Magnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients

doi:10.1016/S1081-1206(10)60471-1

Annals of Allergy, Asthma & Immunology

Volume 100, Issue 5, May 2008, Pages 457-462

https://doi.org/10.1016/S1081-1206(10)60471-1 Get rights and content

Background

Late asthmatic response (LAR) to allergen challenge is a validated method for studying the pathogenesis of and new treatments for asthma in the laboratory.

Objective

To evaluate the relationship between the magnitude of allergen-induced LAR and clinical and biological determinants, including sputum and blood eosinophil percentages and eosinophil cationic protein concentrations.

Methods

Thirty-eight untreated mild asthmatic patients (mean age, 21.2 years) were selected for the presence of allergen-induced early asthmatic response (EAR) and LAR. Each patient measured methacholine responsiveness (provocation dose that caused a decrease in forced expiratory volume in 1 second of 20% [PD₂₀FEV₁]) at baseline, differential blood cell counts and eosinophil cationic protein levels in blood and induced sputum, and serum neutrophil chemotactic activity at baseline and 24 hours after allergen challenge.

Results

A correlation was found between LAR (as area under the curve [AUC]) and sputum eosinophil percentages at baseline (r = 0.51; P = .001) and 24 hours after allergen challenge (r = 0.44; P < .007). Furthermore, we found significant correlations between AUC LAR and AUC EAR, baseline methacholine PD₂₀FEV₁, baseline blood eosinophil percentages, and baseline serum neutrophil chemotactic activity. A stepwise multiple regression analysis showed that the stronger determinants of AUC LAR were baseline sputum eosinophilia and AUC EAR.

Conclusion

Baseline sputum eosinophilia and functional findings are determinants of the magnitude of allergen-induced LAR.

Section snippets

INTRODUCTION

Early asthmatic response (EAR) and late asthmatic response (LAR) are characteristic features of bronchial allergen challenge in appropriately sensitized individuals,¹ but it is not clear which determinants affect the development and the magnitude of LAR. Only approximately 50% of patients with EAR have LAR,² and its development is related to certain determinants, especially hyperresponsiveness to direct stimuli and allergic sensitivity. Both these findings can predict the presence of LAR.3, 4, 5

Patients

Thirty-eight patients (12 females and 26 males; mean age, 21.2 years [range, 15-37 years]) with mild asthma were selected. All the patients were examined during a stable phase of disease, without respiratory tract infections and asthma exacerbations in the previous 4 weeks. In a preliminary evaluation, each patient had positive skin prick test reactions to at least 1 of the following: Dermatophagoides pteronyssinus, Dermatophagoides farinae, Graminaceae, and Parietaria officinalis (mean wheal

RESULTS

Allergen inhalation caused EAR and LAR in all the patients. The mean values of functional and biological findings measured before and after allergen challenge are reported in Table 2. As expected, methacholine PD₂₀FEV₁ significantly reduced during LAR compared with baseline values (0.052 vs 0.353 μg; P < .001). Sputum samples were successfully obtained from all the patients except 1 at baseline and 2 at 24 hours after allergen challenge testing. In the baseline evaluation, the median (range)

DISCUSSION

The main finding of the present study is that baseline and allergen-induced sputum eosinophilia are significantly associated with the magnitude of LAR in a group of patients with EAR plus LAR after allergen challenge. The hypothesis that the baseline level of airway inflammation can be a determinant of the development or magnitude of LAR has been previously investigated. Only 2 studies4, 5 examined the relationship between allergen-induced airway responses and baseline sputum eosinophilia. Both

ACKNOWLEDGMENTS

We thank Elisa Masino and Mariella De Santis for performing functional measurements in the laboratory.

