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An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist.

There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli. Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists. In a double-blind placebo-controlled crossover study in 12 patients with mild asthma, we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol (200 micrograms) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol. Patients were randomized to be treated for 3 wk with inhaled budesonide (800 micrograms twice a day) or placebo; salmeterol (50 micrograms twice a day) was added during the third week. Airway responsiveness to methacholine was measured 15 min after albuterol, both before and exactly 12 h [corrected] after the last salmeterol dose. Mean FEV1 increased significantly after 2 wk of budesonide (p < 0.05) and increased further after salmeterol (p < 0.05) compared with placebo. After 2 wk, the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo (3.4 versus 2.4 doubling dilutions; p < 0.05), consistent with an improvement in airway hyperresponsiveness with budesonide therapy. However, regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge, both with budesonide and with placebo (-1.1 +/- 0.42 and -1.41 +/- 0.30 doubling dilutions, respectively). There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods. Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy.

Administration, Inhalation↗

Dose-dependent effects of inhaled mometasone furoate on airway function and inflammation after allergen inhalation challenge.

Comparisons of the potency of different inhaled corticosteroids, delivery devices, and treatment regimens in the management of asthma can only be made when outcome measurements display a dose-dependent effect. These outcomes have been difficult to identify. In this study, we compared in a randomized, double-blind, crossover design, the effects of 6 d treatment with placebo and three doses (50, 100, and 400 microg, twice daily) of mometasone furoate delivered by dry powder inhaler (MF-DPI) on responses after allergen inhalation challenge. Twelve mild asthmatic subjects with dual responses after allergen inhalation were studied. Outcome measurements included early and late asthmatic responses, the change in methacholine airway responsiveness 24 h after challenge, and sputum eosinophilia measured 7 and 24 h after challenge. All three doses of MF-DPI demonstrated similar attenuation of early responses and allergen-induced airway hyperresponsiveness relative to placebo (p < 0.05). The late maximal %fall in FEV(1) after placebo treatment was 23.5% and was significantly reduced in a dose-dependent manner to 12.3%, 11.0%, and 5.9% for the 50-, 100-, and 400-microg twice-daily treatments (p = 0.007). The allergen-induced increase in sputum eosinophilia (x10(4) cells/ml) 24 h after challenge during placebo treatment was 60.2 and was significantly reduced to 24.0, 15.3, and 6.2 for the 50-, 100-, and 400-microg twice-daily treatments. MF-DPI is effective at attenuating allergen-induced early and late responses, airway hyperresponsiveness, and sputum eosinophilia, and dose-response effects exist for the attenuation of the late response.

Administration, Inhalation↗

Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study.

RATIONALE: Zinc oxide is a common, biologically active constituent of particulate air pollution as well as a workplace toxin. Ultrafine particles (< 0.1 microm diameter) are believed to be more potent than an equal mass of inhaled accumulation mode particles (0.1-1.0 microm diameter). OBJECTIVES: We compared exposure-response relationships for respiratory, hematologic, and cardiovascular endpoints between ultrafine and accumulation mode zinc oxide particles. METHODS: In a human inhalation study, 12 healthy adults inhaled 500 microg/m3 of ultrafine zinc oxide, the same mass of fine zinc oxide, and filtered air while at rest for 2 hours. MEASUREMENTS AND MAIN RESULTS: Preexposure and follow-up studies of symptoms, leukocyte surface markers, hemostasis, and cardiac electrophysiology were conducted to 24 hours post-exposure. Induced sputum was sampled 24 hours after exposure. No differences were detected between any of the three exposure conditions at this level of exposure. CONCLUSIONS: Freshly generated zinc oxide in the fine or ultrafine fractions inhaled by healthy subjects at rest at a concentration of 500 microg/m3 for 2 hours is below the threshold for acute systemic effects as detected by these endpoints.

Administration, Inhalation↗

Single-dose and steady-state pharmacokinetic and pharmacodynamic evaluation of therapeutically clinically equivalent doses of inhaled fluticasone propionate and budesonide, given as Diskus or Turbohaler dry-powder inhalers to healthy subjects.

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.

Administration, Inhalation↗

Novel system to investigate the effects of inhaled volume and rates of rise in simulated inspiratory air flow on fine particle output from a dry powder inhaler.

