Guidelines for the management of chronic cough in adults. Endorsed by the French speaking society of respiratory diseases (Société de Pneumologie de Langue Française, SPLF), the Société Française d'Oto-Rhino-Laryngologie et de Chirurgie de la Face et du Cou (SFORL), the Société Française de Phoniatrie et de Laryngologie (SFPL), the Société Nationale Française de Gastro-entérologie (SNFGE).

Patients with chronic cough experience a high alteration of quality of life. Moreover, chronic cough is a complex entity with numerous etiologies and treatments. In order to help clinicians involved in the management of patients with chronic cough, guidelines on chronic cough have been established by a group of French experts. These guidelines address the definitions of chronic cough and the initial management of patients with chronic cough. We present herein second-line tests that might be considered in patients with cough persistence despite initial management. Experts also propose a definition of unexplained or refractory chronic cough (URCC) in order to better identify patients whose cough persists despite optimal management. Finally, these guidelines address the pharmacological and non-pharmacological interventions useful in URCC. Thus, amitryptilline, pregabalin, gabapentin or morphine combined with speech and/or physical therapy are a mainstay of treatment strategies in URCC. Other treatment options, such as P2 × 3 antagonists, are being developed.

Early exposure to farm dust in an allergic airway inflammation rabbit model: Does it affect bronchial and cough hyperresponsiveness?

INTRODUCTION: Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model. METHOD: A specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement. RESULTS: A total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge. CONCLUSION: Early exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed.

Trajectories of cough without a cold in early childhood and associations with atopic diseases.

BACKGROUND: Although children can frequently experience a cough that affects their quality of life, few epidemiological studies have explored cough without a cold during childhood. OBJECTIVES: The objective of the study was to describe the latent class trajectories of cough from one to 10 years old and analyse their association with wheezing, atopy and allergic diseases. METHODS: Questions about cough, wheeze and allergic diseases were asked at 1, 1.5, 2, 3, 4, 5, 6 and 10 years of age in the European prospective cohort of Protection against Allergy: STUdy in Rural Environment (PASTURE). Specific IgE assays were performed at 10 years of age. Questions regarding a cough without a cold were used to build a latent class model of cough over time. RESULTS: Among the 961 children included in the study, apart from the never/infrequent trajectory (59.9%), eight trajectories of cough without a cold were identified: five grouped acute transient classes (24.1%), moderate transient (6.8%), late persistent (4.8%) and early persistent (4.4%). Compared with the never/infrequent trajectory, the other trajectories were significantly associated with wheezing, asthma and allergic rhinitis. For asthma, the strongest association was with the early persistent trajectory (ORa  = 31.00 [14.03-68.51]), which was inversely associated with farm environment (ORa  = 0.39 [0.19-0.77]) and had a high prevalence of cough triggers and unremitting wheeze. Late and early persistent trajectories were also associated with food allergy. Atopic sensitization was only associated with the late persistent trajectory. CONCLUSION: Late and early persistent coughs without a cold are positively associated with atopic respiratory diseases and food allergy. Children having recurrent cough without a cold with night cough and triggers would benefit from an asthma and allergy assessment. Growing up on a farm is associated with reduced early persistent cough.

A Physical Analog to Assess Surgical Face Mask Air Flow Resistance During Tidal Ventilation.

A large variety of disposable face masks have been produced since the onset of the COVID-19 pandemic. Decreased resistance to inspiration improves adherence to the use of the mask; the so called breathability is usually estimated by the measurement of air flow across a section of the tissue under a given pressure difference. We hypothesized that the mask pressure-flow relationship studied in conditions that mimic tidal breathing could allow a more comprehensive characterization of airflow resistance, a major determinant of mask comfort. A physical analog was made of a plaster cast dummy head connected through a pneumotachograph to a series of bellows inflated/deflated by a respirator. Pressure was measured at the mock airway opening over which the mask was carefully secured. The precision of the measurement equipment was quantified using two estimates of measurement error: repeatability coefficient (RC) and within-mask coefficient of variation (CVwm). The airflow resistance of 10 surgical masks was tested on 4 different days. Resistance means did not differ significantly among four repeated measures (0.34 hPa.s.L-1; 0.37 hPa.s.L-1; 0.37 hPa.s.L-1; and 0.37 hPa.s.L-1; p = 0.08), the estimated RC was 0.08 hPa.s.L-1 [95%CI: 0.06-0.10 hPa.s.L-1], and CVwm was 8.7% [95%CI: 1.5-12.2%]. Multiple comparisons suggest the presence of a learning effect by which the operator reduced the error over the course of repetitive resistance measurements. Measurement precision improved considerably when the first set of measures was not taken into account [RC ~ 0.05 hPa.s.L-1 (95%CI: 0.03-0.06 hPa.s.L-1); CVwm~4.5% (95%CI: 1.9-6.1%)]. The testing of the face mask resistance (R) appears simple and highly repeatable in conditions that resemble tidal breathing, once operator training was assured. The procedure adds further to the current standard assessment of breathability and allows estimating the maximal added respiratory load, about 10-20% of the respiratory resistance reported in heathy adult subjects.

