Performance of the Cough and Sputum Assessment Questionnaire (CASA-Q) in COPD: Evidence from Clinical and Online Patient Interaction Studies

Introduction

COPD is a common disease with a prevalence ranging from 10% to 15%^1,2 and is the third leading cause of death worldwide.³ COPD is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles/gases, in particular cigarette smoke. Chronic bronchitis, a key phenotype amongst COPD patients, is characterized by chronic cough and mucus.⁴

Chronic bronchitis symptoms in COPD have been linked to increased disease burden and health-care costs due to increased exacerbation rates and severity, disease progression, and potential mortality.^5,6 However, despite various debilitating effects associated with cough and excess mucus production, current treatments such as smoking cessation, chest or respiratory physiotherapy, expectorants and mucolytics, etc., inadequately manage these symptoms resulting in significant unmet need in patients living with COPD and chronic bronchitis.^7,8 The current therapeutic focus has been mostly on outcomes targeted by existing treatments, such as lung function, exacerbations, and shortness of breath. However, cough and sputum present an important part of the daily symptom burden in patients with COPD with chronic bronchitis,^9,10 and relying on patient-reported improvement in symptoms of cough and sputum along with lung function by FEV₁ enables better phenotyping of COPD symptoms. Patient-reported outcomes measures (PROMs) are increasingly used to assess subjective concepts of health and add value to the clinical development and evaluation process. PROMs play a key role in measuring the overall impact of a disease on a patient’s health-related quality of life (HRQoL). Understanding patient needs and expectations related to this disease and its treatments is essential to ensure that clinical development addresses what matters to patients.¹¹

The cough and sputum assessment questionnaire (CASA-Q) was developed to measure the severity and impact of cough and sputum in patients with COPD and chronic bronchitis.¹² It was developed in accordance with the 2006 US Food and Drug Administration (FDA) draft guidance to industry on the use of PROMs.¹³ In keeping with the guidance, the developers of CASA-Q involved patients in the concept elicitation and cognitive debriefing phases to ensure content validity. The questionnaire focuses not only on the severity of physical symptoms of cough and sputum production, but also on the emotional, social, and psychological impact on the patient’s life. The psychometric properties were established through an independent validation study and another subsequent study.^12,14

CASA-Q is a 20-item questionnaire with a 7-day recall period. The development and validation of the instrument have been described in detail,¹² and the responsiveness has also been assessed.¹⁴ The domains include cough symptom severity (COUS) with 3 items, cough impact (COUI) with 8 items, sputum symptom severity (SPUS) with 3 items and sputum impact (SPUI) with 6 items. Each item is answered on a 5-point Likert scale ranging from “never” to “always” for frequency or from “not at all” to “a lot/extremely” for intensity.¹⁴ The CASA-Q does not have a total score, and each domain is scored separately. The scores for each domain range from 0 to 100, with higher scores indicating fewer/less severe symptoms and less impact.

The CASA-Q was developed by interviews with patients, ensuring the questionnaire measures those concepts most relevant to patients, thus establishing the PROM’s clinical relevance and content validity. Content validity of a PROM is emphasized by regulatory agencies, including the US FDA and the European Medicines Agency, and is the yardstick to determine whether a PROM is fit-for-purpose.^15,16 It relies on qualitative research methods, such as interviews or focus groups with patients, caregivers, physicians, and other experts, to identify relevant concepts. It also includes the cognitive interview process to evaluate the patients’ comprehension of the instruments’ items, wording, recall periods, and format. Rothman et al proposed social media as having great potential to support the content validity of PROMs.¹⁷

This study addresses two aims: 1) to describe the performance of the CASA-Q in relation to primary endpoints in published COPD clinical studies; and 2) to describe a novel approach for evaluating and documenting content validity using recently published qualitative Social Media Listening (SML)⁹ and Online Bulletin Board (OBB)¹⁰ data to determine the extent to which the instrument’s content validity remains stable over time (eg, from first publication to date).

