A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements.

BACKGROUND: The accurate diagnosis of latent tuberculosis infection (LTBI) is an important component of any tuberculosis control programme and depends largely on tuberculin skin testing. The appropriate interpretation of skin test results requires knowledge of the possible confounding factors such as previous BCG vaccination. Uncertainty about the effect of BCG vaccination on tuberculin skin testing and the strength with which recommendations are made to individual patients regarding treatment of LTBI have identified a need to analyse the available data on the effect of BCG on skin testing. A meta-analysis of the evidence for the effect of BCG vaccination on tuberculin skin testing in subjects without active tuberculosis was therefore performed. METHODS: Medline was searched for English language articles published from 1966 to 1999 using the key words "BCG vaccine", "tuberculin test/PPD", and "skin testing". Bibliographies of relevant articles were reviewed for additional studies that may have been missed in the Medline search. Articles were considered for inclusion in the meta-analysis if they had recorded tuberculin skin test results in subjects who had received BCG vaccination more than 5 years previously and had a concurrent control group. Only prospective studies were considered. The geographical location, number of participants, type of BCG vaccine used, type of tuberculin skin test performed, and the results of the tuberculin skin test were extracted. RESULTS: The abstracts and titles of 980 articles were identified, 370 full text articles were reviewed, and 26 articles were included in the final analysis. Patients who had received BCG vaccination were more likely to have a positive skin test (5 TU PPD: relative risk (RR) 2.12 (95% confidence interval (CI)1.50 to 3.00); 2 TU RT23: 2.65 [corrected] (95% CI 1.83 to 3.85). The effect of BCG vaccination on PPD skin test results was less after 15 years. Positive skin tests with indurations of >15 mm are more likely to be the result of tuberculous infection than of BCG vaccination. CONCLUSIONS: In subjects without active tuberculosis, immunisation with BCG significantly increases the likelihood of a positive tuberculin skin test. The interpretation of the skin test therefore needs to be made in the individual clinical context and with evaluation of other risk factors for infection. The size of the induration should also be considered when making recommendations for treatment of latent infection.

Severe hepatic complications of antituberculous therapy.

Hepatotoxicity from antituberculous therapy is well described, but fortunately severe complications are rare. The optimal methods of monitoring for significant hepatotoxicity while on treatment are uncertain. Some authorities recommend measuring liver enzymes only if symptoms develop, whereas others recommend regular liver enzyme monitoring throughout the course of therapy. In British Columbia, from 1990 to 1997, 2624 active and approximately 8000 chemoprophylaxis cases have been treated, but only two severe complications directly related to antituberculous therapy have occurred. A 33-year-old male developed fulminant hepatic failure seven months after starting isoniazid chemoprophylaxis and required a liver transplant. The other patient died from hepatic failure that developed in the first month of triple-drug therapy for proven active pulmonary tuberculosis. The early and late onset of hepatic failure associated with antituberculous therapy in these cases underline the difficulties in identifying a monitoring protocol that will totally negate the risk of severe complications.

Anti-inflammatory effects of salmeterol compared with beclomethasone in eosinophilic mild exacerbations of asthma: a randomized, placebo controlled trial.

