Abstract
Background
Chronic pruritus (CP) and chronic cough (CC) are prevalent conditions with shared underlying mechanisms, including neuronal sensitisation and inflammation. While previous studies identified associations between pruritus and CC, limited data exist on their interplay when accounting for confounders such as smoking and asthma.
Methods
This cross-sectional study analysed middle-aged and older participants from a population-based cohort, the Rotterdam Study. Logistic regression models assessed associations between demographic and lifestyle factors (e.g. smoking), CC (categorised as new-onset or persistent based on longitudinal data), asthma, and CP, reported as odds ratios with 95% confidence intervals. Sensitivity analyses sequentially excluded participants with atopic dermatitis, asthma and a combination of atopic conditions.
Results
In total, 4364 participants (age range 48–99 years, median age 71; 58.8% women) were included. Persistent CC was strongly associated with CP, doubling the odds in multivariable analyses (OR 2.07, 95% CI 1.43–3.00). Smoking was independently associated with CP, with the highest odds in current smokers (OR 1.46, 95% CI 1.10–1.92). The association between persistent CC and CP remained robust across all sensitivity analyses.
Conclusions
Persistent CC is strongly associated with CP, emphasising shared pathogenic mechanisms. Smoking emerged as a modifiable risk factor for CP. Longitudinal studies are needed to establish causality and optimise therapeutic and management strategies.
Shareable abstract
Persistent chronic cough is strongly linked to chronic pruritus, independent of atopic conditions such as asthma, underscoring shared neuronal and inflammatory pathways; smoking emerges as a significant, modifiable risk factor for chronic pruritus https://bit.ly/4nzRkyk
Introduction
Itch (pruritus) is a protective mechanism evolved to expel pathogens and irritants from the skin through scratching [1]. Chronic pruritus (CP), lasting 6 weeks or more, arises from various causes, including skin diseases such as atopic dermatitis (AD), systemic diseases, neuropathic conditions or combinations of these [1, 2]. The persistence of CP involves a complex interplay of immune mediators and neuronal sensitisation, leading to amplified itch sensations (hyperknesis) and the misinterpretation of normal stimuli as itchy (alloknesis) [3, 4].
Similarly, cough is a physiological response to clear the respiratory tract [5]. Chronic cough (CC) is clinically defined as lasting more than 8 weeks. It involves, in short, sensitisation combined with (subclinical) inflammation and affects up to 18% of the general population, with smoking as a major risk factor [5, 6]. Causes include infections, chronic airway diseases such as asthma and COPD, gastro-oesophageal reflux disease, angiotensin-converting-enzyme inhibitor use and idiopathic cough (i.e. unexplained CC). Similarly to CP, CC involves heightened sensitivity to low-level stimuli (hypertussia) and coughing triggered by normally nontussive stimuli (allotussia), drawing parallels to an “airway itch” [7–10].
Asthma, a key contributor to CC, involves variable expiratory airflow limitation, chronic airway inflammation, airway hyperresponsiveness and mucus hypersecretion [11]. Based on the level of type 2 (T2) inflammation, it can be categorised into T2-high and T2-low asthma. T2-high asthma includes early-onset allergic asthma, which is associated with elevated immunoglobulin E serum levels and atopic conditions such as allergic rhinitis and AD, a major cause of CP [11–13].
Despite overlapping mechanisms, the relationship between CC and CP remains underexplored, particularly in older populations where both conditions are prevalent. Evidence from the United States All of Us database and a European survey study has suggested positive associations between pruritus and CC, although methodological constraints made it challenging to account for potential confounders such as smoking [14, 15].
This study investigates associations between lifestyle and demographic factors, CC, and CP, and the influence of atopic conditions on these relationships, within the Rotterdam Study, a population-based cohort of middle-aged and older adults.
Methods
Study population: the Rotterdam study
The Rotterdam Study is a population-based cohort study conducted in Ommoord, Rotterdam, The Netherlands. Detailed descriptions of its study design, objectives and methodologies are documented elsewhere [16]. The Rotterdam Study started in 1990 with the RS-I cohort, which included 7983 individuals aged 55 years and older (response rate 78%). A second cohort (RS-II) was added in 2000 with 3011 participants, also aged 55 years and older (response rate 67%). In 2006, a third cohort (RS-III) started with 3932 participants of 45 years and older (response rate 65%). The most recent cohort, RS-IV, started in 2016 with 3005 participants aged 40 years and older (response rate 45%). Follow-up assessments occur every 3–6 years, involving examinations and interviews.
The Rotterdam Study has been approved by the Medical Ethics Committee of Erasmus MC and the Dutch Ministry of Health, Welfare and Sport. All participants provided written informed consent.
Questionnaires
This cross-sectional study used data from a structured Dutch questionnaire distributed to all consenting participants in the four Rotterdam Study cohorts. Distributed either on paper (10 May 2023) to participants’ home addresses or digitally (12 May 2023), based on participant preference, the questionnaire included mostly closed-ended items addressing health topics such as CP, CC and asthma. Nonresponders received a reminder on 16 June 2023.
The prevalence of CP was assessed using three validated questions (translated and back-translated from German to Dutch by official translators): whether participants had ever experienced CP (lifetime CP), experienced CP in the past 12 months and if they were currently experiencing CP [17, 18].
