Mechanical induction of cough in Idiopathic Pulmonary Fibrosis
© Jones et al; licensee BioMed Central Ltd. 2011
Received: 19 September 2010
Accepted: 10 April 2011
Published: 10 April 2011
Patients with idiopathic pulmonary fibrosis (IPF) frequently develop a dry, irritating cough which often proves refractory to anti-tussive therapies. The precise pathogenetic mechanisms responsible for this cough are unknown. We hypothesised that changes in nerves modulating mechanical sensitivity in areas of interstitial fibrosis might lead to enhanced cough response to mechanical stimulation of the chest in IPF.
We studied 27 non-smoking subjects with IPF (63% male), mean (SD) age 71.7 (7) years and 30 healthy non-smokers. Quality of life (Leicester Cough Questionnaire), cough symptom scores and cough severity scores (visual analog scales) were recorded. Percussion stimulation was applied over the posterior lung base, upper anterior chest and manubrium sternum at sequential frequencies (20 Hertz (Hz), 40 Hz and 60 Hz) for up to 60 seconds and repeated twice at two minute intervals. The number of subjects achieving two and five-cough responses, total cough counts and cough latency were recorded. In separate experiments, the effect of mechanical stimulation on the pattern of breathing was determined in eight IPF subjects and five control subjects.
In patients with IPF, we demonstrated strong correlations between subjective cough measurements, particularly the cough symptom score and Leicester Cough Questionnaire (r = -0.86; p < 0.001). Mechanical percussion induced a true cough reflex in 23/27 (85%) IPF subjects, but only 5/30 (17%) controls (p < 0.001). More patients with IPF reached the two-cough response at a lower frequency (20 Hz) posteriorly than at other positions. Highest mean cough totals were seen with stimulation at or above 40 Hz. Mechanical stimulation had no effect on respiratory rate but increased tidal volume in four (50%) subjects with IPF, particularly at higher frequencies. It was associated with increased urge to cough followed by a true cough reflex.
This study demonstrates that patients with IPF show enhanced cough reflex sensitivity to mechanical stimulation of the chest wall whilst normal individuals show little or no response. The observation that low frequency stimulation over the lung base, where fibrosis is most extensive, induces cough in more patients than at other sites supports the hypothesis that lung distortion contributes to the pathogenesis of cough in IPF.
Idiopathic pulmonary fibrosis (IPF) is a disease characterised by lung parenchymal distortion by fibroblastic proliferation with extracellular matrix deposition and an inflammatory cell infiltration. Patients typically present with progressive breathlessness but the majority develop an irritating cough during the course of the disease[1, 2]. This cough is typically dry and proves resistant to conventional anti-tussive therapies.
The majority of respiratory diseases associated with cough, such as chronic bronchitis, asthma and acute viral infections, predominantly affect the airways or upper respiratory tract where sensory innervation is dense. By contrast, pathological changes in IPF principally affect the lung parenchyma and alveoli, where innervation is sparse. It is therefore surprising that cough is so common in this disorder. The mechanisms which cause cough in IPF are unknown but several theories have been proposed. These include modulation of nerves in larger airways by neurotrophins generated within diseased lung parenchyma, mechanical lung distortion from fibrosis altering the activation of cough receptors and gastro-oesophageal reflux disease (GORD), which is known to be present in approximately 80% of patients with IPF.
Cough reflex sensitivity to chemical stimulation from inhaled capsaicin and substance P has been shown to be increased in patients with IPF, suggesting functional upregulation of pulmonary c-fibres[5, 6]. However, as far as we are aware, there have been no studies of the cough response to mechanical stimulation of the lungs in IPF.
Crystal et al.  reported that 80% of surgical lung biopsies showing characteristic changes of usual interstitial pneumonia (UIP) had evidence of peribronchiolar fibrosis and/or inflammation, with the majority of biopsies displaying evidence of both narrowed and dilated airways. It is therefore possible that mechanical distortion of peripheral airway architecture could sensitise rapidly adapting receptors (RARs) in small airways thereby lowering the cough threshold. Alternatively, c-fibres in the pulmonary interstitium, which have been reported to inhibit the cough reflex in certain species, could be destroyed by the progressive fibrotic process[7, 8].