Impact of Inhaled Corticosteroids on the Modulation of Respiratory Defensive Reflexes During Artificial Limb Exercise in Ovalbumin-Sensitized Rabbits.

INTRODUCTION: Cough is a major lower airway defense mechanism that can be triggered by exercise in asthma patients. Studies on cough reflex in experimental animal models revealed a decrease of cough reflex sensitivity during exercise in healthy animals, but a lack of desensitization in ovalbumin-sensitized rabbits. The aim of our study is to evaluate the impact of inhaled corticosteroids on cough reflex during artificial limb exercise in an animal model of eosinophilic airway inflammation. MATERIALS AND METHODS: Sixteen adult ovalbumin-sensitized rabbits were randomly divided into two groups. The "OVA-Corticoid" group (n = 8) received inhaled corticosteroids (budesonide; 1 mg/day during 2 consecutive days) while the "OVA-Control" (n = 8) group was exposed to saline nebulization. The sensitivity of defensive reflexes induced by direct mechanical stimulation of the trachea was studied in anesthetized animals, at rest and during artificial limb exercise. Cell count was performed on bronchoalveolar lavage fluid and middle lobe tissue sections to assess the level of eosinophilic inflammation. RESULTS: All rabbits were significantly sensitized but there was no difference in eosinophilic inflammation on bronchoalveolar lavage or tissue sections between the two groups. Artificial limb exercise resulted in a significant (p = 0.002) increase in minute ventilation by 30% (+ 209 mL.min-1, ± 102 mL/min-1), with no difference between the two groups. 322 mechanical tracheal stimulations were performed, 131 during exercise (40.7%) and 191 at rest (59.3%). Cough reflex was the main response encountered (46.9%), with a significant increase in cough reflex threshold during artificial limb exercise in the "OVA-Corticoid" group (p = 0.039). Cough reflex threshold remained unchanged in the "OVA-Control" group (p = 0.109). CONCLUSION: Inhaled corticosteroids are able to restore desensitization of the cough reflex during artificial limb exercise in an animal model of airway eosinophilic inflammation. Airway inflammation thus appears to be involved in the physiopathology of exercise-induced cough in this ovalbumin sensitized rabbit model. Inhaled anti-inflammatory treatments could have potential benefit for the management of exercise-induced cough in asthma patients.

Assessment of bronchial obstruction and its reversibility by shape indexes of the flow-volume loop in asthmatic children.

Asthma assessment by spirometry is challenging in children as forced expiratory volume in 1 s (FEV1) is frequently normal at baseline. Bronchodilator (BD) reversibility testing may reinforce asthma diagnosis but FEV1 sensitivity in children is controversial. Ventilation inhomogeneity, an early sign of airway obstruction, is described by the upward concavity of the descending limb of the forced expiratory flow-volume loop (FVL), not detected by FEV1. The aim was to test the sensitivity and specificity of FVL shape indexes as ß-angle and forced expiratory flow at 50% of the forced vital capacity (FEF50)/peak expiratory flow (PEF) ratio, to identify asthmatics from healthy children in comparison to "usual" spirometric parameters. Seventy-two school-aged asthmatic children and 29 controls were prospectively included. Children performed forced spirometry at baseline and after BD inhalation. Parameters were expressed at baseline as z-scores and BD reversibility as percentage of change reported to baseline value (Δ%). Receiver operating characteristic curves were generated and sensitivity and specificity at respective thresholds reported. Asthmatics presented significantly smaller zß-angle, zFEF50/PEF and zFEV1 (p ≤ .04) and higher BD reversibility, significant for Δ%FEF50/PEF (p = .02) with no difference for Δ%FEV1. zß-angle and zFEF50/PEF exhibited better sensitivity (0.58, respectively 0.60) than zFEV1 (0.50), and similar specificity (0.72). Δ%ß-angle showed higher sensitivity compared to Δ%FEV1 (0.72 vs. 0.42), but low specificity (0.52 vs. 0.86). Quantitative and qualitative assessment of FVL by adding shape indexes to spirometry interpretation may improve the ability to detect an airway obstruction, FEV1 reflecting more proximal while shape indexes peripheral bronchial obstruction.