CC and self-reported asthma were assessed using the screening version of the European Community Respiratory Health Survey questionnaire [19, 20]. CC was defined as coughing almost daily for at least 3 months annually. Unlike the self-administered questionnaire used currently, chronic cough status was assessed during home interviews by research assistants in two previous Rotterdam Study rounds. The availability of longitudinal data facilitated further categorisation of CC as follows: if reported in the current assessment and at least one of the previous two assessments, it was classified as persistent CC; if only reported in the current assessment, it was classified as new-onset CC [21].
In the current questionnaire assessment, participants were also asked whether they had ever had asthma and physician-diagnosed asthma was verified independently through medical record review. Having allergic rhinitis was self-reported. Only participants with complete responses for lifetime CP, CC and asthma were included in the analysis.
Covariates
Covariates were selected based on literature and derived from follow-up research centre visits and home interviews closest to the date of questionnaire completion. For RS-I, data from the seventh follow-up were used (visit: RS-I-7, between 2018 and 2020), for RS-II the fifth follow-up (RS-II-5, 2021–2024), for RS-III, the third follow-up (RS-III-3, 2021–2024), and for RS-IV, baseline data (RS-IV-1, 2016–2020).
Sex and birthdate were recorded at enrolment, with age calculated at the time of questionnaire completion. Body mass index (BMI) was calculated using weight and height measured during research centre visits. Dermatology-trained physicians assessed skin colour (pale-to-white, white-to-olive or dark) and AD during full-body skin examinations (FBSEs).
Additional covariates were collected through home interviews. Smoking status was categorised as never, former or current smoker of cigarettes, with pack-years calculated where data were available. Alcohol consumption was classified as nondrinker, light drinking (≤1 occasion per month, any quantity), moderate drinking (multiple occasions per month, ≤9 drinks per occasion) or heavy drinking (multiple occasions per week, ≥10 drinks regularly). Education level was categorised as low (primary education), medium (lower to intermediate vocational education) or high (general secondary education or higher). Possible AD history was assessed using the UK Working Party criteria based on self-reported history of an itchy skin condition affecting skin creases [22]. The maximum interval between questionnaire completion and covariate data collection was 7.8 years for home interview data for the RS-IV cohort.
Statistical analyses
Participant characteristics and prevalence of CP, CC and asthma were summarised using medians with interquartile ranges (IQRs) for skewed continuous data and counts with percentages for categorical variables. Chi-square tests assessed the relationship between CC and self-reported asthma, with crude odds ratios and 95% confidence intervals calculated.
For logistic regression analyses, the primary outcome was lifetime CP, with secondary analyses using CP in the past 12 months and current CP as alternative outcomes.
Model 1: lifestyle and demographic model
First, the associations between lifestyle and demographic factors (sex, age, smoking status, BMI, education level, alcohol consumption and skin colour) and CP outcomes were evaluated in a unified model.
Model 2: adjusted individual respiratory condition model
Second, statistically significant variables from the lifestyle and demographic model (model 1); specifically, sex, age and smoking status, were retained. The independent effects of respiratory conditions were evaluated by adding one of the following exposures: CC, persistent CC, self-reported asthma and physician-diagnosed asthma, with each analysed separately. An interaction term (smoking status×CC) was included when analysing CC to assess whether the effect of smoking on CP depends on CC presence and vice versa.
Model 3: combined respiratory conditions models
Finally, three multivariable models evaluated the combined effects of significant lifestyle and demographic variables (from model 1); specifically, sex, age and smoking status, and combinations of key respiratory exposures (from model 2). Model 3.1 (CC and self-reported asthma model) added CC, self-reported asthma and their interaction term. Model 3.2 (persistent CC and self-reported asthma model) added persistent CC and self-reported asthma, and model 3.3 (persistent CC and physician-diagnosed asthma model) added persistent CC and physician-diagnosed asthma. An overview of all models is provided in a flow diagram in supplementary figure S1.
Sensitivity analyses
Exclusion of participants with atopic conditions
The impact of atopy on regression results was assessed by excluding participants in three steps. First, those with self-reported possible AD history or observed AD during FBSE; second, those with self-reported asthma; and third, those with (possible) AD, self-reported asthma and/or allergic rhinitis.
Smoking exposure (in pack-years) in cohort RS-IV
Cumulative smoking exposure was evaluated by replacing smoking status with pack-years using the lifestyle and demographic model (model 1) in participants from cohort RS-IV, where pack-year data was most complete. Pack-years were analysed continuously (log-transformed) and categorically (nonsmokers (0 pack-years) and exposure levels: low (1–6), moderate (7–20) and high (20+)).
Analyses were performed using SPSS Statistics version 28 (IBM, Armonk, NY, USA), with p<0.05 considered statistically significant. Reporting adhered to STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [23].