Mechanical stimulation of the throat and trachea has been shown to induce cough in patients with upper respiratory tract infection but little or no cough in healthy subjects[9, 10]. In one such study, chest wall vibration over the manubrium sternum was performed using a chest percussor originally developed to assist clearance of bronchial secretions. This novel technique is potentially a non-invasive and safe method for inducing mechanical vibration of the underlying lung and hence physical deformation of sensory receptors such as RARs, independent of chemical stimuli.
In this context, the present study was devised with the following aims:
To examine whether mechanical stimulation of the chest wall can induce cough in patients with IPF and if so, whether this response is reliable and reproducible.
To assess whether varying the frequency of vibration and the site of stimulation induces different patterns of cough in patients with IPF.
To correlate measures of any cough induced by mechanical stimulation with subjective measures of cough assessed by validated questionnaires.
To determine whether mechanical stimulation of the chest wall has any effects on the pattern of breathing in patients with IPF or controls.
Study Exclusion Criteria
History of smoking within 1 year
Evidence of respiratory tract infection within 6 weeks
History of untreated rhino-sinusitis
Untreated gastro-oesophageal reflux disease
Asthma or other respiratory disease other than IPF
History of asbestos exposure
History of collagen vascular diseases
Other severe, systemic co-morbidity
Drug therapy with angiotensin-converting enzyme inhibitors
Chest wall deformity precluding mechanical percussion
Subjective Assessment of Cough
Cough symptom score
Cough for one short period
Cough on waking only
Cough for two or more short periods
Wake once or early due to cough
Frequent coughing, which did not interfere with usual daytime activities
Frequent waking due to cough
Frequent coughing, interfering with usual daytime activities
Frequent coughs most of the night
Distressing cough for most of the day
Distressing cough most of the night
Mechanical cough stimulation
Subjects attended the laboratory between 09:00 and 11:00, following abstinence from caffeine-containing drinks for at least six hours and fasted for at least two hours. They were asked to sit comfortably on a chair for a six minute acclimatisation period during which their spontaneous cough frequency was measured and subsequently used to calculate the background cough frequency. Each subject was asked to rotate 90 degrees in the chair and the percussor was applied with a uniform pressure, sequentially to the following areas of the chest wall:
the base of the right lung in the posterior axillary line,
the anterior right chest over the 2nd intercostal space in the mid-clavicular line and
over the manubrium sternum.
Using an initial stimulation frequency of 20 Hz, percussion was applied for a maximum of one minute but switched off if the subject coughed within the one minute period. Any vibration-induced cough that occurred within two minutes from the start of percussion was counted. After two minutes, this procedure was then repeated and at each area of the chest wall in triplicate. The total number of coughs in the three stimulation periods (corrected for background cough), was recorded as the six minute cough frequency. The number of subjects who achieved a two-cough and a five-cough response were recorded as C2 and C5 cough thresholds respectively. For determination of C2 and C5 responses, only coughs occurring during or within 15 seconds of cessation of mechanical stimulation were counted, in accordance with guidelines for other cough challenges. Cough latency (time to first cough) was also recorded. Percussion was then repeated in an identical manner at stimulation frequencies of 40 Hz and 60 Hz in immediate succession. Subjects who did not cough were recorded as non-responders. To assess the reproducibility of the technique, six patients with IPF underwent a repeat study using the above protocol at least one week after the initial study.
To determine any effects of mechanical stimulation on the pattern of breathing, the above protocol was repeated in eight patients with IPF (six who had previously coughed in response to mechanical stimulation and two who had not) and five normal volunteers using a portable recording device designed for the diagnostic assessment of cardio-respiratory sleep disorders (Alice PDx Diagnostic Systems, Philips-Respironics, Murrysville, PA, USA). This equipment provides measurement of: airflow from a nasal pressure cannula and oral thermistor; movements of abdominal and chest wall from effort belts, oxygen saturation and pulse using pulse oximetry. A built-in microphone also records associated sounds simultaneously. At the end of the recording period, all subjects were asked to describe subjective feelings of urge to cough, change in pattern of breathing or feelings of breathlessness.