Desensitization of the Cough Reflex Induced by Corticosteroids in Ovalbumin-Sensitized Rabbits During Artificial Limb Exercise.

INTRODUCTION: Cough is a major symptom frequently experienced during exercise, mainly in asthmatic patients. Inhaled glucocorticoids represent the keystone treatment in the management of asthma, but little is known about interactions between cough and exercise, especially in controlled patients. During exercise, cough reflex (CR) appears downregulated in healthy animal models whereas a lack of desensitization of CR has been shown in ovalbumin-sensitized animal models, mimicking asthmatic disease. AIMS AND OBJECTIVES: The goal of our study was to clarify the potential modulation of the CR induced by inhaled corticosteroids (CS) in ovalbumin (OVA) sensitized rabbits during artificial limb exercise. MATERIALS AND METHODS: Seventeen OVA sensitized rabbits were studied. Among them, 9 were treated with CS delivered intravenously (OVA-Corticoids). The ventilatory response to direct tracheal stimulation, performed at rest and during exercise, was determined to assess the incidence and the sensitivity of the CR. Broncho-alveolar lavage (BAL) and cell counts were performed to determine the level of airway inflammation. Exercise was mimicked by electrically induced hindlimb muscular contractions (EMC). RESULTS: Compared to rest values, EMC increased minute ventilation by 28% without any decrease in respiratory resistance (Rsr). Among 322 tracheal stimulations, 172 (53%) were performed at rest and 150 (47%) during exercise. The sensitivity of CR decreased during artificial limb exercise compared to baseline in OVA-Corticoids rabbits (p = 0.0313) while it remained unchanged in OVA rabbits (p = NS). CONCLUSION: Corticosteroids appear to restore the desensitization of the CR in OVA sensitized rabbits during artificial limb exercise, suggesting the potential role of airway inflammation in the pathophysiology of cough during exercise in asthmatics.

Modulation of protective reflex cough by acute immune driven inflammation of lower airways in anesthetized rabbits.

Chronic irritating cough in patients with allergic disorders may reflect behavioral or reflex response that is inappropriately matched to the stimulus present in the respiratory tract. Such dysregulated response is likely caused by sensory nerve damage driven by allergic mediators leading to cough hypersensitivity. Some indirect findings suggest that even acid-sensitive, capsaicin-insensitive A-δ fibers called "cough receptors" that are likely responsible for protective reflex cough may be modulated through immune driven inflammation. The aim of this study was to find out whether protective reflex cough is altered during acute allergic airway inflammation in rabbits sensitized to ovalbumin. In order to evaluate the effect of such inflammation exclusively on protective reflex cough, C-fiber mediated cough was silenced using general anesthesia. Cough provocation using citric acid inhalation and mechanical stimulation of trachea was realized in 16 ovalbumin (OVA) sensitized, anesthetized and tracheotomised rabbits 24h after OVA (OVA group, n = 9) or saline challenge (control group, n = 7). Number of coughs provoked by citric acid inhalation did not differ between OVA and control group (12,2 ±6,1 vs. 17,9 ± 6,9; p = 0.5). Allergic airway inflammation induced significant modulation of cough threshold (CT) to mechanical stimulus. Mechanically induced cough reflex in OVA group was either up-regulated (subgroup named "responders" CT: 50 msec (50-50); n = 5 p = 0.003) or down-regulated (subgroup named "non responders", CT: 1200 msec (1200-1200); n = 4 p = 0.001) when compared to control group (CT: 150 msec (75-525)). These results advocate that allergen may induce longer lasting changes of reflex cough pathway, leading to its up- or down-regulation. These findings may be of interest as they suggest that effective therapies for chronic cough in allergic patients should target sensitized component of both, reflex and behavioral cough.