Results
Population characteristics and prevalence of CP, CC and asthma
A total of 7009 questionnaires were sent to Rotterdam Study participants, with 4541 responding (64.8% response rate). Of these, 4364 (96.1%) provided complete data and were included in the analyses (flow diagram in figure 1). Excluded participants were older than included participants (supplementary table S1). Among included participants, the median age was 71 years (range 48–99, IQR 63–78) and 58.8% were female. Lifetime CP affected 823 participants (18.9%) (see table 1 for characteristics of those with and without lifetime CP). CP in the past 12 months was reported by 461 (10.6%) and current CP by 377 (8.6%) (prevalence rates in table 2). CC was reported by 731 participants (16.8%), including 168 (3.8%) with persistent CC. Self-reported asthma was indicated by 519 participants (11.9%), while physician-diagnosed asthma was determined in 412 (9.4%). Figure 2 illustrates the overlap of lifetime CP, CC and self-reported asthma through a proportional Venn diagram.
FIGURE 1.
Flow diagram of inclusion of participants.
TABLE 1.
Population characteristics (n=4364)
| Variable | Ever chronic pruritus# (n=823, 18.9%) | Never chronic pruritus# (n=3541, 81.1%) |
|---|---|---|
| Sex, n (%) | ||
| Male | 278/823 (33.8) | 1520/3541 (42.9) |
| Female | 545/823 (66.2) | 2021/3541 (57.1) |
| Age (years), median (IQR) | 70 (62–77) | 72 (63–79) |
| BMI¶, median (IQR) | 27 (24–30) | 27 (24–30) |
| Skin colour+, n (%) | ||
| Pale-to-white | 585/691 (84.7) | 2508/2962 (84.7) |
| White-to-olive | 63/691 (9.1) | 311/2962 (10.5) |
| Dark | 43/691 (6.2) | 143/2962 (4.8) |
| Education level§, n (%) | ||
| Low | 71/820 (8.7) | 269/3522 (7.6) |
| Medium | 456/820 (55.6) | 1984/3522 (56.3) |
| High | 293/820 (35.7) | 1269/3522 (36.0) |
| Smoking statusƒ, n (%) | ||
| Never-smoker | 265/759 (34.9) | 1271/3228 (39.4) |
| Former smoker | 402/759 (53.0) | 1682/3228 (52.1) |
| Current smoker | 92/759 (12.1) | 275/3228 (8.5) |
| Pack years##, median (IQR) | 3 (0–21) | 1 (0–16) |
| Alcohol consumption¶¶, n (%) | ||
| Nondrinker | 168/759 (22.1) | 621/3228 (19.2) |
| Light drinking | 164/759 (21.6) | 632/3228 (19.6) |
| Moderate drinking | 250/759 (32.9) | 1134/3228 (35.1) |
| Heavy drinking | 177/759 (23.3) | 841/3228 (26.1) |
| Self-reported possible atopic dermatitis and/or observed atopic dermatitis++, n (%) | 216/742 (29.1) | 334/3175 (10.5) |
| Allergic rhinitis§§, n (%) | 321/818 (39.2) | 965/3527 (27.4) |
BMI: body mass index; IQR: interquartile range. #: Lifetime chronic pruritus based on question from questionnaire: “Have you ever had itch for more than 6 weeks in your life?”. ¶: BMI calculated as weight (kg)/height (m2). +: Skin colour determined by physician during full-body skin examination. §: Low: primary education; medium: lower vocational education, lower secondary education or intermediate vocational education; high: general secondary education, higher vocational education or university. ƒ: Self-reported never, former or current smoker of cigarettes. ##: Pack-years were calculated by multiplying the number of packs smoked per days by the number of years the participant has smoked, self-reported during interviews. ¶¶: Nondrinker: never consumes alcohol; light drinking: ≤1 occasion per month (any quantity); moderate drinking: multiple occasions per month with ≤9 drinks per occasion; heavy drinking: multiple occasions per week with ≥10 drinks regularly. ++: Possible atopic dermatitis defined by positive responses to UK Working Party criteria: “Did you ever have an itchy skin condition? Did this itchy skin condition affect the skin creases?” and/or physician-observed atopic dermatitis at full-body skin examination. §§: Allergic rhinitis based on question from questionnaire: “Do you suffer from allergic rhinitis, hay fever included?”.
TABLE 2.
Prevalence of chronic pruritus, chronic cough and asthma
| Variable | Total included participants (n=4364, 100%) | Ever chronic pruritus# (n=823, 18.9%) | Never chronic pruritus# (n=3541, 81.1%) |
|---|---|---|---|
| Chronic pruritus | |||
| Chronic pruritus in past 12 months¶, n (%) | 461/4361 (10.6) | 461/817 (56.0) | NA |
| Current chronic pruritus+, n (%) | 377/4360 (8.6) | 377/460 (45.8) | NA |
| Chronic cough | |||
| Chronic cough§, n (%) | 731/4364 (16.8) | 196/823 (23.8) | 535/3541 (15.1) |
| Persistent chronic coughƒ, n (%) | |||
| Yes, persistent chronic cough | 168/4364 (3.8) | 53/823 (6.4) | 115/3541 (3.2) |
| New-onset chronic cough | 563/4364 (12.9) | 143/823 (17.4) | 420/3541 (11.9) |
| No chronic cough at all | 3633/4364 (83.2) | 627/823 (76.2) | 3006/3541 (84.9) |
| Asthma | |||
| Self-reported asthma##, n (%) | 519/4364 (11.9) | 142/823 (17.3) | 377/3541 (10.6) |
| Physician-diagnosed asthma based on medical records¶¶, n (%) | 412/4363 (9.4) | 101/823 (12.3) | 311/3541 (8.8) |
NA: not applicable. #: Lifetime chronic pruritus based on question from questionnaire: “Have you ever had itch for more than 6 weeks in your life?”. ¶: Chronic pruritus in past 12 months based on question from questionnaire: “Have you experienced itch for more than 6 weeks in the past 12 months?”. +: Current chronic pruritus based on question from questionnaire: “Have you currently had itch for more than 6 weeks?”. §: Chronic cough based on question from questionnaire: “Do you cough almost daily for at least 3 months a year?”. ƒ: Persistent chronic cough: chronic cough reported in current and prior questionnaires; new-onset chronic cough: reported in current questionnaire only. ##: Self-reported lifetime asthma based on question from questionnaire: “Have you ever had asthma to date?”. ¶¶: Physician-diagnosed asthma based on medical records.
