[Immunotherapy in allergic diseases. Indications and clinical effects of immunotherapy in allergy to insect stings].
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Biomedical subjects
Publications and source records attributed to B Weeke.
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The bronchodilator activity and side-effects of treatment for 4 days with either 0.085, 0.170 or 0.34 mg/kg bambuterol b.i.d. (a prodrug of terbutaline) or 0.071 mg/kg terbutaline t.i.d. have been evaluated over 12 h, in a double-blind, randomized crossover trial in 19 asthmatic out-patients. Plasma terbutaline concentrations after bambuterol administration were smoother, with a ratio between the maximum and minimum values of about 1.4 compared to 2.6 for terbutaline. The plasma terbutaline level rose with dose, but by less than the increase in dose. The bronchodilator effect was related to the plasma terbutaline concentration in each treatment group, so bambuterol produced more prolonged bronchodilatation than treatment with terbutaline. Tremor and cardiac side-effects were most pronounced after administration of bambuterol 0.34 mg/kg. No severe side-effects were seen. Bambuterol produced stable plasma levels of terbutaline, indicating that as a prodrug of terbutaline it might possibly be administered once daily with good antiasthmatic effect.
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Standardized bronchial allergen provocation was performed twice (with an interval of median 14 days (range 14-44)) in 19 extrinsic, well-defined asthmatic patients to study the reproducibility of the bronchial response. Smoking and medications were strictly withheld prior to the provocation. Ten-fold increasing concentrations of allergen solution 0.9 ml were inhaled by tidal volume breathing for 5 min at 10-min intervals. The actual dose given was expressed by the concentration of the solution used. Forced expiratory volume in the first second (FEV1) was used to determine responses, and the provocation continued until an allergen concentration (allergen PC20) was reached which caused at least 20% decrease of the post-saline FEV1. All provocations were followed by a bronchial reaction within clinically acceptable limits. The reproducibility was high, evaluated by the Spearman rank correlation coefficient Rho = 0.90 (P less than 0.01). It is concluded that bronchial provocation with allergens performed as outlined in this study represents a reproducible test which can be applied in routine allergy diagnostics, and in further investigations concerning specific bronchial reactivity.
Thirty-three adult asthmatic patients suspected of mould allergy were investigated by in vivo and in vitro tests in order to establish a specific diagnosis of asthma caused by the mould species Cladosporium. The patients were evaluated by daily symptom scores in the peak Cladosporium season, bronchial provocation test (BPT), skin prick test (SPT), RAST, histamine release from basophil granulocytes (HIST), and crossed radioimmunoelectrophoresis (CRIE), and the results were scored as negative (score 0), equivocal (score 1) or positive (score 2). Based on daily symptom scores and the result of BPT the patients were classified as being manifest allergic (asthma) to Cladosporium (positive allergy), inconclusive or negative. Positive allergy was defined as asthma symptoms oscillating with the spore concentration and a BPT score 2 (positive at allergen concentration less than 10,000 BU). Negative allergy was defined as no asthma symptoms and a negative BPT (score 0) and inconclusive in the case of symptoms and BPT sum of score 1-3. According to the classification a final diagnosis (positive or negative) could be established in 85% of the patients. "False positive" tests were found: for BPT in 27%, SPT 18%, RAST 0%, HIST 18%, and CRIE 0%. The corresponding figures for "false negative" were: BPT 0%, SPT 0%, RAST 27%, HIST 18%, and CRIE 23%. The relative risk of being allergic in spite of a negative test result was 0% for BPT and SPT, and 25-30% with RAST, HIST, and CRIE. In the case of positive test the risk was 90-100%. Excluding BPT, SPT was found to be the optimal single test to predict/rule out clinical allergy. A stepwise combination of positive SPT and positive RAST was found exclusively in patients clinically evaluated as positive, and does not call for an additional BPT. Using a potent allergenic extract a negative SPT excluded clinically important allergy. The primary conclusion of the study, however, is that the final diagnosis of Cladosporium asthma could not be based on a positive BPT alone (due to "false positive"), but only on a combination of clinical symptoms during the spore season and a positive BPT.
Monomethoxy polyethylene glycol (mPEG) modified honey bee venom (HBV) immunotherapy (IT) has been studied in 14 patients allergic to honey bee venom. Doses could be increased more rapidly and higher doses were reached compared to regular venom immunotherapy. No general side effects were seen, although large local swellings were found somewhat more often than with regular HBV. Most patients could easily be switched from the modified to the unmodified venom. Eight patients experienced and tolerated field stings. Skin testing showed a decreased allergenicity of the mPEG-HBV. The mean HBV-specific IgE level was below pre-treatment level already after only 6 weeks of IT. The HBV-specific IgG response was very good.
Antibody responses to honey bee venom (HBV) were studied in 13 patients during a 4-month course of immunotherapy with monomethoxy polyethyleneglycol (mPEG) modified venom. There was a rise of HBV-specific IgG antibodies as measured by IgG-RAST in all patients and a slight decrease of IgE antibody in most of them. The IgG-antibody responses during mPEG-HBV treatment as examined by crossed radioimmunoelectrophoresis were directed to phospholipase A, hyaluronidase, acid phosphatase and to another allergen, antigen 1. Thus, despite a high degree of mPEG-modification of HBV, the immunogenicity of the most important HBV allergens was retained.