A Calibration Device to Compare Body Plethysmographs Among Pediatric Lung Function Laboratories.

Multi-center studies in specific airway resistance have shown significant inter laboratory variability. Comparison of plethysmographic equipment using a lung model easily transportable from one site to another should be of help to international normative studies. A resistor made of parallel capillary tubes - insuring adequate linearity within 1 L/sec - was connected to a glass bottle. Thermal time constants were measured while the bottle was empty and while stuffed with steel wool. In the latter, isothermal condition was estimated to occur only at very low frequency (around 0.01 Hz) and gas compression was polytropic up to 0.6 Hz. With the empty analog, adiabatic gas compression was estimated to occur at frequencies ≥0.2 Hz, and more accurate volume estimation was obtained. The empty analog volume and specific resistance measured in a body plethysmograph on different days indicated within 5% accuracy as well as intersession repeatability. It is concluded that a physical analog built out of simple material provides accurate measurements of specific resistance. The apparatus should be of help to compare plethysmographic equipments from different laboratories.

Expiratory Flow - Vital Capacity: Airway - Lung Dysanapsis in 7 Year Olds Born Very Preterm?

An index normalizing airway dimension for lung size derived from spirometry was found inversely correlated to lung size in school children born very preterm, indicating larger alveolar volumes draining into comparatively smaller airways. In contrast in children born full term the index was independent of lung size.

Modulation of defensive airway reflexes during continuous positive airway pressure in the rabbit.

Lung hyperinflation may alter the pattern of ventilatory reflexes in chronic respiratory disorders. The aim of the study was to test the effect of continuous positive airway pressure (CPAP) on ventilatory responses to mechanical stimulation of the trachea.

More Relaxation by Deep Breath on Methacholine- Than on Exercise-Induced bronchoconstriction during the Routine Testing of Asthmatic Children.

Deep inspiration (DI) dilates normal airway precontracted with methacholine. The fact that this effect is diminished or absent in asthma could be explained by the presence of bronchial inflammation. The hypothesis was tested that DI induces more relaxation in methacholine induced bronchoconstriction-solely determined by the smooth muscle contraction-than in exercise induced bronchoconstriction, which is contributed to by both smooth muscle contraction and airway wall inflammation. The respiratory conductance (Grs) response to DI was monitored in asthmatic children presenting a moderately positive airway response to challenge by methacholine (n = 36) or exercise (n = 37), and expressed as the post- to pre-DI Grs ratio (GrsDI). Both groups showed similar change in FEV1 after challenge and performed a DI of similar amplitude. GrsDI however was significantly larger in methacholine than in exercise induced bronchoconstriction (p < 0.02). The bronchodilatory effect of DI is thus less during exercise- than methacholine-induced bronchoconstriction. The observation is consistent with airway wall inflammation-that characterizes exercise induced bronchoconstriction-rendering the airways less responsive to DI. More generally, it is surmised that less relief of bronchoconstriction by DI is to be expected during indirect than direct airway challenge. The current suggestion that airway smooth muscle constriction and airway wall inflammation may result in opposing effects on the bronchomotor action of DI opens important perspective to the routine testing of asthmatic children. New crossover research protocols comparing the mechanical consequences of the DI maneuver are warranted during direct and indirect bronchial challenges.

Bronchial or Laryngeal Obstruction Induced by Exercise?

A child suspected of exercise-induced laryngeal obstruction and asthma is examined by laryngoscopy and respiratory resistance (Rrs) after exercise challenge. Immediately at exercise cessation, the visualized adduction of the larynx in inspiration is reflected in a paroxystic increase in Rrs. While normal breathing has apparently resumed later on during recovery from exercise, the pattern of Rrs in inspiration is observed to reoccur following a deep breath or swallowing. The procedure may thus help diagnosing the site of exercise-induced obstruction when laryngoscopy is not available and identify re-inducers of laryngeal dysfunction.

