Guideline for the management of chronic obstructive pulmonary disease (COPD): 2004 revision.

OBJECTIVE: To revise the South African Guideline for the Management of Chronic Obstructive Pulmonary Disease (COPD) in the light of new insights into the disease and the value of new treatment approaches and drugs. New aspects considered include: A growing awareness of the impact of COPD in South Africa, and the urgent need for prevention strategies. The role of concurrent exposures to domestic and occupational atmospheric pollution, and previous lung infections including tuberculosis. The need to consider as goals of treatment both prevention of exacerbations and improvement of quality of life (health status) of patients with COPD. The development of both long-acting beta2-agonist and anticholinergic drugs for use in COPD. Emerging evidence on a limited role for inhaled corticosteroids in the treatment of COPD. RECOMMENDATIONS: These include primary and secondary prevention; early diagnosis; staging of severity; assessment of reversibility with bronchodilator and, in some, responsiveness to corticosteroids; use of bronchodilators and other forms of treatment; rehabilitation; and treatment of complications. Advice is provided on the management of acute exacerbations, and the approach to air travel, prescribing long-term oxygen, and lung surgery including lung volume reduction surgery. Prevention, both primary and secondary, remains the most cost-effective measure in the management of COPD, and deserves more emphasis, particularly on the part of health care professionals. Primary prevention involves reducing public exposure to cigarette and other forms of smoke, and reduction of atmospheric pollution, and secondary prevention limits exposure and resultant progression in those with established disease. Spirometry is essential for the diagnosis of COPD and in staging severity. In addition, a new classification of severity that considers other indices of functional impairment is provided. Treatment involves a progression from 'as-needed' bronchodilators, through the addition of other more effective bronchodilators, usually in combination, in more severe stages. The importance of assessing potential reversibility in every patient with persistent symptoms, and of the limited role of oral and inhaled corticosteroids (ICS), is emphasised. These approaches also reduce exacerbations and may result in cost savings and improved prognosis. A practical low-cost approach to rehabilitation is proposed. OPTIONS: Treatment recommendations are based on the following: the recommendations of the Global Obstructive Lung Disease (GOLD) initiative, which provides an evidence-based comprehensive and up-to-date review of treatment options; independent evaluation of the level of evidence in support of some of the new treatment trends; and consideration of factors that influence COPD management in South Africa, including lung co-morbidity and drug availability and cost. OUTCOMES: The use of bronchodilators is driven by the presence of symptoms, but regular assessment of benefit, based on objective criteria, is essential. Several forms of treatment reduce exacerbations, the most effective of these is smoking cessation. EVIDENCE: Working group of clinicians and clinical researchers following detailed literature review, particularly of studies performed in South Africa, and the GOLD guidelines. BENEFITS, HARMS AND COSTS: The guideline pays particular attention to cost-effectiveness in South Africa, and promotes the initial use of less costly options. It rejects empirical use of corticosteroids both oral and inhaled, and promotes smoking cessation, and selection of treatment based on objective evidence of benefit. It also rejects a nihilistic or punitive approach, even in those who are unable to break the smoking addiction. VALIDATION: The COPD Working Group comprised experienced pulmonologists representing all university departments in South Africa and some from private practice. All contributed to the development of the previous version of the South African guideline, and attend international meetings. One (JRJ) represents South Africa on the GOLD Guideline Executive. GUIDELINE SPONSOR: The meeting of the Working Group of the South African Thoracic Society was sponsored by an unrestricted educational grant from Boehringer Ingelheim (South Africa) (Pty) Ltd.

Guideline for office spirometry in adults, 2004.

OBJECTIVE: To provide clinical guidelines for office spirometry in South Africa. OPTIONS: More stringent guidelines are required for diagnostic laboratories and research. OUTCOMES: To minimise variations in standard practice and improve the quality and usefulness of spirometry in the clinical setting. EVIDENCE: Recommendations are based on key international publications as well as research publications regarding reference values for South Africans. BENEFITS, HARM AND COSTS: The medical, social and economic benefits and costs of standardisation of office spirometry in South Africa were considered in the recommendations. VALIDATION: The document has been reviewed and endorsed by the South African Thoracic Society. CONCLUSIONS: The indications for spirometry must be specific and clear. Spirometry equipment must meet internationally accepted performance standards and carry proof of validation. Equipment must be regularly calibrated and maintained. Individuals performing spirometry must be adequately trained and demonstrate a high level of competence. Subject preparation, testing and quality control of results must be carried out according to published guidelines. Finally, test results must be interpreted according to current diagnostic guidelines, taking into account the purpose of the test, appropriateness of reference values and the clinical evaluation.

