Abstract
Introduction
This study aims to characterize the patient journey for refractory chronic cough (RCC) or unexplained chronic cough (UCC) before visiting the Isala Chronic Cough Clinic (ICCC) in the Netherlands.
Method
Data from 152 patients with RCC or UCC was collected between January 2017 and September 2021from General Practitioner (GP) and hospital charts, the EQ-5D-5L questionnaire, and a patient survey about the care pathway and cough impact on everyday life, based on a single-centre, observational, retrospective study design.
Results
Mean age at first ICCC visit was 60.3 ± 11.6 years; 66.4% of patients was female. More patients had RCC (80.9%) than UCC (19.1%). Mean cough duration before ICCC visit was 8.5 ± 6.5 years. 41.4% of patients reported cough >10 years. Common patient-reported problems were social embarrassment (58.0%), exhaustion (54.2%), and sleep disturbance (45.0%). Urinary incontinence was prevalent among women (48.9%). Prior to ICCC, 59.2% had consulted 2–4 specialists for their cough and 16.2% had seen more than 4.
Conclusion
This study highlights the long time to diagnosis of RCC or UCC, and the negative effect on patients’ physical and psychological health, and everyday activities. Increased awareness may shorten time for diagnosis, and novel therapies may help reduce this disease burden.
Keywords
Introduction
Chronic cough (defined as cough lasting >8 weeks) is common and it impacts approximately 6.5% to 7,5% of adults in Germany and France, respectively, and up to 10% of adults in the Netherlands.1–3 A comparable prevalence has been observed worldwide. 4 However, heterogeneity in the definitions may have biased the prevalences. A worldwide survey of cough clinics found that two-thirds of patients were female and the most common age for presentation was between 60 to 69 years. 5 The importance of cough as a clinical problem globally has led to multiple societies publishing guidelines over the last couple of years for specialists on the diagnosis and management of cough.6,7
Traditionally chronic cough was considered a consequence of either gastroesophageal reflux disease (GERD), asthma, and/or postnasal drip. Other causes included recent or active respiratory infection, smoking, medications such as angiotensin-converting enzyme inhibitors (ACEI). 8 Currently, refractory or unexplained chronic cough is considered a disease rather than a symptom 6 ; cough hypersensitivity is now considered as the central mechanism behind most chronic cough, although it is commonly missed in many patients7,9 In 9.5% of patients seeking medical attention specific to their cough, no cause could be identified, even after extensive investigations in specialized cough clinics (unexplained chronic cough [UCC]). 10 In addition, in a larger number of patients (37.5%), cough persisted despite appropriate treatment of the underlying condition (refractory chronic cough [RCC]). 10 With the overarching concept of cough hypersensitivity, the division in UCC and RCC becomes less relevant, as is demonstrated by similar improvements in phase 3 trials with gefapixant. 11
Many individuals with RCC or UCC experience a negative impact on their quality of life (QoL). The impairment of QoL is comparable to other chronic respiratory disorders such as chronic obstructive pulmonary disease (COPD). 12 Physical, psychological, and social domains of health are commonly affected and patients with RCC or UCC frequently report musculoskeletal chest pains, sleep disturbance, GERD, heartburn, and regurgitation. 13 In addition, the prevalence of urinary incontinence in women with chronic cough has been found to be 66% compared with 9.9%–36.1% in women without chronic cough. 14 This impaired health status combined with the high prevalence causes a substantial burden of disease worldwide.12,15,16
The current patient journey from the start of symptoms until diagnosis for RCC or UCC in the Netherlands is not well understood, including current referral and treatment patterns; and the time from the onset of symptoms until diagnosis is unknown. Furthermore, specific data on RCC or UCC (as compared to the broader field of chronic cough) is still sparse.
The main aim of this study was to describe the patient journey of RCC or UCC from the general practitioner (GP) to the Isala Chronic Cough Clinic (ICCC) in the Netherlands.
Material and methods
Study design
This single-centre, observational, registry study was performed at the ICCC, an outpatient clinic in the Department of Pulmonology of Isala Hospital in Zwolle, the Netherlands. All data were pseudo-anonymized, and all patients provided signed informed consent. The research protocol was approved by the Daily Board of the Medical Ethics Committee, Isala, Zwolle, the Netherlands; no additional consent was required.
Objectives
The primary objective of this study was to describe the patient journey including diagnosis and time from the first chronic cough GP visit until the first visit to the ICCC. The secondary objective was to describe patient journey, including referral patterns and healthcare utilization, and the relationship between patient characteristics, such as age, sex, RCC or UCC diagnosis, and the time until the first visit at the ICCC.