Down-Regulation of Cough during Exercise Is Less Frequent in Healthy Children than Adults. Role of the Development and/or Atopy?

Cough is typically associated with physical activity in children with asthma, but the characteristics of the relationship between cough and exercise has not been established under physiological conditions. The aim of the study was to describe the effect of exercise on the reflex cough response elicited by a single breath of capsaicin in non-asthmatic children. A group of non-asthmatic adults was studied as reference. Thirty children and 29 adults were recruited. The cough reflex sensitivity to capsaicin was first determined to establish the dose that provokes 5 cough efforts (C5). The number of coughs elicited by C5 (NC5) was then compared at baseline and during a standardized submaximal treadmill exercise. Data are expressed as median (interquartile range). Children and adults showed a significant decrease in NC5 (respectively from 5.0 (4.0-6.0) to 2.5 (2.0-4.0), p < 0.0005 and from 6.0 (5.0-7.0) to 2.0 (0.0-3.0, p < 0.0005). During exercise, NC5 was observed to decrease in all adult subjects, but in only 24/30 children (80%, p = 0.02). A trend for a higher incidence of personal and familial atopy was observed in children that lacked cough down-regulation during exercise compared with other children. It is concluded that the cough reflex response to capsaicin is down regulated by exercise in both children and adults. The effect however is less consistently observed in the former. The difference may reflect maturation of descending inhibitory pathways of the cough reflex, but may also be associated to atopy. The data stress the importance of assessing the time relationship of cough and exercise in questionnaire studies of asthma.

Epinephrine but not vasopressin attenuates the airway response to anaphylactic shock in rats.

PURPOSE: The two life-threatening signs of anaphylactic shock (AS) are severe arterial hypotension and bronchospasm. Guidelines recommend epinephrine as first-line treatment. Arginine vasopressin (AVP) has been proposed as an alternative if epinephrine does not correct arterial hypotension. These two drugs may have beneficial, neutral or deleterious effects on airflow either directly or by modifying factors that regulate vasodilatation and/or edema in the bronchial wall. AIM OF THE STUDY: To compare the effects of epinephrine and AVP on airflow and airway leakage in a rat model of AS. MATERIALS AND METHODS: Thirty-two ovalbumin-sensitized rats were randomized into four groups: control (CON), AS without treatment (OVA), AS treated with epinephrine (EPI), and AS treated with AVP (AVP). Mean arterial pressure (MAP), respiratory resistance and elastance and microvascular leakage in the airways were measured. RESULTS: All OVA rats died within 20 minutes following ovalbumin injection. Ovalbumin induced severe arterial hypotension and airway obstruction (221 ± 36 hPa.s.L-1 vs. vehicle 52 ± 8 hPa.s.L-1; p < 0.0001) associated with microvascular leakage distributed throughout the trachea, bronchi and intra-pulmonary airways. EPI and AVP extended survival time; EPI restored a higher level of MAP than AVP. Airway obstruction was attenuated by epinephrine (146 ± 19 hPa.s.L-1; p < 0.0001), but not by AVP (235 ± 58 hPa.s.L-1; p = 0.42). CONCLUSIONS: Epinephrine was superior to AVP for alleviating the airway response in a rat model of AS. When bronchospasm and severe arterial hypotension are present during AS, epinephrine should be the drug of choice.

Maturation of Airway Defensive Reflexes Is Related to Development of Feeding Behavior during Growth in Rabbits.

Introduction: Cough and expiration reflex are major lower airway defense mechanisms that have not been studied throughout development in relation with the feeding behavior. Aim: To describe airway defense reflexes evoked by mechanical stimulation of the trachea in developing rabbit pups. Material and Methods: Sixty one pups were allocated to 3 groups according to their feeding behavior: suckling (n = 22), weanling (n = 21) and weaning (n = 18) group. The incidence and sensitivity of defense reflexes triggered by mechanical tracheal stimulation were studied in anesthetized and tracheotomized animals. Data are expressed as median (25th to 75th percentile). Results: The overall incidence of defensive responses (cough and/or expiration reflex) was found to be significantly higher in suckling [100% (50-100%); p = 0.01] and weanling [75% (40-100%); p = 0.05] animals when compared to weaning ones [37.5% (0-75%)]. However, cough motor pattern accounted for only 29% (0-62%) of all defensive responses in suckling rabbits and its frequency was significantly lower in this group when compared with weanling [100%(50-100%); p = 0.006] or weaning group [62%(50-100%), p = 0.05]. In other word the expiration reflex was the dominant response in suckling animals. Conclusion: Incidence and motor pattern of defensive responses were found to be linked to the pup feeding behavior and the expiration reflex was the major response triggered in suckling pups. The results suggest that this reflex is especially fitted to occur during the coordinated swallowing - breathing fast activities of sucking.

Lack of desensitization of the cough reflex in ovalbumin-sensitized rabbits during exercise.

INTRODUCTION: Cough is a major symptom of asthma frequently experienced during exercise but little is known about interactions between cough and exercise. The goal of our study was to clarify the potential modulation of the cough reflex (CR) by exercise in a spontaneously breathing anaesthetized animal model of airway eosinophilic inflammation. MATERIALS & METHODS: Ten ovalbumin (OVA) sensitized adult rabbits and 8 controls were studied. The ventilatory response to direct tracheal stimulation, performed both at rest and during exercise was determined to quantify the incidence and the sensitivity of the CR. Broncho-alveolar lavages (BAL) and cell counts were performed to assess the level of the airway inflammation following OVA-induced sensitization. Exercise was mimicked by Electrically induced hindlimb Muscular Contractions (EMC). RESULTS: Among 494 tracheal stimulations, 261 were performed at rest and 233 at exercise. OVA challenges in sensitized rabbits caused a significant increase in the percentage of eosinophils (p = 0.008) in BAL. EMC increased minute ventilation by 36% and 35% in OVA and control rabbits respectively, compared to rest values. The sensitivity of the CR decreased during exercise compared to baseline in control rabbits (p = 0.0313) while it remained unchanged in OVA rabbits. CONCLUSION: The desensitization of the CR during exercise in control rabbits was abolished in OVA rabbits. The precise role of airway inflammation in this lack of CR desensitization needs to be further investigated but it might contribute to the exercise-induced cough in asthmatics.

Impact of Air Pollution on Age and Gender Related Increase in Cough Reflex Sensitivity of Healthy Children in Slovakia.

BACKGROUND: Numerous studies show higher cough reflex sensitivity (CRS) and cough outcomes in children compared to adults and in females compared to males. Despite close link that exists between cough and environment the potential influence of environmental air pollution on age- and gender -related differences in cough has not been studied yet. PURPOSE: The purpose of our study was to analyse whether the effects of exposure to environmental tobacco smoke (ETS) from parental smoking and PM10 from living in urban area are implied in age- and gender-related differences in cough outcomes of healthy, non-asthmatic children. Assessment of CRS using capsaicin and incidence of dry and wet cough was performed in 290 children (mean age 13.3 ± 2.6 years (138 females/152 males). RESULTS: CRS was significantly higher in girls exposed to ETS [22.3 µmol/l (9.8-50.2 µmol/l)] compared to not exposed girls [79.9 µmol/l (56.4-112.2 µmol/l), p = 0.02] as well as compared to exposed boys [121.4 µmol/l (58.2-253.1 µmol/l), p = 0.01]. Incidence of dry cough lasting more than 3 weeks was significantly higher in exposed compared to not exposed girls. CRS was significantly higher in school-aged girls living in urban area [22.0 µmol/l (10.6-45.6 µmol/l)] compared to school-aged girls living in rural area [215.9 µmol/l (87.3-533.4 µmol/l); p = 0.003], as well as compared to teenage girls living in urban area [108.8 µmol/l (68.7-172.9 µmol/l); p = 0.007]. No CRS differences were found between urban and rural boys when controlled for age group. No CRS differences were found between school-aged and teenage boys when controlled for living area. CONCLUSIONS: Our results have shown that the effect of ETS on CRS was gender specific, linked to female gender and the effect of PM10 on CRS was both gender and age specific, related to female gender and school-age. We suggest that age and gender related differences in incidence of cough and CRS might be, at least partially, ascribed to the effect of environmental pollutants. The role of age and gender in the effect of air pollution on cough strongly suggest some interplay of development with biological and behavioral factors.