Therapeutic equivalence study of two formulations (innovator v. generic) of beclomethasone dipropionate in adult asthmatic patients.

OBJECTIVE: To study the therapeutic equivalence of two formulations (innovator v. generic) of beclomethasone dipropionate (BDP) 400 micrograms twice daily administered per metered dose inhaler (MDI), in adults with moderate to severe asthma. METHODS: A double-blind randomised parallel-group trial was performed with a 2-week run-in and an 8-week treatment period. Thirty-six symptomatic adult asthmatics on a mean daily dose of 750 micrograms inhaled corticosteroids during run-in, a mean forced expiratory volume in 1 second (FEV1) of 70% predicted normal and a mean histamine concentration provoking a 20% reduction in FEV1 (histamine PC20) of 0.11 mg/l were randomised to one of the two treatment groups. Primary variables were morning peak expiratory flow (mPEF), FEV1 and histamine PC20. Secondary variables were beta 2-agonist use, symptom score and nocturnal awakening. The Schuirmann two one-sided tests procedure was used for the statistical analysis. Ninety-five per cent confidence intervals (CIs) were calculated for the differences in means. RESULTS: The mean differences end of treatment to baseline for the two formulations (Becotide and Beclate) respectively were: mPEF 5.6 l/min (CI - 16.4-27.6) and -22.3 l/min (CI -35.6(-)-9); FEV1 -2.9% (CI -11-5.2) and 0.2% (CI -4.8-5.2); Histamine PC20 -0.04 mg/ml (CI -0.15-0.06) and 0.02 mg/ml (CI -0.37-0.4). Changes in clinical variables were not conclusive. The mean differences with CIs for primary variables were contained within the limits set for equivalence. The sample size was sufficient to differentiate the groups for mPEF, but this was not of clinical significance. CONCLUSION: After 8 weeks of treatment the two formulations of BDP, delivered by MDI through a large-volume spacer, were therapeutically equivalent in moderate-to-severe asthmatic adults.

Treatment of progressive pulmonary sarcoidosis with cyclosporin A. A randomized controlled trial.

Conventional treatment of sarcoidosis is often only partially effective. We examined the effect of cyclosporin A (CsA) combined with prednisone for the treatment of sarcoidosis. Thirty-seven patients with biopsy-proven sarcoidosis were treated with either prednisone 20 mg/d in a prospectively tapered regimen (P) or with combination therapy consisting of prednisone 20 mg/d in a prospectively tapered regimen and cyclosporin A, 5 to 7 mg/kg/d (P-CsA) for up to 18 mo in an open-label randomized controlled trial. Evaluation was done at baseline and at 3, 9, and 18 mo of the degree of dyspnea, pulmonary function, chest radiographs, bronchoalveolar lavage (BAL), and adverse events. Criteria for a good therapeutic response, improvement, treatment failure, and relapse were defined. Thirty-seven patients were treated for at least 9 mo and 18 mo. Six patients in remission were included in an intention-to-treat-analysis at 18 mo. The groups did not differ significantly with respect to therapeutic response from baseline. A significant (p < 0.05) improvement was observed in dyspnea until 9 mo (P) and 18 mo (P-CsA), and in lung function until 9 mo (P) and 3 mo (P-CsA). BAL results showed a significant decrease in lymphocyte counts at 9 mo for the P group only (p < 0.05). More side effects were observed in the P-CsA group than in the P group, including elevation of the mean serum creatinine concentration at 3 and 9 mo (p < 0.05), and a doubling of the number of infections in this group. Relapse after an initially good therapeutic response occurred in two of nine patients in the P group and five of seven patients in the P-CsA group (p < 0.07). Although CsA may have theoretical benefits in the treatment of sarcoidosis, our results do not support its use in this disease.

Organophosphate and carbamate poisoning.

Organophosphate insecticides may cause serious poisoning either accidentally or by deliberate ingestion. Toxic symptoms are produced by acetylcholine accumulation at cholinergic receptors. Diagnosis is based on history of exposure or ingestion, symptoms and signs of cholinergic overactivity and a decrease in serum pseudocholinesterase levels. Following diagnosis, grading of disease severity may identify patients with serious poisoning who should receive treatment in intensive care using adequate doses of anticholinergic drugs. Complications, particularly ventricular arrhythmias, central nervous system depression or seizures, and respiratory failure, should be anticipated and treated. Relapse may occur after seemingly successful treatment. Public education with regard to symptoms of toxicity must be encouraged, and physicians must provide skilled treatment for a potentially lethal condition.

