The safety and feasibility of the inhaled mannitol challenge test in young children

To the Editor:

The mannitol challenge is an indirect challenge that increases airway surface liquid osmolality resulting in bronchoconstriction [1, 2]. Mannitol challenge tests are used clinically to diagnose asthma and, in particular, exercise-induced broncoconstriction (EIB) in adults and children above 6 years of age [3]. To date, mannitol has not been used as a challenge agent in children under 6 years of age and the feasibility and safety of its use in this age group is unknown.

The assessment of bronchial responsiveness in young children is difficult and limited by the cooperation of the child. The standardisation of lung function tests suitable for use in young children, such as the interrupter technique or the forced oscillation technique (FOT), provide an opportunity to assist in the assessment of bronchial responsiveness in young children and a variety of challenge tests using FOT have been reported in young children [4].

The aim of this preliminary study was to assess the feasibility and safety of the mannitol challenge test in young children using the FOT as the objective outcome measure.

20 children aged 3–7 years were recruited; 10 of these children were healthy and 10 children had a history of parentally reported exercise-induced symptoms (EIS) in the past year. The mannitol challenge test (Aridol; Pharmaxis, Frenchs Forest, Australia) was performed as previously published [2], with the exceptions that the respiratory resistance at 8 Hz (R_rs8) from the FOT was used as the primary outcome and the definition of a positive response was altered, as detailed below.

Prior to the mannitol challenge test the children were trained on the use of the mannitol dry powder inhaler using an inspiratory flow meter (In check; Clement Clarke International, Harlow, UK) configured to ensure that inhalation ranged between 30 and 50 L·min⁻¹ to optimise deposition of mannitol. An examination including chest auscultation, baseline heart rate (HR), arterial oxygen saturation measured by pulse oximetry (S_pO2) and lung function using FOT (I2M; Chess Medical; Ghent, Belgium) was performed in all children. During the mannitol inhalation challenge FOT was performed 1 min after each stage and 15 min after salbutamol inhalation at the end of the challenge. For baseline, control and post-salbutamol measurements, the R_rs8 was an average of all acceptable FOT measurements at that stage; while the highest R_rs8 following each mannitol inhalation was used as previously reported by our group [5]. The S_pO2 and HR were continually monitored throughout the test and the chest was auscultated within 1 min of each step of the mannitol inhalation.

A positive response to the challenge was recorded if there was one of the following: 1) an increase in R_rs8 by 50% from the control inhalations; 2) persistent cough after mannitol inhalation; 3) wheeze on auscultation and 4) a drop in S_pO2 to <90%. At the end of the challenge all children received 600 μg of salbutamol using a metered-dose inhaler through a large volume spacer regardless of response and all children were discharged when R_rs8 was within 20% of baseline.

The mannitol challenge was considered feasible if the child completed the test to the maximum dose of 635 mg, or until a positive response was noted. We considered the challenge safe if no serious adverse events were recorded, i.e. a fatal or life-threatening event, an event requiring inpatient hospitalisation, an event resulting in persistent or significant disability, or considered a medically important event or reaction.

All 10 children with EIS and seven healthy children completed the challenge (table 1). Three healthy children did not complete the challenge and refused to continue at different stages; all were 3 years old. None of the 17 children that completed the test developed any serious adverse events, according to the study criteria, and all participants were discharged in a stable condition. Based on the response criteria listed on the Aridol (Pharmaxis) product approved label, one child would be classified as having a serious adverse event during the mannitol challenge with both wheeze and a decrease in S_pO2 to 87% (subject 14). The family of this child also reported wheeze requiring reliever 2–4 h following discharge for which the parents administered salbutamol.

The mean (range) test duration in children that did not respond to the mannitol challenge was 45 (37–54) min and longer than the test duration in children with a positive response (31 (13–38) min). Transient cough during mannitol inhalation was present in 95% of the children, with intermittent cough post-inhalation noted in 70% and 20% of the EIS and healthy groups, respectively. Six of the 10 children with EIS responded to the mannitol challenge, while none of the healthy children had a positive response (table 1).

In this preliminary study we report that an inhaled mannitol challenge protocol, using FOT as an outcome, is feasible and safe in children aged 4–7 years, with 100% of children in this age group completing the test. The three children that failed to complete the test were 3 years-old and did not complete the test due to difficulty sustaining attention.

In this study there were no symptoms of serious respiratory distress noted during the challenge. One parent did report wheeze requiring reliever within 24 h following the challenge. Post-challenge asthma exacerbation within 24 h of a mannitol challenge has been reported in 0.2% of adults and older children [3]. Further, larger studies are required to accurately define the safety profile of mannitol testing in this younger age group.

Six of the 10 children in the EIS group responded to the mannitol challenge and none of the healthy children responded. While this study was not designed to assess the ability of the mannitol challenge test to identify EIB in young children, these results provide initial evidence that mannitol challenge tests may be useful in this young age group. Three of the six children that responded to the mannitol challenge did so by an increase in R_rs8, suggesting that FOT can be used with mannitol challenge to facilitate the diagnosis of EIS in young children.

We used a 50% increase in R_rs8 as a positive response. Previous studies using FOT with an inhaled challenge test used cut-off levels ranging from a 25% to 50% increase in R_rs [5–7]. If a 25% increase in R_rs8 is used to define a positive response the response rate in the EIS group would remain unchanged, with three of the healthy children being classified as having a positive response. Further studies to establish appropriate cut-off limits to be used for the mannitol challenge test with FOT as a primary outcome in young children are required.

In older subjects the mannitol challenge test is highly specific for a diagnosis of EIB when compared to exercise and hypertonic saline challenge tests [2, 3]. This preliminary study did not attempt to compare the mannitol challenge test with a free-running exercise challenge test [7], examine the reproducibility of the mannitol test in young children or explore methods for shortening the challenge test, and studies of this nature are required.

In summary, this preliminary study reports that mannitol challenge tests appear to be safe and feasible in children aged 4–7 years when combined with FOT to measure bronchial responsiveness. Further research exploring the role of mannitol testing in young children is required.

• Received March 7, 2013.
• Accepted July 5, 2013.

• ©ERS 2013