Bronchial Asthma and Rest Angina: Is It Safe to Perform Acetylcholine Spasm Provocation Tests in These Patients?

Objective Acetylcholine (ACh) use in patients with bronchial asthma (BA) is contraindicated. We examined the clinical usefulness and safety of ACh spasm provocation tests in rest angina patients with BA. Patients The study subjects were 495 rest angina patients (mean age: 64.4±10.9 years old, male: 81.0%). Organic stenosis was found in 69 patients (13.9%). Methods We investigated 495 rest angina patients who underwent ACh spasm provocation tests. ACh was injected in incremental doses of 20/50/100/200 μg into the left coronary artery and 20/50/80 μg into the right coronary artery. Provoked positive spasm was defined as transient ≥90% luminal narrowing and usual chest pain or ischemic electrocardiogram changes. Results Among 495 rest angina patients, 13 (2.6%) were complicated with BA. Eleven patients with BA were controlled under medications, and two patients had a history of medication for BA. The clinical characteristics were not markedly different between rest angina patients with and without BA. The rate of multi-vessel spasm was markedly higher in patients with BA than that in those without BA. No complications during ACh spasm provocation tests were recognized in rest angina patients with BA, whereas major complications in those without BA were observed in eight patients including two ventricular fibrillations, three non-sustained ventricular tachycardias, and three shocks. We were able to perform all 495 ACh spasm provocation tests without any irreversible complications, while electrical defibrillation was necessary for 2 patients without BA. Conclusion We were able to perform ACh spasm provocation tests in rest angina patients with BA irrespective of the off-label use of ACh.     

Evaluation of the Diagnostic Accuracy of Non-Specific Bronchial Provocation Tests in the Diagnosis of Asthma: A Randomized Cross-Over Study

IntroductionThe role of bronchial provocation tests in the diagnosis of asthma remains to be fully explored. We aimed to evaluate methacholine and mannitol challenge testing, and explore the factors associated with this broncoprovocation response.MethodsObservational, cross-over, randomized trial evaluating adult cases with suspected asthma, naïve to treatment, with normal pre-bronchodilator spirometry, and negative bronchodilator test. Patients were randomized to start with methacholine or mannitol. The diagnosis of bronchial asthma was confirmed if there was a good functional and clinical response to one month with twice daily formoterol/budesonide 9/320. The diagnostic profile and the concordance were calculated. Factors associated with a positive provocation test were entered into a multivariate binomial logistic regression analysis, and classification trees were created for both tests.ResultsThe study included 108 cases (50.0% diagnosed with asthma and 51.9% cases starting with methacholine). The percentage of cases positive to methacholine and mannitol were 30.6% and 25.0% respectively. Kappa values were 0.40 (p < 0.001). The diagnostic profile for methacholine was sensitivity 59.3% and specificity 98.1%, while for mannitol it was sensitivity 48.1% and specificity 98.1%. Variables associated with a positive methacholine response included sex, atopy, FEV₁, FEV₁/FVC and FENO, whereas they were FEV₁/FVC and FENO for mannitol. A FENO value > 26 ppb, FEV1 ≤ 103.3% and female sex correctly classified 78.7% of methacholine responders. FENO value > 26 ppb was enough to correctly classify 81.5% of mannitol responders.ConclusionsOur study confirms the diagnostic profile of methacholine and mannitol challenge tests and describes the variable associated to their positivity with new proposed cutoff values.     

Exhaled Breath Condensate Formate after Inhaled Allergen Provocation in Atopic Asthmatics In Vivo

