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. 2023 Apr 4;17:17534666231162246. doi: 10.1177/17534666231162246

Similarities and differences between the cough suppression test and the cough challenge test

Kun Zhao 1,*, Xiao Bai 2,*, Siwan Wen 3, Shengyuan Wang 4, Xianghuai Xu 5,✉, Li Yu 6
PMCID: PMC10074627  PMID: 37013420

Abstract

In recent years, a new test method namely the cough suppression test has been proposed to measure cough suppression in patients with chronic cough. The cough suppression test is a modified test based on capsaicin tussive challenge. There are similarities and differences between it and the more established cough challenge test in detection method, purpose and clinical significance. In this article, we will introduce and compare the concepts, application and methodology of the cough suppression test and the cough challenge test, summarize this research progress and problems of the two methods, and predict the possible role of both in the further study of chronic cough.

Keywords: cough challenge test, cough hypersensitivity syndrome, cough sensitivity, cough suppression test

Cough is a common respiratory symptom, which is defined as chronic when it lasts for more than 8 weeks. When etiology of chronic cough is unclear, or the etiology is identified but treatment has poor efficacy, it is called unexplained chronic cough or chronic refractory cough (CRC). 1 Severe cough can have serious negative impacts on the quality of life (QoL). 2 During the past 10 years, cough hypersensitivity syndrome (CHS) has been widely accepted as a new paradigm.3,4 Cough sensitivity, the sensitivity of cough reflex arc, is defined as the responsiveness of cough reflex to external stimuli.5,6 At present, there are many subjective and objective tests or tools to assess cough sensitivity, among which the cough challenge test is widely used. 7 Drawing on the cough challenge test, researchers have recently proposed the cough suppression test to demonstrate that the cough suppression ability of patients with chronic cough is weaker than the normal population.8,9 Herein, we review the similarities and differences between these two tests in terms of clinical significance, related mechanisms, operation methods and clinical application.

The concepts and clinical significance of the cough challenge test and the cough suppression test

Concepts

The cough challenge test involves patients inhaling aerosol particles, commonly capsaicin, by means of atomization to cause cough. In the cough challenge test, subjects are instructed to cough freely without any attempt to suppress any coughs. 10 Cough sensitivity is indicated by the minimum concentration of tussive agent required to elicit two coughs (C2) or five coughs (C5). 11 Both C2 and C5 have their own advantages, although C5 seems to be more widely used. Therefore, European Respiratory Society (ERS) recommended that both C2 and C5 should be recorded. 10

The cough suppression test is based on the standard cough challenge test, but subjects are instructed to suppress cough during the test. The concentrations of the tussive agent causing one cough (CS1), two coughs (CS2) and five coughs (CS5)8,9,12 are recorded.

Clinical significance

The cough challenge test is the most established and commonly used method to assess cough sensitivity. The decrease of C5 in participants indicates an enhancement in cough sensitivity, which including increased sensitivity of peripheral receptors and disorders of the cough centre. 13

The cough suppression test evaluates the suppression ability of the cough centre. The decrease of CS5 suggests the decrease of the cough suppression function, which may be caused by the central nervous system circuit disorders including the amplification of incoming sensory inputs and the loss of central suppression. 12

Comparison of the mechanisms of the cough challenge test and the cough suppression test

In 2010, Morice et al. 14 proposed the concept of CHS, which is defined as a condition where chronic cough is the only or most significant symptom. Cough hypersensitivity is considered a general characteristic of chronic cough. CHS involves the neural pathway mechanism and provides new directions for the diagnosis and treatment of chronic cough. 15 These studies into the neural pathways involved in chronic cough, have suggested that the mechanism of chronic cough includes increased sensitivity of the peripheral vagus nerve and imbalance of excitatory/inhibitory function of central nervous system. 16 Therefore, the cough challenge test assesses the dysregulation of the neural pathway, in which the suppression function of the cough centre can be evaluated by the cough suppression test. This neural pathway is illustrated in Figure 1.

Figure 1.

Figure 1.

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Central and peripheral neural pathways in refractory chronic cough and cough hypersensitivity syndrome. (a) Proposed central neural pathways in cough hypersensitivity syndrome. Vagus nerves receive stimulation and transmit to the vagus ganglion (nodose ganglia and jugular ganglia). The two ganglions project to the brain stem, specifically the nTS and the Pa5. The stimulus travels up through the brain stem to the cortex, and finally through the efferent nerve to produce the cough. If there is an imbalance of the excitatory/inhibitory functions of the higher brain regions, probably including the midbrain, forebrain and cortex, 17 the patients may have cough hypersensitivity syndrome. nTS, nucleus of the solitary tract; Pa5, the paratrigeminal nucleus. (b) Activation of peripheral sensory neurons. Ion channels expressed by vagal nerves respond to various stimuli, which result in the influx of calcium and the release of neuropeptides. Neuropeptides may perpetuate further afferent nerve activation and upregulate cough sensitivity. P2X3 and P2X2/3 receptors can be activated by ATP. The NaVs are opened in response to the activation of other channels and the vagus nerve generates action potentials transmitted to the central nervous system. In addition, there may be GPCRs involved in the regulation of the cough reflex.

GPCR, G protein–coupled receptor; NaV, voltage-gated sodium channel; P2X, ATP-gated (purine) cation channel; TRP, transient receptor potential; TRPA, TRP ankyrin; TRPM, TRP melastatin; TRPV, TRP vanilloid.