This study evaluated the effect of inhaled volume and simulated inspiratory flow rate ramps on fine particle output from dry powder inhalers (DPIs). A simple, robust system was developed to account for "rate of rise" (ramp) effects while maintaining a constant air flow through a multi-stage liquid impinger (MSLI), used for sizing the emitted particles. Ramps were programmed to reach 30 and 60 L/min over 100 milliseconds; 500 milliseconds; and 1, 2, and 3 seconds. Rotahaler was chosen as the test DPI. Testing was done with simulated inhalation volumes of 2 L and 4 L. Testing was also carried out using the USP apparatus 4. At 30 L/min, for a 2 L volume, the amount of drug exiting the device in fine particle fraction (FPF) increased from 2.33 microg to 6.04 microg from the 3-second ramp to the 100-millisecond ramp, with 11.64 microg in FPF for the USP (no ramp) method. At the same flow rate, for a 4 L volume, FPF increased from 2.23 microg to 8.45 microg, with 10.25 microg for the USP method. At 60 L/min, similar trends were observed. In general, at both flow rates, an increase in FPF was noted going from the shallowest to the steepest ramp. However, there were no significant differences in FPF when a 2 L inhaled volume was compared with a 4 L volume at each flow rate. Overall, these data suggest that the existing USP apparatus may overestimate FPF at flow rates lower than those recommended by the USP.

Administration, Inhalation↗

[The influence of peak inspiratory flow and inhalation technique on inhaled steroid to patients with bronchial asthma].

We investigated the correlation of peak inspiratory flow (PIF) with peak expiratory flow (PEF) in 29 bronchial asthma patients, and the improvement of inhalation technique with a dry powder inhaler (DIP) before and after medical consultation in 3 patients. There was a significant positive correlation (R = 0.772, p < 0.001) between PIF and PEF in asthmatics. Furthermore, PIF and PEF the values were low in elderly women with combined complications of emphysema. Two of 3 patients who had experienced the problem of residual medicine improved their inhalation technique after the medical consultation compared with before. These results indicate that the clinical examination of PIF and PEF and medical consultation on inhaled steroid use in bronchial asthma patients could be important.

Administration, Inhalation↗

Clickhaler (a novel dry powder inhaler) provides similar bronchodilation to pressurized metered-dose inhaler, even at low flow rates.

STUDY OBJECTIVE: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma. DESIGN: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 microg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol. Active (albuterol via pMDI inhaled at 30 L/min) and placebo controls were included. SETTING: Single center study at the chest/allergy unit of a teaching hospital in Canada. PATIENTS: Sixteen patients with moderate to moderately severe stable asthma. MEASUREMENTS AND RESULTS: Efficacy end points were FEV1, FVC, FEV1/FVC, maximum expiratory flow, and forced expiratory flow between 25% and 75% of vital capacity. Safety end points included heart rate, BP, and tremor. There was no significant difference between the bronchodilator response to albuterol via the CH at 15, 30, and 60 L/min inspiratory flow rate and, at all flow rates, no significant difference was found comparing albuterol CH with the pMDI. All of the techniques for delivering albuterol provided significantly better bronchodilatation than placebo. Adverse events were minimal and did not differ between CH and pMDI or between the various flow rates inhaled through the CH. CONCLUSION: A novel passive albuterol DPI (CH) provides a similar bronchodilator response at 15, 30, and 60 L/min inspiratory flow rates compared with a pMDI used optimally.

Administration, Inhalation↗

Inhaled human insulin ((insulin human [rDNA origin]) Inhalation Powder) in diabetes mellitus.

Inhaled human insulin ((insulin human [rDNA origin]) Inhalation Powder) is a prandial insulin approved in the EU and the US for the treatment of adults with diabetes. Its glycaemic control is comparable to subcutaneous insulin in Type 1 and 2 diabetes, and has superior efficacy versus oral antidiabetic agents in Type 2 diabetes. Hypoglycaemia and mild-to-moderate cough are the main side effects. The treatment group differences in pulmonary function occur early, and are small, nonprogressive for up to 2 years and reversible following discontinuation. Patient-reported outcomes data displays higher diabetes treatment satisfaction, improvements in some quality-of-life scores, and treatment preference with inhaled human insulin versus traditional means. Availability of inhaled insulin may increase insulin acceptance and thus improve glycaemic control in patients with diabetes.

