Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three cases.

The clinical radiologic, and pathologic features of three patients with a combination of pulmonary lymphocytic infiltration and amyloid deposition are presented. We report the distinctive high-resolution computed tomography features that are common to these cases.

Reversibility of the allergen-provoked late asthmatic response by an inhaled beta 2-adrenoceptor agonist.

There is uncertainty about the relative contributions of bronchial smooth muscle contraction, mucosal oedema and mucus plugging to airflow obstruction in the allergen-induced late asthmatic response (LAR). We systematically studied the ability of the inhaled beta 2-agonist salbutamol to reverse the LAR in eight subjects after allergen bronchoprovocation. Salbutamol reversed the LAR by restoring FEV1 to a level similar to the initial value measured at the same time of day (18.00 h) on the previous evening. For the eight subjects studied, this initial FEV1 value, measured after abstaining from beta-agonists for 8 h, was a mean +/- SEM 90.7 +/- 5.6% of predicted, which suggests further bronchodilation may have been possible at this time. We then studied six of the eight subjects in an identical protocol with saline challenge substituted for allergen bronchoprovocation to answer the question whether further bronchodilation was possible at that time after salbutamol in the absence of an LAR. After salbutamol on the allergen challenge day the FEV1 for the six subjects was 84.1 +/- 7.0% of predicted, compared with 94.0 +/- 3.7% of predicted at the same point on the saline challenge day (P < 0.05). We conclude that, although the LAR may be effectively reversed by beta 2-agonists, there is evidence for some residual airway narrowing, presumably related to mucosal oedema, exudate and mucus plugging.

Hemoptysis: comparative study of the role of CT and fiberoptic bronchoscopy.

PURPOSE: A prospective study was performed to compare results of computed tomography (CT) and fiberoptic bronchoscopy in diagnosis of cancer in patients with hemoptysis. MATERIALS AND METHODS: Ninety-one patients (64 men, 27 women) with hemoptysis underwent thin-section CT and fiberoptic bronchoscopy. RESULTS: CT scans demonstrated all 27 tumors seen at bronchoscopy and an additional seven, five of which were beyond bronchoscopic range. In patients with normal chest radiographs, bronchial carcinoma was detected in 5% at both bronchoscopy and CT. In patients with abnormal findings on radiographs, bronchoscopy allowed both location and histologic diagnosis in 78% of carcinomas but was unreliable in locating peripheral tumors demonstrated at CT. CT was insensitive in demonstrating early mucosal abnormalities, bronchitis, squamous metaplasia, and a benign papilloma, all detected at bronchoscopy. CONCLUSION: The initial examination should be bronchoscopy when there is high clinical suspicion of carcinoma and relevant radiographic abnormality, and CT when strong clinical suspicion of carcinoma is not substantiated at bronchoscopy in patients with normal findings on chest radiographs.

Does baseline airway caliber affect measurements of airway responsiveness to histamine.

Considerable controversy exists over the influence of baseline airway caliber on indexes of bronchial responsiveness in asthma. To directly investigate this, we used inhaled methacholine to alter baseline airway caliber to determine whether this altered the airway response to subsequent bronchoprovocation with inhaled histamine. Seventeen stable asthmatic subjects were studied; their median age was 22 yr, baseline forced expiratory volume in 1 s (FEV1) was 101.5 +/- 3.7% (SE) predicted, and geometric mean provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) was 0.87 mg/ml. Initially the time course of bronchoconstriction to inhaled methacholine was determined. Subsequently the airway response to inhaled histamine administered as a single concentration was determined, both before and after reductions in baseline FEV1 by saline or methacholine of 0, 15, 25, and 35%, on 4 separate days. Altering baseline airway caliber had no effect on the subsequent response of the airways to inhaled histamine when calculated as percent fall from the new baseline. The power of the study to detect an effect of altering baseline FEV1 on the measured PC20 histamine of 0.5 doubling dilutions was > 55%, and the power to detect an effect of 1.0 doubling dilutions was > 98%.

Albuterol and nedocromil sodium affect airway and leukocyte responses to allergen.

We investigated the effects of inhaled nedocromil sodium and albuterol administered prior to allergen challenge in the late asthmatic response (LAR) and circulating cells in a double-blind placebo-controlled study. An additional control day (no allergen) was included to determine diurnal variation. On the control day no change in airway caliber occurred, but a diurnal increase in the numbers of all circulating leukocytes except basophils was seen. Placebo premedication followed by allergen challenge caused both an early asthmatic response (EAR) and a late asthmatic response (LAR). Following allergen challenge after placebo the diurnal increase in eosinophils at 8 h was abolished, and elevated eosinophil and basophil counts were observed at 24 h. Nedocromil sodium attenuated both the EAR and the LAR, and it restored the eosinophil and basophil responses toward normal. Albuterol abolished the EAR and attenuated the LAR and the 24-h increase in circulating basophils. No changes in lymphocyte subpopulations were seen. We conclude that during the LAR there is entrainment of eosinophils within the lung, with a subsequent bone marrow response increasing peripheral populations of eosinophils and basophils. Nedocromil sodium may act by inhibiting the recruitment of inflammatory cells, particularly eosinophils, possibly by affecting the generation of cytokines and the expression of leukocyte-specific adhesion molecules. Albuterol may have similar actions as shown by an effect on basophils.