Cough challenge test

These studies suggest that the increased cough sensitivity in patients with chronic cough is related to a series of cationic channels expressed by the terminals of vagal sensory nerves, such as transient receptor potential (TRP) family, purinergic P2X family, voltage-gated sodium channels (NaVs) and so on 18 (Figure 1(b)). TRPV1 and TRPA1 are the most studied receptors in the TRP family. TRPV1 is sensitive to stimuli such as capsaicin, acid, inflammatory mediators and high temperature (> 42°C), TRPA1 is sensitive to stimuli such as acrolein, cinnamaldehyde and low temperature (<17°C irritation. Activation of TRPV1 and TRPA1 stimulates C-fibre endings, produces neurogenic inflammation, releases neuropeptides such as substance P and calcitonin gene-related peptide, and upregulates cough sensitivity. 19 P2X3 and P2X2/3 receptors, the most well-studied in ATP-gated (purine) cation channel (P2X) family, can be activated by ATP. The activation of the two receptors stimulates the afferent nerve to release inflammatory cytokines, which promotes inflammation and induces cough. NaVs can generate action potentials in response to the activation of other channels. NaV1.7, NaV1.8 and NaV1.9 seem to be selectively expressed in the cough reflex in guinea pigs. 20 In addition, there may be G protein–coupled receptors (GPCRs) involved in the regulation of the cough reflex. 21

The most used stimulus, capsaicin, which acts on TRPV1, opening the non-selective cation channel of C-fibre, leading to the influx of calcium ions and sodium ions, and finally leading to the activation of vagal afferent C-fibre.22,23 In addition to capsaicin, other stimuli include (1) allyl isothiocyanate (AITC) and cinnamaldehyde, which are considered as TRPA1 agonists; 24 (2) citric acid (the mechanisms not completely clear and may be involved in TRPA1, TRPV1 and acid-sensing ion channels);25,26 (3) hypertonic aerosols including mannitol and hypertonic saline, which may cause excitation of airway sensory nerve by hyperosmolality; 26 (4) ATP, which could be involved in TRPV4-ATP-P2X3 axis. 27 The cough challenge test can reflect sensitization of the participants’ peripheral cough–related receptors.

The cough suppression test

The cough reflex central pathway is not fully understood. These studies suggest that the vagus nerve endings in certain parts of the airway receive corresponding stimulation and transmit to the vagus ganglion (nodose ganglia and jugular ganglia), and the two ganglions project to the corresponding cough centre–nucleus of the solitary tract (nTS) and the paratrigeminal nucleus (Pa5), respectively. The stimulus travels up through the brain stem to the cortex, and finally through the efferent nerve to produce the cough28,29 (Figure 1(a)). Substance P, glutamate and other neurotransmitters may be involved in this pathway, causing central sensitization, the imbalance of excitatory/inhibitory function of the cough centre and ultimately leading to the generation of chronic cough. The cough suppression test assesses the function of the response inhibition neural circuit.

Applications

The cough challenge test can be used for (1) the assessment of cough reflex sensitivity;22,30 (2) the development and evaluation of efficacy of peripheral antitussive drugs; (3) the assessment of voluntary coughing in stroke patients to predict the risk of aspiration pneumonia. 31

The cough suppression test can be used to (1) assess the ability of the cough centre to suppress cough in patients with chronic cough or other diseases with cough symptoms;8,12 (2) potentially assist in the identification of central therapy for chronic cough, such as speech and language therapy;32,33 (3) potentially guide the development and evaluate the efficacy of central antitussive drugs, especially for patients with poor efficacy of peripheral receptor antagonists. 34

Comparison of the methodology of the cough challenge test and the cough suppression test using capsaicin

Preparation and storage of capsaicin

Capsaicin (30.5 mg) is dissolved in pure ethanol (1 mL) and Polysorbate 80 (Tween 80, 1 mL), which is stored at 4°C. Before the test, this solution is further diluted with normal saline. Each subject inhales normal saline as the control, followed by increasing concentrations of capsaicin.9,10

Method of capsaicin inhalation

The inhalation methods of capsaicin include tidal-breath inhalation 35 and dosimeter-controlled inhalation. 10 The method of tidal-breath inhalation is that the increasing concentrations of capsaicin solution are atomized and inhaled with tidal-breath for 15 s each time. And the number of coughs within 1 min from the beginning of inhalation of capsaicin solution is observed. The advantages of tidal-breath inhalation are simple equipment and easy operation. However, the main disadvantage is that tidal volume and respiratory rate vary from person to person and even between each inhalation, and thus it is difficult to accurately quantify inhaled doses. 36 Dosimeter-controlled inhalation is recommended for cough challenge test according to ERS guidelines for cough assessment. 10 In the method of dosimeter-controlled inhalation, a special nebuliser controlled by a dosimeter is used and the straw and baffle assembly of the nebuliser is welded in place. Given that exact output of a nebuliser is stable, adjusting the duration of aerosol delivery could determine the aerosol output per inhalation.37,38 Before each dose, the subjects are required to exhale to just below functional residual volume (FRC). The capsaicin solution is then inhaled at the corresponding concentration starting from low to high through the specific atomizer. After inhalation, the number of coughs within 15 s is observed and recorded.

The cough challenge test

The ERS guidelines for the assessment of cough (2007) proposed the standardization recommendations for the cough challenge test. 10 Subjects are instructed not to suppress cough, and avoid talking. When using the single-breath dosimeter-control method, the number of coughs within 15 s (or 30 s according to Chinese national guideline on diagnosis and management of cough (2021)) 11 after inhaling each capsaicin concentration is recorded. The reason for this difference is that the recording time has not been standardized,39–42 and cough induced by capsaicin usually occurs within seconds and lasts no more than 10 s. 9 These two times are commonly used in research.10,38,39,43,44 The concentrations of capsaicin that elicit one cough, two coughs and five coughs, respectively, are termed as C1, C2 and C5. The test is stopped when C5 is recorded or the maximum concentration (1000 μmol/L) is reached.

Because individual cough sensitivity of subjects varies so greatly, different reference values are set for the cough challenge test for different populations and research centres. In 2013, Chen et al. 45 reported the general reference value of C5 in capsaicin test in the Chinese population of ⩾ 125 μmol/L. Some scholars also proposed that the maximum capsaicin cough response may have more diagnostic and predictive value than C5. 46

The cough suppression test

Subjects are asked to try to suppress coughing during the test, and not informed of the end-point. The number of coughs within 15 s after inhaling each capsaicin concentration is recorded, to determine CS1, CS2 and CS5. The test is stopped when CS5 is recorded or the maximum concentration (1000 μmol/L) is reached.