REFERENCES (32)

MJ Alvarez-Puebla et al.
Determinants of allergen-induced late asthmatic responses in mild asthmatics
Chest
(2001)
FL Dente et al.
Reproducibility of early and late asthmatic responses to allergen challenge in a large group of asthmatics
Respir Med
(2000)
JV Fahy et al.
Analysis of cellular and biochemical constituents of induced sputum after allergen challenge: a method for studying allergic airway inflammation
J Allergy Clin Immunol
(1994)
PG Woodruff et al.
Relationship between airway inflammation, hyperresponsiveness, and obstruction in asthma
J Allergy Clin Immunol
(2001)
H Herxheimer
The late bronchial reaction in induced asthma
Int Arch Allergy
(1952)
SL Spector
Allergen inhalation: challenge procedures
L Bancalari et al.
Blood markers of early and late airway responses to allergen in asthmatic subjects: relationship with functional findings
Allergy
(1997)
PC Avila et al.
Predictors of late asthmatic response: logistic regression and classification tree analysis
Am J Respir Crit Care Med
(2000)
PM O'Byrne et al.
Late asthmatic responses
Am Rev Respir Dis
(1987)
JGR DeMonchy et al.
Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions
Am Rev Respir Dis
(1985)

GA Rossi et al.

Late-phase asthmatic reaction to inhaled allergen is associated with early recruitment of eosinophils in the airways

Am Rev Respir Dis

(1991)

AM Bentley et al.

Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen challenge in atopic asthmatics

Am J Respir Cell Mol Biol

(1993)

MJ Van der Veen et al.

The late asthmatic response is associated with baseline allergen-specific proliferative responsiveness of peripheral T lymphocytes in vitro and serum interleukin-5

Clin Exp Allergy

(1999)

GM Gauvreau et al.

Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation

Am J Respir Crit Care Med

(1999)

E Bacci et al.

Comparison between hypertonic and isotonic saline-induced sputum in the evaluation of airway inflammation in subjects with moderate asthma

Clin Exp Allergy

(1996)

E Bacci et al.

Induced sputum is a reproducible method to assess airway inflammation in asthma

Mediators Inflamm

(2002)

Cited by (16)

