Management of chronic asthma in adults in diverse regions of the world.

Asthma is a chronic inflammatory disease of the lungs associated with significant morbidity and mortality worldwide. Adoption of current treatment guidelines that propose inhaled corticosteroids (ICS) as the foundation for asthma treatment should control most patients with chronic asthma. Rapid-acting inhaled beta (beta) 2-agonists are best reserved for acute symptom relief. Long-acting beta-2-agonists in combination with ICS are the most effective asthma treatment currently available when asthma is not controlled on low-dose ICS alone; however, they are not universally available due to cost. Slow-release theophylline may be an alternative cost-effective add-on therapy to ICS in resource-poor areas, although its potential for toxicity has limited its use over the last decade. New targeted anti-inflammatory therapies lack the broad anti-inflammatory activity of ICS and are unaffordable in most settings. Implementation of guidelines for asthma care is an unresolved challenge, and major gaps in asthma care are consistent across the globe. Review of asthma management worldwide shows that control of the disease in relation to the Global Initiative for Asthma (GINA) goals of asthma treatment is not achieved in a large proportion of patients, despite the widespread availability of guidelines and even with access to effective treatment in resource-rich settings. Many resource-poor countries have the additional challenge of lack of access to basic asthma treatment such as ICS. The challenge is to provide global access to core asthma medications, particularly ICS, at affordable prices, to improve implementation of treatment guidelines and to encourage better health care provider and patient education.

Underdiagnosis of chronic obstructive pulmonary disease: a rationale for spirometry as a screening tool.

Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality. It is the fourth leading cause of death in the United States, and its impact on quality of life can be severe. The debate on spirometry as a screening tool has been raised and dropped on various occasions over the past 30 years. This paper readdresses the debate in the light of recent evidence from population studies. Spirometry is an underused, easy to perform office-based procedure that has been further facilitated by the advent of modern technology. Despite the fact that spirometry is the gold standard for the diagnosis and assessment of COPD, mass screening using this tool remains controversial. This article provides a discussion based on a recent review of the literature regarding the current and future status of spirometry as a screening tool. A thoughtful approach to spirometry screening should include assessments of the magnitude of underdiagnosis, potential effectiveness of intervention, predictive value of spirometry and clinical profile of patients with COPD.

The placebo effect in asthma drug therapy trials: a meta-analysis.

A meta-analysis of randomized controlled asthma drug therapy trials published in the English literature from January 1991 to June 1995 was performed to estimate the magnitude and direction of the placebo effect in stable ambulatory asthmatic patients. Among placebo groups, the mean absolute increase in forced expiratory volume in 1 sec (FEV1), weighted for sample size and variance, was 0.11 L/min, and the mean percent increase in FEV1 was 4.81%. The corresponding placebo group changes in peak expiratory flow (PEF) were in an opposite direction to those of FEV1; there was a mean absolute decrease of 2.24 L/min, and a mean percent decrease of 4.21%. Changes for active treatment groups were greater in magnitude. However, there were no statistically significant differences in mean changes comparing the placebo groups to the treatment groups, for any of the outcome measures. Mean increases in PEF and FEV1 exceeded 10% in 5 of 33 placebo groups, as compared to 13 of 33 active treatment groups. In conclusion, in well-designed long-term drug therapy studies in stable asthmatics the pooled placebo effect is small but measurable, with FEV1 and PEF showing different directions of response. Moreover, a modest number of patients receiving placebo have changes in pulmonary function that might be interpreted as clinically significant.

Comparative efficacy and safety of inhaled corticosteroids in asthma.