FIGURE 2.
Proportional Venn diagram of participants with lifetime chronic pruritus, chronic cough and self-reported asthma.
Chi-square analysis showed a significant association between CC and self-reported asthma (χ2=204.04, p<0.001, ϕ=0.22), with a crude odds ratio of 3.95 (95% CI 3.24–4.82). Reversing the variables yielded the same odds ratio, indicating that the odds of reporting asthma were four times higher among individuals with CC and the same for the reverse association.
Logistic regression analyses
Model 1: lifestyle and demographic model
In the model adjusted for all demographic and lifestyle variables, female sex (OR 1.42, 95% CI 1.19–1.70) and both current smoking (OR 1.65, 95% CI 1.24–2.21) and former smoking (OR 1.23, 95% CI 1.02–1.49) were significantly associated with lifetime CP (table 3). Age showed no significant association with lifetime CP or CP in the past 12 months (supplementary table S2), but it was associated with current CP (OR 1.01, 95% CI 1.00–1.03) (supplementary table S3). Other lifestyle and demographic factors showed no significant associations across CP outcomes.
TABLE 3.
Logistic regression analyses of lifetime chronic pruritus
| Variable | OR# | 95% CI | p-value |
|---|---|---|---|
| Model 1: lifestyle and demographic model, all demographic and lifestyle variables unified in one model | |||
| Sex | |||
| Female | 1.42 | 1.19–1.70 | <0.001 |
| Age | 1.00 | 0.99–1.00 | 0.22 |
| Smoking status | |||
| Never-smoker | Ref | ||
| Former smoker | 1.23 | 1.02–1.49 | 0.03 |
| Current smoker | 1.65 | 1.24–2.21 | <0.001 |
| Body mass index | 1.00 | 0.98–1.02 | 0.97 |
| Education level | |||
| Low education | Ref | ||
| Medium education | 0.90 | 0.65–1.26 | 0.55 |
| High education | 0.89 | 0.63–1.26 | 0.51 |
| Alcohol consumption | |||
| Nondrinker | Ref | ||
| Light drinking | 0.95 | 0.74–1.23 | 0.71 |
| Moderate drinking | 0.85 | 0.67–1.08 | 0.18 |
| Heavy drinking | 0.81 | 0.62–1.05 | 0.12 |
| Skin colour | |||
| Pale-to-white | Ref | ||
| White-to-olive | 0.82 | 0.61–1.10 | 0.19 |
| Dark | 1.21 | 0.84–1.74 | 0.30 |
| Model 2: adjusted individual respiratory condition model, adjusted for sex, age and smoking status | |||
|---|---|---|---|
| Chronic cough | 1.70 | 1.39–2.07 | <0.001 |
| Persistent chronic cough | |||
| No chronic cough at all | Ref | ||
| New-onset chronic cough | 1.56 | 1.25–1.94 | <0.001 |
| Yes, persistent chronic cough | 2.28 | 1.58–3.29 | <0.001 |
| Self-reported asthma | 1.77 | 1.42–2.20 | <0.001 |
| Physician-diagnosed asthma | 1.39 | 1.09–1.79 | 0.009 |
| Model 3.1: combined respiratory conditions model: chronic cough and self-reported asthma, adjusted for sex, age and smoking status | |||
|---|---|---|---|
| Sex | 1.46 | 1.23–1.72 | <0.001 |
| Age | 0.99 | 0.99–1.00 | 0.04 |
| Smoking status | |||
| Never-smoker | Ref | ||
| Former smoker | 1.21 | 1.01–1.44 | 0.04 |
| Current smoker | 1.46 | 1.10–1.92 | 0.008 |
| Chronic cough | 1.55 | 1.26–1.90 | <0.001 |
| Self-reported asthma | 1.58 | 1.26–1.99 | <0.001 |
| Model 3.2: combined respiratory conditions model: persistent chronic cough and self-reported asthma, adjusted for sex, age and smoking status | |||
|---|---|---|---|
| Sex | 1.46 | 1.23–1.73 | <0.001 |
| Age | 0.99 | 0.99–1.00 | 0.03 |
| Smoking status | |||
| Never-smoker | Ref | ||
| Former smoker | 1.20 | 1.01–1.43 | 0.04 |
| Current smoker | 1.46 | 1.10–1.92 | 0.008 |
| Persistent chronic cough | |||
| No chronic cough at all | Ref | ||
| New-onset chronic cough | 1.43 | 1.14–1.80 | 0.002 |
| Yes, persistent chronic cough | 2.07 | 1.43–3.00 | <0.001 |
| Self-reported asthma | 1.58 | 1.26–1.98 | <0.001 |
| Variable | OR# | 95% CI | p-value |
|---|---|---|---|
| Model 3.3: combined respiratory conditions model: persistent chronic cough and physician-diagnosed asthma, adjusted for sex, age and smoking status | |||
| Sex | 1.47 | 1.24–1.74 | <0.001 |
| Age | 0.99 | 0.98–1.00 | 0.02 |
| Smoking status | |||
| Never-smoker | Ref | ||
| Former smoker | 1.21 | 1.01–1.44 | 0.04 |
| Current smoker | 1.44 | 1.09–1.90 | 0.01 |
| Persistent chronic cough | |||
| No chronic cough at all | Ref | ||
| New-onset chronic cough | 1.51 | 1.21–1.89 | <0.001 |
| Yes, persistent chronic cough | 2.22 | 1.53–3.21 | <0.001 |
| Physician-diagnosed asthma | 1.27 | 0.98–1.63 | 0.07 |
Ref: reference variable. Values in bold represent statistical significance (p<0.05). #: The odds ratio measures the association between lifetime chronic pruritus and never having pruritus, for each analysed variable.