Which patients with asthma are most likely to benefit from allergen immunotherapy?
2022, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Airway eosinophilia has been associated with poor asthma control,65 and blood eosinophils have been associated with lung function decline.66 Several studies have shown that the LAR is associated with a pronounced airway eosinophilia when compared with the EAR only after an allergen challenge test,67-71 with a correlation between the size of the LAR and the degree of airway eosinophilia.72,73 After allergen exposures, significant differences were also observed in terms of systemic inflammation, particularly in individuals with dual asthmatic-responses, who had increased blood eosinophilia compared with EAR-only individuals73-76; in addition, differences are observed in circulating eosinophil progenitors at 12 and 24 hours.76-79
If allergen immunotherapy (AIT) is to be considered as a treatment option for allergic asthma, it must undergo the same developmental steps as other antiasthmatic drugs. The bronchial allergen challenge model has demonstrated excellent negative predictive value for the development of new therapies for asthma. Subcutaneous immunotherapy appears to have a clinical and significant effect on the early asthmatic response to mite, cat, and birch and grass pollens in children and adults. Use of AIT in children with asthma is widely practiced but not supported by as strong a level of evidence as in adults. House dust mite sublingual immunotherapy tablets demonstrate efficacy in asthma exacerbations and other outcomes when used as add-on therapy in adult patients. Using a biologic to improve the patient’s lung functions and asthma control before initiating AIT can transform unsuitable candidates for AIT into appropriate candidates. Because AIT is a form of personalized medicine, phenotyping the most suitable patient is necessary. Field studies of adults and children have suggested that polysensitized patients with rhinitis and Global Initiative for Asthma class 2 to class 4 asthma appear the most likely to be good responders. We hypothesized that AIT responders are those who demonstrate a high eosinophilic response to natural or experimental exposure.
Adjustment of sensitisation and challenge protocols restores functional and inflammatory responses to ovalbumin in guinea-pigs
2015, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
The late asthmatic response is associated with an influx of a range of inflammatory cells including eosinophils and T lymphocytes (Nabe et al., 2005). Eosinophilia is correlated with the magnitude of the LAR, both being significantly increased in humans and animal models following allergen challenge (Dente et al., 2008; Evans et al., 2012; Gauvreau et al., 1999). Additionally, corticosteroids which reduce eosinophil and lymphocyte numbers also decrease the LAR (Kawayama et al., 2008; Leigh et al., 2002).
Inhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced these 4 features (Smith & Broadley, 2007). However, the responses of guinea-pigs to Ova challenge have recently declined, producing no LAR or AHR and diminished EAR and cells. By making cumulative modifications to the protocol, we sought to restore these features.
Guinea-pigs were sensitised with Ova (i.p. 100 or 150 μg) on days 1 and 5 or days 1, 4 and 7 and challenged with nebulised Ova (100 or 300 μg/ml, 1 h) on day 15. Airway function was measured in conscious guinea-pigs by whole-body plethysmography to record specific airway conductance (sGaw). Airway responsiveness to aerosolized histamine (0.3 mM) was determined before and 24 h after Ova challenge. Bronchoalveolar lavage was performed for total and differential inflammatory cell counts. Lung sections were stained for counting of eosinophils.
Lack of AHR and LAR with the original protocol was confirmed. Increasing the Ova challenge concentration from 100 to 300 μg/ml restored AHR and eosinophils and increased the peak of the EAR. Increasing the number of sensitisation injections from 2 to 3 did not alter the responses. Increasing the Ova sensitisation concentration from 100 to 150 μg significantly increased total cells, particularly eosinophils. A LAR was revealed and lymphocytes and eosinophils increased when either the Al(OH)₃ concentration was increased or the duration between the final sensitisation injection and Ova challenge was extended from 15 to 21 days.
This study has shown that declining allergic responses to Ova in guinea-pigs could be restored by increasing the sensitisation and challenge conditions. It has also demonstrated an important dissociation between EAR, LAR, AHR and inflammation.
Chemokine profiles in blood associated with delayed asthmatic response to allergen challenge
2013, Respiratory Medicine
Role of CXCL13 in asthma: Novel therapeutic target
2012, Chest
B cells play an important role in allergic asthma. However, the mechanisms by which these cells are activated in the airways remain poorly understood.
We used a mouse model of ovalbumin (OVA)-induced allergic inflammation to study CXCL13 and to investigate the concentration of this chemokine in the BAL fluid derived from asthmatic and normal control subjects.
We found that OVA-challenged mice upregulate the CXCL13/CXCR5 axis, which is associated with several changes in their airways, including recruitment of B and CD4⁺ cells, development of bronchial-associated lymphoid tissue, and airway inflammation. Treating sensitized mice with an anti-CXCL13 antibody reduced cell recruitment, bronchial-associated lymphoid tissue formation, and airways inflammation. Interestingly, measurements of CXCL13 using enzyme-linked immunosorbent assay showed that levels of this cytokine were significantly elevated in BAL fluid from subjects with asthma compared with control subjects (median, 162 [range, 120-296] vs 31 [range, 120-156] pg/mL; P = .005).
All together, these findings suggest that CXCL13 is involved in the allergic airway inflammatory process, and targeting this chemokine may constitute a novel approach in asthma.
Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor α antibody, in a phase I study of subjects with mild asthma
2010, Journal of Allergy and Clinical Immunology
Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations. IL-5 is responsible for eosinophil differentiation, proliferation, and activation; IL-5 receptors are expressed on eosinophils and their progenitors, and targeting such receptors induces eosinophil apoptosis.
To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor α chain.
Single, escalating, intravenous doses (0.0003-3 mg/kg) of MEDI-563 were administered to subjects with mild atopic asthma (n = 44) over ∼3 to 30 minutes in this open-label study. Pulmonary function, symptom scores, adverse events, MEDI-563 pharmacokinetics, and levels of C-reactive protein (CRP), IL-6, eosinophil cationic protein (ECP), and eosinophils were evaluated.
Mean peripheral blood (PB) eosinophil levels decreased in a dose-dependent fashion (baseline ± SD, 0.27 ± 0.2 × 10³/μL; 24 hours postdose, 0.01 ± 0.0 × 10³/μL); 94.0% of subjects receiving ≥0.03 mg/kg exhibited levels between 0.00 × 10³/μL and 0.01 × 10³/μL. Eosinopenia lasted at least 8 or 12 weeks with doses of 0.03 to 0.1 and 0.3 to 3 mg/kg, respectively. ECP levels were reduced from 21.4 ± 17.2 μg/L (baseline) to 10.3 ± 7.0 μg/L (24 hours postdose). The most frequently reported adverse events were reduced white blood cell counts (34.1%), nasopharyngitis (27.3%), and increased blood creatine phosphokinase (25.0%). Mean C-reactive protein levels increased ∼5.5-fold at 24 hours postdose but returned to baseline by study end; mean IL-6 levels increased ∼3.9-fold to 4.7-fold at 6 to 12 hours postdose, respectively. Pharmacokinetic activity was dose proportional at doses of 0.03 to 3 mg/kg.
Single escalating doses of MEDI-563 had an acceptable safety profile and resulted in marked reduction of PB eosinophil counts within 24 hours after dosing.
New anti-inflammatory therapies for the treatment of COPD
2008, Drug Discovery Today: Therapeutic Strategies
Citation Excerpt :
New therapies for asthma are aimed at some of the relatively well-validated targets involved in the asthmatic airway inflammation. In this regard, because eosinophils seem to play an important role in inflammation [9], and reduction of eosinophil numbers in sputum leads to better asthma control [10], new approaches are also being directed at anti-eosinophil targets. These approaches can be divided into targets that block eosinophil-stimulating signals (e.g. anti-interleukin [IL] 5 monoclonal antibody [mAb]; mepoluzimab/reslizumab) [11] and those directed at the eosinophils themselves to induce apoptosis (e.g. anti-IL5 receptor [r] antibody; MEDI-563) [12].
Chronic obstructive pulmonary disease (COPD) encompasses three different phenotypes, chronic severe asthma, chronic bronchitis and emphysema. Although COPD is currently treated with long-acting bronchodilators and inhaled corticosteroids, new therapies are needed that with acceptable safety profile will maintain pulmonary function over time, accompanied by reduced morbidity and mortality and improved quality of life. Several new therapies are presently under development for COPD, and those aiming to modify relatively new targets are discussed in this review.