BACKGROUND: Salmeterol is a potent long acting beta-agonist that is effective in relieving the symptoms and airflow limitation of asthma. OBJECTIVE: To determine whether the effect of salmeterol on clinical parameters in a mild eosinophilic exacerbation of asthma was similar to that of beclomethasone dipropionate (BDP) and, thus, is due to an anti-inflammatory property. PATIENTS AND METHODS: Thirty-four asthmatics with a persistent increase in symptoms for at least two weeks and an increase of sputum eosinophils of 4% or more were randomized in a double-blind fashion to one of three groups that received daily treatment with 100 mg salmeterol, 1 mg BDP or placebo in divided doses using identical pressurized inhalers. Patients were treated with study medications for three weeks, followed by one week of open label BDP (500 mg bid). Patients were seen at weekly intervals, and sputum and blood were obtained on each visit. The primary outcome measure was a change in sputum eosinophils, and secondary outcomes were changes in blood eosinophils, eosinophilic cationic protein (ECP) and clinical parameters. Three patients (one in each group) could not produce any sputum after randomization and were excluded from the analysis. RESULTS: Twelve patients received salmeterol, 10 received BDP and nine received placebo. Salmeterol treatment had no effect on sputum eosinophils geometric mean, (from 35.5 [24.9] to 26.9% [25.8]), blood eosinophils (from 7.6 [4.8] to 7.2% [3.9]) or ECP (from 33.1 [18.1] to 27.8 [16.3] mg/L) but improved morning peak expiratory flow (PEF) and diurnal variation of PEF, and decreased the use of rescue medication more than placebo (P<0.05 for all comparisons). In contrast, BDP improved both inflammatory indexes (sputum eosinophils from 22.5 [17.9] to 5.7% [6.8], blood eosinophils from 9.0 [5.5] to 2.1% 1.0, and serum ECP from 36.5 [22.0] to 16.1 [10.1] mg/L) as well as clinical parameters. CONCLUSIONS: These results show that salmeterol improves the symptoms and airway function of patients with asthma, but has no effect on eosinophilic airway infiltration. These findings support current asthma guidelines, which recommend the initial use of inhaled steroid to maximize clinical improvement. While salmeterol also produces clinical improvement, it does not suppress sputum eosinophilia. The analysis of induced or spontaneous sputum for inflammatory indexes may be a valuable clinical test to guide the use of inhaled steroid and/or a long acting beta-agonist.

Potential masking effects of salmeterol on airway inflammation in asthma.

We hypothesized that regular use of long-acting beta-agonists could delay recognition of ("mask") increasing airway inflammation. We studied steroid-sparing and "masking" effects of salmeterol versus placebo in 13 asthmatic individuals requiring >= 1,500 microgram inhaled corticosteroid daily. Corticosteroid doses were reduced weekly until criteria were met for an exacerbation or the corticosteroid was fully withdrawn. Subjects were restabilized on their original dose of inhaled corticosteroid for 4 wk before crossover to the alternative treatment. Subjects maintained symptom and peak expiratory flow (PEF) diaries, and underwent weekly spirometric, methacholine challenge, sputum eosinophil, and serum eosinophil cationic protein (ECP) measurements. Mean corticosteroid dose was reduced by 87% during salmeterol treatment, versus 69% with placebo (p = 0.04). Sputum eosinophils increased before exacerbation despite stable symptoms, FEV1, and PEF. In the week before clinical exacerbation, sputum eosinophil counts were higher in the salmeterol-treatment arm (19.9 +/- 29.8% [mean +/- SD], versus placebo 9.3 +/- 17.6%; p = 0.006). Five subjects showed > 10% sputum eosinophilia before exacerbation during salmeterol treatment, as compared with two receiving placebo. In this model, salmeterol controlled symptoms and lung function until inflammation became significantly more advanced. We conclude that the bronchodilating and symptom-relieving effects of salmeterol can mask increasing inflammation and delay awareness of worsening asthma.

Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma.

We prospectively recruited patients admitted to the hospital with severe asthma to comprehensively evaluate the association of historical and physiologic features with the risk of near-fatal asthma (NFA). A case-control study design was used. All patients admitted with NFA (cases) were identified prospectively and compared with asthma patients admitted during the same period without respiratory failure (controls). Nineteen cases (age: 40.2 +/- 12.0 yr) (mean +/- SD) and 80 controls (age: 36 +/- 13.5 yr) were enrolled. Duration of asthma, gender, smoking status, ethnicity, and prevalence of atopy were similar in the case and control groups. More than 80% of patients in both groups reported worsening symptoms for more than 48 h before admission, and more than 50% were worse for longer than 7 d. There was no difference in degree of airways obstruction or bronchial hyperresponsiveness (PC20). Perception of dyspnea was similar in the cases and controls, but among cases the males had greater impairment than the females (Borg score: 1.9 +/- 1. 4 versus 3.9 +/- 1.2: p = 0.05). Univariate analysis identified a history of previous mechanical ventilation (OR: 27.5; 95% CI: 6.60 to 113.7), admission to the intensive care unit (ICU) (OR: 9.9; 95% CI: 3.0 to 32.9), history of worse asthma during January and February (OR: 3.5; 95% CI: 1.0 to 11.8), and use of air-conditioning (OR: 15.0; 95% CI: 1.3 to 166) as risk factors for NFA. Of concern was the dependence of most patients (59.8%) on the emergency department (ED) for initial care, and the small number of cases (16%) in which patients visited a physician before admission to the hospital. We have confirmed risk factors identified previously in retrospective studies of fatal and NFA, and have also shown that hospitalized patients with asthma, irrespective of severity of their asthma, share several characteristics, especially in terms of their failure to respond to worsening asthma.