Methods

Targeted Literature Review of Clinical Studies

A targeted literature review was conducted on the OvidSP database for literature published between 2008 (the year the CASA-Q development study was published) and 2021, including clinical studies and clinical trials registered on clinicaltrials.gov before Nov 2020. The search terms used were “patient-reported outcome”, “self-reported outcome”, “COPD”, “QoL”, “HRQoL”, “health-related quality of life”, and “CASA-Q.” Findings by study design and year are presented in Table 1. Publications on the initial development and validation studies by Crawford et al and Monz et al were excluded.^12,14 The retrieved studies were assessed by year, intervention (if applicable) and reported results on primary endpoints CASA-Q domains. For clinical trials, we report the responsiveness of the CASA-Q domains in relation to the primary endpoints.

Table 1 Summary of Studies Using the CASA-Q Identified in the Targeted Literature Search and Summary of Main Results

Content Validity Using Patient Insights from Social Media Listening (SML) and Online Bulletin Board (OBB)

Content validity for CASA-Q was initially established by Crawford et al in 2008.¹² Applying the approach proposed by Rothman et al,¹⁷ the content validity of the CASA-Q was assessed using the information provided in the publications pertaining to qualitative data obtained from SML⁹ and OBB¹⁰ studies. The SML study was conducted to gather COPD patients’ perspectives on symptoms, diagnosis and comorbidities associated with COPD and its impact on patients’ quality of life, while the OBB study was used as a qualitative research tool to evaluate the effect of cough and mucus on COPD patients with persistent cough and excessive mucus. The methodology and results of SML and OBB have been previously published^9,10 and are summarized in the results section.

Insights available in the two publications resulting from the qualitative SML and OBB studies regarding topics related to cough and mucus mattering most to patients living with COPD were first grouped by a study team member into the four CASA-Q domains. In a second step, this grouping was checked by a second reviewer. The final grouping was unanimously endorsed by the study team. Next, the qualitative data grouped under the four CASA-Q domains were mapped to the items in each of those domains where they fitted best according to the judgement of a study team member. This mapping was again reviewed by a second reviewer. The final mapping was unanimously endorsed by the study team. For example, insights (eg, patient quotes) as reported in the two SML and OBB publications related to mucus characteristics (eg, frequency of bringing up mucus) were grouped under the sputum symptoms (SPUS) domain. Similarly, insights from the qualitative studies associated with cough (eg, frequency of coughing) were grouped under the cough symptoms (COUS) domain. Finally, the qualitative findings related to physical, emotional and functional disturbances due to mucus and cough were grouped into the sputum impact (SPUI) and cough impact (COUI) domains, respectively.

Results

Responsiveness of CASA-Q in COPD Studies

The targeted literature search identified nine studies of COPD where the CASA-Q had been used as an endpoint. A study by Goosens et al mentioned the use of CASA-Q, but CASA-Q-related results were not available in the publication and were therefore excluded.¹⁸ Of the remaining eight studies, seven were identified from published literature^19–25 and one was reported on “ClinicalTrials.gov”.²⁶ Five studies assessed pharmacological interventions,^{19–21,23,26} one study was a non-pharmacological study,²² while two were non-interventional or observational.^24,25

Pharmacological Intervention Studies

The CASA-Q was used in five pharmacological interventional studies (Table 1; presented in chronological order).

The WISDOM trial (NCT00975195) used the CASA-Q as part of a trial assessing lung function changes and exacerbations upon stepwise inhaled corticosteroid (ICS) withdrawal.²⁶ There was a significant improvement in mean trough FEV₁ in ICS maintenance group compared to the withdrawal group, but no change in time to exacerbations or in the cough and sputum-related CASA-Q domains was observed between both arms.

In a study comparing indacaterol/glycopyrronium (IND/GLY) vs tiotropium plus theophylline, Kirishi et al reported a higher increase in FEV₁ in the IND/GLY group compared to the comparator group.¹⁹ In the IND/GLY group, CASA-Q cough symptom and cough impact domains improved, with tiotropium plus theophylline showing no improvement in the cough-related domains compared to baseline. Sputum-related domains remained unchanged in both groups.