Total cough counts during six minutes of stimulation are expressed as mean (SEM) and compared by the unpaired t-test. The unpaired t test was also used to compare baseline variables between groups. Non-parametric data are expressed as median (IQR) and compared by the Mann-Whitney U test and Wilcoxon's signed rank test. When analysing multiple comparisons of mean cough counts at different stimulation frequencies within individuals, a repeated measures one-way analysis of variance (ANOVA) was applied to normally distributed data with Tukey's pairwise analysis for determining true differences. Fisher's exact test was used to analyse categorical data and Spearman's rank correlation coefficient to assess association between variables. p values less than 0.05 were considered statistically significant. All data was analysed by using GraphPad Prism 5 (GraphPad Software Inc., CA, USA).
Baseline characteristics of the study subjects
n = 30
n = 27
Sex, male : female
21 : 9
17 : 10
Body Mass Index, kg/m2
26.3 ± 3.5
29.3 ± 4.6
Ever smoking: (% with ≥1 pack-year)
FEV1, % predicted
FVC, % predicted
DLCO ,% predicted
TLC, % predicted
LDQ score, median (IQR)
Corticosteroid use, n (%)
Subjective measures of cough
Cough induction with mechanical percussion
In healthy subjects, mechanical percussion induced very little cough and 25 out of 30 subjects (85%) exhibited no cough at any frequency at any site of stimulation. By comparison, 23 out of 27 patients (80%) with IPF coughed on percussive stimulation (p < 0.0001). Of the four patients with IPF who did not cough at all, three were receiving prednisolone.
• Posterior chest
• Anterior chest
Nineteen subjects with IPF achieved a two-cough response. This was achieved by nine subjects at 20 Hz, six at 40 Hz and four at 60 Hz (Figure 3a). In fifteen of these subjects, a five-cough response was induced during at least one period of mechanical stimulation (Figure 3b). Four healthy subjects exhibited a two-cough response to mechanical stimulation, at 40 Hz in two individuals and 60 Hz in two others. None exhibited a five-cough response.
• Manubrium sternum
Of the IPF group, 13 subjects demonstrated a two-cough response. This occurred in five subjects at 20 Hz, seven at 40 Hz and one at 60 Hz (Figure 3a). In eight of these individuals, a five-cough response was also detected (Figure 3b). Only one healthy subject demonstrated both a two and five-cough response, which was in response to stimulation at 20 Hz.
Total Cough Count
In IPF subjects who coughed in response to mechanical stimulation, the mean time to first cough (cough latency) ranged from 32.7 to 57.3 seconds at each stimulation frequency in each location tested. No clear pattern emerged in relation to site of chest wall stimulated, frequency of stimulation or subjective measures of cough (data not shown).