In 2019, the cough suppression test was used by Cho et al. 8 in patients with CRC and demonstrated the impaired cough suppression function in CRC patients. In this research, 30 CRC patients and 23 healthy controls completed the cough suppression test. One of the important conclusions was that the cut-off value to distinguish CRC from healthy people was 39 μmol/L. 8 At present, cough suppression test has not been widely used and, therefore, there is a lack of further researches on cut-off value.

Recent progresses in clinical applications of the cough challenge test and the cough suppression test

Cough challenge test

Improvement of stimulus

The cough challenge test has been used in studies on cough sensitivity assessment for decades. The further development of the cough challenge test in clinical practice has been limited due to its high requirements of reagents and equipment, as well as the poor diagnostic value. 47 Thus, cough-provocation tests with hypertonic aerosols (CPTHAs) or with ATP as the stimulus were introduced recently.

Hypertonic aerosols including hypertonic saline and mannitol, are commonly used in cough challenge. The advantages these have over capsaicin, citric acid and other traditional stimuli, are ease of acquisition and storage, and less indoor air pollution. The review of Koskela et al. 48 introduced CPTHAs in detail. They concluded that CPTHAs could be advantageous compared with traditional cough challenge test due to the simplicity of the equipment and higher safety. It should be noted that CPTHAs have a higher value in the diagnosis of asthma than capsaicin-based cough provocation tests. 48 Koskela et al. 48 suggested that CPTHAs had higher sensitivity of five coughs per 100 mg (C5) and higher specificity of 12 coughs per 100 mg (C12) in the diagnosis of abnormal cough reflex function.

Considering the role of P2X3 ATP receptor in the pathogenesis of CRC, Fowles et al. 49 have applied ATP and AMP as stimuli in the cough challenge test. The mechanism of ATP inducing cough may be related to the activation of Aδ afferent vagus nerve fibres mediated by TRPV4, or the activation of C fibres mediated by TRPV1. The results showed that patients with chronic cough were more sensitive to ATP and AMP than healthy subjects, but that these stimuli did not perform better than capsaicin or citric acid, so were not suitable and effective to be routine stimuli for cough challenge tests.

Application in various cough-related diseases

The diagnostic value of the cough challenge test is limited because of the large variability of response in healthy subjects, but there are many other clinical applications that deserve to be actively explored. Chronic cough patients have been found to be hypersensitive to common cough stimuli, such as capsaicin,50,51 citric acid,52,53 ATP 49 and mannitol 52 in cough challenge test. It was also found that patients with gastroesophageal reflux–associated cough were more sensitive to citric acid and capsaicin than healthy volunteers.54,55 The studies on patients with chronic obstructive pulmonary disease (COPD) are conflicting. 5 In one study, patients with COPD were hypersensitive to capsaicin but not to citric acid, 56 but another study came to the exact opposite conclusion. 57 However, most studies support that COPD patients have a higher cough sensitivity compared with healthy subjects.57,58 A study by Cho et al. 12 suggested that the higher cough sensitivity for capsaicin is associated with chronic cough in COPD patients, which is an inspiration for subsequent studies. As for asthma, the cough sensitivity of patients with stable asthma do not differ from healthy subjects, while the cough sensitivity of cough variant asthma is significantly increased. 5 In a recent study, increased cough sensitivity was also found to be a significant risk factor for poor asthma control and frequent exacerbations. 59 Besides, Guan et al. 60 found that C2 and C5 were significantly reduced in patients with bronchiectasis, reflecting the increased sensitivity of cough reflex in patients with bronchiectasis. They also found that increased cough sensitivity could indirectly reflect the severity of bronchiectasis. The applications of cough challenge test in respiratory cough diseases still needs further studies.

Cough challenge tests have other uses. Through the cough challenge tests, it was found that acute viral upper respiratory tract infection (URI) patients had increased cough sensitivity, 61 some of which would develop chronic cough. 62 We suppose that URI patients with the lower C5 may be more likely to develop the chronic cough; however, this needs further studies. Besides, angiotensin-converting enzyme inhibitors (ACEIs) are known to increase cough sensitivity in patients. 30 This is a major side effect of ACEIs that can cause patient distress. This side effect can be monitored by cough challenge testing, thus guiding the clinical use of ACEIs.

Cough suppression test

Evaluation of central suppression function in patients with CRC

As early as 1993, the cough suppression test was used by researchers to test the cough suppression ability of healthy volunteers, 9 but due to the limitations of the equipment and research progress at that time, the cough suppression test was not fully developed.

In 2009, Young et al. 63 compared the cough suppression ability of CRC patients and healthy volunteers using the citric acid inhalation cough suppression test. This study showed that both CRC patients and healthy subjects had significant cough suppression ability, and that suppression was more effective in healthy subjects. In 2019, Cho et al. 8 applied the capsaicin cough suppression test to patients with CRC. They found that there was no statistically significant difference between CS5 and C5 in CRC patients, while healthy volunteers had a high degree of cough suppression ability, indicating that the cough suppression ability of CRC patients was significantly impaired. Both studies showed that CRC patients could not suppress their cough as effectively as healthy subjects. However, the impaired cough suppression in CRC patients observed by Young et al. 63 was not as significant as that observed by Cho et al. 8 This may be due to the relatively small number of subjects included in Young et al. 63 with only 10 healthy volunteers and 10 CRC patients completing the cough suppression test, compared with 30 CRC patients and 23 healthy volunteers completing the cough suppression test in the Cho et al. 8 study.

The study by Cho et al. 8 showed that 39 μmol/L of CS5 had a good specificity and sensitivity for distinguishing CRC patients from healthy people, which indicated that the subject with CS5 < 39 μmol/L may be a CRC patient with impaired cough suppression. In 2021, Cho et al. 12 applied the cough suppression test to COPD patients, and found that the increased cough sensitivity in COPD patients with chronic cough rather than those without chronic cough, but the cough suppression ability still existed.

