METHODS

Children (6–17 years) with recurrent cough (two or more episodes of cough, each lasting at least two weeks in the past 12 months) were recruited from the Royal Children’s Hospital outpatient department during a coughing episode. The children were assigned to one arm of a double blind placebo randomised controlled trial (inhaled salbutamol) as previously reported.¹⁵ On days 1 and 7, the children performed the capsaicin CRS test, and wore an ambulatory cough meter for a 24 hour period.¹⁶ Parents and children also completed separate colour coded cough diary cards.⁶ Formal consent was obtained and the study was approved by the hospital’s Ethics Committee on Human Research.

A reliable method of performing the capsaicin CRS test in children was utilised.¹⁰ Briefly, capsaicin (Sigma-Aldrich, Australia) diluted in 20% alcohol, was delivered through a nebuliser, controlled by a dosimeter (MB3, MEFAR, Italy) in a configuration that allowed regulation of the inspiratory flow and pattern. The dosimeter was set at 0.7 s inhalation time; normal saline and diluent controls were given before doubling concentrations of capsaicin (1.23 μmol to 1250 μmol) were inhaled. The number of coughs in the subsequent 30 seconds was counted by an independent observer. CRS measures were the lowest concentration of capsaicin required to stimulate 2–4 coughs (C2) and ≥5 coughs (C5). The cough meter used was a validated ambulatory cough meter¹⁶ that continuously records simultaneous electromyogram (EMG) and acoustic signals for 24 hours.

The parent(s) and child were given a colour coded chart and were asked to separately rate the severity of the child’s cough using a visual analogue scale (VAS). The VAS is a vertical scale from 1 to 10, with 10 representing the presence of the most severe cough and 1 representing the absence of cough.

RESULTS

Forty three children enrolled in the study. The cough meter analysis was unsatisfactory in three children: microphone dislodged in one; and cough meter removed because of intolerable itch in two. Data from these children were omitted from the analysis. The median age of the remaining 40 children (23 girls, 17 boys) was 9.4 years (range 6.2–17). Of these children, three pulled out of the trial and day 7 data were therefore incomplete.

The median number of coughs/24 hours was 75 for day 1 (range 9–719) and 44 for day 7 (0–500). On day 1, median value of child recorded VAS was identical to parent recorded VAS (median 4, range 1–10) and that for day 7 was 2 (range 1–10) and 3 (range 1–10) respectively. Not all children obtained a C2 value as their first outcome measure in the CRS test resulted in five or more coughs. Mean log C2 was 0.80 (geometric mean 6.37, 95% CI 0.6 to 1.01) and that for C5 was 1.31 (geometric mean 20.6, 95% CI 12.02 to 34.67) on day 1. C2 and C5 values both increased (representing reduced cough sensitivity) on day 7. The respective values for day 7 were 0.90 (geometric mean 8.0, 95% CI 4.66 to 13.8) for C2 and 1.5 (geometric mean 31.8, 95% CI 18.62 to 53.7) for C5.

On day 1, log cough frequency significantly correlated with parent and child recorded cough score and significantly negatively correlated with C2 (fig 1⇓) but not C5 (table 1⇓). Neither CRS outcome measure related to the subjective cough score (parent or child). On day 7, the relation between cough frequency and CRS measures was lost, although C2 had a weak but significant relation to parent recorded cough score (r_s = −0.38, p = 0.047). When the differences (changes) of the log values were taken (table 2⇓), C5 related significantly to cough frequency, and the relation with C2 was just outside statistical significance (p = 0.06) as shown in fig 2⇓. While 37 data points were available for C5, only 23 were available for C2.

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Figure 1

Log cough frequency measured using an ambulatory cough meter significantly correlated with log C2 (concentration of capsaicin required to stimulate 2–4 coughs); r_s = −0.5 (95% CI −0.74 to −0.18), p = 0.005.

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Figure 2

The change in measurements of the two occasions the tests were undertaken. (A) The correlation between the change in log cough frequency with change in log C2 was just outside statistical significance, r_s = −0.4 (95% CI −0.7 to 0.02), p = 0.06. (B) Change in log cough frequency significantly correlated with change in log C5, r_s = −0.38 (95% CI −0.63 to −0.07), p = 0.03.

DISCUSSION

This study shows that objectively measured cough frequency related to both subjective cough scores and CRS. The change in log cough frequency also related to the changes between cough scores and CRS. However, the relations between these commonly used indices of cough were modest and complex, and CRS measures related poorly to cough scores.

In a recent international symposium on cough, the lack of knowledge of the predictability of the capsaicin response and the relation of the response to objective markers were highlighted.¹ To date, there are no published data on the relation between CRS and objectively measured cough frequency or that between CRS and cough scores. This study shows that CRS related to cough frequency inconsistently and in a complex manner. The change in log values of cough frequency was significantly related to the change in log C5 value. This confirms the complex relation between cough frequency and CRS measurements. In contrast, the relation between cough frequency and cough scores was consistently significant. However, the relation was also not simple, reflected both in single time measurements and changes between measurements. We have previously shown a much stronger relation between cough scores and log cough frequency (r_s = 0.6 to 0.69),⁶ and the smaller correlation coefficient values in this study may reflect the smaller sample size (75 in previous study versus 40 in this study).

While objective measurements of cough frequency and subjective cough scores are easy to conceptualise, that of CRS is not as straightforward. CRS measures the ease of cough receptor stimulation by the tussive agent¹⁰ and hypersensitive (hyperresponsive) states have been documented in adults with idiopathic chronic cough, gastro-oesophageal reflux, rhinitis, viral respiratory tract infections,^7,11,18 and children with recurrent cough and cough dominant asthma.^13,14 There are different classes of cough receptors in any species type and interspecies differences are significant.^19,20 In humans, capsaicin stimulates vallinoid sensitive neurones.²¹ Changes in CRS have no relation to airway calibre changes.^14,22 Although measures of CRS have been shown to be useful in research for more than a decade, its relation to the different types of airway inflammation in the human airway is largely unknown. In children with cough and asthma, eosinophilic inflammation markers have no relation with CRS measures.²³ Neurogenic inflammation is closely linked to cough²⁴ and it is likely that markers of neurogenic (rather than neutrophilic or eosinophilic) inflammation have the closest relation to cough sensitivity.²⁵ Understanding these factors would be beneficial in the development of a cough suppressant agent that diminishes the hypersensitive response while preserving the cough expiratory reflex. This would be clinically useful in some conditions.¹

While CRS and subjective cough scores related in some manner with objective cough frequency, the relation between CRS and subjective cough scores was poor. It is likely that these different outcome indices measure different aspects of cough, although it is difficult to explain this further. The most clinically relevant index is thus, yet to be defined. At this stage, as with asthma airway hyperresponsiveness,²⁶ the most relevant outcome measure for cough will depend, at least in part, on the reason for performing the measurement. We conclude that in children, CRS has a modest relation with objectively measured cough frequency, and that subjective cough score has stronger and consistent relation to cough frequency. These cough severity indices measure different aspects of cough that are not interchangeable. The choice of which determinant to use thus depends on the reason for performing the measurement.