Administration, Inhalation↗

Inhaled nedocromil sodium as additional treatment to high dose inhaled corticosteroids in the management of bronchial asthma.

Thirty five asthmatic patients were included in a randomized, double-blind, placebo-controlled, parallel group study of inhaled nedocromil sodium (4 x 4 mg daily) as an additional treatment to high dose (greater than or equal to 1,000 micrograms) inhaled corticosteroids in the management of bronchial asthma. Following a four week baseline, patients received nedocromil sodium (17) or placebo treatment (18) for eight weeks. Five patients (four in the group subsequently randomized to nedocromil sodium) used short course oral corticosteroid therapy during the baseline and four placebo treated patients used oral steroid therapy during treatment. Fifteen patients (11 nedocromil sodium) reported unusual symptoms. Two nedocromil sodium treated patients were withdrawn owing to treatment taste and vomiting. Statistically significant treatment differences in favour of nedocromil sodium were seen for daytime symptoms (p = 0.03) and morning peak expiratory flow (PEF) (p = 0.012) during weeks 5-8, and for clinician opinion (p = 0.02). Patient opinion (p = 0.053) and evening PEF (p = 0.08) failed to reach statistical significance. Eight out of fifteen and three out of seventeen patients considered nedocromil sodium and placebo, respectively, to be very or moderately effective. The results indicate that the addition of nedocromil sodium (4 mg four times daily) to moderate to severe asthmatics not fully controlled on a regimen of greater than or equal to 1,000 micrograms inhaled corticosteroids and inhaled bronchodilators can produce improvements in symptoms and pulmonary function.

Administration, Inhalation↗

The bronchodilator response from increasing doses of terbutaline inhaled from a multi-dose powder inhaler (Turbuhaler).

Twelve adult asthmatics inhaled single doses of 0.5, 2.0 or 4.0 mg of terbutaline, respectively, via Turbuhaler, on three separate days. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and pulse rate were measured 15, 30, 45 and 60 min after inhalation from the inhaler and then hourly up to 8 h. The results showed that a more rapid onset of action, a greater maximal response and a longer duration of action can be achieved by exceeding the standard dose of terbutaline of 0.5 mg. The incidence of adverse effects was very low even at the highest dose, 4 mg. This study emphasizes the need for individual dosing of inhaled bronchodilators.

Administration, Inhalation↗

Initiating the risk assessment process for inhaled particulate materials: development of short term inhalation bioassays.

This study describes a short term inhalation bioassay in rats to predict the potential for inhaled particles to produce chronic lung disease in humans (e.g., pulmonary fibrosis). To validate the method, rats were exposed for 6 h or 3 days to various concentrations of two reference materials: (1) a known fibrogenic material (i.e., aerosolized alpha-quartz silica particles in the form of Berkeley Min-U-Sil (Pennsylvania Glass and Sand Company, Pittsburgh, PA), or (2) carbonyl iron (CI) particles, as a negative control. Cells and fluids from groups of sham and dust exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase and protein values were measured in BAL fluids at several times postexposure. Cells were identified, counted, and evaluated for viability. The lungs of additional exposed animals were processed for histopathology. Although particle deposition patterns for the two dusts were similar, brief exposures to silica particles produced a persistent pulmonary inflammatory response characterized by neutrophil recruitment at sites of particle deposition and consistently elevated biomarkers of cytotoxicity in BAL fluids. In addition, alveolar macrophage clearance functions were impaired. Progressive histopathologic lesions were observed within 1 mo after a 3-day exposure. Light and electron microscopy of silica exposed lung tissue revealed a chronically active pulmonary inflammatory response characterized by hyperplasia of Type II alveolar epithelial cells and the infiltration of macrophages and neutrophils into alveoli and interstitial compartments. The lesions were progressive, leading to the development of a multifocal, granulomatous-type pneumonitis within 2 mo postexposure. In contrast to the observed effects of silica, 3-day exposures to CI particles produced no significant adverse biochemical or histopathological effects on pulmonary tissues. These results demonstrate that short term, high dose inhalation exposures of silica produce effects similar to those previously observed using intratracheal instillation or chronic inhalation models and lend support to this method as a reliable short term bioassay for evaluating the pulmonary toxicity and mechanisms associated with exposure to new and untested respirable materials.

Administration, Inhalation↗

Pressurised metered dose inhalers versus all other hand-held inhaler devices to deliver beta-2 agonist bronchodilators for non-acute asthma.