The impaired central suppression function in CRC patients were confirmed by a series of studies using the cough suppression test, and this may be a characteristic of chronic cough patients. This finding provides a basis for the development of central therapeutic methods for CRC patients. In addition, we suppose that the cough suppression test may have the potential to identify CRC patients, especially who could benefit from central antitussive therapies, such as opioids. This conjecture needs to be demonstrated by further researches and could be a direction for the following studies.

Application in other diseases with cough as the main symptom

The cough suppression test has great potential in the evaluation of other diseases in which cough is one of the main symptoms. Hutchings et al. 64 analysed whether voluntary cough suppression could be used as an index of symptom severity in URI. The study found that some of subjects suppressed coughing less than 12.6 min (cough break group), while others could suppress for more than 20 min. The baseline cough frequency, post-cough suppression frequency and subjective cough severity scores of the cough break group were significantly higher than those of another group. Therefore, although the causes are not clear, impaired cough suppression seemed to signify worse severe cough symptom in patients with URI. 64 This study provided novel ideas for the future application of the cough suppression test. Similarly, more studies could be conducted using the cough suppression test in a range of respiratory diseases such as asthma, chronic bronchitis, and so on to evaluate their use in the classification, diagnosis and treatment of these diseases.

Application in the localization of higher cough centres in the brain

Tests like cough suppression tests have been used in functional brain imaging study.65,66 Mazzone and Farrell’s group first used functional neuroimaging to demonstrate reduced activities in central cough suppression. Based on their findings, the cough suppression test study was modified to investigate the central neural pathways suppressing cough. Specifically, during the test, subjects were instructed to suppress their cough as much as possible. The concentration of capsaicin that caused two coughs (recorded as C2, but more like CS2 in terms of definition) using the method of limits was determined. At least three sets of capsaicin concentrations were set: below C2, equal to C2, or above C2, and subjects were instructed to breathe through their mouths through a specific nebulizer. In each magnetic resonance imaging (MRI) scan, low to high concentrations of aerosolized capsaicin were inhaled to obtain imaging results of brain functional activity. Capsaicin stimulation was associated with activation of the primary sensorimotor cortex, anterior insula, anterior central cingulate cortex, prefrontal cortex, supplementary motor area and cerebellum and cough suppression may be associated with inferior frontal gyrus, dorsolateral prefrontal cortex and anterior middle cingulate cortex and so on.17,65–67 The results showed that in patients with chronic cough, some brain regions were activated and some brain regions were inhibited, suggesting that dysregulation of excitation and/or suppression in related brain regions is one of the important causes of chronic cough. Currently, all studies use C2 or CS2 as the research index, and more studies are needed to determine whether the accuracy of CS5 can be improved.

Application in the evaluation of the efficacy of central cough medications

In general, cough suppression can be divided into voluntary suppression and involuntary suppression. 68 Cough has a strong propensity to be influenced by subconscious, 68 as shown by the fact that placebo can significantly reduce urge-to-cough rates. 69 This property reflects involuntary suppression of cough. Currently, the effect of antitussive agents commonly used in clinical practice is probably in large part due to the placebo effect, 70 which is considered a manifestation of involuntary suppression of cough. For voluntary suppression treatments, cough suppression test could become a tool to identify and evaluate the efficacy of centrally acting antitussives. Opioid agonists are recommended as centrally acting effective antitussives.2,71 However, the mechanism of opioid agonists remains unclear, and the effects of opioid agonists on cough suppression test have been found to be contradictory. In 1994, Hutchings and Eccles. 72 found that codeine could not increase voluntary suppression of capsaicin induced cough. In comparison, in 2016, Kelly et al. 34 used citric acid as a cough stimulus in the cough suppression test to assess the effect of fentanyl on adult cough, concluding that fentanyl can enhance the cough suppression ability of healthy people. The results suggested that fentanyl was more potential to be central antitussive than codeine for patients with chronic cough. Cough suppression test is promising to assist in the development and evaluation of additional centrally acting treatments in the subsequent studies.

Advantages and disadvantages of the cough challenge test and the cough suppression test

The cough suppression test and the cough challenge test both have important clinical and research applications. From the perspective of symptomology, the abnormal results of the two tests reflect the sensitivity to cough provocation of patients, as well as the cough severity. It has been proven that both tests have good sensitivity and specificity. However, from a pathophysiological perspective, the two tests assess cough reflex sensitivity and central cough suppression functions, respectively, which explains chronic cough from different perspectives. Therefore, although the two tests both have their strengths and weaknesses in certain areas (Table 1), they are functionally complementary but not substitutable.

Table 1.

Comparison of advantages and disadvantages of the cough suppression test and the cough challenge test.

Item Cough challenge test Cough suppression test
Repeatability High High
Association with the subjective quality of life scale Low Low
Follow-up value Limited Limited
Interference factors Mainly objective factors Probably subjective factors
The value of CRC identification Limited Higher
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CRC, chronic refractory cough.

The cough suppression test seems to be more valuable in distinguishing patients with CRC from healthy people

Although both the cough challenge test and the cough suppression test have good sensitivity and specificity, the cough suppression test seems to be more sensitive and specific in distinguishing patients with CRC from healthy people. 8 Many studies have confirmed that one of the biggest shortcomings of the cough challenge test is that cough sensitivity in individuals varies greatly, resulting in a lack of population specificity of cough sensitivity, and a large overlap of C5 between healthy people and patients with chronic cough. 73 This makes the diagnostic significance of C5 insufficient. It is hard to spot the cough patients from the healthy population using the cough challenge test. 74 The cough suppression test could overcome this deficiency. Besides, Cho et al. 8 also showed the good repeatability of cough suppression test with a 5-day interval, and CS5 is more repeatable than CS2. However, more studies are needed to confirm the repeatability of cough suppression test. By contrast, a lot of studies have confirmed the repeatability of cough challenge test, ranging from 20 min to 6 months. 38 Current cut-off value of the cough suppression test was reported only in one study, in which 39 μmol/L of CS5 (using capsaicin) is considered as the critical point to distinguish healthy people from patients with CRC. 8 Patients with CS5 lower than 39 μmol/L may have impaired central cough suppression function, thus, central antitussive therapy should be taken into consideration. Further studies are needed to verify the sensitivity, specificity, repeatability and reference values of the two methods.

Both the tests are objective assessments, and the correlation with subjective assessment remains to be further studied

Like cough challenge test, cough suppression test was also found to be significantly correlated with objective cough frequency in patients with chronic cough.8,50 However, according to the existing studies,8,12,50 the relationship between cough suppression test and objective cough frequency seems to be less significant than that of cough provocation test, which may be attributed to the lack of studies on cough suppression test. However, no significant association was observed between the cough suppression test results and the subjective QoL scale results currently. 8 And only weak correlation was found between capsaicin/citric acid cough challenge test and subjective assessment results.8,47 This may be because both cough suppression test and cough challenge test are parts of the complex mechanism of chronic cough, and subjective evaluation and objective evaluation of chronic cough are two different dimensions with low correlation.50,75 In a mannitol cough challenge study, cough sensitivity was found being associated with Leicester cough questionnaire (LCQ) scores in chronic cough patients; 76 however, this may be due to a small sample size and narrow distribution of LCQ scores. 52 In subsequent studies, no correlation was found between LCQ and hypertonic saline/mannitol cough test.48,77 In summary, research so far suggest that the association between these two tests and subjective assessment is not significant.

The two tests complement each other in clinical practice

The improvement in cough symptom after the treatment of opioid without any change in C5, 78 suggested a poor correlation between symptom improvement and changes of objective test results. It is speculated that opioids primarily act centrally and thus cough challenge tests is unavailable in follow-up. Considering the complex mechanism of chronic cough, neither cough challenge test nor cough suppression test may be ideal when used alone. The results can be more indicative when they are used together.

In practice, however, tachyphylaxis and desensitization should be taken into consideration if the two tests are to be used. Researches have found that continuous inhalation of citric acid, capsaicin or distilled water over 1 min resulted in a significant reduction in cough frequency, and repeated cough challenge test at 10-min intervals also resulted in significant tachyphylaxis. 79 In addition, capsaicin has been found to reduce cough sensitivity.80,81 Although the mechanism is not clearly understood, some scholars suggest that capsaicin may deplete neuropeptides in the sensory nerve endings.82,83 Similarly, the increase of cough thresholds was observed after inhaling increasing concentrations of citric acid. 84 This means that when we need to use the two tests, we should pay attention to the duration of inhalation and the frequency of the tests. It may be better to choose exactly which method to use according to the purpose.

Comparison of the influencing factors on the test results

The cough challenge test is prone to be influenced by a few factors, such as smoking, gender and body mass index (BMI). Taking smoking as an example, it is known that smoking may lead to the desensitization of cough receptors and excessive mucus secretion covering the receptors.85,86 As a result, the cough reflex sensitivity of smokers is lower than who quit smoking and non-smokers. 86 This means that when cough challenge test is used for measuring the cough reflex sensitivity, the effect of smoking on the results needs to be taken into account. Smoking and other factors limit the application of cough challenge test. In the cough suppression test, no significant difference in CS5 was observed so far between smokers and quitters. 12 The influence of emotion on voluntary cough inhibition ability has been proposed and observed in the study of cold-induced cough. 87 Therefore, the mood effect on the cough suppression test should be taken into consideration, although no significant effects have been observed currently. 8 Considering that the cough suppression test assesses the central inhibition, factors that may cause changes in central activity, such as the mental condition, may affect the accuracy of CS5. It is notable that if subjective factors affect the results of the cough suppression test, this will be more difficult to control than objective effects. However, the cough challenge test reflected the cough threshold and was not easily to be interfered by subjective factors. 7

Conclusion

The cough challenge test has good reproducibility and sensitivity, so it is the most widely used, most studied and most complete method to assess cough sensitivity. However, the diagnostic value of the cough challenge test is limited, which effects its clinical application, while the cough suppression test may have higher sensitivity, higher specificity and better repeatability than the cough challenge test in identifying patients with chronic cough, especially patients with refractory chronic cough. In addition, the cough suppression test hints the impairment of the central suppression network in chronic cough patients, which provide the rationale for the central antitussive treatment. The cough challenge test and the cough suppression test have many similarities in methodology and complement each other in mechanism and application. The combination of these two tests can play an important role in the chronic cough research.

Acknowledgments

None.

Footnotes

Contributor Information

Kun Zhao, Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.

Xiao Bai, Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.

Siwan Wen, Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.

Shengyuan Wang, Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.

Xianghuai Xu, Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China.

Li Yu, Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China.

Declarations

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Author contributions: Kun Zhao: Conceptualization; Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Xiao Bai: Conceptualization; Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Siwan Wen: Conceptualization; Methodology; Writing – review & editing.

Shengyuan Wang: Conceptualization; Methodology; Writing – review & editing.

Xianghuai Xu: Conceptualization; Validation; Writing – review & editing.

Li Yu: Conceptualization; Validation; Writing – review & editing.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the National Natural Science Foundation of China (No. 82070102 and 82270114); the Project of Science and Technology Commission of Shanghai Municipality (No. 21Y11901400 and 20ZR1451500); the Programme of Shanghai Academic Research Leader (No. 22XD1422700), the Fund of Shanghai Youth Talent Support Programme, the Fund of Shanghai Municipal Health Commission for Excellent Young Scholars (No. 2018YQ01) and the Shanghai Sailing Programme (No. 19YF1444100).

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Availability of data and materials: Not applicable.

