Target Population

Mannitol challenges are used to assess airway hyperresponsiveness in adults and children 6 years of age and older. The mannitol challenge is as sensitive as methacholine for diagnosing asthma and has positive/negative predictive values of 79%/48% in a population without clearly diagnosed asthma (Spector et al. 2009; Stickland et al. 2011). The test can also be used to evaluate subjects with COPD (de Nijs et al. 2011).

Safety Considerations

The mannitol challenge can be safely carried out in adults and children using only a simple dry powder inhaler device. Mannitol is recognized to cause cough, which can be severe in some patients (Brannan et al. 2005).

Outcomes and Interpretation of Results

The mannitol challenge model has been a helpful clinical tool for assessing changes in AHR following intervention. Reproducibility of the test is suitable (Anderson et al. 1997), and the standardized test kit purchased from the supplier provides identical

Percent change in forced expiratory volume in 1 s

FIGURE 10.4 Percent change in forced expiratory volume in 1 s (FEVj) during inhalation challenge with doses of mannitol (mg) in patients with asthma without treatment (left) and following treatment with inhaled corticosteroids (ICSs) (right). The provocative dose of mannitol causing a 15% fall in FEV1 (PD15) shifts approximately 4 doubling doses higher with ICS treatment.

methodology for use in multicenter clinical trials. To date, there have been several airway therapeutics tested using mannitol challenges. After regular treatment with corticosteroids, the response to mannitol is significantly reduced (Figure 10.4) and in some patients inhibited completely (Koskela et al. 2003). The response to mannitol is also significantly reduced by sodium cromoglycate and nedocromil sodium (Anderson et al. 2010), which suggests that mannitol responsiveness reflects activation of airway.

In a study by Lipworth, mannitol inhalation challenge and the measurement of airway hyperresponsiveness were utilized as tools to titrate ICSs (ciclesonide) to improve asthma control and reduce airway inflammation (Lipworth 2012). The results of the study demonstrated that mannitol inhalation challenge and the associated increases in AHR facilitated the exposure of primary care patients to higher doses of ICS (Lipworth 2012). Furthermore, the levels of eosinophil cationic protein (ECP) and the fraction of exhaled nitric oxide (FENO) were lowered in the patients exposed to mannitol compared to the control group. This study suggested that mannitol challenge was tolerated well in mild to moderate asthmatics in the primary care setting; however, larger trials utilizing mannitol need to be conducted to evaluate severe asthmatics to further validate and explore the utility of mannitol.

Another study by Torok et al. utilized the mannitol inhalation challenge to determine the effects of budesonide and montelukast treatment on the pediatric population undergoing an exercise challenge (Torok et al. 2014). The main outcome of this study was to evaluate AHR after mannitol and exercise challenge. Torok et al. found that combination therapy with budesonide (bronchodilator) and montelukast (mast cell stabilizer) decreased AHR to both exercise and mannitol challenge compared to no treatment or budesonide alone (Torok et al. 2014). This highlights the utility of mannitol in evaluating the efficacy of drug therapeutics in the treatment of asthma.

Although mannitol inhalation (indirect) challenge is able to evaluate AHR, methacholine (direct) inhalation challenge is also able to evaluate AHR, and several studies have been completed to compare the mannitol and methacholine inhalation challenges (Anderson and Lipworth 2012; Lemiere et al. 2012).

Lemiere et al. compared methacholine and mannitol inhalation tests in people with occupational asthma (Lemiere et al. 2012). When comparing subjects with methacholine PC20 < 4 mg/mL and mannitol PD15 < 635 mg, there were no striking differences in symptom scores, FENO, sputum eosinophils, and FEVj. Based on this, direct and indirect bronchoprovocation tests appear to yield no differences in bronchial responses or airway inflammatory indices.

Another study published by Anderson and Lipworth compared different severities of asthmatics (mild, moderate, severe) and the ICS dose, FENO levels, FEVj, and ECP levels for those who have undergone mannitol and methacholine challenges (Anderson and Lipworth 2012). Mild asthmatics showed similar values in FEV1 and ECP levels in both the mannitol and methacholine challenge groups; however, FENO was lower in the mannitol group, while ICS dose was lower in the metha- choline group. Moderate asthmatics showed similar values in ICS dose, FENO levels, FEVj, and ECP levels in both the mannitol and methacholine challenge groups. Severe asthmatics showed similar values in FEVj and ECP levels; however, FENO was lower in the methacholine group, while ICS dose was lower in the mannitol group. Generally, the values of ICS dose, FENO levels, FEV1, and ECP level were consistent across disease severity groups (Anderson and Lipworth 2012). In the mannitol group, FENO levels increased as disease severity increased, and methacholine PC20 decreased as disease severity increased. However, in the methacholine group, FENO levels decreases as disease severity increased (opposite result compared to the mannitol group), and mannitol PD15 increased as diseases severity increased (same result compared to the methacholine group) (Anderson and Lipworth 2012). The different trends seen in FENO may be due to the difference in challenge targets (directs versus indirect); however, more studies comparing methacholine and mannitol are warranted in order to make any definitive conclusions.

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