Objective. The dual actions of S-nitrosoglutathione reductase comprise reduction of S-nitrosoglutathione, a potent endogenous airway smooth muscle relaxant that is depleted in asthmatics, and detoxification of formaldehyde to formate. Airway formate production is increased in children with asthma, suggesting increased activity of S-nitrosoglutathione reductase. We determined formate in exhaled breath condensate from adult atopic asthmatics with asthma exacerbation produced by inhaled allergen in vivo, Methods. Twenty-two adult atopic asthmatics underwent inhaled allergen challenge using specific allergen. Exhaled breath condensate was collected at baseline, 1 h after inhalation of the provocative dose of allergen, and then every 2 h for 8 h during the challenge. Formate was analyzed by ion chromatography, Results. Eleven asthmatics developed an isolated early airway response, and another 11 volunteers early response followed by late airway response (dual response). Formate concentrations doubled 1 h post-challenge in asthmatics with dual-airway response but essentially unchanged in patients with an isolated early reaction, Conclusions. Dual-airway response to allergen in atopic asthmatics could be associated with increased activity of S-nitrosoglutathione reductase as suggested by greater concentrations of formate in exhaled breath condensate. Measurement of formate in exhaled breath condensate could serve as a noninvasive biomarker of S-nitrosoglutathione reductase activity in vivo. Our results need to be confirmed in a larger group of asthmatics.     

Changes in Exhaled Nitric Oxide Levels After Bronchial Allergen Challenge

Background  

Fractional exhaled nitric oxide (FeNO) is a marker of inflammation of the airways accompanying changes in the clinical condition of asthma. Allergen exposure has been associated with a delayed elevation of FeNO. The aim of this study was to assess airway inflammation with FeNO measurements during bronchial allergen challenge (BAC), and to determine the diagnostic performance of FeNO changes.     

Airway Eosinophilic Inflammation and Bronchial Hyperresponsiveness after Allergen Inhalation Challenge in Asthma

Allergen exposure in atopic asthmatic patients is associated with recruitment and activation of eosinophils in the airways. Once activated, eosinophils release toxic products, including the eosinophil cationic protein (ECP), able to damage bronchial structures and to increase bronchial hyperresponsiveness. With this background, the present study was designed to evaluate whether ECP levels in bronchoalveolar lavage (BAL) fluid could reflect, better than BAL eosinophil counts, the cellular activation that follows allergen exposure in atopic asthmatics. Twenty-two atopic patients attended the laboratory on two separate days. On the 1st day, they underwent methacholine (MCh) inhalation challenge to detect the degree of nonspecific bronchial hyperresponsiveness. On the 2nd day, they underwent fiberoptic bronchoscopy and BAL, at baseline or 4–6 h after allergen inhalation challenge. In this latter patient group, MCh challenge was repeated 3–5 h after allergen challenge, 1 h before fiberoptic bronchoscopy. The analysis of the mean baseline FEV₁ values and the degree of bronchial reactivity to MCh (MCh Pd₂₀) on the 1st study day did not demonstrate differences between the two patient groups (p > 0.1, each comparison). In addition, in the allergen-challenged group, MCh Pd₂₀ was decreased significantly after allergen challenge (151.4 μg/ml and 67.6 μg/ml, respectively, before and after challenge; p < 0.05). Evaluation of the different BAL cell types demonstrated that the proportions of eosinophils and epithelial cells were increased significantly in the allergen-challenged group compared with the group evaluated at baseline (p < 0.01 and p < 0.05, respectively). Moreover, ECP levels, corrected by the correspondent albumin levels (ECP/Alb), were higher in the allergen-challenged group compared with the group evaluated at baseline (p < 0.05). In addition, although a positive correlation was demonstrated between BAL eosinophil percentages and ECP/Alb values (r= 0.72, p < 0.05) in the group evaluated at baseline, no links were found between these parameters in the allergen-challenged group (p > 0.1). However, in this latter group, a weak positive correlation was demonstrated between eosinophil percentages and ΔMch, i.e., the increased nonspecific bronchial reactivity, which is observed after allergen challenge (r= 0.55; p < 0.05). Thus, in stable asthmatic patients an ongoing activation of eosinophils parallels their migration, but this eosinophilic inflammation is not strictly related to bronchial reactivity to Mch. By contrast, after allergen inhalation challenge, eosinophil recruitment and activation seem to follow different temporal kinetics, and eosinophilic inflammation may be partially associated with the degree of airway hyperresponsiveness. Accepted for publication: 15 September 1997     

Bronchial and Bronchoalveolar Inflammation in Single Early and Dual Responders after Allergen Inhalation Challenge

