F.E. Hargreave

Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia

BACKGROUNDnEosinophilic inflammation, which may be a consequence of interleukin-5 action, is a characteristic feature of some forms of asthma. However, in three previous clinical trials involving patients with asthma, blockade of this cytokine did not result in a significant improvement in outcomes. We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood, symptoms, and airflow limitation.nnnMETHODSnIn this randomized, double-blind, parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment, we assigned 9 patients to receive mepolizumab (administered in five monthly infusions of 750 mg each) and 11 patients to receive placebo.nnnRESULTSnThere were 12 asthma exacerbations in 10 patients who received placebo, 9 of whom had sputum eosinophilia at the time of exacerbation. In comparison, only one patient who received mepolizumab had an asthma exacerbation, and this episode was not associated with sputum eosinophilia (P=0.002). Patients who received mepolizumab were able to reduce their prednisone dose by a mean (+/-SD) of 83.8+/-33.4% of their maximum possible dose, as compared with 47.7+/-40.5% in the placebo group (P=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. Improvements in eosinophil numbers, asthma control, and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion. There were no serious adverse events.nnnCONCLUSIONSnMepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment. (ClinicalTrials.gov number, NCT00292877.)

Allergen‐induced increase in non‐allergic bronchial reactivity

Non‐allergic bronchial hyper‐reactivity is a feature of most patients with asthma. We have measured non‐allergic bronchial reactivity to inhaled histamine and methacholine in thirteen asthmatic subjects before and after allergen inhalation in the laboratory. The allergen inhalation produced mild early asthmatic responses (19–40% FEV1 fall) in all thirteen, additional definite late asthmatic responses (17–29% FEV1 fall) in four, and equivocal late asthmatic responses (5–11% FEV1 fall) in five. Following allergen inhalation, non‐allergic bronchial reactivity increased in seven for up to 7 days. The seven included all four with definite late asthmatic responses and three of the five with equivocal late asthmatic responses. We conclude that allergens make asthma worse, partly through non‐allergic mechanisms, and that avoidance of allergens is important in reducing non‐allergic bronchial hyper‐reactivity.

Allergen-induced increase in bronchial responsiveness to histamine: relationship to the late asthmatic response and change in airway caliber☆

Abstract Allergen-induced late asthmatic responses are associated with an increase in bronchial responsiveness to histamine. We have examined the relationship between the magnitude of the late asthmatic response and the magnitude and duration of increased histamine responsiveness. Allergen inhalation tests were carried out in 12 asthmatic subjects to induce a mild early asthmatic response (16% to 40% reduction in FEV 1 in the first hour after allergen inhalation); the response was followed over 8 hr to identify the occurrence and magnitude of any late asthmatic response (maximum fall in FEV 1 from baseline between 3 and 8 hr). The provocation concentration of histamine causing a decrease in FEV 1 of 20% (PC 20 ) was measured before and after inhalation of allergen. The magnitude of decrease in PC 20 correlated with the magnitude of the late asthmatic response as measured by the percent fall in FEV 1 (r = 0.8, p 20 was from 2 to 74 days and this also correlated with the magnitude of the late response (r = 0.53, p 1 , maximal expiratory flow-volume curves (on air and He-O 2 ), and histamine responsiveness were also measured before and at intervals after allergen inhalation. Four of seven subjects still had a reduction in PC 20 when the TLC, RV, FEV 1 , maximal expiratory flow-volume rates on air (V 50 air) and He-O 2 (V 50 He-O 2 ) (measured at an absolute volume corresponding plus 50% of control vital capacity) and ratio of V 50 He-O 2 to V 50 air were back t preallergen inhalation levels. In two of these subjects volume of isoflow was also back to ±10% of preallergen inhalation levels when the PC 20 was still significantly reduced. The results suggest that allergen-induced late asthmatic responses can be associated with an increase in bronchial responsiveness to histamine by mechanisms other than a reduction in baseline airway caliber alone.

Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations

One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal. A total of 117 adults with asthma were entered into a multicentre, randomised, parallel group-effectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils ≤2%; symptoms and spirometry were used to identify clinical control, exacerbations and other treatments. Patients were blind to sputum cell counts in both strategies and physicians were blind in the CS, thus removing bias. First, the minimum treatment to maintain control was identified in 107 patients (Phase 1) and then this treatment was continued (Phase 2) for the remaining of the 2u2005yrs. The primary outcomes were the relative risk reduction for the occurrence of the first exacerbation in Phase 2 and the length of time without exacerbation. The current authors also examined the type and severity of exacerbations and the cumulative dose of inhaled steroid needed. The duration and number of exacerbations in Phase 1 were similar in both groups. In Phase 2 there were a 126 exacerbations of which 79 occurred in the CS (62.7%) and 47 (37.3%) in the SS groups. The majority of the 126 exacerbations (101; 80.1%) were mild. The majority of the 102 exacerbations, where sputum examination was performed before any treatment (nu200a=u200a70), were noneosinophilic. In the SS patients, the time to the first exacerbation was longer (by 213 days) especially in those considered to need treatment with a long acting β2-agonist (by 490 days), the relative risk ratio was lower (by 49%), and the number of exacerbations needing prednisone was reduced (5 versus 15). This benefit was seen mainly in patients needing treatment with inhaled steroid in a daily dose equivalent to fluticasone >250 μg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups. Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations.