A randomized trial comparing peak expiratory flow and symptom self-management plans for patients with asthma attending a primary care clinic.

Great emphasis is placed on educating asthmatics to use action plans to achieve better control of symptoms. The use of peak flow meters (PFM) has been recommended as an important part of self-management plans. We studied 92 (47 F) adult patients with asthma in a primary care setting to compare the effectiveness of action plans using either peak flow monitoring or symptoms to guide self-management. Each patient was instructed in the use of the action plan in the context of a 6-mo asthma education program taught by a nurse. Patients were already using inhaled corticosteroids or were newly prescribed corticosteroids by their family physician. Forty-four patients were randomized to the PFM group and 48 to the symptoms group. Spirometry, symptom scores, quality of life, medication use, and measures of health care utilization and morbidity (emergency department visits, hospitalizations, unscheduled doctor visits, and days lost from work or school) were recorded at baseline and throughout the study period. PC20 methacholine was measured at the first and at the final visits. There were significant improvements within groups for FEV1, symptoms score, PC20 methacholine, and quality of life, but no between-group differences. A significant shift from higher to lower daily use of beta-agonists (p < 0.008 for both groups) and significant shifts to higher daily doses of inhaled steroids (p < 0.001) occurred in each group. Adherence to the self-management plans was only 65% in the PFM group and 52% in the symptoms group. Outcomes for health care utilization were similar except for fewer patients making unscheduled doctor visits within the PFM group. Our findings show that education, regular follow-up, and an action plan are effective in improving asthma control and quality of life, but the routine use of PFM to guide interventions is not the only way to accomplish these objectives.

Bronchodilator delivery in acute airflow obstruction. A meta-analysis.

OBJECTIVE: To compare the effect of bronchodilator delivery by use of a metered-dose inhaler (MDI) or wet nebulizer on objective measurements of acute airflow obstruction in adult patients. METHODS: Published and unpublished research was identified by MEDLINE searches for articles published from 1966 to 1994, review of scientific citations, review of article bibliographies, communication with experts in the area of asthma therapy and aerosol delivery, primary investigators, and a manufacturer of spacer devices. Eighteen studies were selected from 159 potentially relevant articles by independent review in triplicate. Selection criteria included randomized trials that compared bronchodilator delivery by use of an MDI and wet nebulizer in adults with acute exacerbations of asthma or chronic obstructive pulmonary disease who were treated in an emergency department or a hospital. Data for patient characteristics, study setting, bronchodilator doses, outcomes, and methodological quality were independently extracted. RESULTS: Twelve studies with a total of 507 patients had sufficient data to calculate an effect size (in SD units) for improvement in airflow obstruction after bronchodilator delivery. All but 2 studies used spacer devices with the MDI. The overall treatment effect size was -0.02 (95% confidence interval [CI], -0.20 to 0.16) that favored the MDI, but the magnitude of the effect size was not clinically or statistically significant. No significant effect was observed in the subgroup analyses that compared the diagnosis: asthma, -0.17 (CI, -0.41 to 0.07) compared with chronic obstructive pulmonary disease, 0.23 (CI, -0.35 to 0.81); bronchodilator dose; or methodological quality. The results of a sensitivity analysis that included 5 of 6 excluded studies supported the findings from the primary analysis: 0.05 (CI, -0.11 to 0.20). CONCLUSIONS: Bronchodilator delivery by means of an MDI or wet nebulizer is equivalent in the acute treatment of adults with airflow obstruction. Spacer devices were used for bronchodilator delivery with an MDI in most studies and are recommended for the treatment of acute airflow obstruction. The choice of the delivery method will depend on the need for expedient treatment, availability of staff, consideration of costs, and findings from studies designed to evaluate treatment effects from larger than standard doses of bronchodilators delivered by use of an MDI.

Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators.

BACKGROUND: The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12-14 hours. However, the precise role of formoterol in the maintenance treatment of asthma is still under debate. A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma. METHODS: In a multicentre double blind, placebo controlled, parallel group study 239 subjects with mild to moderate asthma were randomly assigned to treatment with either inhaled formoterol 24 micrograms twice daily (n = 125) or placebo (n = 114) during eight months. The study consisted of a four week run in period, a 24 week treatment period, and a four week washout period. All subjects were using regular inhaled corticosteroids (100-3200 micrograms daily) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief. The study was performed in 10 outpatient clinics in Canada, and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherlands. Twice daily self-reported peak expiratory flow (PEF) measurements, symptom scores, and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures. Spirometric values were measured at entry, at the start of treatment, after four, 12 and 24 weeks of treatment, and after four weeks washout. RESULTS: One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo. Baseline FEV1 was 67.1% predicted and mean bronchodilator reversibility was 26%. The mean total asthma symptom score was 3.6 (maximum possible 21). A significant decrease in symptoms in favour of formoterol (difference from placebo -0.64, 95% CI -0.04 to -1.23, p = 0.04) was observed. Compared with placebo, morning PEF increased (difference from placebo 28 l/min, 95% CI 18.3 to 37.7, p = 0.0001) and the use of short acting beta 1 agonists decreased (daytime difference from placebo -1.1 inhalation, 95% CI -1.4 to -0.7, p = 0.0001) in the formoterol group. PEF returned to baseline following discontinuation of formoterol, as did asthma symptom scores. Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study (58 and 55 courses, respectively). CONCLUSIONS: Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF, and decreasing the use of rescue beta 2 agonists. There was no apparent loss of asthma control during 24 weeks of treatment with formoterol.

Delivering asthma education to special high risk groups.

Patients at high risk from their asthma and therefore worthy of more focused asthma education are those at risk of fatal and near fatal asthma(NFA). In recent years the characteristics of these patients have been better defined. The most important risk factor appears to be a prior history of NFA. Other important features include prior emergency room visits or hospitalization for asthma. Excess use of beta-agonists, especially in the absence of inhaled corticosteroids, also confers increased risk. High risk groups also share similar psychosocial barriers as well as economic deprivation. The benefits of asthma education in these groups have been assessed in a number of studies. In general, asthma education has been shown to have an impact on these patients. Greater effects have been achieved where there has been consistent follow-up by the same physician. Patients require frequent reinforcement of their asthma management, especially regarding their response to acute exacerbations. A sub-group of patients with more severe asthma appear to have a problem perceiving dyspnoea and may therefore benefit from peak flow monitoring but the problem of compliance with this intervention is significant. Behaviour modification plays an important role as does ensuring the patient has adequate resources to purchase medications especially the more expensive anti-inflammatory therapy. Future studies should focus on optimizing the potential benefits of educating high risk patients as they are not only those at greatest risk of death but also consume a disproportionate amount of health care resources.

A review and economic evaluation of bronchodilator delivery methods in hospitalized patients.