References

  • 1.Zhang M, Wang S, Yu L, et al. The role of ATP in cough hypersensitivity syndrome: new targets for treatment. J Thorac Dis 2020; 12: 2781–2790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Visca D, Beghè B, Fabbri LM, et al. Management of chronic refractory cough in adults. Eur J Intern Med 2020; 81: 15–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Morice AH.Chronic cough hypersensitivity syndrome. Cough 2013; 9: 14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Song WJ, Chung KF.Exploring the clinical relevance of cough hypersensitivity syndrome. Expert Rev Respir Med 2020; 14: 275–284. [DOI] [PubMed] [Google Scholar]
  • 5.Koskela HO, Nurmi HM, Birring SS.Utility of cough provocation tests in chronic cough and respiratory diseases: a comprehensive review and introduction of new reference ranges for the capsaicin test. Allergy Asthma Immunol Res 2021; 13: 833–849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Mei H, Gu W, Ran L, et al. Evaluation methods and influencing factors of cough sensitivity. Ther Adv Respir Dis 2022; 16: 17534666211070134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Mai Y, Fang L, Zhong S, et al. Methods for assessing cough sensitivity. J Thorac Dis 2020; 12: 5224–5237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Cho PSP, Fletcher HV, Turner RD, et al. Impaired cough suppression in chronic refractory cough. Eur Respir J 2019; 53: 1802203. [DOI] [PubMed] [Google Scholar]
  • 9.Hutchings HA, Morris S, Eccles R, et al. Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers. Respir Med 1993; 87: 379–382. [DOI] [PubMed] [Google Scholar]
  • 10.Morice AH, Fontana GA, Belvisi MG, et al. ERS guidelines on the assessment of cough. Eur Respir J 2007; 29: 1256–1276. [DOI] [PubMed] [Google Scholar]
  • 11.Asthma Group of Chinese Thoracic Society. Chinese national guideline on diagnosis and management of cough (2021). Zhonghua Jie He He Hu Xi Za Zhi 2022; 45: 13–46. [DOI] [PubMed] [Google Scholar]
  • 12.Cho PSP, Fletcher HV, Patel IS, et al. Cough hypersensitivity and suppression in COPD. Eur Respir J 2021; 57: 2003569. [DOI] [PubMed] [Google Scholar]
  • 13.Fujimura M, Sakamoto S, Kamio Y, et al. Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid. Thorax 1992; 47: 441–445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Morice AH.The cough hypersensitivity syndrome: a novel paradigm for understanding cough. Lung 2010; 188(Suppl. 1): S87–S90. [DOI] [PubMed] [Google Scholar]
  • 15.Song WJ, Morice AH.Cough hypersensitivity syndrome: a few more steps forward. Allergy Asthma Immunol Res 2017; 9: 394–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Singh N, Driessen AK, McGovern AE, et al. Peripheral and central mechanisms of cough hypersensitivity. J Thorac Dis 2020; 12: 5179–5193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Ando A, Smallwood D, McMahon M, et al. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax 2016; 71: 323–329. [DOI] [PubMed] [Google Scholar]
  • 18.Mazzone SB, McGarvey L.Mechanisms and rationale for targeted therapies in refractory and unexplained chronic cough. Clin Pharmacol Ther 2021; 109: 619–636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Xu X, Chen Q, Qiu Z, et al. Association of cough hypersensitivity with tracheal TRPV1 activation and neurogenic inflammation in a novel guinea pig model of citric acid-induced chronic cough. J Int Med Res 2018; 46: 2913–2924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Muroi Y, Undem BJ.Targeting voltage gated sodium channels NaV1.7, Na V1.8, and Na V1.9 for treatment of pathological cough. Lung 2014; 192: 15–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Taylor-Clark T, Undem BJ.Transduction mechanisms in airway sensory nerves. J Appl Physiol 2006; 101101: 950–959. [DOI] [PubMed] [Google Scholar]
  • 22.Morice AH, Kastelik JA, Thompson R.Cough challenge in the assessment of cough reflex. Br J Clin Pharmacol 2001; 52: 365–375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Groneberg DA, Niimi A, Dinh QT, et al. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 2004; 170: 1276–1280. [DOI] [PubMed] [Google Scholar]
  • 24.Brozmanova M, Mazurova L, Ru F, et al. Comparison of TRPA1-versus TRPV1-mediated cough in guinea pigs. Eur J Pharmacol 2012; 689: 211–218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Canning BJ, Farmer DG, Mori N.Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs. Am J Physiol Regul Integr Comp Physiol 2006; 291: R454–R463. [DOI] [PubMed] [Google Scholar]
  • 26.Belvisi MG, Birrell MA.The emerging role of transient receptor potential channels in chronic lung disease. Eur Respir J 2017; 50: 1601357. [DOI] [PubMed] [Google Scholar]
  • 27.Bonvini SJ, Birrell MA, Grace MS, et al. Transient receptor potential cation channel, subfamily V, member 4 and airway sensory afferent activation: role of adenosine triphosphate. J Allergy Clin Immunol 2016; 138: 249–261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Bautista TG, Leech J, Mazzone SB, et al. Regional brain stem activations during capsaicin inhalation using functional magnetic resonance imaging in humans. J Neurophysiol 2019; 121: 1171–1182. [DOI] [PubMed] [Google Scholar]
  • 29.Behrens R, McGovern AE, Farrell MJ, et al. Mini review: central organization of airway afferent nerve circuits. Neurosci Lett 2021; 744: 135604. [DOI] [PubMed] [Google Scholar]
