Chronic cough is the most common symptom in outpatients with respiratory disorders. In China, patients with chronic cough account for more than one-third of respiratory outpatients, most of whom are never-smokers. Persistent cough symptoms seriously impair the quality of life of these patients and pose a huge burden on public health resources (1–3). Approximately 30–50% of patients with chronic cough exhibit eosinophil infiltration and aggregation, which further leads to the development of airway inflammation (4). A considerable proportion of patients with chronic cough do not reach the stage of asthma or chronic obstructive pulmonary disease (COPD), but lung function tests suggest the presence of small airway dysfunction (SAD) (5).

Small airways are defined as those with a lumen diameter <2 mm (6). According to a recent national cross-sectional study, more than 40% of adults have SAD in China (5). An increasing number of studies have confirmed that SAD is closely related to a multitude of respiratory diseases and can be a precursor sign of asthma and COPD that appears before pulmonary radiological changes (7, 8). Moreover, SAD is associated with asthma severity and progression. Individuals presenting with obvious symptoms usually reach the stage of irreversible lung function impairment (9). Therefore, early identification and effective intervention for SAD in patients with chronic cough are of clinical significance to avoid further damage to lung function.

Previous studies have identified multiple risk factors for SAD, including smoking status, age, gender, urbanization, and education level (5, 10). However, risk factors for SAD in the non-smoking population with chronic cough as the chief complaint remain unclear. Therefore, a retrospective case-control study was conducted to summarize the clinical features of non-smokers with chronic cough and to explore the potential risk factors for SAD.

Herein, we conducted a retrospective study to analyze the clinical characteristics of non-smoking patients presenting with chronic cough, and explore the risk factors for SAD in this subpopulation. This study is the first to demonstrate that SHS exposure is an independent risk factor for SAD in non-smokers with chronic cough.

Small airways, known as the “silent zone” of the lung disease, have a large surface area and strong reserve capacity. SAD is recognized as a precursor to chronic airway diseases such as asthma and COPD (8, 15). From a structural point of view, the total volume and collective surface area of distal airways greatly exceed those of central airways (16). Small airways contain little or no cartilage and are easily collapsible, making them the predominant site of airflow resistance (17). From a functional point of view, SAD leads to premature airway closure, air trapping and peripheral heterogeneity of ventilation, which significantly contributes to increased airflow resistance in patients with chronic airway diseases (18). From a cellular perspective, cells of the small airway epithelium, ciliated cells and goblet cells undergo various morphological and/or functional alterations, eventually resulting in airway remodeling. Moreover, increased immune cell infiltration in the small airways, including macrophages, neutrophils and T lymphocytes, correlates with the degree of airflow obstruction and contributes to lung damage in chronic airway diseases (19–21). More importantly, SAD occurs earlier than tissue destruction, as well as clinically detectable airflow limitation. It does not usually cause clinical symptoms and is often overlooked (22, 23). Proper small airway diagnostic assessment in routine clinical practice with early recognition of SAD is essential for lowering the risk of developing chronic airway diseases. While many studies consider cigarette smoking as a risk factor for SAD and enroll smokers as participants, it is worth noting that the majority of patients presenting with chronic cough are lifelong non-smokers (24, 25). Therefore, the present study focused on non-smokers with chronic cough as the main symptom, with the purpose of analyzing the potential risk factors for SAD in this subpopulation.