To characterize the cellular inflammation at the bronchial and bronchoalveolar levels, we evaluated 43 patients with asthma who were sensitized to house dust mites. On 2 consecutive days patients underwent methacholine challenge and allergen bronchial challenge. In addition, 6, 24, or 72 h after allergen challenge, fiberoptic bronchoscopy with bronchial lavage (BL) and bronchoalveolar lavage (BAL) was performed. Patients belonging to the 6-h, 24-h, or 72-h group were divided further into two subgroups: those with isolated early response to allergen (LAR⁻), and those with dual response to allergen (LAR⁺). The percentage of eosinophils and of epithelial cells in BAL fluid was significantly higher in LAR⁺ than in LAR⁻ patients in the 6-h group (p < 0.05, each comparison), but not 24 or 72 h after (p > 0.05, each comparison). Similarly, the proportion of BL eosinophils was also higher in LAR⁺ than in LAR⁻ patients, both in the 6-h and in the 24-h group (p < 0.05, each comparison). In addition, increased proportions of BL neutrophils were present in the LAR⁺ patients belonging to the 24-h group (p < 0.05). Comparing ``proximal' = BL vs ``distal' = BAL data, we found a significantly higher proportion of epithelial cells in BL compared with BAL, in both LAR⁻ and LAR⁺ subjects, either 6, or 24, or 72 h after challenge (p < 0.01, each comparison) and increased percentages of BL neutrophils and eosinophils in LAR⁺ patients (p < 0.05, each comparison), but not in LAR⁻ patients, in the 24-h group. The percentages of BL or BAL macrophages and lymphocytes did not differ significantly among the different patient groups. These data indicate that the development of LAR after allergen inhalation challenge is associated with an early recruitment of eosinophils and with epithelial desquamation in the airways. In addition, after allergen challenge epithelial desquamation is more pronounced in the proximal than in the distal airways, independently of the type of bronchial response. Accepted for publication: 7 January 1997     

冠状动脉内乙酰胆碱激发试验与麦角新碱激发试验的对比研究

目的 :比较选择性冠状动脉内乙酰胆碱 (Ach)和麦角新碱 (ER)激发试验对冠状动脉痉挛性心绞痛诊断的敏感性、特异性和安全性。　　方法 :79例患者中对 41例患者实施了Ach激发试验 ,根据冠状动脉造影及有无心绞痛和ST段改变分为AchⅠ组和AchⅡ组 ,注药剂量右冠状动脉依次为Ach 2 0 μg和 50 μg ,左冠状动脉依次为 2 0 μg、 50 μg和 10 0 μg ;另 3 8例患者实施了ER激发试验 ,根据冠状动脉造影及有无心绞痛和ST段改变分为ERⅠ组和ERⅡ组 ,右冠状动脉注入ER 2 0 μg ,左冠状动脉注入 3 2 μg。以注入Ach或ER后冠状动脉出现完全或接近完全闭塞 (≥ 99%狭窄 )为激发试验阳性。　　结果 :Ach法诊断冠状动脉痉挛性心绞痛的敏感性为 90 % ,ER法的敏感性为 72 % ,二者差异无显著性 (P >0 0 5) ,二者的特异性均为 10 0 %。影响血流动力学的并发症Ach法 9 8% (4/ 41) ,ER法 2 8 9% (11/ 3 8) ,二者差异性显著 (P <0 0 5)。激发多支血管痉挛阳性率AchⅠ组 15 0 % (3 / 2 0 ) ,ERⅠ组 5 6% (1/ 18) ,二者差异无显著性 (P >0 0 5)。　　结论 :两种方法诊断冠状动脉痉挛性心绞痛均有较高的敏感性、特异性和安全性 ,Ach法更为安全 ,并且有利于多支血管痉挛的研究     

Comparison of Three Bile Acid Provocation Tests: Intravenous Cholecystokinin,a Standard Test Meal,and an Oral Bile Acid Load in Healthy Subjects