  • 30.Fuller RW, Choudry NB.Increased cough reflex associated with angiotensin converting enzyme inhibitor cough. Br Med J (Clin Res Ed) 1987; 295: 1025–1026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Fuller RW.Cough provocation tests: their clinical value. Pulm Pharmacol Ther 2002; 15: 273–276. [DOI] [PubMed] [Google Scholar]
  • 32.Chamberlain Mitchell SA, Garrod R, Clark L, et al. Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial. Thorax 2017; 72: 129–136. [DOI] [PubMed] [Google Scholar]
  • 33.Vertigan AE, Theodoros DG, Gibson PG, et al. Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy. Thorax 2006; 61: 1065–1069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Kelly HE, Shaw GM, Brett CN, et al. The effect of titrated fentanyl on suppressed cough reflex in healthy adult volunteers. Anaesthesia 2016; 71: 529–534. [DOI] [PubMed] [Google Scholar]
  • 35.Fujimura M, Kasahara K, Kamio Y, et al. Female gender as a determinant of cough threshold to inhaled capsaicin. Eur Respir J 1996; 9: 1624–1626. [DOI] [PubMed] [Google Scholar]
  • 36.Chen R, Lai K, Liu C, et al. Establishment and safety evaluation of capsaicin cough challenge test. Zhonghua Jie He He Hu Xi Za Zhi 2005; 11: 19–22. [Google Scholar]
  • 37.Nejla S, Fujimura M, Kamio Y.Comparison between tidal breathing and dosimeter methods in assessing cough receptor sensitivity to capsaicin. Respirology 2000; 5: 337–342. [PubMed] [Google Scholar]
  • 38.Dicpinigaitis PV.Short- and long-term reproducibility of capsaicin cough challenge testing. Pulm Pharmacol Ther 2003; 16: 61–65. [DOI] [PubMed] [Google Scholar]
  • 39.Couto M, de Diego A, Perpiñi M, et al. Cough reflex testing with inhaled capsaicin and TRPV1 activation in asthma and comorbid conditions. J Investig Allergol Clin Immunol 2013; 23: 289–301. [PubMed] [Google Scholar]
  • 40.Hoffmeyer F, Sucker K, Rosenkranz N, et al. Reproducibility of sensitivity to capsaicin assessed by single breath inhalation methodology. Adv Exp Med Biol 2013; 755: 71–78. [DOI] [PubMed] [Google Scholar]
  • 41.Smith JA, Decalmer S, Kelsall A, et al. Acoustic cough-reflux associations in chronic cough: potential triggers and mechanisms. Gastroenterology 2010; 139: 754–762. [DOI] [PubMed] [Google Scholar]
  • 42.Nieto Cabrera ML, de Diego Damiá A, Perpiñá Tordera M, et al. Cough-inducing capsaicin challenge test in a healthy population. Arch Bronconeumol 2001; 37: 292–296. [DOI] [PubMed] [Google Scholar]
  • 43.Nieto L, de Diego A, Perpiñá M, et al. Cough reflex testing with inhaled capsaicin in the study of chronic cough. Respir Med 2003; 97: 393–400. [DOI] [PubMed] [Google Scholar]
  • 44.Long L, Yao H, Tian J, et al. Heterogeneity of cough hypersensitivity mediated by TRPV1 and TRPA1 in patients with chronic refractory cough. Respir Res 2019; 20: 112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Chen R, Lai K, Liu C, et al. A pilot study on normal reference value of capsaicin cough sensitivity. Int J Respir 2013; 33: 1334–1337. [Google Scholar]
  • 46.Hilton EC, Baverel PG, Woodcock A, et al. Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point. J Allergy Clin Immunol 2013; 132: 847–855. [DOI] [PubMed] [Google Scholar]
  • 47.Wallace E, Guiu Hernandez E, Ang A, et al. A systematic review of methods of citric acid cough reflex testing. Pulm Pharmacol Ther 2019; 58: 101827. [DOI] [PubMed] [Google Scholar]
  • 48.Koskela HO, Nurmi HM, Purokivi MK.Cough-provocation tests with hypertonic aerosols. ERJ Open Res 2020; 6: 00338–2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Fowles HE, Rowland T, Wright C, et al. Tussive challenge with ATP and AMP: does it reveal cough hypersensitivity? Eur Respir J 2017; 49: 1601452. [DOI] [PubMed] [Google Scholar]
  • 50.Birring SS, Matos S, Patel RB, et al. Cough frequency, cough sensitivity and health status in patients with chronic cough. Respir Med 2006; 100: 1105–1109. [DOI] [PubMed] [Google Scholar]
  • 51.Lai K, Long L, Yi F, et al. Age and sex distribution of Chinese chronic cough patients and their relationship with capsaicin cough sensitivity. Allergy Asthma Immunol Res 2019; 11: 871–884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Nurmi HM, Lätti AM, Brannan JD, et al. Comparison of mannitol and citric acid cough provocation tests. Respir Med 2019; 158: 14–20. [DOI] [PubMed] [Google Scholar]
  • 53.Rai ZL, Fowles HE, Wright C, et al. The effect of pH on citric acid cough challenge: a randomised control trial in chronic cough and healthy volunteers. Respir Physiol Neurobiol 2018; 257: 51–54. [DOI] [PubMed] [Google Scholar]
  • 54.Ziora D, Jarosz W, Dzielicki J, et al. Citric acid cough threshold in patients with gastroesophageal reflux disease rises after laparoscopic fundoplication. Chest 2005; 128: 2458–2464. [DOI] [PubMed] [Google Scholar]
  • 55.Qiu Z, Yu L, Xu S, et al. Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non-acid gastro-oesophageal reflux. Respirology 2011; 16: 645–652. [DOI] [PubMed] [Google Scholar]
  • 56.Belvisi MG, Birrell MA, Khalid S, et al. Neurophenotypes in airway diseases. Insights from translational cough studies. Am J Res Crit Care Med 2016; 193: 1364–1372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Wong CH, Morice AH.Cough threshold in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 62–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Smith J, Owen E, Earis J, et al. Cough in COPD: correlation of objective monitoring with cough challenge and subjective assessments. Chest 2006; 130: 379–385. [DOI] [PubMed] [Google Scholar]