The effect of H1-receptor blockade on the development of early- and late-phase bronchoconstriction and increased bronchial responsiveness in allergen-induced asthma.

BACKGROUND: Allergen challenge of subjects with asthma produces an early asthmatic response, late asthmatic response, and increases bronchial responsiveness. Histamine partly mediates the early asthmatic response, and may play a role in late-phase responses. Azelastine has antiallergic properties and has been proposed as a treatment for asthma. We therefore investigated the contribution of histamine to late-phase responses with the use of the potent H1-receptor antagonist azelastine. METHODS: Ten subjects with atopic asthma were studied in a double-blind, randomized, placebo-controlled trial. Azelastine was administered over 4 days before allergen challenge. Changes in airway caliber were followed with measurements of forced expiratory volume in 1 second, and changes in bronchial responsiveness were followed by methacholine and prostaglandin D2 bronchial provocation tests. RESULTS: Azelastine significantly inhibited the development of the early asthmatic response. Azelastine had no effect on the late asthmatic response or on the development of allergen-induced increases in bronchial responsiveness. The power of the study was sufficient to have had a high probability of detecting any important differences between placebo and azelastine during the late phase. CONCLUSIONS: Azelastine had no significant effect on the late-phase response model of asthma. This study does not support the hypothesis that histamine is an important mediator of the late asthmatic response or allergen-induced increases in bronchial responsiveness.

The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma.

It is widely held that inhaled beta 2-adrenoceptor agonists inhibit the early asthmatic response (EAR) but not the late response (LAR) or attendant increase in bronchial responsiveness. In this study of 10 atopic asthmatic subjects, we have investigated the effects of a high dose of nebulized albuterol (2.5 mg) on the allergen-provoked EAR, LAR, and increase in histamine responsiveness. In a randomized blinded fashion, study subjects inhaled the following combinations: albuterol followed 10 min later by allergen, placebo followed by allergen, albuterol followed by saline (albuterol, placebo, and control study periods, respectively). Airway caliber was measured as FEV1 and followed at regular intervals for 7.5 h postallergen. Bronchial responsiveness to histamine was measured and recorded as the PC20 value before and at 1.5, 3.5, 5.5, and 7.5 h after allergen or control challenge. During the placebo study period, allergen challenge caused mean 29.6 +/- 6.4 and 24.4 +/- 6.4% falls in FEV1 at 20 min and 7.5 h, respectively (both p less than 0.05), and a progressive decrease in PC20 amounting to a geometric mean of 1.9 doubling dilutions at 7.5 h (p less than 0.05). Albuterol followed by allergen resulted in a 13.1 +/- 2.2% increase in FEV1 prior to allergen followed by abolition of the EAR and inhibition of the LAR with only a 9.2 +/- 3.5% fall in FEV1 at 7.5 h, significantly different from that of placebo at 7.5 h (p = 0.048). Similarly, PC20 histamine fell by only 0.64 doubling dilutions at 7.5 h, not significantly different from baseline values but different from placebo values (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma.

Previous work suggests a role for mast cell derived mediators in exercise induced asthma. The contribution of newly generated contractile prostaglandins to exercise induced asthma was assessed by using a potent and orally active thromboxane (TP1) receptor antagonist, GR32191. The effect of 120 mg GR32191 on exercise induced asthma was observed in 12 asthmatic subjects. For the exercise challenge the subjects performed six minutes of treadmill exercise, breathing dry air at a work load that had previously been shown to induce a fall in FEV1 of 25% or more from the pre-exercise baseline. No effect of GR32191 on pre-exercise baseline airway calibre was evident. There was no significant difference in the mean maximum percentage fall in FEV1 from baseline after exercise between drug and placebo (placebo 30.2%, GR32191 day 31.6%). It is concluded that the thromboxane antagonist GR32191 has no effect on exercise induced asthma. This suggests that prostaglandins, including PGD2, that act via the thromboxane receptor do not have an important role in exercise induced asthma.

Protection against allergen-induced asthma by salmeterol.

The effects of the long-acting beta 2-agonist salmeterol on early and late phase airways events provoked by inhaled allergen were assessed in a group of atopic asthmatic patients. In a placebo-controlled study, salmeterol 50 micrograms inhaled before allergen challenge ablated both the early and late phase of allergen-induced bronchoconstriction over a 34 h time period. Salmeterol also completely inhibited the allergen-induced rise in non-specific bronchial responsiveness over the same time period. These effects were shown to be unrelated to prolonged bronchodilatation or functional antagonism. These data suggest novel actions for topically active long-acting beta 2-agonists in asthma that extend beyond their protective action on airways smooth muscle.

Mucosal inflammation in asthma.