BACKGROUND: A number of different inhaler devices are available to deliver beta2-agonist bronchodilators in asthma. These include hydrofluoroalkane (HFA) or chlorofluorocarbon (CFC)-free propelled pressurised metered dose inhalers (pMDIs) and dry powder devices. OBJECTIVES: To determine the clinical effectiveness of pMDI compared with any other available handheld inhaler device for the delivery of short-acting beta-2 agonist bronchodilators in non-acute asthma in children and adults. SEARCH STRATEGY: The Cochrane Collaboration Clinical Trials register was searched for studies as well as separate additional searches carried out on MEDLINE, EMBASE, CINAHL and also on the Current Contents Index as well as the Science Citation Index. In addition, 17 individual online respiratory journals and 12 electronically available clinical trial databases were also searched. The UK pharmaceutical companies who manufacture inhaled asthma medication were contacted in order to obtain details of any published or unpublished studies. SELECTION CRITERIA: - The full texts of all potentially relevant articles were reviewed independently by two reviewers. DATA COLLECTION AND ANALYSIS: Fixed and random effect models were used. Dichotomous outcomes were assessed using Odds Ratios or Relative Risks (RR) with 95% Confidence Intervals (95%CI). MAIN RESULTS: Eighty-four randomised controlled trials were included in this review, but few could be combined to assess a specific outcome for a given delivery device comparison. Only two studies required demonstration of adequate pMDI technique as an entry requirement. There were no difference between a standard CFC containing pMDI and any other device for most outcomes. Regular use of HFA-pMDI containing salbutamol reduced the requirement for short courses of oral corticosteroids (3 trials, 519 patients: RR 0.67; 95% CI 0.49, 0.91); however the total number of exacerbations were unchanged (3 trials, 1271 patients: RR 1.0; 95% CI 0.75, 1.33). REVIEWER'S CONCLUSIONS: In patients with stable asthma, short-acting beta-2 bronchodilators in standard CFC-pMDI's are as effective as any other devices. The effect of HFA-pMDI on requirement for oral corticosteroid courses to treat acute exacerbations should be confirmed. Effectiveness studies that use an intention-to-treat analysis are required.

Adrenergic beta-Agonists↗

A scintigraphic study to evaluate the deposition patterns of a novel anti-asthma drug inhaled from the Cyclohaler dry powder inhaler.

A scintigraphic study was performed, in 10 healthy volunteers, to determine the deposition patterns of a novel anti-asthma drug, LAS 31025, inhaled from a dry powder inhaler, the Cyclohaler. In addition, plasma concentrations of drug following inhalation were determined to investigate their relationship to the deposition patterns. Increasing doses of LAS 31025 were inhaled by the volunteers on four separate study days; 2.25, 4.5, 9.0 and 18.0 mg. The average lung deposition values corresponding to these dose levels were 19.1, 20.9, 19.5 and 17.5%, respectively. Deposition patterns within the lungs were similar on each of the four study days, with slightly more of the dose deposited in the central and intermediate regions compared to the peripheral lung region. The scintigraphic data were supported by the pharmacokinetic measurements as there was an increase in the maximum plasma concentration and area under the concentration-time curve corresponding to the increased doses of LAS 31025 on successive study days.

Journal Article↗

Efficacy and safety of mometasone furoate dry powder inhaler vs fluticasone propionate metered-dose inhaler in asthma subjects previously using fluticasone propionate.

OBJECTIVE: To compare the efficacy and safety of mometasone furoate dry powder inhaler (DPI) administered once daily in the evening with fluticasone propionate metered-dose inhaler (MDI) administered twice daily. METHODS: An 8-week, randomized, open-label, parallel-group study compared mometasone furoate DPI, 400 microg every evening (1 puff daily), with fluticasone propionate MDI, two 125-microg puffs twice daily, in 167 adults and adolescents with moderate persistent asthma previously using fluticasone propionate. The primary efficacy variable was the change in forced expiratory volume in 1 second (FEV1) from baseline to the end point. Variables such as response to therapy and subject satisfaction with the inhaler devices were also analyzed. RESULTS: Improvement in FEV1 was noted at the week 2 visit with both treatments. This improvement was maintained at the 4- and 8-week visits and at the end point for both groups. The mean percent change in FEV1 from baseline to the end point was 4.58% with mometasone furoate DPI and 6.98% with fluticasone propionate MDI (P = .35). At the end point, physicians rated 62% of the mometasone furoate DPI group as "improved" or "much improved" compared with 47% of the fluticasone propionate MDI group (P = .007). A significantly greater proportion of subjects in the mometasone furoate DPI group "liked the inhaler a lot" vs subjects in the fluticasone propionate MDI group (46.8% vs 22.4%; P = .01). Both treatments were well tolerated. CONCLUSION: Mometasone furoate DPI, 400 microg every evening, provided comparable efficacy as fluticasone propionate MDI, two 125-microg puffs twice daily, in subjects with moderate persistent asthma previously treated with fluticasone propionate.