Current guidelines emphasize the efficacy of inhaled corticosteroids for anti-inflammatory activity in asthma, and recommend higher doses and earlier initiation of therapy than previous guidelines. Concern over possible side effects with long term use has prompted an evaluation of the available literature to determine the optimal dose that may be administered without fear that significant side effects might occur (e.g., growth retardation in children, adrenal suppression, reduction in bone mineral density, cataract formation). Regular treatment with the following drugs in adults and children, respectively, is unlikely to result in any clinically significant effects on the above parameters: beclomethasone dipropionate less than 1500 micrograms and 400 micrograms, budesonide less than 1600 micrograms and 400 micrograms, flunisolide less than 2000 micrograms and 1000 micrograms, fluticasone propionate approximately 500 micrograms and 200 micrograms, and triamcinolone acetonide less than 1600 micrograms and 1200 micrograms. Systemic effects are influenced by potency and bioavailability. Inhaled corticosteroids owe their favourable safety profile to a high topical to systemic potency ratio compared with that of oral corticosteroids. In terms of relative topical potency, fluticasone propionate is more potent than budesonide, which is more potent than beclomethasone dipropionate, which is more potent than flunisolide and triamcinolone acetonide. The delivery device has an important influence on the amount of drug reaching the patient. A spacer device attached to a metered dose inhaler or a Turbuhaler reduces oropharyngeal deposition and increases lung deposition. As a result, a dosage reduction may be possible, and local side effects of dysphonia and oral candidiasis may be reduced. Patients requiring continued high doses by the inhaled route should be monitored for systemic effects and be considered for osteoporosis prevention therapy if appropriate.

Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides.

Atovaquone suspensions (750 mg and 1500 mg once a day) were compared with aerosolized pentamidine (300 mg once a month) for the prevention of Pneumocystis carinii pneumonia (PCP) in subjects with human immunodeficiency virus (HIV) infection who were intolerant to trimethoprim or sulfonamides (or both). Median time using the assigned therapy was 6.6 months, and the median follow-up was 11.3 months. Intent-to-treat analyses (n=549) showed no statistically significant differences among subjects with regard to the incidence of PCP (26%, 22%, and 17%, respectively) or mortality (20%, 13%, and 18%, respectively). The incidence of treatment-limiting adverse events with atovaquone was significantly higher (P<.01). There was, however, no significant difference in the time using therapy. Incidences of PCP and death were higher in subjects receiving 750 mg of atovaquone than in subjects receiving 1500 mg. Atovaquone suspension at 1500 mg once a day has an efficacy similar to that of aerosolized pentamidine for prevention of PCP in HIV-infected subjects and is a safe, effective alternative in those who are intolerant to trimethoprim or sulfonamides.

Use of inhaled medications and urgent care services. Study of Canadian asthma patients.

OBJECTIVE: To determine asthma patients' patterns of disease and knowledge of asthma. DESIGN: Telephone survey of patients with diagnosed asthma. SETTING: Residences in 10 Canadian provinces. PARTICIPANTS: Patients with asthma diagnosed by a doctor: 829 men and women with a mean age of 38 +/- 7 years. MAIN OUTCOME MEASURES: Classes of asthma medications, patterns of use, frequency and severity of asthma symptoms use of emergency departments and urgent medical services, participation in asthma education programs, presence of environmental triggers, and knowledge of asthma pathophysiology and treatment. RESULTS: Four hundred fifty-six patients (55%) reported daily symptoms of asthma; 431 patients (52%) used inhaled beta 2-agonists daily. Only 340 patients (41%) used inhaled corticosteroids (IC), and many used them irregularly. A total of 579 (72%) respondents reported no unscheduled visits to a family physician for worsening asthma, but one third of patients had been to an emergency department for uncontrolled asthma in the last 5 years, and most of these visits had occurred during the last year. As to knowledge, 406 patients (49%) disagreed with the statement that asthma is a lifelong condition that cannot be cured. Among IC users, only 101 (30%) knew that IC reduced airway inflammation; among beta 2-agonist users, only 33% agreed that beta 2-agonists opened the bronchial tubes. Two hundred forty patients (29%) reported being current cigarette smokers, and 381 (46%) reported having pets at home. CONCLUSIONS: Daily symptoms and daily use of beta 2-agonists are common among Canadian asthma patients, and this is in excess of what is considered acceptable by current asthma care guidelines. Underuse of IC, inadequate knowledge of asthma symptoms and treatments, and failure to avoid asthma triggers were common in the population studied.

Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a fourth-generation cephalosporin.