Relationship between total cough counts, subjective cough scores and lung function tests
Relationship between total six minute cough counts and subjective cough scores (LCQ, CSS and cough VAS) in subjects with IPF
Total six minute cough count
r = -0.29
r = -0.42
r = -0.24
r = -0.2
r = -0.42
r = -0.65
r = -0.06
r = -0.31
r = -0.41
p = 0.14
p = 0.028*
p = 0.231
p = 0.324
p = 0.028*
p =< 0.001*
p = 0.758
p = 0.116
p = 0.032*
r = 0.4
r = 0.51
r = 0.4
r = 0.39
r = 0.62
r = 0.73
r = 0.09
r = 0.48
r = 0.49
p = 0.038*
p = 0.007*
p = 0.038*
p = 0.043*
p =< 0.001*
p =< 0.001*
p = 0.638
p = 0.011*
p = 0.01*
r = 0.34
r = 0.28
r = 0.23
r = 0.22
r = 0.43
r = 0.63
r = 0.14
r = 0.23
r = 0.18
p = 0.079
p = 0.158
p = 0.241
p = 0.28
p = 0.024*
p =< 0.001*
p = 0.49
p = 0.243
p = 0.373
Reproducibility of mechanically induced cough
Effects of mechanical stimulation on patterns of breathing
This is the first study to investigate the effects of mechanical chest wall percussion on the cough reflex and patterns of breathing in patients with IPF. The technique appears to induce a true cough rather than an expiratory reflex in the majority of subjects with IPF, but has little or no effect on healthy controls in whom any cough was minor and short-lived. The latter observation is consistent with previous studies in healthy humans[10, 19, 20]. In particular, the observation that low frequency stimulation (20 Hz) over the lung base (where fibrosis is usually most extensive in IPF) induces a C2 cough response in more patients than at other sites is consistent with the hypothesis that distortion of lung architecture contributes to the pathogenesis of cough in IPF, possibly by a mechanism involving rapidly adapting receptors (RARs).
RARs terminate in the intrapulmonary airways of all mammalian species and are exquisitely sensitive to mechanical stimulation[21–23]. They are dynamic, afferent receptors that demonstrate sustained rapid activation to alterations in airway mechanics, but are relatively insensitive to capsaicin or inflammatory mediators such as histamine, bradykinin and prostaglandins. Studies on animals suggest that reduced lung compliance increases the discharge rate of RARs. RARs demonstrate rapid adaptation (1-2 seconds) to continued lung inflation and are very responsive to changes in dynamic lung compliance. It is therefore possible that reduced lung compliance in IPF may alter the firing rate of RARs resulting in an enhanced cough sensitivity as demonstrated in this study. Another possible explanation for our observations is that transmission of vibrated impulses from peripheral lung parenchyma to better innervated larger bronchi is enhanced in fibrotic lungs, thereby providing a greater mechanical stimulus to induce cough.
In this study, we excluded patients with chest wall deformities in order to minimise this as a confounding factor. However, stimulation over different areas of the chest wall may result in variability in the percussive stimulus exerted on the underlying lung due to differences in chest wall anatomy or thickness. As a group, the Body Mass Index of our patients with IPF was significantly greater than controls. Thus, any reduced transmission of the vibration due to increased chest wall thickness would favour a null hypothesis.
We cannot be certain that direct stimulation of RARs by mechanical vibration contributed to the cough response seen in patients with IPF. Indeed, the precise distribution and structure of RAR terminations in the intrapulmonary airways of patients with this condition are unknown [21, 22]. Furthermore, the vibratory stimulus applied in these experiments would likely result in stimulation of sensory nerves in both chest wall and airways and it is plausible that chest wall receptors in IPF may be altered by changes in the lung mechanics and volumes seen in this disease. However, by excluding smokers, subjects with concurrent respiratory disease and other causes of cough, we attempted to minimise the possible confounding factor of mucus in the distal airways stimulating mechanical receptors, although this cannot be entirely ruled out. Finally, in preliminary studies on patients using the percussor without (sham vibration stimulus) and with the right angle directional stroking adaptor (true vibration stimulus) to optimise the oscillatory effect, cough was only induced when the adaptor was applied whilst in sham experiments, no cough was observed.
This implies the mechanical vibration applied in the subsequent experiments was a true stimulatory impulse.
In contrast to the C2 response, fewer patients with IPF achieved the C5 threshold at any frequency. These results are similar to those of a previous study which used chemical stimulation with capsaicin to induce cough in IPF patients. This observation could be explained by the adaptation of RARs following their initial activation resulting in a short-lived cough response. Another possibility is that some individuals voluntarily suppress cough, an observation previously noted in normal volunteers inhaling capsaicin, whilst others may cough in more prolonged paroxysms. These findings add further support to the notion that the two-cough response is a more reliable measure of cough reflex sensitivity in IPF than the C5 response.