Three different bile acid provocation tests—an intravenous stimulation with cholecystokinin (CCK), a test meal, and an oral bile acid load of 500 mg chenodeoxycholic acid (CDAF—were compared in 12 healthy subjects. Blood samples were drawn every 30min for 3 h, and serum bile acids (SBA) were measured by an enzymatic method (Enzabile®). The CCK stimulation gave significant SB A elevations only at 30 min. After the test meal and the CDA loading tests SB A elevations were observed from 30 min and throughout the observation period. Maximal increases were obtained at 120 min after the test meal but already at 30 min after the CDA loading test. We conclude that among these three bile acid provocation tests the oral CDA loading test is to be preferred because it gives marked and rapid elevation of SBA in all subjects and is independent of bile acid pool size and normal function of the gallbladder.     

西北地区过敏性疾病食物过敏原点刺试验结果

目的了解西北地区引起过敏性疾病的主要食物性过敏原。方法对西北地区1039例过敏性疾病患者实施40种食物性过敏原皮肤点刺试验(skin prick tests,SPT)。结果 1039例过敏性疾病患者对40种食物性过敏原SPT阳性率为53.51%,SPT强阳性者155例,食物SPT强阳性率为14.92%。不同年龄组SPT强阳性食物种类不同,0～4岁儿童主要SPT强阳性食物为鸡蛋、马铃薯、牛奶、玉米,阳性率分别为7.14%、3.17%、2.38%、2.38%;5～14岁儿童主要SPT强阳性食物为玉米、花生、河蟹、大豆,阳性率分别为4.17%、3.75%、2.92%、2.08%;成人组主要SPT强阳性食物为河蟹、花生、玉米、海蟹,阳性率分别为4.75%、4.61%、3.86%、3.57%。结论西北地区食物性过敏原与国内外其他地区相比具有一定程度相似性,同时具有较强的地区特点。     

A Cerebrovascular Event After Single-Dose Administration of Recombinant Factor VIIa in a Patient with Esophageal Variceal Bleeding

Upper gastrointestinal bleeding (UGIB) is a life-threatening complication of cirrhosis that develops from esophageal varices in almost 70% of patients. The mortality rate from the bleeding episodes is reported to be 30% [1–4]. Standard management of UGIB of cirrhotic patients is vasoactive therapy combined with endoscopic procedures such as endoscopic sclerotherapy and band ligation [5]. Currently, it is reported that recombinant activated fVIIa (Novoseven, NovoNordisc) can correct the prothrombin time in decompensated cirrhotic patients and also can be used safely in Child's B and C cirrhotic patients with UGIB [6–8]. Herein, we describe the first case report in the literature of a cerebrovascular event after the administration of a single dose of fVIIa in a cirrhotic patient with esophageal variceal bleeding.     

Intranasal Corticosteroid Administration Reduces Nonspecific Bronchial Hyperresponsiveness and Improves Asthma Symptoms

Introduction. Rhinitis and asthma are currently recognized as manifestations of a single syndrome, the chronic allergic respiratory syndrome. Nearly all individuals with asthma have rhinitis, and severe rhinitis has been associated with worse outcomes in asthma patients. Intranasal treatment has been reported to be beneficial for the lower airways. Methods. This was a randomized, double-blind, placebo-controlled study. The objective was to evaluate the effects that treatment with intranasal beclomethasone dipropionate (BDP; 400 μ g/d) has on nasal and bronchial symptoms, as well as on lung function test results and bronchial responsiveness to histamine in patients with allergic rhinitis and asthma. We evaluated 33 patients, divided into two groups: treatment (n = 17); and placebo (n = 16). Over the course of the 125-day study period, each patient reported daily rhinitis and asthma symptoms, as well as the need for additional medication. All patients were submitted to spirometry and histamine challenge at baseline and at each subsequent evaluation (on days 50 and 75). Results. In comparison with the patients in the placebo group, those in the BDP treatment group presented significantly fewer nasal symptoms on day 50 and fewer asthma symptoms on day 75 (p < 0.01 for both); required rescue medications less often; and presented a significantly lower degree of bronchial responsiveness to histamine on day 75 (p < 0.01). Conclusion. In this study, intranasal BDP was effective in treating rhinitis as well as asthma. The benefits for the lower airways were observed only after prolonged treatment and might be better evaluated through nonspecific bronchial challenge.     