In a prospective, multicentre double-blind trial, 151 patients over the age of 65 years were randomly assigned to receive either cefepime 2 g every 12 h for a minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum of 3 days and up to 14 days. Antibiotics were maintained until 48 h after fever had resolved; no other antibiotics were permitted. The average age in each group exceeded 77 years and significant co-morbidity was found in the majority of patients. The mean total duration of therapy was 5.8+/-2.4 days for the cefepime group and 6.7+/-2.7 days for the ceftriaxone group (P = 0.06). The clinical success rate at the end of therapy was 79.1% with cefepime and 75.4% with ceftriaxone (P = 0.62). At the end of follow-up, 91.7% of the cefepime-treated patients and 86.5% of the ceftriaxone patients had a satisfactory clinical response (P = 0.38). In 35 bacteriological evaluable patients, potential pathogens were eradicated in all but one patient receiving cefepime. Seven patients in each group died during the study period but in each case the death was unrelated to study drug. The commonest side-effect was diarrhoea (cefepime, five patients; ceftriaxone, two patients). The clinical and microbiological efficacy of cefepime is similar to that of ceftriaxone in elderly patients with community-acquired pneumonia requiring hospitalization. Cefepime is an appropriate choice for the treatment of community-acquired respiratory tract infections in the elderly.

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.

A practical guide for the diagnosis and treatment of acute sinusitis.

OBJECTIVE: To develop guidelines for the diagnosis and management of acute sinusitis. OPTIONS: Diagnostic clinical criteria and imaging techniques, the role of antimicrobial therapy and duration of treatment, and the role of adjunct therapy, including decongestants, glucocorticosteroids and nasal irrigation. OUTCOMES: Improved accuracy of clinical diagnosis, better utilization of imaging techniques and rational use of antimicrobial therapy. EVIDENCE: A MEDLINE search for relevant articles published from 1980 to 1996 using the MeSH terms "sinusitis," "acute sinusitis," "respiratory infections," "upper respiratory infections," "sinusitis" and "diagnosis," "sinusitis" and "therapy," "sinusitis" and "etiology," and "antimicrobial resistance" and search for additional articles from the reference lists of retrieved articles. Papers referring to chronic sinusitis, sinusitis in compromised patients and documented nonbacterial sinusitis were excluded. The evidence was evaluated by participants at the Canadian Sinusitis Symposium, field in Toronto on April 26-27, 1996. VALUES: A hierarchical evaluation of the strength of evidence modified from the methods of the Canadian Task Force on the Periodic Health Examination was used. Strategies were identified to deal with problems for which no adequate clinical data were available. Recommendations arrived at by consensus of the symposium participants were included. BENEFITS, HARMS AND COSTS: Increased awareness of acute sinusitis, accurate diagnosis and prompt treatment should reduce costs related to unnecessary investigations, time lost from work and complications due to inappropriate treatment. As well, physicians will be better able to decide which patients will not require antimicrobial therapy, thus saving the patient the cost and potential side effects of treatment. RECOMMENDATIONS: Clinical diagnosis can usually be made from the patient's history and findings on physical examination only. Five clinical findings comprising 3 symptoms (maxillary toothache, poor response to decongestants and a history of coloured nasal discharge) and 2 signs (purulent nasal secretion and abnormal transillumination result) are the best predictors of acute bacterial sinusitis (level I evidence). Transillumination is a useful technique in the hands of experienced personnel, but only negative findings are useful (level III evidence). Radiography is not warranted when the likelihood of acute sinusitis is high or low but is useful when the diagnosis is in doubt (level III evidence). First-line therapy should be a 10-day course of amoxicillin (trimethoprim-sulfamethoxazole should be given to patients allergic to penicillin) (level I evidence) and a decongestant (level III evidence). Patients allergic to amoxicillin and those not responding to first-line therapy should be switched to a second-line agent. As well, patients with recurrent episodes of acute sinusitis who have been assessed and found not to have anatomic anomalies may also benefit from second-line therapy (level III evidence). VALIDATION: The recommendations are based on consensus of Canadian and American experts in infectious diseases, microbiology, otolaryngology and family medicine. The guidelines were reviewed independently for the advisory committee by 2 external experts. Previous guidelines did not exist in Canada.

An effectiveness community-based clinical trial of Respirgard II and Fisoneb nebulizers for Pneumocystis carinii prophylaxis with aerosol pentamidine in HIV-infected individuals. Toronto Aerosol Pentamidine Study (TAPS) Group.