Model 2: adjusted individual respiratory condition model
As sex and smoking status were significant in the first model for all CP outcomes and age was significant for current CP, these variables were retained.
CC showed a strong association with lifetime CP (OR 1.70, 95% CI: 1.39–2.07), with persistent CC (OR 2.28, 95% CI 1.58–3.29) having a stronger association than new-onset CC (OR 1.56, 95% CI 1.25–1.94) (table 3). The interaction term of smoking status×CC was not statistically significant. Self-reported asthma also increased the odds (OR 1.77, 95% CI 1.42–2.20). Physician-diagnosed asthma showed a weaker association (OR 1.39, 95% CI 1.09–1.79). These patterns were similar for the secondary CP outcomes.
Model 3: combined respiratory conditions models
In comparison to the adjusted individual respiratory conditions model (model 2), associations slightly decreased in strength but remained significant in the combined respiratory conditions models (model 3), except for physician-diagnosed asthma (table 3). In model 3.1 (CC and self-reported asthma), adjusting for sex, age and smoking status, CC (OR 1.55, 95% CI 1.26–1.90), and self-reported asthma (OR 1.58, 95% CI 1.26–1.99) remained strong predictors of CP, independent of each other, as the interaction term of CC×self-reported asthma was not statistically significant.
When CC was categorised into persistent and new-onset in model 3.2 (persistent CC and self-reported asthma model), persistent CC (OR 2.07, 95% CI 1.43–3.00) showed higher odds than new-onset CC (OR 1.43, 95% CI 1.14–1.80).
In model 3.3 (persistent CC and physician-diagnosed asthma model), persistent CC still had the strongest association (OR 2.22, 95% CI 1.53–3.21). Similar patterns were observed for CP in the past 12 months and current CP outcomes.
Sensitivity analyses
Exclusion of participants with atopic conditions
Excluding participants with possible AD history or observed AD during FBSE showed that sex and smoking remained significantly associated with CP (supplementary table S4). While self-reported asthma remained significant in the adjusted individual respiratory condition model (model 2) (OR 1.40, 95% CI 1.06–1.86)), its effect size decreased compared to the main analysis (table 3) and was no longer significant in model 3.1 (CC and self-reported asthma model) (OR 1.26, 95% CI 0.94–1.69). However, persistent CC remained strongly associated with CP (OR 2.02, 95% CI 1.30–3.13).
Excluding participants with self-reported asthma further strengthened the association between persistent CC and CP (OR 2.27, 95% CI 1.47–3.51) (supplementary table S5). This pattern persisted when excluding a combination of atopic conditions (AD, self-reported asthma and allergic rhinitis), with persistent CC still showing a strong association (OR 2.35, 95% CI 1.28–4.33) (supplementary table S6).
Pack-years in RS-IV
In cohort RS-IV, log-transformed pack-years was significantly associated with lifetime CP (OR 1.12, 95% CI 1.03–1.22). When categorising pack-years, the high exposure (20+ pack-years) category showed a notable association (OR 1.56, 95% CI 1.12–2.18). These results suggest a dose–response relationship (supplementary table S7).
Discussion
This cross-sectional study of middle-aged and older participants identified significant associations between female sex, age, cigarette smoking, CC, asthma and CP. Persistent CC was most strongly linked to CP, with twice the odds of CP, remaining robust after excluding participants with atopic conditions. These findings align with previous studies reporting associations between pruritus and CC, with adjustment for confounders, such as smoking, being a unique aspect of this study [14, 15].
Cigarette smoking was significantly associated with CP, with the highest odds in current smokers and those with over 20 pack-years of exposure. Prior research has similarly linked smoking to CP across various age groups [24–26] and to itchy skin diseases such as psoriasis and AD [27, 28], though findings are inconsistent [29, 30]. In this study, the smoking-CP association remained after excluding participants with possible AD, indicating broader mechanisms. Smoking-related changes to the skin barrier may enhance skin sensitivity and hinder repair [31]. Systemically, smoking induces epigenetic modifications and dysregulation of immune responses, amplifying inflammation and sensitisation, potentially exacerbating itch [32]. These findings underscore the potential benefits of smoking cessation in managing CP. However, confounding by indication remains a possibility, as smoking is also associated with specific psychological factors (e.g. anxiety) [33] and personality traits (e.g. higher neuroticism) [34], which in turn have been linked to itching and scratching [35–37].