View all citing articles on Scopus

: Disclosures: Authors have nothing to disclose.

View full text

Original Articles: Mechanisms of Allergic and Immune DiseasesMagnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients

Background

Objective

Methods

Results

Conclusion

Section snippets

INTRODUCTION

Patients

RESULTS

DISCUSSION

ACKNOWLEDGMENTS

Chest

Respir Med

J Allergy Clin Immunol

J Allergy Clin Immunol

The late bronchial reaction in induced asthma

Int Arch Allergy

Allergen inhalation: challenge procedures

Blood markers of early and late airway responses to allergen in asthmatic subjects: relationship with functional findings

Allergy

Predictors of late asthmatic response: logistic regression and classification tree analysis

Am J Respir Crit Care Med

Late asthmatic responses

Am Rev Respir Dis

Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions

Am Rev Respir Dis

Late-phase asthmatic reaction to inhaled allergen is associated with early recruitment of eosinophils in the airways

Am Rev Respir Dis

Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen challenge in atopic asthmatics

Am J Respir Cell Mol Biol

The late asthmatic response is associated with baseline allergen-specific proliferative responsiveness of peripheral T lymphocytes in vitro and serum interleukin-5

Clin Exp Allergy

Kinetics of allergen-induced airway eosinophilic cytokine production and airway inflammation

Am J Respir Crit Care Med

Comparison between hypertonic and isotonic saline-induced sputum in the evaluation of airway inflammation in subjects with moderate asthma

Clin Exp Allergy

Induced sputum is a reproducible method to assess airway inflammation in asthma

Mediators Inflamm

Original Articles: Mechanisms of Allergic and Immune Diseases
Magnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients