Pubblicato online: 20 apr 2023
Pagine: 1 - 7
Ricevuto: 25 gen 2023
Accettato: 10 feb 2023
DOI: https://doi.org/10.2478/acm-2023-0001
Parole chiave
© 2023 Miert A. et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Cough is defined as a three-phase expulsive motor act characterized by an inspiratory effort (first phase), followed by a forced expiratory effort against a closed glottis (second phase) and then by opening of the glottis and rapid expiratory air flow (third phase) (1, 2). Under physiological circumstances, cough is a complex protective reflex of respiratory organs triggered by mechanical or chemical stimulation of sensitive fibers in respiratory airways. The main function of cough reflex is disposal of various endo- and exogenic substances from respiratory airways and thus protection of lung and airways (3, 4). Despite coughs protective function, various conditions may lead to excessive and chronic cough that loses its protective function and negatively affects patient’s health and quality of life (4, 5, 6). Cough is one of the most common reasons why patients seek medical attention, either a general practitioner or a respiratory specialist. Chronic cough is the most frequent reason why patients seek a respiratory specialist, while it is estimated that chronic cough affects approximately 10 percent of adult population worldwide (7, 8, 9, 10). Cough, especially chronic cough, is also associated with significant psychological and physiological morbidity (11).
During past two decades, significant advances in cough research were made including the development of tools for assessing and objectifying cough (7, 12, 13, 14, 15). Up to this day, there are various subjective and objective methods for cough assessment available. In order to achieve a complex assessment of cough (especially in research conditions), a combination of methods that focus on different aspects of cough shall be used (2). Out of all different aspects of cough, the most frequently investigated ones include: cough count and frequency, cough severity, impact of cough on health and quality of life, and cough reflex sensitivity (7, 12, 15).
There are various validated subjective methods for cough assessment available including cough diaries, questionnaires, cough scores, or visual analogue scale (Tab. 1) (7, 15). All these methods assess cough by asking the patient about his/her perception of various aspects of cough including cough severity, cough frequency, impact of cough on his/her daily life (7). These subjective methods enable us to get information about the patient’s personal experiences of cough and about psychosocial aspect of cough which are often overlooked and unrecognized (12). These methods are fairly simple and practical, especially in a longitudinal comparison, however they are not so reliable for a horizontal comparison and are susceptible to individual factors (9). Subjective methods for cough assessment can be further divided into two main groups according to which aspect of cough they focus on. The first group of methods focuses mainly on cough severity and the second group focuses on cough-related quality of life (QoL), which addresses the impact of cough on general health (12).
Out of the subjective methods that focus on cough severity, the visual analogue scale (VAS) is the most frequently used tool for assessing cough severity both in clinical and research settings. The cough VAS consists of 100 mm linear scale marked from zero (which stands for no cough) to 100 mm (which stands for the worst possible cough), where patient can indicate the severity of cough. Higher the number on the scale means more severe cough (2, 7, 12, 15). This subjective method is very simple, brief, easily repeatable, responsive, and can be easily used in any clinical setting, especially for assessing chronic cough (2, 7, 12, 15, 16). However, this method did not undergo such rigorous validation as another methods like quality of life questionnaires (16). When compared to other subjective methods, there is only a moderate correlation between VAS and quality of life questionnaires. Furthermore, VAS does not relate well to cough reflex sensitivity and other objective methods (2).
Another subjective method for cough severity assessment is a cough severity diary (CSD). CSD is a simple daily seven-item diary developed to evaluate cough severity using feedback from patients. This tool correlates weakly with other objective methods assessing cough frequency, however, CSD outcomes strongly correlate with VAS scores. Furthermore, self-completed diaries for children correlate better with other objective tools and have a good responsibility. To fully assess usefulness, reproducibility, and responsiveness of CSD, further evaluation and exploration of this tool is needed (2, 12, 15, 17).
The second main group of subjective methods for assessing cough comprises of health-related quality of life (HRQoL) questionnaires that focus on the impact of cough on patient’s daily life, his/her physical and psychical health and the quality of life (7, 12, 15, 16). These tools enable the patient’s perspective being brought into account (2). When compared to VAS, they capture a wider impact of cough on the patient (12, 15). There are many disease specific (cough specific HRQoL) and also many generic questionnaires available, however the usage of cough-specific tools is recommended in cases where cough is an important part of the symptomatology (2,7,15). It is because cough related questionnaires are simpler and more responsive than generic questionnaires (2,12,15). Out of the cough-specific HRQoL questionnaires, the Leicester cough questionnaire (LCQ) and the cough-specific quality of life questionnaire (CQLQ) are most widely used either in clinical practice and research to assess longitudinal changes in patients with chronic cough and identify the specific health domains affected (2,12,15).