Population
The ICCC is the main cough clinic in the Netherlands and has a registry containing structured data on 4,000 patients with chronic cough, adding data from 400 new patients annually. Although the ICCC is a national clinic, most patients (90%) are from the region in the Netherlands where the ICCC is.
Patients with RCC or UCC were selected from a previous study by van den Berg et al., 10 that investigated characteristics of RCC or UCC patients at the ICCC, between the period January 2017 and April 2019, and from a new subsequent cohort between the period May 2019 and September 2021, using the same selection criteria. RCC and UCC categorization were based on diagnostic tests, presence of any underlying conditions, and responses to health-related quality of life (HRQoL) questionnaires, as detailed in the previous study. 10
Procedures
Data were retrospectively collected via chart reviews from hospital and primary care records, the EQ-5D-5L, and prospectively from an additional patient survey designed for the patient population. After qualifying and providing consent, patients were administered the survey and the EQ-5D-5L to assess the impact of RCC or UCC on their HRQoL.
The GPs were asked to provide a digital copy of the patient’s chart. The International Classification of Primary Care (ICPC) codes were used to identify the type of cough (R05 cough; R74 acute upper respiratory infection; R75 sinusitis; R78 acute bronchitis; R81 pneumonia), as determined by the GPs. Diagnosis data, referral patterns with corresponding dates were manually extracted from GP charts, entered into the study database, and integrated into the ICCC registry.
Patients were also asked about the duration of their cough and how they perceived their cough with respect to everyday life using the patient survey. Chronic cough duration, as a function of the length of time from the first identification in GP files until the first ICCC visit, was presented as a combination of the date from the GP file and patient anamnesis. The date of the first GP visit for chronic cough was based on the ICPC codes mentioned previously and/or the anamnestic description of chronic cough.
Statistical analysis
Continuous variables, such as the mean duration of chronic cough, were presented by mean and/or median and measures of dispersion (standard deviation [SD], range, interquartile range). Categorical data were presented as n or percentage.
For the secondary endpoint of demographic characteristics or comorbidities associated with a delay in diagnosis, the time until diagnosis was compared between men and women, and between different phenotypes (descriptively). Correlation between age and time till diagnosis were tested. Stratified analyses were performed when needed. For the secondary endpoint of number of visits per type of healthcare professional (HCP), these were presented as n or percentage.
For the exploratory analysis of QoL, health states by EQ-5D-5L were converted to utility values using the Dutch tariff. 17
Missing data were not imputed, and statistical analyses were performed using IBM SPSS version 28.
Results
Demographics
During the study period, 367 patients were diagnosed with RCC or UCC at the ICCC. Patients who met the inclusion criteria (n=352) were invited to participate in the study, of which 166 patients did. The patient survey was filled in by 165 patients, and 137 files were received from GPs (Figure 1). Study inclusion flow chart. GP, general practitioner; ICCC: Isala Chronic Cough Clinic; N: number of patients; RCC: refractory chronic cough; UCC: unexplained chronic cough.
Patient characteristics.
COPD: chronic obstructive pulmonary disease; ICCC: Isala Chronic Cough Clinic; NA: not applicable; PND: post-nasal drip; RCC: refractory chronic cough; UCC: unexplained chronic cough.
Most respondents lived with a partner (63.9%) or family (19.4%), and a substantial proportion were still working (38.6%) or on sick leave (6.9%), alongside a large, retired group (47.6%).
Time from the first identification of chronic cough by GP until the first visit at the ICCC
The mean duration of chronic cough from first identification by the GP until the first visit at the ICCC was 8.5±6.5 years (bootstrapped 95% confidence interval [CI]: 7.4–9.7), as measured by ICPC code R05 and anamnesis (Supplemental table 1). The mean duration of the first identification of chronic cough until visit to a pulmonologist was 4.5±6.3 years (Supplemental table 1).
The mean duration of other types of chronic cough according to the underlying reasons for cough: were 8.5±6.5 years for acute upper respiratory infection (ICPC-R74 code); 8.0±6.3 years for acute/chronic sinusitis (ICPC-R75 code); 10.6±7.1 years for acute bronchitis/bronchiolitis (ICPC-R78 code); and 7.7±5.8 for pneumonia (ICPC-R81 code).