A study by Tagaya et al, testing the effect of tiotropium on mucus hypersecretion and airway clearance, showed an improvement in FEV₁ and FEV₁/FVC with tiotropium. Similarly, a significant improvement in all four CASA-Q domains compared to baseline was observed.²¹

The study by Siler et al, comparing effects on lung function with fluticasone furoate (FF) plus vilanterol (FF/VI) to VI alone, found that FF/VI improved trough FEV₁. There was a nominal difference in favor of the VI group for SPUS and SPUI domains but no difference for the COUS and COUI domains of the CASA-Q were observed.²⁰

Bennett et al assessed the effect of hypertonic saline on mucociliary clearance and clinical outcomes in COPD patients with chronic bronchitis. They found that hypertonic saline does not result in any significant FEV₁ changes. Similarly, no effect was observed on CASA-Q domains.²³

Non-Pharmacological Interventions

CASA-Q was used in one non-pharmacological intervention study (Table 1).

Rebelo et al measured cough and sputum change using the CASA-Q after a 12-week pulmonary rehabilitation program.²² The study observed a significant improvement in the COUI domain, which correlated with the patients’ global rating of change scales (GRC) for cough. The changes in COUS domain correlated significantly with the St. George’s respiratory questionnaire (SGRQ), the COPD Assessment Test (CAT) and the patients’ GRC for cough. Changes in both CASA-Q sputum domains (SPUI and SPUS) significantly correlated with the change in SGRQ.

Validation of CASA-Q in COPD Studies from Observational Studies

Published results from two observational studies provided insight into the validity of CASA-Q scores (Table 1). Deslee et al assessed the impact of cough and sputum on HRQoL in patients with COPD and found that all CASA-Q domain scores were significantly lower in a subset of patients with chronic bronchitis. Multivariate analysis of all CASA-Q domains considering all other clinical variables found that the COUI score was significantly associated with the SGRQ score,²⁴ indicating the adverse impact of cough was associated with an impairment in overall health status in these patients.

An observational study examining the impact of gastroesophageal reflux symptoms on cough and sputum symptoms reported a significant cross-sectional correlation between the COUS and SPUS scores and the CAT cough and sputum item scores,²⁵ offering further support of the relationship between cough and sputum impact and overall COPD health status.

Mapping Qualitative Patient Insights to CASA-Q Items and Domains

Methods and results of the two qualitative SML and OBB studies used to further assess content validity of the CASA-Q have been reported elsewhere.^9,10 The main findings are summarized here for convenience: In these studies, patients emphasized that high symptom load and poor HRQoL associated with COPD significantly disrupted patients’ lives on multiple levels. The SML study reported that relief from cough, mucus, and shortness of breath were the most valuable aspects of disease management from the patients’ perspective. In the OBB study, the patients mentioned that COPD has an impact on both proximal concepts, ie, those which directly affect health such as persistent cough and difficulty clearing sputum and also more distal concepts, ie, those that indirectly affect health such as a low emotional and social well-being.¹⁰ Cough and mucus impeded physical activities and social interactions, which influenced the patient’s relationships with friends and family, and their daily tasks and routine, thus impacting their overall functional, emotional, social and economic quality of life.¹⁰

The results of thematically grouping qualitative data from the SML and OBB studies to the four CASA-Q domains are presented in Table 2.