Adolescent↗

The characterisation of inhalation devices by an inhalation simulator: The Electronic Lung.

The Electronic Lung is an inhalation simulator designed for the characterisation of breath-actuated inhalation devices. It enables the in-vitro evaluation of devices under conditions that have been produced in-vivo. Data generated on the Serevent Diskhaler inhaler have highlighted the reproducibility of particle size distribution of drug delivered from the device over a range of inhalation parameters.

Computer Simulation↗

Inhaler technique of elderly patients: comparison of metered-dose inhalers and large volume spacer devices.

Large volume spacers (LVSs) reduce systemic absorption of steroid from metered-dose inhalers (MDIs) but there are no data to support the widespread belief that LVSs are easy for older people to use. MDI and LVS technique was examined in 40 inhaler-naive patients [19 men; 70-92 (mean 78.3) years] with chronic airways disease and mental test scores > 7/10. On day 1, technique was taught and errors corrected if possible. Technique was scored and patients asked which device they preferred. They were prescribed the device with which they were most competent. Those competent with both were given a device randomly. Technique was reassessed on day 29 without further tuition. On day 1 only three patients (8%) had inadequate technique for LVS vs. 12 (30%) for MDI (chi 2 = 6.90; p = 0.032). The main problems were inability to trigger the device (two patients with both devices), problems co-ordinating triggering and inhalation (20 patients with MDI), problems inserting the MDI into the LVS (seven patients), and unnecessary repetitive firing of the LVS (three patients); 28 (70%) preferred LVSs. On day 29, 29/30 (97%) with LVSs used them adequately, as did 13/15 (87%) using MDIs (five patients used both). LVSs have advantages over MDIs for elderly patients in terms of patient preference and inhaler technique.

Adrenal Cortex Hormones↗

Collection, validation and generation of bitumen fumes for inhalation studies in rats Part 3: Regeneration of bitumen fumes, inhalation setup, validation.

Undertaking a chronic inhalation study on bitumen fume presents a challenge in terms of generating sufficient amounts of representative fume. The objective of the study described in this and in previous publications was to collect sufficient fume and use this to develop a laboratory-generated exposure atmosphere, for use in chronic inhalation toxicity studies in rats that resembles, as closely as possible, personal exposures seen in workers during road paving operation. To achieve this goal, atmospheric workplace samples were collected at road paving work sites and compared with bitumen fume condensate samples collected from the headspace of hot bitumen storage tanks. In Parts 1 and 2, we described the collection and analysis of workplace samples, the strategy for in-line extraction of a suitable fraction of bitumen fume collected from the headspace of a bitumen storage tank and the comparison of the collected condensate to the workplace samples. This paper (Part 3) describes the regeneration of bitumen fume for inhalation and the exposure setup used for inhalation studies.

Aerosols↗

Life-threatening inhalant allergy: typical anaphylaxis induced by inhalational allergen challenge in patients with idiopathic recurrent anaphylaxis.

Eight patients, referred to an allergy service because of anaphylactic syndromes, were investigated for the usual causes (drugs, foods, insect stings etc.) without satisfactory results. All were atopic by history and/or allergy skin testing. Inhalation challenges, using nebulized common inhalant allergens to which the patients were positive by skin tests, were performed to test whether such inhaled allergens could be causing the anaphylactic episodes. Four of the eight patients developed anaphylactic episodes similar to the spontaneous attacks. Two of the other four patients developed precipitous asthma with some suggestion of non-pulmonary anaphylactic features. It is suggested that inhaled allergens may be a common cause of recurrent anaphylaxis where other recognized causes have been excluded.

Adolescent↗