Smoking is also a well-established risk factor for CC [38], which in turn was independently associated with CP. This finding aligns with findings from a large matched case–control study from the All of Us research programme in the United States, despite differences in cohort size and study design [14]. Notably, the current study is the first to show that persistent CC has a stronger link to CP than new-onset CC, emphasising the importance of cough duration. Even after excluding participants with atopic conditions, persistent CC remained strongly associated with CP. These findings highlight the potential overlap in mechanisms induced by scratching and coughing that sustain chronicity, with peripheral nerve sensitisation, central sensitisation, neuroimmune interactions and tissue remodelling [7]. This overlap suggests potential therapeutic avenues, including specific agents targeting receptors such as P2X3, as discussed in a recently published review on CC and CP [7].
Asthma, a known driver of CC, was associated with CP. While asthma and CC showed a strong correlation, their interaction did not significantly influence CP risk, suggesting independent effects. The association between asthma and CP weakened after excluding participants with possible AD, indicating that atopy partially explains this relationship. However, persistent CC remained strongly associated with CP, pointing to shared nonatopic pathways. Interestingly, self-reported asthma showed stronger associations than physician-diagnosed asthma, potentially reflecting a subgroup of participants with mild physician-diagnosed asthma which has been in remission for many years.
This study has several limitations. Its cross-sectional design limits causal inference. Reliance on self-reported data may introduce recall and reporting biases, although validated questionnaires were used to minimise this risk. Residual confounding from unmeasured factors, such as medication use or environmental exposures, cannot be excluded despite adjustment for multiple covariates. Importantly, as our study population comprised individuals aged 48 years and older, the findings may not be generalisable to younger populations. Additionally, while longitudinal data were used to categorise CC as either persistent or new-onset, the study was unable to determine whether cases of CC were refractory [39]. Future studies should specifically focus on refractory CC to better understand its exact relationship with chronic pruritus.
Despite these limitations, this study has notable strengths. The size of the Rotterdam Study, the inclusion of multiple CP outcomes (lifetime, past 12 months and current), adjustment for important confounders such as smoking and stratification by persistent and new-onset CC enhanced the validity and robustness of the findings.
Conclusion
This study provides new insights into the associations between smoking, CC, asthma and CP in older adults from a large population-based cohort. Smoking was independently associated with CP. Persistent CC showed the strongest association with CP, which remained after excluding participants with atopic conditions, highlighting shared mechanisms involving neuronal sensitisation and inflammation. These findings highlight the importance of addressing modifiable risk factors such as smoking in the management of CP and suggest therapeutic strategies targeting shared pathogenic pathways in CC and CP. Longitudinal studies are needed to establish causality and to optimise therapeutic and management strategies.
Acknowledgements
The authors thank David Gunn (Unilever Research and Development, UK) for his valuable support. Additionally, we also extend our gratitude to the participants of the Rotterdam Study, the dedicated staff, and the general practitioners and pharmacists who contributed to the study.
Footnotes
Provenance: Submitted article, peer reviewed.
Ethics statement: The Rotterdam Study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre (registration number MEC 02.1015), and by the Dutch Ministry of Health, Welfare and Sport (Population Screening Act WBO, license number 1071272-159521-PG). The Rotterdam Study has been entered into the Netherlands National Trial Register (https://onderzoekmetmensen.nl/en) and into the WHO International Clinical Trials Registry Platform (https://apps.who.int/trialsearch/) under shared catalogue number NTR6831. All participants provided written informed consent to participate in the study and to have their information obtained from treating physicians.
Author contributions: Conceptualisation and methodology: J.F. Bollemeijer, S. Riemann, T.E.C. Nijsten, G. Brusselle and L.M. Pardo. Formal analysis and writing (original draft): J.F. Bollemeijer and L.M. Pardo. Data curation: J.F. Bollemeijer, S. Riemann, G. Brusselle and L.M. Pardo. Writing (review and editing): J.F. Bollemeijer, S. Riemann, H.B. Thio, T.E.C. Nijsten, G. Brusselle and L.M. Pardo. Supervision: H.B. Thio, T.E.C. Nijsten, G. Brusselle and L.M. Pardo.
Conflicts of interest: S. Riemann reports nonfinancial support from AstraZeneca and GlaxoSmithKline outside the submitted work. H.B. Thio received honoraria for consultancy and invited presentations from AbbVie, Almirall, AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Janssen, LeoPharma, Sanofi and UCB. G. Brusselle has received fees for attending advisory boards and giving lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis and Sanofi Regeneron. The other authors declare no conflict of interest within the scope of the submitted work.