One of the most interesting findings of the present study is that SHS exposure emerges as an risk factor for SAD in non-smokers with chronic cough. SHS is defined as tobacco smoke produced by an active smoker, both from the exhalation of smoked tobacco and the burning end of the cigarette, that is inhaled by nonsmokers (26, 27). Previous studies have reported that smoking is associated with an increased risk of SAD (28). However, most studies have focused on the effects of active smoking on small airway function (29), ignoring the dangers of exposure to SHS. As research has evolved, the damage caused by SHS exposure on lung function has been confirmed and may even play a role in the progression to chronic airway diseases such as asthma (30, 31). In this study, multivariable logistic regression analysis confirmed that SHS exposure was independently associated with a higher risk of SAD in non-smokers with chronic cough after adjusting for potentially related variables, indicating that more attention should be paid to patients with SAD who are exposed to SHS, especially in non-smokers presenting with chronic cough. As early as 1980, a study suggested that passive smoking may reduce small airway function, and that the effects vary with the degree of smoke exposure (32). Exposure to SHS leads to an increase in the number of circulating neutrophils and increased chemotaxis (33), which also activates the release of inflammatory factors, such as interleukin-17A (34), thus promoting an inflammatory response. Moreover, continuous exposure to SHS disrupts the balance between Th1 and Th2 cells in the lungs (35), promoting the aggregation of Th2 cells and production of inflammatory factors, which in turn promote inflammatory responses. In addition, previous studies have confirmed that the small airways are the main site of inflammatory effects of cigarette smoke in humans (36). Therefore, we speculate that SHS exposure can activate the production of multiple inflammatory factors that promote the inflammatory response of the small airways and may promote the development of SAD. Currently, SHS exposure is a critical global public health issue. It is estimated that 600,000 individuals die each year owing to the effects of SHS (37). Our study showed links between SHS exposure and SAD, further emphasizing the importance of reducing SHS exposure to improve lung health. Since the World Health Organization Framework Convention on Tobacco Control was signed, exposure to SHS among non-smokers has gradually declined in China from 2010 to 2015; nevertheless, it remains a serious issue. Based on our data, SHS exists in various surrounding environments, including home, working areas and entertainment venues. A considerable proportion of patients in this study were exposed to SHS in public spaces, which highlights the necessity of banning active smoking in public spaces. Introducing a legislative smoking ban (especially in public spaces), spreading awareness about the hazards of SHS, and increasing tobacco prices and taxes can be effective ways to reduce SHS exposure (38, 39).

Existing evidence on the correlation between gender and SAD is lacking so far. Our data suggest that female gender might be associated with SAD in non-smokers with chronic cough. It has been reported that lung function is influenced by female sex hormones (40), and androgens affect lung function by inhibiting lung surfactant production in a variety of species through mechanisms that involve altering epidermal growth factor and transforming growth factor-β signaling (41). However, whether these factors ultimately affect small airway function remains unclear. In addition, long-term exposure to cooking oil fumes may be related to SAD in traditional Chinese women. In China, women play a leading role in domestic cooking. Therefore, in a typical domestic context, women have several periods per day of intense exposure to cooking oil fumes. It has been reported that 85.0% of women reported cooking at home (42); these women are at risk of exposure to toxic compounds from the burning of fuel and fumes when cooking. Different cooking methods, especially frying, emit large amounts of PM 2.5 (43), and exposure to PM 2.5 increases the risk of SAD (5), further highlighting the importance of reducing the burden of home cooking for women. Other effective interventions include the use of environmentally friendly fuels, improved ventilation systems and cooking technology (44).

In the present study, patients in the SAD group had slightly but statistically significantly lower FVC, FEV₁% pred, FEV₁/FVC ratio, and PEF% pred than those in the non-SAD group. This suggests that the non-smokers with chronic cough combined with SAD may present with a trend of airflow obstruction, which in turn supports that SAD is an early stage of chronic airway diseases. Previous studies have demonstrated that FeNO levels negatively correlate with small airway indexes in non-smokers, rather than smokers (45, 46). In our study, no significant association was observed between FeNO and SAD in non-smokers. This may be explained by the fact that almost half of the non-smokers in our study were exposed to SHS.

The present study have several limitations. First, this is a single-center retrospective study with a relatively small sample size, thus inherent bias and confounding effects of unrecognized factors are unavoidable. This could be an important reason why the association between female gender and SAD was not clearly determined in logistic regression. Second, quantification of exposure to SHS was not performed, which presents a line of inquiry worthy to pursue in future studies. Finally, long-term follow-up of these patients is lacking to observe the dynamic changes in lung function parameters, especially small airway function parameters. Large-scale prospective studies are required to determine how the frequency, duration and category of SHS exposure affect small airway function and whether small airway function parameters can be improved by avoiding exposure to SHS in non-smokers.

Exposure to SHS is an independent risk factors for SAD in non-smokers with chronic cough. Therefore, it is important to conduct lung function tests in non-smokers with chronic cough. Reduction or avoidance of SHS exposure may be beneficial for improving small airway function, thus lowering the risk of chronic airway diseases.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of Xiangya Hospital, Central South University (Changsha, Hunan, China). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

JJ and BZ: study concept and design and critical revision of the manuscript. BZ, LB, RW, YW, LQ, QX, PP, and CH: acquisition of data. RW and LB: statistical analysis. JJ, BZ, and LB: analysis and interpretation of data. JJ and LB: drafting of the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the National Key Technology R&D Program of China (2015BAI12B10), National Natural Science Foundation of China (82100099 and 82170041), and the Innovative Research Platform of Hunan Development and Reform Commission (2021-212).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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