Lack of Association Between Helminthic Infestations and Bronchial Asthma in Singapore

Summary: Stools from 108 cases of bronchial asthma and 300 controls were examined for presence of Ascaris , hook-worm and Strongyloides infections. Ascaris and hookworm infections were slightly more common in the asthmatic group while Strongyloides infection was slightly more common in the control group; these differences were not significant ( p > 0.05). Our findings show that in Singapore (a tropical city) Ascaris hookworm and Strongyloides infection are endemic and these infections are not significantly more common in cases of asthma. It is concluded that there is no correlation in the tropics between the presence of helminthic infections and bronchial asthma.     

Methacholine Dose-Response Slopes from Maximal Bronchial Challenge Tests in Asthmatic Children: Methodological Aspects

To determine whether the slope of a maximal bronchial challenge test (in which FEV₁ falls by over 50%) could be extrapolated from a standard bronchial challenge test (in which FEV₁ falls up to 20%), 14 asthmatic children performed a single maximal bronchial challenge test with methacholine (dose range: 0.097–30.08 μmol) by the dosimeter method. Maximal dose-response curves were included according to the following criteria: (1) at least one more dose beyond a ΔFEV₁≥ 20%; and (2) a MFEV₁≥ 50%. PD₂₀ FEV₁ was calculated, and the slopes of the early part of the dose-response curve (standard dose-response slopes) and of the entire curve (maximal dose-response slopes) were calculated by two methods: the two-point slope (DRR) and the least squares method (LSS) in % ΔFEV₁×μmol⁻¹. Maximal dose-response slopes were compared with the corresponding standard dose-response slopes by a paired Student's t test after logarithmic transformation of the data; the goodness of fit of the LSS was also determined. Maximal dose-response slopes were significantly different (p < 0.0001) from those calculated on the early part of the curve: DRR_20% (91.2 ± 2.7 ΔFEV₁% ·μmol⁻¹) was 2.88 times higher than DRR_50% (31.6 ± 3.4 ΔFEV₁% ·μmol⁻¹), and the LSS_20% (89.1 ± 2.8% ΔFEV₁·μmol⁻¹) was 3.10 times higher than LSS_50% (28.8 ± 1.5% ΔFEV₁·μmol⁻¹). The goodness of fit of LSS_50% was significant in all cases, whereas LSS_20% failed to be significant in one. These results suggest that maximal dose-response slopes cannot be predicted from the data of standard bronchial challenge tests. Accepted for publication: 12 December 1996     

两种链格孢霉变应原提取方法的比较

目的比较传统方法和新方法对链格孢霉变应原浸出液蛋白质含量、组分及生物活性的影响。方法将经空气曝皿获得、中国科学院鉴定为链格孢霉的菌株于26℃恒温下培养4周，取12份5g湿重的菌苔，6份用传统方法（风干，高速粉碎机粉碎后，搅拌提取），6份采用新方法（液氮研磨＋超声破碎。再搅拌提取）提取蛋白质：然后用改良的Bradford法进行蛋白质含量测定；SDS-PAGE分析两种方法提取的蛋白质组分的差别．放射性变应原吸附（RAST）抑制试验比较两者间变应原生物活性的差异。结果传统方法和新方法提取的蛋白质含量分别为（0．205±0．019）和（0．532±0．023）g／ml，所得到变应原的50％抑制率分别为5．96和1．25μg／ml。结论两种提取方法中．新方法能够得到较高的蛋白质含量及更多的蛋白质组分，对于低丰度蛋白的获得及生物学活性即效价的提高具有十分重要的意义。     

A Bronchial Response Comparison of Exercise and Methacholine in Asthmatic Subjects