Support statement: J.F. Bollemeijer is supported by Unilever. S. Riemann is supported by a predoctoral mandate granted by Ghent University (BOF23/DOC/013). G. Brusselle has received an Investigator-Initiated Study grant (MISP #101797) from Merck Sharp & Dohme. The Rotterdam Study is a Core Facility of the Erasmus University Medical Centre. External funding include the Netherlands Research Organization (NWO), Netherlands Organization for Health Research and Development (ZonMw), European Commission (FP6, FP7, Horizon2020 and ERC), and the National Institutes of Health. Funding information for this article has been deposited with the Open Funder Registry.
Supplementary material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00364-2025.SUPPLEMENT
Data availability
Data can be obtained upon request. Requests should be directed towards the management team of the Rotterdam Study (datamanagement.ergo@erasmusmc.nl), which has a protocol for approving data requests. Due to restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository.
References
- 1.Auyeung KL, Kim BS. Emerging concepts in neuropathic and neurogenic itch. Ann Allergy Asthma Immunol 2023; 131: 561–566. doi: 10.1016/j.anai.2023.08.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Stander S, Weisshaar E, Mettang T, et al. Clinical classification of itch: a position paper of the International Forum for the Study of Itch. Acta Derm Venereol 2007; 87: 291–294. doi: 10.2340/00015555-0305 [DOI] [PubMed] [Google Scholar]
- 3.Andersen HH, Akiyama T, Nattkemper LA, et al. Alloknesis and hyperknesis-mechanisms, assessment methodology, and clinical implications of itch sensitization. Pain 2018; 159: 1185–1197. doi: 10.1097/j.pain.0000000000001220 [DOI] [PubMed] [Google Scholar]
- 4.Yosipovitch G, Rosen JD, Hashimoto T. Itch: From mechanism to (novel) therapeutic approaches. J Allergy Clin Immunol 2018; 142: 1375–1390. doi: 10.1016/j.jaci.2018.09.005 [DOI] [PubMed] [Google Scholar]
- 5.Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008; 371: 1364–1374. doi: 10.1016/S0140-6736(08)60595-4 [DOI] [PubMed] [Google Scholar]
- 6.Song WJ, Chang YS, Faruqi S, et al. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Respir J 2015; 45: 1479–1481. doi: 10.1183/09031936.00218714 [DOI] [PubMed] [Google Scholar]
- 7.Brooks SG, King J, Smith JA, et al. Cough and itch: common mechanisms of irritation in the throat and skin. J Allergy Clin Immunol 2024; 155: 36–52. doi: 10.1016/j.jaci.2024.09.012 [DOI] [PubMed] [Google Scholar]
- 8.Gibson PG. Cough is an airway itch? Am J Respir Crit Care Med 2004; 169: 1–2. doi: 10.1164/rccm.2310009 [DOI] [PubMed] [Google Scholar]
- 9.Lavinka PC, Dong X. Molecular signaling and targets from itch: lessons for cough. Cough 2013; 9: 8. doi: 10.1186/1745-9974-9-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Misery L. Are pruritus and scratching the cough of the skin? Dermatology 2008; 216: 3–5. doi: 10.1159/000109351 [DOI] [PubMed] [Google Scholar]
- 11.Porsbjerg C, Melén E, Lehtimäki L, et al. Asthma. Lancet 2023; 401: 858–873. doi: 10.1016/S0140-6736(22)02125-0 [DOI] [PubMed] [Google Scholar]
- 12.Kuruvilla ME, Lee FE, Lee GB. Understanding asthma phenotypes, endotypes, and mechanisms of disease. Clin Rev Allergy Immunol 2019; 56: 219–233. doi: 10.1007/s12016-018-8712-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Maspero J, Adir Y, Al-Ahmad M, et al. Type 2 inflammation in asthma and other airway diseases. ERJ Open Res 2022; 8: 00576-2021. doi: 10.1183/23120541.00576-2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Sharma D, Pulsinelli J, Correa da Rosa J, et al. Association of pruritus and chronic cough: an all of us database study. J Dermatolog Treat 2024; 35: 2355976. doi: 10.1080/09546634.2024.2355976 [DOI] [PubMed] [Google Scholar]
- 15.Ficheux A-S, Brenaut E, Taieb C, et al. Chronic cough, itch, skin pain and other unpleasant skin sensations are frequently associated: results from survey on 8077 individuals. JEADV Clinical Practice 2023; 3: 100–109. doi: 10.1002/jvc2.248 [DOI] [Google Scholar]
- 16.Ikram MA, Kieboom BCT, Brouwer WP, et al. The Rotterdam Study. Design update and major findings between 2020 and 2024. Eur J Epidemiol 2024; 39: 183–206. doi: 10.1007/s10654-023-01094-1 [DOI] [PubMed] [Google Scholar]
- 17.Matterne U, Strassner T, Apfelbacher CJ, et al. Measuring the prevalence of chronic itch in the general population: development and validation of a questionnaire for use in large-scale studies. Acta Derm Venereol 2009; 89: 250–256. doi: 10.2340/00015555-0641 [DOI] [PubMed] [Google Scholar]
- 18.Matterne U, Apfelbacher CJ, Loerbroks A, et al. Prevalence, correlates and characteristics of chronic pruritus: a population-based cross-sectional study. Acta Derm Venereol 2011; 91: 674–679. doi: 10.2340/00015555-1159 [DOI] [PubMed] [Google Scholar]