Management and prognosis of massive hemoptysis. Recent experience with 120 patients.

A retrospective analysis was done of 120 consecutive patients with life-threatening hemoptysis (greater than 200 ml of discharge per 24 hours) cared for between 1983 and 1990 at our institution. Seventy-nine percent of the patients (95/120) had hemoptysis exceeding 500 ml/24 hr. Inflammatory lung disease was the underlying cause in at least 85% of cases (n = 103); and of these, pulmonary tuberculosis was the primary diagnosis in 85% (88/103). Fifty-two patients (43%) had had a prior episode of massive hemoptysis, usually within 3 months of their admission. Urgent examination with rigid endoscope in 97 patients (81%) localized the bleeding in only 42 (43%). The overall hospital mortality rate was 10% (12/120) and was similar for those having pulmonary resection (7.1%, 3/42), and those assisted medically (11.5%, 9/78) (p = not significant). However, of these hospital survivors on whom 6-month follow-up was available, 36.4% (20/55) of those with medical management and none (0/39) (p < 0.001) of those with surgical management had recurrent massive hemoptysis. Forty-five percent of these cases were fatal. Current management of massive hemoptysis has resulted in improved hospital outcome. However, the high risk of recurrent and often fatal hemoptysis mandates the definitive management of the bronchial arteries before discharge from the hospital. Recent reports suggest that percutaneous embolization may be effective in nonsurgical candidates.

The effects of an oral thromboxane TP receptor antagonist BAY u 3405, on prostaglandin D2- and histamine-induced bronchoconstriction in asthma, and relationship to plasma drug concentrations.

1. The potent bronchoconstrictors prostaglandin (PG) D2, PG F2 alpha and thromboxane A2 are thought to have a role in the pathogenesis of asthma, mediated via the thromboxane (TP) receptor. 2. BAY u 3405 is a new potent selective competitive TP receptor antagonist. 3. The effect of single oral doses of 20 mg and 50 mg BAY u 3405 was examined against histamine and PG D2 bronchial provocation at 90 min after drug ingestion and, for the 20 mg dose alone, at 60 min after ingestion, in randomised, double-blind placebo controlled crossover studies. A time course study was performed with the 20 mg dose. 4. BAY u 3405 protected against PG D2 bronchial provocation. The 20 mg dose increased the amount of PG D2 required to produce a fall of 20% in the forced expiratory volume in 1 s by 6-fold and 16-fold at 60 min and 90 min after ingestion respectively, and the 50 mg dose by 14-fold at 90 min after ingestion. 5. The specificity of the drug was confirmed in vivo in that there was no significant protection against histamine bronchial provocation at either dose or at either time point. 6. The time course study showed significant protection against PG D2 bronchial provocation at 1 h and at 3 h after a single 20 mg oral dose. 7. There was no correlation between subjects in plasma BAY u 3405 concentration and drug effect. Within the subjects performing the time course study there was a strong correlation in time between drug effect and plasma BAY u 3405 concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of measures of asthma severity and response to treatment to outcome in acute severe asthma.

BACKGROUND: It would be helpful if patients with asthma who require admission to hospital for an acute attack could be identified. METHODS: The relation between the severity of an attack of asthma as determined by admission assessment and the eventual outcome was studied in 52 asthmatic patients aged 14 to 44 years and admitted to an asthma emergency room. The patient's history, including medication and previous admissions to hospital, was recorded and a clinical assessment, including a full inspiratory and expiratory flow-volume loop, was performed on four occasions: on admission, at two hours and at 12-18 hours after the start of a standardised treatment, and two weeks later on an outpatient basis. Patients who were discharged and who had an uneventful follow up at the two week assessment were defined as good responders. Patients who had to be admitted to hospital after 12 to 18 hours or were readmitted during the two weeks, or both, were defined as poor responders. RESULTS: Thirty eight patients were good responders and 14 were poor responders (seven admitted at 12 to 18 hours, seven returned to hospital). All four patients with a raised arterial carbon dioxide tension (PaCO2) (> or = 6 kPa) and the three with cyanosis were in the poor responder group, and this group had lower peak expiratory flow (PEF) values (21% v 30% predicted) on admission. There was, however, considerable overlap in PEF between the two groups and no clinical measure was able to distinguish between the good and the poor responders reliably. Poor responders had a history of more chronic systemic steroid administration, regular use of inhaled beta agonists, and asthma related hospital admissions. Nearly all the subjects showing a good response to standardised treatment had a PEF > 75% predicted and an FEV1 > 65% predicted 12 to 18 hours after the start of treatment. CONCLUSION: Prediction of outcome at admission was not possible in individual patients. A history of poor long term control of asthma, a PEF < 30% of predicted, a PaCO2 > or = 6 kPa, the presence of cyanosis, and lack of early response to treatment indicated a group of asthmatic patients who are less likely to respond to conventional emergency treatment over a short period.