Over the past decade, it has become increasingly recognized that airways inflammation is one of the major components of asthma. Until recently, measurements of bronchial responsiveness and mediators of allergic reactions were the only methods of studying pathogenetic mechanisms in asthma. With improved diagnostic procedures such as fiberoptic bronchoscopy, it has become possible to investigate these mechanisms and the resulting inflammatory changes in situ. BAL has highlighted the presence of mast cells and eosinophils and has given proof of their mediator participation in airways inflammation and hyperresponsiveness. Endobronchial biopsies have so far yielded results that are similar to those obtained from postmortem studies, although it appears that there are varying degrees of inflammation in living asthmatics. Even in mild disease, the histopathologic features of bronchial asthma are consistent with chronic inflammation. Indirect evidence obtained from allergen challenge leading to increased bronchial hyperresponsiveness during LAR, and direct evidence of inflammatory cells and their mediators in the airway mucosa and lumen after allergen challenge argue for an active role of cells in bringing about inflammatory changes. At present, however, it is not possible to relate precisely the findings obtained by bronchoscopy to the clinical presentation and progression of asthma. Cell activation with production of potent mediators of inflammation may be more relevant to inflammation than the simple presence of these cells in the airways. Almost all the inflammatory cells present in the bronchial wall and lumen have been implicated in the pathogenesis of mucosal inflammation in asthma, but with our current state of knowledge, none can be singled out as the most important contributor. The mast cell was the first to be investigated in depth, and despite the accumulation of large amounts of data concerning its ultrastructure and function, it remains uncertain to what extent this cell is involved in inflammatory responses. Thus, while its main role appears to be that of initiator of allergen-induced responses, the eosinophil has attracted more attention as a proinflammatory cell rather than as an antiinflammatory cell with a capacity to be selectively recruited from the circulation in response to IgE-dependent signals. The eosinophil secretes potent mediators that cause damage to the bronchial epithelium and lead to bronchoconstriction. The role of other cells is at present not as well defined.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of an increase in inhaled allergen dose after rimiterol hydrobromide on the occurrence and magnitude of the late asthmatic response and the associated change in nonspecific bronchial responsiveness.

We have used a short-acting beta 2-adrenoceptor agonist, rimiterol hydrobromide, to allow a larger dose of allergen to be administered to previous single "early allergen responders" to investigate if an increased dose of allergen could induce a late asthmatic response (LAR) and whether this would influence the subsequent level of allergen-acquired nonspecific bronchial hyperresponsiveness. Pretreatment with inhaled rimiterol hydrobromide 400 microgram enabled an increase in allergen dose inhaled by a geometric mean of 8.9-fold (range, 2 to 29.1) in eight atopic subjects with mild asthma who initially were classified as single early responders with a maximal fall in FEV 3 to 8 h after allergen challenge (Lmax) of less than 15% from baseline value. The magnitude of the early asthmatic response was similar to that obtained on the control day when allergen challenge was performed in the absence of rimiterol hydrobromide. Five subjects were converted to dual allergen responders with Lmax of greater than 15% from premedication baseline value. For the whole group, there was a significant increase in the magnitude of LAR whether calculated as Lmax (p less than 0.05) or as area under the FEV1 time response curve between 3 and 8 h postchallenge (p less than 0.01). The provocation concentrations of methacholine causing a 20% fall in FEV1 (PC20) at 8 h postchallenge were significantly reduced on both days when compared with the corresponding prechallenge values (p less than 0.05 on control day, p less than 0.01 on rimiterol day). However, despite the increase in the magnitude of LAR on the rimiterol day, the reduction in postchallenge PC20 did not differ significantly from that occurring on the control day.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary and secondary effector cells in the pathogenesis of bronchial asthma.

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H1-receptor antagonists such as terfenadine and astemizole. Additional inhibition (approximately 30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D2. In man, PGD2 is selectively metabolised to 9 alpha 11 beta-PGF2, a unique prostaglandin which shares with PGD2 contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 micrograms) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of beta-adrenergic blockade on respiratory and metabolic responses to exercise.

The responses to oral propranolol (80 mg) and placebo were compared in normal subjects during three studies on a cycle ergometer (progressive exercise and two 5-min constant work rate studies at 50 and 70% maximum). Heart rate (HR), ventilation (VE), CO2 output (VCO2) and O2 uptake (VO2) were measured in each study and metabolites in venous blood in the 70% study. Propranolol reduced HR in all studies and endurance time during progressive exercise. During constant-work-rate exercise the changes with propranolol depended on time and work rate. At 50% max, VO2, VCO2, and VE were reduced in early exercise but were similar by min 5. At 70% max, VO2 and VCO2 were again lower initially with propranolol but then rose more rapidly. By min 5 VE was greater with propranolol, coinciding with a rapidly rising venous lactate. We interpret the initial reduction in VO2 and VCO2 to reduced cardiac output and muscle perfusion with propranolol. The resulting increase in anaerobic metabolism during heavy exercise would explain the increased VE at min 5. The metabolic data are compatible with glycogen being the predominant muscle fuel.