- 19.Burney PG, Luczynska C, Chinn S, et al. The European community respiratory health survey. Eur Respir J 1994; 7: 954–960. doi: 10.1183/09031936.94.07050954 [DOI] [PubMed] [Google Scholar]
- 20.European Community Respiratory Health Survey . Questionnaires and protocols. Date last accessed: 14 March 2025. Date last updated: 2018. www.ecrhs.org/questionnaires-and-protocols
- 21.Arinze JT, de Roos EW, Karimi L, et al. Prevalence and incidence of, and risk factors for chronic cough in the adult population: the Rotterdam Study. ERJ Open Res 2020; 6: 00300-2019. doi: 10.1183/23120541.00300-2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Williams HC, Burney PG, Pembroke AC, et al. Validation of the UK diagnostic criteria for atopic dermatitis in a population setting. UK Diagnostic Criteria for Atopic Dermatitis Working Party. Br J Dermatol 1996; 135: 12–17. doi: 10.1111/j.1365-2133.1996.tb03599.x [DOI] [PubMed] [Google Scholar]
- 23.von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370: 1453–1457. doi: 10.1016/S0140-6736(07)61602-X [DOI] [PubMed] [Google Scholar]
- 24.Gu X, Su J, Tao J, et al. Characterization of chronic itch in college students in China. Eur J Dermatol 2022; 32: 64–69. doi: 10.1684/ejd.2022.4193 [DOI] [PubMed] [Google Scholar]
- 25.Chen S, Zhou F, Xiong Y. Prevalence and risk factors of senile pruritus: a systematic review and meta-analysis. BMJ Open 2022; 12: e051694. doi: 10.1136/bmjopen-2021-051694 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Matterne U, Apfelbacher CJ, Vogelgsang L, et al. Incidence and determinants of chronic pruritus: a population-based cohort study. Acta Derm Venereol 2013; 93: 532–537. doi: 10.2340/00015555-1572 [DOI] [PubMed] [Google Scholar]
- 27.Armstrong AW, Harskamp CT, Dhillon JS, et al. Psoriasis and smoking: a systematic review and meta-analysis. Br J Dermatol 2014; 170: 304–314. doi: 10.1111/bjd.12670 [DOI] [PubMed] [Google Scholar]
- 28.Kantor R, Kim A, Thyssen JP, et al. Association of atopic dermatitis with smoking: a systematic review and meta-analysis. J Am Acad Dermatol 2016; 75: 1119–1125. doi: 10.1016/j.jaad.2016.07.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Ortiz A, Grando SA. Smoking and the skin. Int J Dermatol 2012; 51: 250–262. doi: 10.1111/j.1365-4632.2011.05205.x [DOI] [PubMed] [Google Scholar]
- 30.Ju Y, Pei H, Kang N, et al. Prevalence and potential risk factors of chronic pruritus among community middle-aged and older population in Beijing, China. J Eur Acad Dermatol Venereol 2022; 36: 1074–1079. doi: 10.1111/jdv.18041 [DOI] [PubMed] [Google Scholar]
- 31.Hergesell K, Paraskevopoulou A, Opálka L, et al. The effect of long-term cigarette smoking on selected skin barrier proteins and lipids. Sci Rep 2023; 13: 11572. doi: 10.1038/s41598-023-38178-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Saint-André V, Charbit B, Biton A, et al. Smoking changes adaptive immunity with persistent effects. Nature 2024; 626: 827–835. doi: 10.1038/s41586-023-06968-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Fluharty M, Taylor AE, Grabski M, et al. The association of cigarette smoking with depression and anxiety: a systematic review. Nicotine Tob Res 2017; 19: 3–13. doi: 10.1093/ntr/ntw140 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Zvolensky MJ, Taha F, Bono A, et al. Big five personality factors and cigarette smoking: a 10-year study among US adults. J Psychiatr Res 2015; 63: 91–96. doi: 10.1016/j.jpsychires.2015.02.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Holle H, Warne K, Seth AK, et al. Neural basis of contagious itch and why some people are more prone to it. Proc Natl Acad Sci USA 2012; 109: 19816–19821. doi: 10.1073/pnas.1216160109 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Kazgan Kılıçaslan A, Yıldız S, Kurt O, et al. Personality characteristics, anxiety sensitivity, anxiety, and depression levels on patients diagnosed with psychogenic pruritus. Alpha Psychiatry 2022; 23: 243–252. doi: 10.5152/alphapsychiatry.2022.21699 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Sanders KM, Akiyama T. The vicious cycle of itch and anxiety. Neurosci Biobehav Rev 2018; 87: 17–26. doi: 10.1016/j.neubiorev.2018.01.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Kou YR, Kwong K, Lee LY. Airway inflammation and hypersensitivity induced by chronic smoking. Respir Physiol Neurobiol 2011; 178: 395–405. doi: 10.1016/j.resp.2011.03.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Irwin RS, Madison JM. Unexplained or refractory chronic cough in adults. N Engl J Med 2025; 392: 1203–1214. doi: 10.1056/NEJMra2309906 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material
00364-2025.SUPPLEMENT
Data Availability Statement
Data can be obtained upon request. Requests should be directed towards the management team of the Rotterdam Study (datamanagement.ergo@erasmusmc.nl), which has a protocol for approving data requests. Due to restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository.