Airway hyper-responsiveness to mannitol provides a good evaluation of atopy in childhood asthma.

Acta Paediatr. 2015 Jul;104(7):718-23. doi: 10.1111/apa.12968.

Airway hyper-responsiveness to mannitol provides a good evaluation of atopy in childhood asthma.


Attanasi M1, Rapino D1, Marcovecchio ML2, Consilvio NP1, Scaparrotta A1, Cingolani A1, Di Pillo S1, Chiarelli F2.
  • 1Allergy and Respiratory Diseases Clinic, Department of Paediatrics, University of Chieti, Chieti, Italy.
  • 2Department of Paediatrics, University of Chieti, Chieti, Italy.



AIM: The relationship between airway hyper-responsiveness (AHR) and atopy has been previously investigated, but there are still some issues to be clarified. The aim of this study was to assess the link between AHR and mannitol and atopy in asthmatic children.

METHODS: We evaluated 44 children with asthma, aged 6-16 years of age, using skin prick tests (SPTs), serum total and specific immunoglobulin E (IgE) levels and the mannitol challenge test (MCT).

RESULTS: We found a good correlation between AHR to mannitol and specific IgE against Dermatophagoides pteronissinus (r = -0.66, p < 0.001) and a weak correlation with specific IgE against dog dander (r = -0.33, p = 0.01) and Aspergillus fumigatus (r = -0.23, p = 0.02). Furthermore, we found a weak correlation between AHR to mannitol and serum total IgE (r = -0.30; p = 0.03), the sum of specific IgE to aeroallergens (r = -0.37, p = 0.01) and the number of positive SPTs (r = -0.31, p = 0.02).

CONCLUSION: Measuring AHR with MCT might provide an accurate evaluation of the degree of atopy in children. The patients with a higher degree of atopy were significantly more reactive to mannitol. In clinical practice, these results indicate that children with asthma who are more atopic may require more intensive treatment strategies to reduce AHR.

KEYWORDS: Airway hyper-responsiveness; Asthma; Atopy; Children; Mannitol

PMID: 25661794



Asthma is a chronic inflammatory airway disease, characterised by airway hyperresponsiveness (AHR) causing bronchoconstriction, and thereby provoking typical symptoms, such as dyspnoea, chest tightness, cough and wheezing. The AHR indicates a temporary airflow limitation when exposed to a bronchoconstricting stimulus. It is measured by airway challenges and it can be a valuable tool for confirming or excluding asthma, as well as for evaluating the efficacy of treatment. However, the origin of AHR is multifactorial and the different challenge tests are not equivalent. It has traditionally been measured by methacholine or histamine, which act directly on airway smooth muscle receptors. Although bronchial challenges with direct stimuli are very sensitive tools for screening airway responsiveness, they are not very specific for asthma diagnosis (1). Unlike the latter, the indirect challenge tests, such as adenosine monophosphate (AMP), hypertonic saline and mannitol challenge test (MCT), cause bronchoconctriction at least in part through the direct or indirect activation of airway mast cells and they are very important to confirm asthma (1).


Professor of Pediatrics, Professor of Medical Science

Figure 1. Relationship between PD15 (provocative dose causing a 15 % decline in FEV1) and specific IgE against Dermatophagoides pteronissinus. Pearson Correlation coefficient rp= -0.66; P<0.001.


The mannitol is an osmotic agent that causes a dehydrating effect on the airway epithelium producing to release of mediators from inflammatory cells in the bronchial mucosa, and ultimately leading to airway smooth muscle contraction and airway narrowing (2). The use of mannitol as a bronchial challenge agent has increased in recent years because of its ease of administration and the relationship that this challenge has to exercise induced bronchoconstriction (3) and to a lesser degree clinical asthma (4). In addition, there is increasing evidence to suggest that achieving control of asthma through monitoring airway inflammation and adjusting treatment based on this instead of simple spirometry and symptoms may provide an ‘‘early warning system’’ or ‘‘inflammometer’’ before asthma symptoms worsen or exacerbations occur (5). Atopy is defined as an abnormal tendency to produce immunoglobuline (Ig) E antibodies in response to common environmental allergens. Atopy and AHR in asthma are closely related (6). Atopy induces airway inflammation as an IgE response to a specific allergen, which induces or amplifies AHR. In atopic subjects, AHR increases or decreases according to the level of exposure to allergens. For seasonal allergens, AHR increases in the relevant season and returns to its normal level out of season, while for a perennial allergen, it varies according to the environment or the specific period (6). An association between increased AHR to indirect stimuli and allergen sensitisation, mainly to aeroallergens, has previously been demonstrated in both children (7) and adults (8). Since the indirect challenge tests are dependent on the presence of airway inflammation (4) and the atopy is a marker of inflammation, the aim of the our study was to evaluate the putative relationship between the airway response to inhaled mannitol and the specific IgE to individual aeroallergens and total atopic load (i.e. serum total IgE, number of positive skin prick tests (SPTs), the sum of specific IgE to aeroallergens). Several studies investigating the relationship between AHR and atopy describe atopy as a simple dichotomous variable, categorising individuals as atopic or non-atopic based on arbitrary cut-off points, either for IgE measurements or SPTs. There is evidence that levels of specific IgE or the size of the wheal diameter following SPT predict the likelihood of having symptomatic allergy.


Figure 2. Relationship between PD15 (provocative dose causing a 15 % decline in FEV1) and serum total IgE. Pearson Correlation coefficient rp= -0.30; P=0.03.


Therefore, in the present study we assess whether the AHR to mannitol correlates with, not only the presence, but also the degree of atopy. We recruited 44 Caucasian children with asthma (27 males), aged six to 16-years-of-age, who had been referred to the Paediatric Allergy and Respiratory Diseases Clinic of the Department of Paediatrics, University of Chieti in Italy between May and August 2011. They underwent SPTs, serum total and specific IgE levels and the MCT. We chose to investigate asthmatics with a FEV1 ≥60% predicted, that is of mild-to-moderate severity, as this group constitutes the majority of cases in the primary care setting. Our results are therefore relevant to real-life everyday practice and tend to reflect the typical patient encountered in clinical settings. Furthermore, for safety reasons bronchial challenge is generally precluded in individuals with more severe disease (FEV1 <60% predicted). Out the 44 enrolled children, 40 had a positive response to mannitol and all children presented an atopic status. The four patients without a positive response to mannitol were excluded from the statistical analyses because they were not representative of the sample of patients with a negative response to mannitol. The study’s findings were: a good correlation between AHR to mannitol and specific IgE against Dermatophagoides pteronissinus (r= -0.66, p<0.001; fig 1); a weak correlation with specific IgE against dog dander (r= -0.33, p=0.01) and Aspergillus fumigatus (r= -0.23, p=0.02); a weak correlation between AHR to mannitol and serum total IgE (r= -0.30; p=0.03; fig 2), the sum of specific IgE to aeroallergens (r= -0.37, p= 0.01; fig 3) and the number of positive SPTs (r= -0.31, p=0.02). The quantification of atopy and AHR may offer additional information because the demonstration of a relationship between degree of atopy and the AHR would support the concept that atopic sensitisation has an impact on AHR. The present study demonstrate that atopy-AHR correlation, albeit weak, is dose-dependent. The patients with higher degrees of atopy were significantly more reactive to mannitol than patients with lower degrees of atopy, supporting the role of the mast cells in the mechanisms of action for the MCT. In addition, the AHR to MCT correlates with allergic sensitisation to house dust mite, aspergillus, and dog (indoor allergens) in asthmatics, but not to grass, trees, and weeds. Those exposed and sensitised to indoor aeroallergens reported greater AHR. We speculate that sensitisation to indoor allergens might more likely to cause AHR because these allergens are more closely associated with airway inflammation than others (9). In according to our results, a review by Custovic (10) underlined the benefits of allergen avoidance in asthma, in particular upon AHR.

In conclusion, we suggest that there is a correlation between allergen exposure and AHR to inhaled mannitol, a useful surrogate inflammatory marker in the evaluation of asthma and a feasible, safe, and well-tolerated indirect bronchial challenge test. This implies that asthmatics who are sensitised to several aeroallergens may require a greater amount of therapy directed towards reducing the degree of AHR. Furthermore, we highlight the clinical benefits that can occur during a period of allergen avoidance. However, the present study has some limitations: the cross-sectional design, the small sample size and the inclusion of only atopic children who were positive to mannitol. Therefore, it is necessary that further studies with a longitudinal design are required on larger populations including non-atopic and mannitol negative subjects to confirm these preliminary findings.


Figure 3. Relationship between PD15 (provocative dose causing a 15 % decline in FEV1) and sum of specific IgE to tested aeroallergens. Pearson Correlation coefficient rp= -0.37; P=0.01.



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