  • 59.Kanemitsu Y, Fukumitsu K, Kurokawa R, et al. Increased capsaicin sensitivity in patients with severe asthma is associated with worse clinical outcome. Am J Respir Crit Care Med 2020; 201: 1068–1077. [DOI] [PubMed] [Google Scholar]
  • 60.Guan WJ, Gao YH, Xu G, et al. Capsaicin cough sensitivity and the association with clinical parameters in bronchiectasis. PLoS ONE 2014; 9: e113057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.O’Connell F, Thomas VE, Studham JM, et al. Capsaicin cough sensitivity increases during upper respiratory infection. Respir Med 1996; 90: 279–286. [DOI] [PubMed] [Google Scholar]
  • 62.Dicpinigaitis PV.Effect of viral upper respiratory tract infection on cough reflex sensitivity. J Thorac Dis 2014; 6(Suppl. 7): S708–S711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Young EC, Brammer C, Owen E, et al. The effect of mindfulness meditation on cough reflex sensitivity. Thorax 2009; 64: 993–998. [DOI] [PubMed] [Google Scholar]
  • 64.Hutchings HA, Eccles R, Smith AP, et al. Voluntary cough suppression as an indication of symptom severity in upper respiratory tract infections. Eur Respir J 1993; 6: 1449–1454. [PubMed] [Google Scholar]
  • 65.Mazzone SB, Cole LJ, Ando A, et al. Investigation of the neural control of cough and cough suppression in humans using functional brain imaging. J Neurosci 2011; 31: 2948–2958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Farrell MJ, Cole LJ, Chiapoco D, et al. Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans. Neuroimage 2012; 61: 1324–1335. [DOI] [PubMed] [Google Scholar]
  • 67.Leech J, Mazzone SB, Farrell MJ.Brain activity associated with placebo suppression of the urge-to-cough in humans. Am J Respir Crit Care Med 2013; 188: 1069–1075. [DOI] [PubMed] [Google Scholar]
  • 68.Mazzone SB, McGovern AE, Farrell MJ.Endogenous central suppressive mechanisms regulating cough as potential targets for novel antitussive therapies. Curr Opin Pharmacol 2015; 22: 1–8. [DOI] [PubMed] [Google Scholar]
  • 69.Leech J, Mazzone SB, Farrell MJ.The effect of placebo conditioning on capsaicin-evoked urge to cough. Chest 2012; 142: 951–957. [DOI] [PubMed] [Google Scholar]
  • 70.Eccles R. Central mechanisms IV: conscious control of cough and the placebo effect. Handb Exp Pharmacol 2009: 241–262. [DOI] [PubMed] [Google Scholar]
  • 71.Morice AH, Millqvist E, Bieksiene K, et al. ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J 2020; 55: 1901136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Hutchings HA, Eccles R.The opioid agonist codeine and antagonist naltrexone do not affect voluntary suppression of capsaicin induced cough in healthy subjects. Eur Respir J 1994; 7: 715–719. [DOI] [PubMed] [Google Scholar]
  • 73.Pullerits T, Ternesten-Hasséus E, Johansson EL, et al. Capsaicin cough threshold test in diagnostics. Respir Med 2014; 108: 1371–1376. [DOI] [PubMed] [Google Scholar]
  • 74.Spinou A, Birring SS.An update on measurement and monitoring of cough: what are the important study endpoints? J Thorac Dis 2014; 6(Suppl. 7): S728–S734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Lai K, Long L.Current status and future directions of chronic cough in China. Lung 2020; 198: 23–29. [DOI] [PubMed] [Google Scholar]
  • 76.Koskela HO, Lake C, Wong K, et al. Cough sensitivity to mannitol inhalation challenge identifies subjects with chronic cough. Eur Respir J 2018; 51: 1800294. [DOI] [PubMed] [Google Scholar]
  • 77.Buday T, Kovacikova L, Ruzinak R, et al. TRPV4 antagonist GSK2193874 does not modulate cough response to osmotic stimuli. Respir Physiol Neurobiol 2017; 236: 1–4. [DOI] [PubMed] [Google Scholar]
  • 78.Morice AH, Menon MS, Mulrennan SA, et al. Opiate therapy in chronic cough. Am J Respir Crit Care Med 2007; 175: 312–315. [DOI] [PubMed] [Google Scholar]
  • 79.Morice AH, Higgins KS, Yeo WW.Adaptation of cough reflex with different types of stimulation. Eur Respir J 1992; 5: 841–847. [PubMed] [Google Scholar]
  • 80.Ternesten-Hasséus E, Johansson EL, Millqvist E.Cough reduction using capsaicin. Respir Med 2015; 109: 27–37. [DOI] [PubMed] [Google Scholar]
  • 81.Slovarp LJ, Bozarth E.Altering cough reflex sensitivity with aerosolized capsaicin paired with behavioral cough suppression: a proof-of-concept study. Ann Transl Med 2019; 7: 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Hoesli RC, Wingo ML, Wajsberg B, et al. Topical capsaicin for the treatment of sensory neuropathic cough. OTO Open 2021; 5: 2473974X211065668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Toukan N, Kulnik ST, Lewko A, et al. Therapeutic applications of capsaicin in humans to target conditions of the respiratory system: a scoping review. Respir Med 2022; 194: 106772. [DOI] [PubMed] [Google Scholar]
  • 84.Wallace E, Guiu Hernandez E, Ang A, et al. Quantifying test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings. Pulm Pharmacol Ther 2019; 58: 101838. [DOI] [PubMed] [Google Scholar]
  • 85.Dicpinigaitis PV.Cough reflex sensitivity in cigarette smokers. Chest 2003; 123: 685–688. [DOI] [PubMed] [Google Scholar]
  • 86.Dicpinigaitis PV, Sitkauskiene B, Stravinskaite K, et al. Effect of smoking cessation on cough reflex sensitivity. Eur Respir J 2006; 28: 786–790. [DOI] [PubMed] [Google Scholar]
  • 87.Broadbent DE, Broadbent MH, Phillpotts RJ, et al. Some further studies on the prediction of experimental colds in volunteers by psychological factors. J Psychosom Res 1984; 28: 511–523. [DOI] [PubMed] [Google Scholar]

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