Patient characteristics associated with the time until the first ICCC visit
The duration of chronic cough from its first documentation in general practice to the initial visit at the chronic cough clinic was long across all patient groups, illustrating substantial diagnostic delays. Patients with refractory chronic cough experienced an average duration of 7.9 years before specialist evaluation, while those with unexplained chronic cough waited even longer, with a mean duration of 11.7 years. Across demographic subgroups, the delays were similarly prolonged: women and men reported mean durations of 8.4 and 8.5 years, respectively. Smoking status showed modest variation, with never-smokers averaging 8.5 years, former smokers 7.2 years, and current smokers 5.7 years before referral. The availability of a chest X ray in GP records did not markedly shorten the delay; patients without an X ray waited 7.9 years on average, compared with 8.8 years among those with documented imaging. Moreover, age did not show a statistically significant correlation with cough duration at the time of first ICCC presentation. Overall, the study highlights that, irrespective of diagnosis, sex, smoking history, or imaging availability, patients typically lived with chronic cough for many years before reaching specialized care.
Healthcare pathway and medication utilization
Questionnaire on the healthcare pathway, in total and stratified by RCC or UCC (source patient survey).
*If one or more response category was answered, the patient was included in the denominator. RCC: refractory chronic cough; UCC: unexplained chronic cough.
Impact of RCC or UCC on aspects of everyday life and on QoL of patients
The patient survey on the healthcare pathway, in total and as stratified by RCC or UCC, is presented in Table 2. When asked when their cough started, 41.4% patients reported a duration of more than 10 years. Most people had between 2 and 4 triggers; the biggest triggers were cold air or change in temperature (59.2%), dust and pollen (54.9%), speaking or laughing (53.5%), and environmental or tobacco smoke (50.7%). Most reported complaints by patients were social embarrassment (58.0%), exhaustion (54.2%) and sleep disturbance (45.0%). Urinary incontinence was more prevalent in women (48.9%) than in men (5.1%).
Questionnaire on the impact on daily life (source patient survey).
RCC: refractory chronic cough; UCC: unexplained chronic cough.
45.4% of all patients reported an impact of cough on their QoL as “quite a bit/very much/an extreme amount”. The greatest cough-related impact on everyday life (>25% reported as “quite a bit/very much/an extreme amount”) was on sleep (30.4%), mood or emotions (27.5%) and everyday activities (26.2%).
EQ-5D-5L.
RCC: refractory chronic cough; SD: standard deviation; Q: quartile; UCC: unexplained chronic cough.
Discussion
This study examined the diagnostic trajectory of patients with RCC or UCC in the Netherlands prior to referral to the ICCC and assessed patient reported perceptions of how chronic cough affects quality of life.
A key finding was the marked delay between the first documented GP consultation for cough and the initial ICCC visit, with a mean interval of 8.5+6.5 years. This duration closely parallels observations from a comparable primary care cohort in the United Kingdom, 18 while shorter durations reported in Spain, 19 South Korea, and Taiwan 20 (8.0+9.4, 6.4 +5.0, 3.45 + 5.13 and 5.75 +7.28 years) likely reflect differences in study design, population characteristics, and healthcare system structure. In the Netherlands, mandatory GP referral may contribute to delay, particularly when awareness of chronic cough and its clinical significance vary among primary care physicians.
The study identified notable variability in GP coding and evaluation of chronic cough, including inconsistent use of diagnostic imaging. The absence of a standardized, evidence-based guideline for the evaluation and management of chronic cough in Dutch primary care may partly explain these inconsistencies. Further research is warranted to clarify the relative contributions of patient related factors, GP decision making, and specialist level processes to the overall diagnostic delay.
The diagnostic journey was prolonged irrespective of age, sex, smoking history, or the eventual diagnosis of RCC versus UCC. Although chronic cough is not inherently difficult to diagnose, the challenge lies in clinicians frequently overlooking the diagnosis. This is also reflected by our finding that many patients consulted multiple specialists, with 75% seeing at least two and 16% more than four specialists before receiving a definitive diagnosis. , underscoring the fragmented and inefficient nature of current care pathways. Previous work by Smith et al. 18 has similarly demonstrated substantial increases in healthcare utilization and costs in the years preceding diagnosis, followed by reductions once a formal diagnosis is established, emphasizing the potential benefits of earlier recognition and streamlined referral pathways.
