deaths: two case reports of rare asphyxial deaths in patients under supervised care.

Café coronary deaths, as initially characterized, denote fatal occlusion of the upper airway by food substances. Such fatalities typically occur in individuals who either are clinically inebriated or have clinically significant neuromuscular dysfunction. Both conditions impair mastication and deglutition. The authors review the accidental deaths of two neurologically compromised patients under supervised care. Both subjects underwent complete medicolegal autopsy. In one case, ingestion of a prescribed emollient laxative precipitated death; in the other, death was attributable to aspiration of a contrast medium during a diagnostic radiographic procedure. These therapy-related deaths, which are regarded as a variation of the traditionally described café coronary fatalities summarized in the discussion, represent adverse events occurring during medical care. The adverse outcomes reviewed here are potentially avoidable and require special attentiveness by the clinicians directed to the particular condition of each patient. Such true aspiration-related deaths are confirmed on autopsy examination and are to be differentiated from the findings of agonal aspiration of gastric contents commonly encountered by the autopsy pathologist investigating deaths due to a great variety of natural and traumatic causes.

Mechanical airway obstruction caused by accidental aspiration of part of a ballpoint pen.

The authors present three cases of death in children aged 4, 9, and 10 years, respectively, that were first thought to be caused by herbal or other poisonings but at autopsy were found to be caused by airway obstruction from aspiration of ballpoint pen parts. Aspiration of a foreign body is a leading cause of accidental death in children, but the circumstances in these cases were unique. In the first case, a 4-year-old child died shortly after a visit to a traditional healer. The child's mother blamed him for the death and fatally assaulted him. The second case was a 9-year-old who died at school. Case 3 was a 10-year-old who collapsed while playing with a ballpoint pen in her mouth. In the latter two cases, the relatives alleged poisoning. At autopsy, there was no evidence of trauma, disease, or poisoning in all three cases. Ballpoint pen parts were present in the larynx, carina, and left main bronchus, respectively. Features of "asphyxial" death were present, and included subconjunctival hemorrhages, subendocardial hemorrhages, and congestion of the face and internal organs. These deaths are preventable by education of children, parents, and teachers. Ballpoint pen manufacturers should also modify the design of these pens to improve their safety.

7-Oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridines as novel inhibitors of human eosinophil phosphodiesterase.

High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).

The effect of of glucocorticoids on grain dust-induced airway disease.

STUDY OBJECTIVES: To determine the effect of glucocorticoids on grain dust-induced airflow obstruction and airway inflammation. DESIGN: Randomized controlled trial. SETTING: University hospital. PARTICIPANTS: Health volunteers. INTERVENTIONS: Two randomized, placebo-controlled trials, each studying 10 healthy volunteers who were pretreated with either triamcinolone acetonide (Azmacort) oral inhaler 4 puffs twice daily (800 microg daily) for 7 consecutive days or IV hydrocortisone (3 microg/kg/min) as a 14-h continuous infusion, then subjected to a controlled inhalation exposure to corn dust extract (CDE) (endotoxin exposure dose of 3 microg/kg). A single-blind, crossover study design was performed for each trial enrolling 10 healthy, lifetime nonsmokers, with no history of lung disease or environmental exposure to grain dust. MEASUREMENTS AND RESULTS: Following each inhalation exposure to CDE, spirometry was performed at regular intervals and BAL was performed at 4 h. Both treatment and placebo groups demonstrated significant decrements in spirometry and increments in BAL cellularity following CDE inhalation compared with placebo. Inhaled steroid treatment resulted in a significantly higher FEV1 only at the 2-h time point following CDE inhalation with no significant differences observed in the BAL total cell concentration or cellular differential compared with placebo. IV hydrocortisone treatment resulted in a significantly higher FEV1 and FVC between 2 and 4 h after CDE inhalation, as well as significant reductions in the BAL total cell, macrophage, and eosinophil concentrations. Interestingly, the concentration of tumor necrosis factor-alpha and interleukin-8 in the BAL fluid was also decreased following treatment with IV glucocorticoids. CONCLUSIONS: These results demonstrate that glucocorticoids, administered IV and perhaps by inhalation, have a mildly protective effect on airflow obstruction and airway inflammation induced by inhalation of grain dust.

Bronchial ligation enhances murine fetal lung development in whole-organ culture.

Evidence exists from both congenital anomalies and animal models that normal fetal lung development is dependent on maintenance of fluid pressure within the developing "airways." Fetal tracheostomy, allowing free egress of airway fluids, results in lung hypoplasia, indicating that some airway distending pressure is required for normal lung development to occur. In contrast, fetal tracheal ligation, which increases fetal airway pressure, reverses lung hypoplasia in animal models. The authors' experiments test the hypothesis that large airway obstruction accelerates the development of murine lungs in vitro in whole-organ culture. Fetuses from time-dated pregnant CD-1 mice at day 14 of gestation were removed (term, 20 days), and the lungs were excised. The left bronchus of each lung was ligated (n = 26), after which the left lung was isolated and cultured at 37 degrees C (95% air, 5% CO2) in BGJb media supplemented with vitamin C and antibiotics. Some fetal lungs were cultured under similar conditions without bronchial ligation (n = 11). After 7 days in culture, the lungs were taken for various analyses. The lungs were fixed in either formaldehyde and processed for paraffin embedding for light microscopic evaluation and morphometric data collection, or were freshly minced and aliquots taken for total protein and DNA content. Several more ligated and unligated lungs were processed for ultrastructural analysis. Morphometric analysis on transverse sections of lungs showed significant differences in the lung tissue size, thickness, epithelial cell height, luminal areas, perimeters, and total number of airspaces (airway + primordial alveolar airspaces). It was evident that bronchial ligation promoted lung development. The ligated lungs displayed thinning of the primordial alveolar walls with cuboidal epithelial cells. The total number of airspaces per field was lower for better developed ligated lungs because of the increased area of airspaces compared with that of the unligated lungs. The dorsoventral tissue thickness (in micrometers) of the ligated lungs was significantly greater than that of the unligated lungs (124.1 +/- 7.0 v 89.6 +/- 8.0); the average outer perimeter of the primordial alveolar airspaces was greater for ligated lungs (404.56 +/- 19.0 microns v 256.85 +/- 17.0 microns). Similarly, the luminal diameter of the spaces of ligated lungs was almost double that of the unligated lungs (38.0 +/- 2.0 microns v 20.3 +/- 2.0 microns), as was the luminal surface area. The morphometric data, which suggest enhanced maturation of the ligated lungs, are supported by results of ultrastructural studies. Ligated lungs had significantly more lamellar bodies. Although total protein and DNA content were greater among the ligated lungs, the protein/DNA ratios did not differ among the groups. The intraluminal pressure (airway pressure) of ligated lungs was 2.9 mm Hg and 3.1 mm Hg at 2 and 4 days in organ culture; the respective pressures for unligated lungs were 1.0 mm Hg and 0.8 mm Hg. These data support the hypothesis that mechanical distending pressure resulting from airway obstruction not only improves pulmonary architecture but also accelerates lung development in vitro. Although these effects have been seen in in vivo models, this is the first proposed in vitro organ culture model. This model may prove to be a powerful tool for the study of molecular mechanisms of mammalian lung development with respect to mechanical and chemical (cytokines, hormones) stimuli.

Tracheobronchial obstruction due to silicosis.

Broncholithiasis can result in airway obstruction through the erosion of calcified lymph nodes into the bronchial lumen or by extrinsic compression of the tracheobronchial tree. We report an unusual case of broncholithiasis in a patient with silicosis who developed airway obstruction from endobronchial polypoid masses of granulation tissue adjacent to calcified mediastinal lymph nodes. The production of granulation tissue may have been the result of broncholiths in the early stages of erosion into the tracheobronchial tree. Efforts to ablate the endobronchial polyps using YAG laser phototherapy were only temporarily successful and surgical removal of the calcified mediastinal lymph nodes was required to halt further polyp growth. Surgical specimens grew Mycobacterium avium-intracellulare (MAI), a common pathogen in patients with silicosis. MAI may have contributed to the local inflammatory milieu provoking the exuberant tissue response.

Quartz but not iron oxide causes air-flow obstruction, emphysema, and small airways lesions in the rat.

Recent epidemiologic studies have suggested that some workers exposed to inorganic dusts develop air-flow obstruction independent of or greater than that produced by cigarette smoke; the morphologic basis of this effect is unknown. To investigate this problem, we administered saline alone, 10 mg iron oxide (an inert dust), or 10 or 30 mg of quartz to rats by intratracheal instillation. Animals were killed after 30 days, and pulmonary function and morphologic changes were examined. The iron oxide group was similar to the saline control group in all functional and morphometric parameters. However, both quartz-exposed groups showed evidence of air-flow obstruction, with more severe abnormalities in the high dose group. These findings correlated with morphometric observations of emphysema and thickened airway walls, with changes again more severe in the high dose group. Early silicotic nodules were also present in the latter animals. We conclude that in addition to the classic lesions of nodular silicosis, quartz can produce morphologic and functional changes of air-flow obstruction; no such changes are seen with iron oxide. These observations may explain the air-flow obstruction seen in workers exposed to mineral dusts.

The development of a new agent for the treatment of inflammatory/allergic conditions.

The search for new drugs for the treatment of reversible obstructive airways disease has been a major pursuit of the pharmaceutical industry for almost two decades. Little progress has been achieved. The acceptance that asthma is a multi-facetted disease state has led to the development of a new complex in vivo screen in the macaque monkey. This model is mediated through mast cells which stain positively with alcian blue/safranin. A new therapeutic agent, nedocromil sodium, was significantly more active than sodium cromoglycate in this primate model of airway disease. Extensive clinical trials have shown that this new agent is effective in the treatment of the reversible component of obstructive airways disease.

Resection of obstructing inferior nasal turbinates.

We report a series of 88 patients in whom 119 obstructing inferior nasal turbinates were resected for airway obstruction, and who have been followed for 3 months to 3 years. The airways were consistently improved and, to date, there have been no undesirable sequelae.