The authors compared the inhaled methacholine and exercise responses in 22 stable unmedicated asthmatic patients. The exercise and methacholine challenges were performed at one to three week intervals. Bronchial responsiveness to methacholine was measured in relation to the concentration of methacholine (PC₂₀M). The response to exercise was expressed as the percentage of fall in FEV₁, from the pre-exercise FEV₁ The findings showed that 21 of 22 subjects demonstrated a fall in FEV₁, of more than 20% after methacholine challenge, while only 9/22 subjects experienced a similar decrease in FEV₁. All 9 of these positive response exercise cases completed three consecutive exercise challenges prior to the methacholine challenge. Of these cases, five were refractory to the repeated exercise challenge, and the PD₂₀M at the nonexercise stage was significantly lower than the postexercise state. In fact, the methacholine challenge sensitivity actually decreased (PD₂₀ increased) after repeated exercise. The authors concluded that methacholine seems to be a more sensitive bronchial provocation test than exercise. Second, only 55.6% of the exercise test-positive subjects were refractory to the second exercise challenge. Therefore, other factors besides the release of mediators should be considered in exercise induced asthma. Third, methacholine sensitivity actually decreased (PD₂₀ increases) after repeat exercise challenge.     

Changes of Soluble ICAM-1 Levels in Serum and Bronchoalveolar Lavage Fluid from Patients with Atopic Bronchial Asthma After Allergen Challenge

Leukocyte-endothelial cell interaction is essential for leukocyte infiltration into inflammatory sites. Initiation of adhesion is through the up-regulated expression of adhesion molecules in the endothelium or epithelium and the activation of adhesion molecules on leukocytes. To our knowledge, there have been few reports concerning soluble intercellular adhesion molecule-1 (s1CAM-1) in patients with atopic bronchial asthma after allergen challenge. If the levels of s1CAM-1 vary between bronchial asthma patients and normal controls, this variance would be useful to assess the state of this disease. Therefore, we measured the levels of s1CAM-1 in sera from 17 patients with atopic bronchial asthma and normal control subjects. Levels of s1CAM-1 in sera from bronchial asthma patients in prechallenge conditions were higher than in normal control subjects. Levels of s1CAM-1 in sera from bronchial asthma patients 8 hr after challenge were higher than those in sera obtained during prechallenge periods. s1CAM-1 levels in bronchoalveolar lavage (BAL) fluids from bronchial asthma patients 8 hr after challenge were higher than at 30 min after challenge. These results suggest that higher levels of s1CAM-1 in sera and BAL fluids reflect the up-regulation of ICAM-1 expression in allergic bronchial asthma and these high levels may contribute to the pathogenesis of atopic bronchial asthma.     

Empirical Comparison of Publication Bias Tests in Meta-Analysis

Background

Decision makers rely on meta-analytic estimates to trade off benefits and harms. Publication bias impairs the validity and generalizability of such estimates. The performance of various statistical tests for publication bias has been largely compared using simulation studies and has not been systematically evaluated in empirical data.

Methods

This study compares seven commonly used publication bias tests (i.e., Begg’s rank test, trim-and-fill, Egger’s, Tang’s, Macaskill’s, Deeks’, and Peters’ regression tests) based on 28,655 meta-analyses available in the Cochrane Library.

Results

Egger’s regression test detected publication bias more frequently than other tests (15.7% in meta-analyses of binary outcomes and 13.5% in meta-analyses of non-binary outcomes). The proportion of statistically significant publication bias tests was greater for larger meta-analyses, especially for Begg’s rank test and the trim-and-fill method. The agreement among Tang’s, Macaskill’s, Deeks’, and Peters’ regression tests for binary outcomes was moderately strong (most κ’s were around 0.6). Tang’s and Deeks’ tests had fairly similar performance (κ?>?0.9). The agreement among Begg’s rank test, the trim-and-fill method, and Egger’s regression test was weak or moderate (κ <?0.5).

Conclusions

Given the relatively low agreement between many publication bias tests, meta-analysts should not rely on a single test and may apply multiple tests with various assumptions. Non-statistical approaches to evaluating publication bias (e.g., searching clinical trials registries, records of drug approving agencies, and scientific conference proceedings) remain essential.