Evaluation of a high-performance thin-layer chromatographic technique for the determination of salbutamol serum levels in clinical trials.

Salbutamol concentrations were determined by high-performance thin-layer chromatography in the sera of two sets of ten volunteers at hourly intervals for 6 h after taking one 8-mg slow-release tablet. The influence of time lapse in processing of serum samples, i.e. centrifugation, extraction and chromatography, was studied. A statistical significant instability of salbutamol in the sera of patients was found which was not present in standard drug-free serum samples spiked with salbutamol and used for construction of standard curves.

Cyclosporin as a treatment for interstitial lung disease of unknown aetiology.

Ten patients with progressive, symptomatic interstitial lung disease of unknown aetiology who were treated with cyclosporin A were reviewed. Five had clinical and histopathological features of cryptogenic fibrosing alveolitis and five a progressive restrictive lung disease characterised by interstitial infiltration with lymphocytes and minimal fibrosis, which could not be classified precisely. Three patients with lymphocytic infiltration showed a response to initial treatment with cyclosporin A alone at high dosage, but toxicity precluded further treatment. All 10 patients then received low doses of cyclosporin A and prednisone. Three of the patients with cryptogenic fibrosing alveolitis and all five patients with lymphocytic infiltration responded with a reduction in dyspnoea or an increase in vital capacity, or both; cyclosporin A appeared to be effective, or at least to have a corticosteroid potentiating effect. A high incidence of side effects occurred, though these do not necessarily prohibit the long term use of cyclosporin A when it is indicated clinically. Cyclosporin A may be effective in the treatment of interstitial lung disease of unknown aetiology. Further studies are required to determine the long term outcome of treatment.

Inhaled beta-stimulants--a study of high-dose v. conventional-dose treatment in asthmatic outpatients.

A randomised double-blind controlled trial was conducted in order to compare pulmonary function and protective effects of salbutamol 200 micrograms v. 1,000 micrograms by inhalation. Twenty-three known asthmatics took part in the study for a period of 12 weeks. Pulmonary function tests were performed at home (peak expiratory flow-rate (PEFR)) and in the laboratory (vital capacity (VC), forced expiratory volume in 1 second (FEV1) and PEFR) before and after treatment. Bronchial responsiveness was measured as the provocative dose of histamine that caused a decrease of 30% of the area under the flow-volume curve (AFVE30) 90 minutes after pre-treatment with the study medication. The 20 patients (10 per treatment group) who completed the study were comparable at base-line in respect of physiological and pulmonary function measurements. Median PEFR, FVC and FVC1 did not differ between the treatment groups for the duration of study. Histamine challenge testing demonstrated a significant decrease in protection that was only seen after 8 weeks of treatment in the high-dose group (P less than 0.05). Changes in pulse rate, blood pressure as well as side-effects were similar in the two groups. Thus treatment with higher doses of beta-stimulants in outpatients had no demonstrable advantage. A significant impairment of the ability to protect against histamine-induced bronchoconstriction was shown; this may relate to beta-receptor down-regulation and hence the development of tachyphylaxis.

Inhaled and oral salbutamol: how effective in the prophylaxis of asthma?

Inhaled and oral salbutamol were compared in 12 asthmatic patients for prophylaxis in antigen-induced asthma. The patients were pretreated with 0.2- and 1.0-mg doses of inhaled salbutamol and with the standard oral 4- and 8-mg slow-release (SR) salbutamol preparations. Bronchodilatation was monitored over the ensuing 3 h and protection against antigen challenge at the end of the period. On each study day the degree of baseline airway hyperreactivity was determined by histamine challenge. Precautions were taken during the antigen challenge to ensure a reproducible response. Blood levels of salbutamol were monitored at hourly intervals for the 3 h after treatment and during the asthmatic reaction subsequent to challenge. Both the 0.2- and 1.0-mg inhalations caused immediate bronchodilation as compared to a placebo (p less than 0.05), but only the 1.0-mg dose protected subjects against antigen challenge (p less than 0.05). In comparison to the placebo, no bronchodilatation was achieved with the standard 4-mg oral preparation in spite of measurable blood levels, nor were the patients protected against antigen challenge at 3 h after pretreatment. However, the 8-mg SR salbutamol caused significant bronchodilatation within 2 h and suppressed antigen challenge responses as compared to placebo (p less than 0.05). It can be concluded that doses of inhaled salbutamol higher than the conventional 0.2- or the standard 4-mg oral preparations are required to protect asthmatics against inadvertent antigen exposure. In patients who are unable to use inhalers effectively, the SR preparation can be considered as an alternative.