Our measurements of chest and abdominal wall movement and airflow at the mouth together with audio-visual recordings demonstrated that the cough we induced by vibration was indeed a true cough and not an expiratory reflex. Interestingly, it appears to be preceded by an increase in tidal volume but not rate of respiration and then followed by an urge to cough. The explanation as to why this should occur is uncertain but may relate to variation in density or sensitivity of RARs between individuals. In a previous study on chest wall vibration in five patients with asthma, the subjects described a sensation of breathlessness similar to an acute exacerbation of asthma but no cough was reported . To our knowledge, there are no reports describing this technique to study cough in patients with other respiratory conditions such as COPD, bronchiectasis or idiopathic cough.
It is noteworthy that a previous study reported an increased cough threshold to citric acid in healthy volunteers during simultaneous vibratory stimulation of the chest wall anteriorly in the right second intercostal space. The authors postulated that this inhibition of cough occurred due to chest wall afferent nerves affecting higher centres. However, the stimulation frequency of 100 Hz used in that study was greater than the maximum frequency that could be achieved by the percussor used in the present study. It is possible that mechanical induction of cough depends upon the balance of inhibitory chest wall afferents and stimulatory RARs within the lung and that the latter predominated in our experiments using lower frequencies.
The total cough response (six minute cough count) in patients with IPF was greater when higher frequency stimulation (40 and 60 Hz) was applied to all three areas of the chest wall, whilst again normal controls showed little or no cough response. This may indicate there is a threshold frequency for induction of cough which is lowered in patients with IPF. Interestingly, the total cough count correlated with some subjective assessments of cough severity, particularly the CSS. A recent study demonstrated strong correlations between objective 24 hour cough frequency and both the VAS and LCQ scores in patients with IPF. These findings suggest that in IPF, mechanical stimulation may be a good method for discerning cough of clinical relevance to patients' quality of life compared to chemical methods which induce cough in all subjects[5, 6].
In the present study, patients were asked to provide three different subjective measure of cough severity, all of which have been previously validated. The median VAS score of 38 mm was similar to results from previous studies[5, 6, 28, 29]. Our findings using the LCQ confirm that cough results in at least moderate impairment in quality of life for a significant number of patients with IPF. Furthermore, the LCQ correlated closely with the CSS. Indeed, all three subjective measure of cough showed good correlation. The CSS also indicated that patients cough significantly less at night than during the daytime, as recently confirmed in a study of diurnal objective cough counts in patients with IPF.
Previous studies in IPF have been unable to demonstrate a correlation between the VAS cough score and measures of disease severity assessed by pulmonary function[5, 6]. The present study similarly failed to demonstrate a relationship between any subjective cough scores and measurements of pulmonary function. These findings would suggest that cough is not a good marker for the severity of IPF and highlight the likely heterogeneity of mechanisms causing cough in this condition, with possible confounders being GORD and corticosteroid therapy. It is possible that HRCT scanning may prove more useful in this regard. However, whilst all our patients underwent HRCT scanning for diagnostic purposes, contemporaneous scans were unavailable for the majority of patients and we did not feel that repeat imaging was justifiable merely for the purpose of correlation.
In summary, this study demonstrates that patients with IPF show an enhanced cough reflex sensitivity to mechanical stimulation of the chest wall. It also shows there is a good correlation between cough induced by mechanical stimulation and subjective measures of cough severity, particularly the CSS. The observation that low frequency stimulation of the postero-basal lung base, where fibrosis is often most extensive, induces cough in more patients than at other sites is consistent with the hypothesis that lung distortion is a contributory factor to the pathogenesis of cough in IPF, possibly by activating RARs or destruction of inhibitory c-fibres. The use of chest wall percussion to induce a true cough reflex may prove a useful additional method for assessing novel anti-tussive therapies for cough in patients with IPF.
Dr K. E. Lewis (Prince Philip Hospital, Llanelli) and Dr. M. J. Ebejer (Neath and Port Talbot Hospital, Port Talbot) for identifying suitable patients for the study. Written consent for publication was obtained for the patient pictured in figure 1. No external funding was obtained for completion of this study.
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