Patients in our cohort reported substantial functional and psychosocial burden attributable to chronic cough. Common triggers—including cold air and, temperature changes (59.2%), speaking or, and laughing (53.5%)—interfered considerably with daily activities. Social embarrassment (58%), fatigue (54.2%), and sleep disturbance (45%) were the most frequently reported effects, consistent with international data demonstrating extensive quality of life impairment among patients with chronic cough. 19 The prevalence of cough induced urinary incontinence among men, although lower than among women, was nevertheless notable and aligns with observations from other studies.18,19 The mean EQ 5D 5L utility score was lower than that of the general Dutch population, indicating meaningful health status impairment, although this measure is not disease specific. 17
This study has several limitations. The absence of a control group limits comparative interpretation. The quality and completeness of GP records varied, reflecting the lack of standardized coding protocols, and some data—including medication use and healthcare utilization—relied on patient self-report, introducing potential recall bias. Finally, because the cohort was derived from a single specialized centre, generalizability to the wider chronic cough population should be approached with caution.
Future research and outlook for patients
Future studies on the optimization of the patient journey in chronic cough should focus on the effects of the current guidelines on the awareness of chronic cough, on the improvement of communication between patients and physicians, and on a structured systematic work-up program using as few investigations as possible.
There is a lack of available and effective treatment; therefore, RCC or UCC remains a major unmet medical need. Novel treatment options targeting the underlying disease mechanism of RCC or UCC are P2X3 receptor antagonists. Gefapixant is the first compound in this class which has shown efficacy (reduction in cough counts) and improvements in QoL in these patients and has been approved by the European Medicine Agency (EMA). Other compounds in this class are also in development.6,11
Conclusion
Results from this study show a lengthy and complex patient journey in the Netherlands, with an average delay of more than 8 years from the initial visit to a GP to their first consultation at the ICCC. Additionally, over half of the patients had seen multiple specialists before being referred to the ICCC. The prolonged diagnostic timeline and reduced QoL reported by patients highlight the need to raise awareness of chronic cough among healthcare providers in a multidisciplinary way, to reduce the delay in time to diagnosis.
Novel therapies targeting the underlying disease mechanisms of RCC or UCC, may address the substantial disease burden associated with this disease.
Supplemental material
Supplemental material - A retrospective study to understand the journey and health status of patients with unexplained or refractory chronic cough in the Netherlands
Supplemental material for A retrospective study to understand the journey and health status of patients with unexplained or refractory chronic cough in the Netherlands by Jan Willem van den Berg, Mireille Edens, Anoe Radha Oedit Doebé, Hester van der Velden, and Maxime Roosje Heezen in Chronic Respiratory Disease.
Footnotes
Acknowledgements
We would like to thank the study team in the Department of Innovation and Science and the Isala Chronic Cough Clinic, for working on the informed consent forms, the patient surveys and QoL questionnaires and for going through the GP files, amongst other things. Professional medical writing assistance was provided by Lola Opeyemi from STWC B.V. (the United Kingdom and the Netherlands).
Ethical considerations
This study protocol was reviewed by the Medical Ethics Review Committee (METC) of Isala Zwolle, the Netherlands (METC number 220804). The METC assessed whether the study falls within the scope of the Dutch Medical Research Involving Human Subjects Act (WMO). The committee concluded that the study involves a medical-scientific research question; however, participants are not subjected to any medical procedures nor are they imposed any behavioural interventions as defined by the WMO. Therefore, the METC determined that the study does not fall within the scope of the WMO and does not require formal WMO approval.
Consent to participate
All participants received an information letter explaining the study purpose, procedures, and their rights, including the voluntary nature of participation. Written informed consent was obtained from all participants prior to inclusion, including consent for the collection and use of their medical data and patient questionnaires. Participants were informed that they could withdraw from the study at any time without consequences. No identifiable data are published in this manuscript.
Author contributions
JWB, ME, AOD, HV, MH: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and Drafting the work or reviewing it critically for important intellectual content; and Final approval of the version to be published; and Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. The funder is responsible for study design, execution, planning, and decision to publish.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Anoe Radha Oedit Doebé and Maxime Roosje Heezen are employees of MSD The Netherlands, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. Hester van der Velden is a former employee of MSD The Netherlands, who may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data Availability Statement
The data that support the findings of this study are not publicly available due to ethical restrictions. Patient consent was obtained solely for the collection and use of data to answer the specific research questions outlined in the study protocol. Access to the anonymized data may be considered on a case-by-case basis upon reasonable request and after additional consent by the patients.
Data protection statement
Participant data were pseudonymized and handled in accordance with applicable privacy laws, including the General Data Protection Regulation (GDPR). Access to identifiable data was restricted to authorized study personnel.
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
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