BACKGROUND: Bronchodilator delivery by metered dose inhaler (MDI) to treat airflow obstruction is considered to be less expensive and as effective as nebulized therapy. OBJECTIVES: To document the utilization of bronchodilator delivery methods in a tertiary care Canadian university teaching hospital and to perform an economic evaluation. METHODS: A prospective 6-week audit of 4 preselected hospital wards (respiratory, thoracic surgery, general surgery, and a general internal medicine clinical teaching unit) and a cost-minimization economic evaluation were performed. Bronchodilator (salbutamol and ipratropium bromide) doses, frequency, and delivery methods, either MDI or wet nebulizer (WN), were recorded for 95 patients treated with aerosolized bronchodilators. Direct costs for medications and hourly wages including benefits and equipment were obtained. Time and motion studies identified time allocated to MDI and WN delivery. We used sensitivity analyses to test assumptions that could significantly affect treatment costs, especially assumptions about medications, labor, and spacer devices. Costs are expressed in Canadian dollars (Can$1 = US$0.75). RESULTS: Sixty-seven patients (70.5%) were treated with WN, 6 (6.3%) with MDI, and 22 (23.2%) with both WN and MDI. Self-administration of salbutamol by MDI was the least expensive: $1.27 for 200-microgram doses and $1.73 for 400-microgram doses compared with $2.62 for a 2.5-mg dose delivered by WN. The difference in cost between equivalent treatments (400-microgram MDI vs 2.5-mg WN) is only $0.89. Sensitivity analyses showed that MDI was the least expensive therapy when self-administration was possible and for all levels of supervision if more than 4 minutes was needed to administer a WN treatment. CONCLUSIONS: Bronchodilator delivery by WN is commonly prescribed for hospitalized patients despite evidence for equivalency of effect using MDI and in the absence of substitution protocols. Previous studies have estimated a far greater cost differential based on unrealistic labor estimates. We found that supervision of patients using MDIs minimized the differential cost between WN and MDI therapy and that cost savings are maximal in patients who can self-administer MDI therapy. Methodologically sound economic evaluations can better identify true cost savings and variables that need further study.

Exacerbations of asthma without sputum eosinophilia.

BACKGROUND: Sputum analysis provides a non-invasive method of examining the airway secretions of subjects with asthma in order to better understand the inflammatory process. Increased proportions of eosinophils are generally seen in the sputum of subjects with asthma, especially when there is an exacerbation. An unexpected observation in the sputum of subjects with mild exacerbations of asthma is reported. METHODS: Thirty four consecutive subjects with symptoms consistent with a mild exacerbation of asthma were recruited for a treatment study. Inclusion criteria required persistent symptoms of chest tightness, dyspnoea, or wheezing for two weeks (without spontaneous improvement or alteration in dose of inhaled corticosteroid) and a forced expiratory volume in one second (FEV1) that was reversible to more than 75% predicted or known best to ensure the exacerbation was mild. Sputum (spontaneous or induced with hypertonic saline) from all subjects was examined for differential cell counts. Eosinophilic sputum was defined as > or = 4% eosinophils on two occasions or > 10% eosinophils once. Clinical characteristics, sputum differential counts, and measurements of airways obstruction were compared between the subjects with and without sputum eosinophilia. RESULTS: Almost half of the subjects (16 of 34) considered to have mildly uncontrolled asthma had no sputum eosinophilia. In comparison with the subjects who had sputum eosinophilia the non-eosinophilic group had less airways obstruction (FEV1% predicted 88% v 70%) and less severe airways hyperresponsiveness (PC20 methacholine 0.45 mg/ml v 0.13 mg/ml). There was no difference between the groups in the type or prevalence of symptoms, history of recent infections, smoking, relevant allergen exposure, or use of inhaled corticosteroid. CONCLUSIONS: Symptoms of mildly uncontrolled asthma are not always associated with eosinophilic airways inflammation as measured by sputum analysis. The causes and treatment of the non-eosinophilic condition require further investigation.

Melioidosis in a diabetic sailor.

Melioidosis was diagnosed in a diabetic sailor who presented with a history and chest radiograph that suggested tuberculosis. Melioidosis is a tropical disease with protean manifestations: from asymptomatic infection to chronic cavitary lung disease to overwhelming sepsis. The diagnosis is easily made, even in nonendemic areas when duly considered by the clinicians and microbiology laboratory. Ceftazidime has dramatically improved outcomes in hospitalized patients with severe melioidosis.