The most widely used subjective methods for cough assessment (modified by 7, 15)
| Subjective methods for cough measurement | |
|---|---|
| 1. Methods assessing cough severity | Visual analogue scale (VAS) |
| Cough severity diary (CSD) | |
| 2. Quality of life questionnaires | Leicester cough questionnaire (LCQ) |
| Cough-specific quality of life questionnaire (CQLQ) | |
There are variety of methods available for objective cough assessment that focus mainly on two aspects of cough including cough reflex sensitivity (assessed by cough challenge tests) and cough frequency (assessed by cough monitors) (Tab. 2) (9, 12). The first attempts by researchers to objectively measure cough (to quantify the amount of coughing per certain time period) date back to 1950s (2, 20). Up to this day, several ambulatory and non-ambulatory methods of cough monitoring have been developed and evaluated. The early methods for cough assessment in non-ambulatory conditions relied on tape recorders with microphones or on observers that count cough as they occurred in subjects. Assessing cough frequency by a manual counting of coughs from sound or video recordings still seems to be the most reliable method of objective cough assessment, however this method is very time consuming, laborious, and greatly limits the size and scope of studies (2, 12).
Thanks to the progress in hardware (battery life and recording capacity) and software development, various semi-automated or automated monitors that count cough over a certain period of time (usually 24 hours) were developed. Leicester Cough Monitor (LCM) and VitaloJak are the most frequently used cough monitors in clinical research. These devices record sound for a certain time period (24 hour or longer) and after that, in VitaloJak the data are digitally processed and compressed to a much shorter recording which is then manually refined by a human operator. LCM is largely automated and only minor refinement by an operator is required (2, 7, 12, 15, 16, 21). The above-mentioned monitors were used in several clinical studies and proved to be useful, sensitive, and repeatable, with a potential to be used in clinical practice, for example to quantify the response to therapy. However, none of these monitors is standardized, clinically acceptable, or commercially available and thus is not deemed to be the gold standard for objective cough measurement in research nor in clinical conditions (2, 7, 12, 15, 16, 21).
Cough reflex sensitivity can be described as either as a reaction intensity of the cough reflex to different stimuli or a reactivity of afferent nerve cell endings in respiratory airways (7, 9). An abnormally high response of cough reflex towards various mechanical, thermal, or chemical stimuli or activation of cough reflex by lower levels of stimuli can be seen in many adults or children with various respiratory disorders, for example bronchial asthma. The exact reason of heightened cough reflex is unknown, there are many possible pathomechanisms involved including central and peripheral sensitization of cough reflex (4, 7, 9, 14, 22).
The cough reflex sensitivity measurement by inhalation cough challenges has proved to be an important component of many research studies, especially to determine the effect of various antitussive agents of cough reflex sensitivity (23). Various methods for assessing cough reflex sensitivity have been developed and tested, however only few of them are standardized. These methods induce cough either by a chemical or mechanical stimulation of airway afferent nerve endings. According to how cough is induced, the methods for measuring cough reflex sensitivity can be divided into two main groups: cough inhalation challenges and mechanical cough challenges, while the former group is most widely used. Stimulus intensity comparison or comparison of response to irritants are used to assess the levels of cough reflex sensitivity (7,9).
All inhalation challenges for cough reflex sensitivity measurement are in principle very similar to bronchial responsiveness assessment tests. Cough in subjects is induced by an inhalation of nebulised tussive agents (15). During past decades, many tussive agents have been used to induce cough reflex mainly by C-fiber activation. There are two main groups of inhalation challenges according to how the tussive agents are delivered during testing (single dose challenges and dose-response challenges) (21). The first group of inhalation challenges – single dose challenge-is based on inhalation of a single dose of tussive agent. These types of inhalation challenges are especially beneficial in epidemiological surveys, mainly because of their simplicity, relatively short duration, and no risk of significant adverse reactions. The second group of inhalation challenges – dose response challenges – can be further divided into two types according to the length of inhalation of a tussive agent: 1. single vital capacity breaths of incremental concentrations of tussive agents, 2. tidal breath inhalations of incremental concentrations of tussive agents during a fixed time period (9). The former type provides more accurate and repeatable results and thus is recommended to be used (24).