Late cutaneous allergic responses in isolated IgE-dependent reactions

Abstract Relationships between IgE-dependent reactions and late cutaneous allergic responses were examined. Heterologous whole antihuman IgE or its pepsin digest F(ab′)2 product injected intracutaneously produced immediate wheal and flare responses followed by late responses. Prausnitz-Kustner reactions were similar in appearance. The late responses were studied morphologically by conventional microscopy and by direct immunofluorescent techniques. The results support the thesis that in man, late cutaneous allergic responses can occur in reactions with an isolated involvement of IgE. There is a discussion of the possible relevance of these observations to antigen-induced allergic reactions in skin and in the respiratory tract.

Asthma and increases in nonallergic bronchial responsiveness from seasonal pollen exposure

Serial measurements of symptoms, peak flow rates, methacholine bronchial responsiveness, and ragweed-specific IgE antibodies were made before and during the ragweed pollen season in 13 sensitized subjects. Allergen inhalation tests were carried out with aerosols of pollen extract out of season in nine subjects; isolated early asthmatic responses were provoked in four, and dual responses (early followed by late) were provoked in five. During the pollen season all subjects developed hay fever and eight had symptoms of asthma. There was a real increase in methacholine responsiveness during the ragweed season. This increase appeared before or after the occurrence of asthma symptoms and changes in flow rates and was greater in subjects with symptoms in the pollen season, dual responses after allergen inhalation tests, and higher levels of ragweed-specific IgE antibodies. The results confirm the occurrence of seasonal asthma and increases in nonallergic (nonspecific) bronchial responsiveness to methacholine from seasonal pollen exposure. They suggest that the occurrence of symptoms is closely linked to the allergic inflammatory reaction and the induction of increased nonallergic responsiveness.

Late asthmatic responses induced by ragweed pollen allergen

Abstract Allergen inhalation tests with ragweed pollen extract were performed in 15 ragweed-allergic asthmatic subjects. Isolated early asthmatic responses were induced in 6 subjects, dual (early and late) responses in 8 subjects, and predominantly or isolated late responses in 1 subject. The frequency and magnitude of late asthmatic responses (LAR) indicate that they are important in the disease. LAR occurred in the more sensitive subjects; in general, these subjects required smaller doses of inhaled ragweed pollen extracts, exhibited larger skin test responses, and had higher serum levels of IgE antibodies to ragweed antigen E. Intradermal tests with ragweed pollen extract elicited early (wheal and flare) or dual (early followed by late) cutaneous allergic responses. With relatively large concentrations of injected ragweed allergen, dual responses could be elicited in virtually all subjects.

Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial.

Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways.

Standardization of inhalation provocation tests: Influence of nebulizer output, particle size, and method of inhalation

Standardization of inhalation tests requires a knowledge of factors that will affect the response. We measured the output and particle size of six types of nebulizers used for inhalation tests. Output varied considerably between nebulizers of different types (0.12 to 1.59 ml/min) and to a lesser extent between nebulizers of the same type. Particle size varied between 0.8 and 5.2 micrometer aerodynamic mass median diameter (AMMD). The influence of these two properties on bronchial response to inhaled methacholine was examined. Nebulizer output but not particle size (between 1.3 and 3.6 micrometer AMMD) altered the response. We also examined the effect of change in inspiratory time during inhalation from residual volume to total lung capacity on lung deposition of radiolabeled aerosol and on the provocative concentration of histamine required to reduce the 1-sec forced expiratory volume (FEV1) by 20% (PC20). A reduction in inspiratory time from 8 to 2 sec resulted in a lower total lung dose, relatively more aerosol deposited in central airways, and a higher PC20. The results emphasize the importance of keeping nebulizer output and pattern of breathing constant when performing inhalation provocation tests if consistent results are to be obtained.

The origin of airway hyperresponsiveness

Consideration of the origin of airway hyperresponsiveness appears central to understanding the origin of asthma. Subjects with and without asthma differ both in the ease with which airway narrowing is produced by inhalation of histamine or methacholine and in the ability to demonstrate a maximal response to these agents. The latter appears, on present evidence, to be due to an added mechanism in asthma rather than the absence of a potent inhibitory process. Airway hyperresponsiveness is probably acquired during life as a result of airway reactions to various stimuli, although genetic factors such as atopy are likely to predispose the person to develop hyperresponsiveness. Environmental stimuli include inhaled allergens, chemical sensitizers, airway infections, immunization, and ozone. Allergen-induced airway hyperresponsiveness occurs in association with late-phase asthmatic responses. This and ozone-induced hyperresponsiveness have been demonstrated to be associated with release of chemical mediators and the cellular phase of inflammation. Their effect does not appear to be accounted for by increase in airway epithelial permeability, decrease in airway caliber, reflex bronchoconstriction, or beta-adrenoceptor blockade. The mechanism(s) responsible for the induced hyperresponsiveness are unknown but may involve airway epithelial damage, edema in and around the airway walls, stimulation of the noncholinergic excitatory or inhibition of the nonadrenergic inhibitory systems, or a change in function of airway smooth muscle. Airway hyperresponsiveness can be transient or persistent. Transient increases in responsiveness are almost certainly associated with mediator release and inflammation. It is not known whether persistent hyperresponsiveness is due to the same process, fired, for example, by leaky mediator-releasing cells and/or to some persisting change in neurogenic or smooth muscle function.