STUDY OBJECTIVE: To compare the effectiveness of a standard jet nebulizer, Respirgard II, and a standard ultrasonic nebulizer, Fisoneb, for the administration of aerosolized pentamidine (AP) as primary and secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in HIV-infected individuals. DESIGN: A retrospective, nonrandomized, parallel group comparative study. SETTING: Patients were enrolled in a community-based AP program (APP) between May 1989 and April 1992 in Ontario, Canada. They received AP in either (1) a centralized treatment facility ("clinic") or (2) their attending physician's office or regionalized centers ("nonclinic"). Clinic administration of pentamidine was via Fisomeb; nonclinic via Respirgard II. PATIENTS: The study group comprised of 1,762 HIV-infected individuals requiring AP for either primary (CD4 < 200/mm3) or secondary PCP prophylaxis. Of these, 1,151 used Fisoneb (clinic) and 611 used Respirgard II (nonclinic). RESULTS: In the primary prophylaxis group, 41 of the 892 patients using Fisoneb (4.6%; mean follow-up, 18 months) compared with 16 of 435 patients using Respirgard II (3.7%; mean follow-up, 14.6 months) developed PCP (p = 0.44). A total of 28 of 259 (10.8%; mean follow-up, 15.3 months) patients using Fisoneb for secondary prophylaxis compared with 11 of 176 (6.3%; mean follow-up, 14.4 months) patients using Respirgard II for secondary prophylaxis developed PCP (p = 0.1). CONCLUSIONS: Despite the difference in dosage (120 mg/mo vs 300 mg/mo), type of nebulizer (ultrasonic vs jet), and frequency of administration (twice vs once monthly), the results of this study indicate that both regimens of AP provide comparable protection against PCP. This study further supports the effectiveness of AP as a solid second-line prophylaxis for HIV-infected individuals who are intolerant to trimethoprim/sulfamethoxazole or dapsone.

Acute and chronic respiratory complications of toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a rare disease resulting in bullous necrosis of the epidermis with partial-thickness loss of skin and mucous membranes. Previous reports of TEN have not focused on respiratory complications. During a 6-year period, 12 patients with biopsy-proven TEN were referred to a regional burn unit at the Wellesley Hospital, Toronto. Five patients required mechanical ventilatory support, and nine showed roentgenographic evidence of respiratory complications that had developed. Intensive therapy in a critical care burn unit resulted in a 75% survival rate. The four nonsurvivors had severe preexisting multisystem disease. Four survivors were observed prospectively, with 3 monthly pulmonary function testings performed. The four survivors tested, even if they did not require mechanical ventilatory support, showed evidence of respiratory involvement. Three patients demonstrated a persistent reduction in carbon monoxide diffusing capacity of up to 35% to 40% below normal. From our case series we suggest that TEN, although primarily a dermatologic condition, may result in life-threatening acute respiratory decompensation requiring ventilatory support and long-term pulmonary function abnormalities. Patients with TEN should be closely monitored for pulmonary complications.

Percutaneous balloon aortic valvuloplasty during pregnancy.

Severe aortic stenosis may potentiate sudden life threatening complications during pregnancy. We report a case of successful percutaneous balloon aortic valvuloplasty in a pregnant patient with severe symptomatic aortic stenosis due to congenital bicuspid aortic valve at 14 weeks' gestation. Use of percutaneous valvuloplasty allowed asymptomatic progression of the pregnancy to term and normal delivery of a healthy 2920 g infant.

Effect of using alcoholic and non-alcoholic skin cleansing swabs when sampling blood for alcohol estimation using gas chromatography.

A study was carried out using 20 volunteers in whom venepuncture through the skin soaked in either ethyl or isopropyl alcohol was performed. A non-alcoholic cetrimide/chlorhexidine swab was used as a control. All subjects were initially alcohol free. Ethyl alcohol was detected in only one blood sample and the level was found to be only 0.4 mg% (roughly the limit of detection of the assay). A slightly higher level of isopropyl alcohol (3 mg%) was found in one of the blood samples. Alcohol estimation was carried out by head-space gas chromatography using a pair of instruments each fitted with a column exhibiting different retention characteristics. The system was similar to that used by other UK Forensic Science Laboratories where accurate, definitive results are a necessity. It was concluded that under very testing conditions only minute ethanol interference is produced by using alcohol-based skin cleansing swabs. This minimal interference is unlikely to affect clinical sample results, and even in a forensic situation the inadvertent use of alcohol-based swabs is unlikely to lead to a miscarriage of justice.