Cough challenge endpoints are usually expressed as C2 or C5, which stands for a tussive agent concentration that caused two (C2) or five (C5) coughs (23). Cough inhalation challenges proved to be very useful tool in both human and animal research studies providing good reproducibility and responsivity. Furthermore, cough inhalation challenges are valuable tool in measuring the ability of various antitussive agents to suppress cough (12). However, the inability of these cough challenges to discriminate patients with cough from healthy subjects is a major factor limiting their use in clinical practice as a diagnostic tool (15,16). Other limiting factors include inability to measure cough severity, raw material availability, complex preparation process of tussive agents, requirement of nebulizer, and device-related maintenance (14,16). In order to ensure optimal results, all subjects also have to be properly instructed before the cough challenge (23).
Tussive agents used to induce cough can be divided into non-acid and acid agents. Out of the non-acid agents, capsaicin is the most frequently used and recommended agent. Out of the acid agents, citric acid is the most commonly used agent.
Capsaicin has been used as a tussive agent for several decades, either in human and animal research studies to assess cough sensitivity (5, 7, 9, 14, 15, 16). Capsaicin, a pungent substance commonly present in chili peppers, induces cough by transient receptor potential vanilloid-1 (TRPV1) activation (5,9). The usage of capsaicin as a tussive agent dates back to 1984 and during past three decades became a method of choice (9, 23, 25). There are several reasons why capsaicin is considered a tussive agent of choice, mainly due to its ability to induce cough in a dose-dependent manner, its reproducibility and safety. Furthermore, there are no serious adverse effects of capsaicin inhalation reported up to this day, most common adverse effect, transient throat irritation, was only present in a minority of subjects. Lastly, the usage of capsaicin as a tussive agent in patients with bronchial asthma is reported to be safe, tolerable, and without any clinically significant bronchoconstriction (23, 24, 26, 27). When compared to citric acid challenge, capsaicin inhalation lacks choking sensation and pharyngeal discomfort, also no significant tachyphylaxis has been reported (28). Inability to distinguish healthy subjects from patients with cough, inability to measure severity of cough and laborious process related to dilution preparation and device maintenance seem to be the most significant limitations of this method (14, 16).
Citric acid is the oldest and one of the most frequently used acid agents for cough induction that has been used since 1950s. The mechanism of cough induction by citric acid is not entirely described, however C-fiber, A-delta fiber, and TRPV1 receptor activation are the most probable mechanisms of cough induction. Citric acid inhalation challenge is safe, well tolerated, and feasible method of cough reflex sensitivity assessment (2,9,23,28). However, the presence of pharyngeal discomfort and choking sensation is more frequent when compared to capsaicin cough challenge. Furthermore, when the challenge is repeated over short 10-minute intervals, tachyphylaxis develops (15). The lack of guidelines and technical standards are other limitations of this method (28).
The most widely used objective methods for cough assessment (modified by 7,15)
| Objective methods for cough measurement | ||
|---|---|---|
| 1. Methods assessing cough frequency | A. Manual counting of coughs from sound or video recordings | |
| B. Cough monitors | Leicester cough monitor (LCM) | |
| VitaloJak | ||
| 2. Methods assessing cough reflex sensitivity | A. cough inhalation challenges | Acid tussive agents (citric acid) |
| Non-acid tussive agents (capsaicin) | ||
| B. mechanical cough challenges | ||
This review was focused on the evaluation of the most frequently used methods for cough assessment, where we pointed out their advantages and limitations. Past two decades brought us a significant development of various methods for cough measurement, which are already well established and standardized for use in cough research and clinical trials. Subjective methods of cough assessment are relatively cheap, simple, and validated, however they are still not widely used in clinical practice. Assessing cough frequency and cough reflex sensitivity measurement are also frequently used, especially in research and in clinical trials providing reliable results. However, there are many factors limiting the use of these objective methods in clinical practice or in larger scale research. COUGH-1 and COUGH-2 (29), the first- ever phase 3 trials of a novel treatment specifically for refractory chronic cough and unexplained chronic cough. Participants were required to have visual analogue scale, electronic cough severity diary, Leicester cough questionnaire was completed, and cough frequency was measured for 24 h. Future development may potentially bring us an improvement of already existing methods, which will make them suitable for use in research and clinical conditions and thus help us understand and treat cough better. The current use of cough objectification is primarily in clinical studies aimed at the treatment of chronic cough.