Absence of pulmonary aspiration of sinus contents in patients with asthma and sinusitis.

The frequent association of asthma and paranasal sinusitis has been ascribed to a nasobronchial reflex, aspiration of sinus secretions, or enhanced beta-adrenergic blockade. We investigated possible pulmonary aspiration in a pilot study (eight patients) and follow-up study (13 patients) by means of a radionuclide technique. In the pilot study, the aim was to demonstrate aspiration as well as visibility of the radionuclide in the thorax during a period of 24 hours. The radionuclide was initially placed bronchoscopically in the bronchial tree in four patients and was still clearly visible in the same position after 24 hours in three patients. Aspiration from the nasopharynx was unequivocally demonstrated in two of four patients with depressed consciousness. The follow-up study population consisted of four patients with maxillary sinusitis only and nine patients with sinusitis and asthma. The radionuclide was placed in a maxillary sinus during therapeutic puncture. In the patients with only sinusitis as well as patients with asthma and sinusitis the radionuclide could be demonstrated in the maxillary sinus, nasopharynx, esophagus, and lower gastrointestinal tract during a 24-hour period. However, no pulmonary aspiration of radionuclide could be demonstrated in any patient. We conclude that seeding of the lower airways by mucopurulent secretions is unlikely to account for coexistent pulmonary disease. The association is probably related to generalized mucosal disease affecting both upper and lower airways.

Identification of a 'disease-associated' antigen in pigeon breeder's disease by western blotting.

Sera from 9 symptomatic and 7 asymptomatic pigeon breeders were analyzed for their reactivity to pigeon serum by western blotting. All 9 symptomatic sera (9/9; 100%) and only 4 of 7 (57%) asymptomatic sera revealed specific antibodies. The immunoreactivity patterns of the sera varied: the majority of the sera reacted to antigens having molecular weights of 220 kD or more (9/16 sera), 98 kD (8/16 sera), and 86 kKD (8/16 sera). However, only sera from symptomatic breeders recognized an antigen of approximate molecular weight of 29-32 kD (9/9; 100% of symptomatics). We conclude that this antigen is 'disease associated' and may be useful in the diagnosis of pigeon breeder's disease.

Pigeon breeder's disease: the effect of antigen-specific antibodies on in vitro T cell responses of normal blood lymphocytes.

The effect(s) of affinity-purified antibodies to pigeon serum immunoglobulins on normal T cell responses in vitro was measured. Our results show that the antibodies partially inhibited the concanavalin-A-induced proliferation of normal lymphocytes (32% at 10 micrograms/ml concentration; p less than 0.001), whilst they had no significant effects at equivalent doses on the phytohemagglutinin-induced response. A study of the kinetics of this inhibition revealed that the antibodies exerted their effect(s) within the first 24 h of culture (p less than 0.001); this is probably due to their interference in early events intimately involved in the de novo synthesis and expression of activation antigens such as HLA-DR and Tac: antibody-treated cultures expressed 51.6 and 41.4% less HLA-DR and Tac, respectively. Two-colour immunofluorescence analysis showed that the specific antibodies bind to a subset of CD8+ cells only.

In vitro reactivities of blood lymphocytes from symptomatic and asymptomatic pigeon breeders to antigen and mitogens.

The proliferation of blood lymphocytes in response to pigeon gammaglobulin in the presence or absence of IL2 was measured in 9 symptomatic and 12 asymptomatic pigeon breeders and 24 controls. The symptomatic breeders exhibited spontaneous lymphocyte proliferation (p less than 0.001) when compared with controls whilst lymphocytes from asymptomatic breeders required the simultaneous addition of IL2 in order to proliferate (p less than 0.001). IL2 alone did not induce cellular proliferation. Both patient groups had abnormal T-cell functions and response to lectins and, in the symptomatic group, there existed an inverse correlation (r = -0.70, p less than 0.001) between specific antibody titres to pigeon gammaglobulin and the Con A response. We conclude that both patient groups have circulating, presensitized antigen-specific lymphocytes but these require different stimulatory signals at the cellular level.