Table 2 Social Media Listening and Online Bulletin Board Findings Grouped Under the CASA-Q Domains Based on Closest Symptom or Concern Match

After grouping the qualitative data by CASA-Q domains, the SML and OBB findings were then mapped to the individual items in each CASA-Q domain. In this process, all original items from the CASA-Q could be matched to important aspects of disease voiced by the patients themselves (as presented in SML and OBB findings). This is consistent with the original qualitative work supporting content-validity of the CASA-Q. As shown in Figure 1, in the SPUI domain, the items about “annoyance by phlegm”, “avoidance of public places”, “interruption of usual activities” and “to bother other people” were supported by feedback received from patients from the OBB, while “breathing difficulty” and “interfering with speaking ability” were supported by findings from SML. Similarly, qualitative data from the SML and OBB corresponded to the items in the remaining domains of the CASA-Q, such as items on “thickness”, “frequency” and “difficulty bringing up sputum” in the SPUS domain and items “tired after coughing”, “avoidance of public places”, “interruption of usual activities”, “sleep interference” and “bothering other people” in the COUI domain. The items from the COUS domain such as “bouts of cough” and cough during the day and mornings were also supported by findings from the SML/OBB qualitative data.

Figure 1 Interlinkage between insights from SML and OBB with CASA-Q items: The qualitative findings obtained from the SML and OBB (in the light and dark gray boxes) were mapped against corresponding items of the CASA-Q (light blue boxes), illustrating the content validity of the CASA-Q. Notes: CASA-Q domains, CASA-Q Items, Online Bulletin Board, Social Media Listening. . * % of patients who mentioned these as the most bothersome, which become severe as the disease progresses.

Discussion

Results of published studies using the CASA-Q to assess cough and sputum symptoms showed that CASA-Q scores are appropriately responsive to change with treatment, moving in the same direction as other endpoints, such as FEV₁ and SGRQ. In addition, the content of the CASA-Q was supported by data from recently conducted qualitative online patient studies, suggesting that since CASA-Q’s development in 2008, the questionnaire continues to be content valid.

The WISDOM trial demonstrated that the stepwise withdrawal of inhaled corticosteroid treatment did not increase the risk of exacerbations as assessed by no difference in time to first exacerbation compared to the corticosteroid-continuation group. In line with the stability of the clinical parameters in the corticosteroid withdrawal group, no changes in cough and sputum on the CASA-Q were observed. Similarly, for the other interventional studies, the CASA-Q scores moved in the same direction as the clinical measurements, in line with the study design and pharmacological intervention’s mechanism of action.

The non-pharmacological pulmonary rehabilitation study showed strong correlation between change in CASA-Q domain scores and change in SGRQ and CAT reference tests supporting the responsiveness of the CASA-Q in COPD symptom evaluation.²² The two observational studies showed moderate or strong correlations between the CASA-Q domain scores and the SGRQ and CAT reference tests.^24,25 These studies offer further support for the validity of the CASA-Q and suggest that reducing symptom impact should improve health status.

Qualitative data from the SML and OBB online patient studies were consistent with the content and structure of the CASA-Q, supporting the content validity since its development. The instrument continues to capture constructs important to patients. Published findings of the qualitative data obtained with the SML and OBB studies confirmed the impact of cough and sputum symptoms and concerns of COPD patients. The fact that all items of the CASA-Q could be matched with findings from these recent qualitative studies shows that the method proposed by Rothman et al¹⁷ can be applied in practice and suggests that the content validity of the CASA-Q remains stable over time.

Limitations

The results presented here are based on published studies reporting results of CASA-Q in COPD patients. There were limited trials using the CASA-Q to evaluate the effects of treatment on the severity and impact of cough and sputum. Content validity evaluation using online patient interactions was limited to secondary analyses of the published results from two previously conducted qualitative studies, namely social media listening and online bulletin boards.

Conclusion

Findings from this literature review suggest CASA-Q can detect changes in cough and sputum symptoms and impact in therapeutic trials of COPD, with observational studies showing a correlation between symptom impact and health status. The successful mapping of qualitative findings from online SML and OBB studies to CASA-Q domains and items suggests that since its development, the CASA-Q remains content valid. Findings of this study suggest that online qualitative data can be used as a promising new additional tool to bolster, rather than replace, qualitative interviews and focus groups, playing a key role in understanding and documenting content validity of PROMs over time. Based on its development history and the evidence presented here, the CASA-Q is a valid and responsive measure of cough and sputum on the lives of people with COPD suitable for use in clinical trials.