Thirty-two patients with previous systemic allergic reaction to yellow jacket stings were randomly allocated to three groups receiving immunotherapy with different preparations of yellow jacket venom: 1) extract adsorbed to aluminium hydroxide (Alutard-SQ), 2) Pharmalgen extract or 3) non-adsorbed extract from Allergologisk Laboratorium (ALK aq.). Regular examinations showed a decrease in skin prick test size in nearly all patients. Specific IgE-antibody (RAST and CRIE scores) showed a similar, but not significant tendency to decrease in all three groups. Specific IgG-antibody increased considerably in the Alutard group only; after 2 years, however, no difference could be detected between the three groups. During dose increase, patients treated with ALK aq. generally had smaller local reactions to injections than those treated with Pharmalgen. Few systemic reactions occurred in all three groups. Nineteen patients treated for 2 1/2-3 1/2 years were challenged in-hospital with stings from yellow jackets. No systemic and only minor local reactions occurred. Consequently, with the dose regimens applied all three extracts seem effective even though no common changes in either specific IgE or IgG could be demonstrated.
The predictive value of a bronchial challenge with histamine was determined in a prospective survey on a population with a high prevalence of asthma (0.62). Without knowledge of the bronchial responsiveness 133 patients were classified as asthmatics (83) or non-asthmatics (50) according to variation in peak expiratory flow rate and medical history. Response to challenge was determined by the interrupter method, and the concentration of histamine inducing a 40% increase in resistance to breathing (PC40-Rt) was calculated from the log dose response curve. When defining a positive test as a test giving PC40-Rt-values below 2.00 mg/ml, the predictive value of a positive test was 0.75 and the predictive value of a negative test was 0.72. By decreasing the limit for a positive test to 0.25 mg/ml the corresponding predictive value was increased to 0.91. When further increasing the limit to 4.00 mg/ml the predictive value of a negative test in the diagnosis of asthma was increased to 0.81. The interrupter technique is suitable for diagnostic purposes in the detection and exclusion of bronchial asthma.
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A placebo-controlled, double-blind study of immunotherapy with the mould species Cladosporium was performed in 22 adult asthmatics. The diagnosis of Cladosporium allergy was based on a combination of bronchial provocation test and daily symptom score in the Cladosporium season. An aqueous preparation of a potent, biologically standardized and purified extract was used in a clustered dose-increase regimen. The clinical efficacy was evaluated by a combination of symptoms (asthma score + peak flow) and consumption of antiasthmatic medication. The mean changes in symptoms and medication consumption over a 10-week registration period (peak Cladosporium season) in 1982 after 5-7 months of immunotherapy were compared with the corresponding 1981 pretreatment 10-week period. A significant (P = 0.03) difference in terms of "improved", "unchanged" and "deteriorated" patients in favour of Cladosporium treatment was found. Approximately 80% in the Cladosporium group showed improved/unchanged symptoms contrary to 30% of the placebo treated. Side effects were observed frequently but only in the Cladosporium-treated. About 70% experienced a large local reaction and 100% had episodes of asthma during dose-increase phase. Only a few severe systemic reactions occurred. Based on the clinical efficacy of the treatment we consider immunotherapy with Cladosporium feasible for highly specialized clinics.
Fifteen asthmatic outpatients were randomly treated during two periods of 14 days each with sustained-release preparations of either enprofylline (3-propyl-xanthine) or theophylline (Theo-Dur) in a double-blind crossover study. After 4 days of treatment the mean daily doses of enprofylline and theophylline, which were 14.1 and 16.2 mg/kg/day, produced mean plasma concentrations of 4.9 and 12.7 micrograms/ml, respectively. Taking into account all the parameters used to evaluate the antiasthmatic effects, the peak expiratory flow, the number of puffs used from a beta-agonist aerosol, the asthma symptom score and the patients' preferred period, enprofylline was found to be better than theophylline. Enprofylline produced more headaches during the 1st week than theophylline did. However, during the 2nd week the score for headaches decreased to the same level as in the theophylline treatment group. Thus, enprofylline and theophylline seem to have comparable bronchodilator properties and side-effects in the long-term treatment of asthma.
Twenty-one stable asthmatic patients were randomly allocated to be treated with either Duovent (ipratropium bromide 40 micrograms and fenoterol 100 micrograms) and Berodual (ipratropium bromide 20 micrograms and fenoterol 50 micrograms) in a cross-over double-blind design over a 12-week period, each treatment period lasting for 6 weeks. During the study, patients used the test medicine 2 puffs 4 times daily. At the day of inclusion, 6 and 12 weeks after start, a dose-response curve was obtained after inhalation of the test medicine used during the previous 6-week period. Asthma symptoms were recorded in a diary card and morning and evening peak flow was measured. Berodual and Duovent showed a significant bronchodilating effect, the effect of Duovent comparatively more pronounced, but the absolute lung function values after Berodual equalized the effect of Duovent. No difference between peak flow values measured in the morning and evening could be demonstrated. We conclude that no preference between either Duovent or Berodual could be established in the treatment of asthma.
A rapid method for determination of non-specific bronchial hyperreactivity was developed. Resistance to breathing was determined by a modified expiratory airway interrupter technique and combined with a dosimeter-controlled nebulizer which made continuous determination of response possible during challenge. The patients inhaled histamine chloride 8 mg/ml at every eighth breath until resistance to breathing (Rt) was increased by 60%. The number of inhalations (NI) or the provocative concentration (PC60-Rt) of histamine increasing Rt by 60% were determined in 68 patients. The new method correlated well to a non-cumulative standard protocol and could be terminated either within 10 min or within 20 inhalations. The results of this new challenge procedure enables us to predict the responsiveness to inhaled histamine precisely enough to separate patients into hyperreactive or normal reactive patients. Furthermore, the repeatability of the new method is comparable or superior to that of standard methods. The 95% confidence interval for the difference between replicates was the observed value +/- 2.4 NI. Thus this new method will be suited for studies of drug modifying effect on bronchial hyperreactivity since individual dose titration is easily performed, and the method could be valuable in epidemiological and occupational surveys as well.
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