Jan Hanacek

The expiration reflex from the trachea and bronchi

The expiration reflex (ER) is a forced expiratory effort against a closed glottis that subsequently opens to eject laryngeal debris and prevent aspiration of material. It is distinct from the cough reflex. Its source is usually assumed to be restricted to the larynx and vocal folds, and its possible origin from the tracheobronchial (TB) tree has been suggested but never studied. The current authors re-analysed previous records with mechanical or chemical stimulation of the TB tree to see if an ER can consistently be elicited, and to see whether it has properties similar to that from the larynx and vocal folds. A random review was made of some of the extensive literature on TB “cough” to see if it confirmed the authors’ conclusions. The TBER was consistently seen in cats and rabbits, either alone or followed by cough. These results are consistent with many studies in other species, including humans. It was enhanced, relative to cough, by inflation of the lungs and by general anaesthesia. Tracheobronchial expiration reflex occurs frequently with mechanical stimulation of the tracheobronchial tree. It differs fundamentally from many of the properties of “true” cough. Its features similar to the laryngeal expiration reflex suggest that both should be labelled “expiration reflexes” and not cough. Its existence should be taken into account in experimental, and possibly clinical, studies on tracheobronchial cough.

Regulation of cough by secondary sensory inputs

We have reviewed the role of afferent inputs and blood chemical changes to the central nervous system, and the way in which they modify the cough and expiration reflexes (CR and ER). Slowly adapting pulmonary stretch receptors (SARs) augment the CR, insofar as when their activity is abolished the CRs from the tracheobronchial (TB) tree and larynx are abolished or weakened. However, stimulation of SARs by lung inflation has an inconsistent effect on the CR. Activation of SARs strongly potentiates the ER from the vocal folds, by a reflex mechanism, and inhibition of SARs weakens the ER. Bronchopulmonary C-fibre receptors inhibit the CR, as do capsaicin-sensitive afferents from the heart and splanchnic bed, cutaneous cold receptors and those that respond to chest wall vibration. Nasal receptors responsive to the irritant agent capsaicin potentiate the reflex. Acute hypoxia also augments the CR, and the reflex is down-regulated by carotid body resection. On the other hand, the CR is inhibited by prolonged hypoxia and hyperoxia, and by hypercapnia. Thus different inputs to the cough-controlling mechanism in the brainstem have very varied effects on the CR. We conclude that the sensitivities of the CR and ER can be modified in a large variety of physiological and clinical conditions, and that there is no clear relationship between the reflexes and changes in breathing caused by the interventions.

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.

The course of lung inflation alters the central pattern of tracheobronchial cough in cat-The evidence for volume feedback during cough.

The effect of volume-related feedback and output airflow resistance on the cough motor pattern was studied in 17 pentobarbital anesthetized spontaneously-breathing cats. Lung inflation during tracheobronchial cough was ventilator controlled and triggered by the diaphragm electromyographic (EMG) signal. Altered lung inflations during cough resulted in modified cough motor drive and temporal features of coughing. When tidal volume was delivered (via the ventilator) there was a significant increase in the inspiratory and expiratory cough drive (esophageal pressures and EMG amplitudes), inspiratory phase duration (CTI), total cough cycle duration, and the duration of all cough related EMGs (Tactive). When the cough volume was delivered (via the ventilator) during the first half of inspiratory period (at CTI/2-early over inflation), there was a significant reduction in the inspiratory and expiratory EMG amplitude, peak inspiratory esophageal pressure, CTI, and the overlap between inspiratory and expiratory EMG activity. Additionally, there was significant increase in the interval between the maximum inspiratory and expiratory EMG activity and the active portion of the expiratory phase (CTE1). Control inflations coughs and control coughs with additional expiratory resistance had increased maximum expiratory esophageal pressure and prolonged CTE1, the duration of cough abdominal activity, and Tactive. There was no significant difference in control coughing and/or control coughing when sham ventilation was employed. In conclusion, modified lung inflations during coughing and/or additional expiratory airflow resistance altered the spatio-temporal features of cough motor pattern via the volume related feedback mechanism similar to that in breathing.

What is chronic cough in children

The cough reflex is modulated throughout growth and development. Cough—but not expiration reflex—appears to be absent at birth, but increases with maturation. Thus, acute cough is the most frequent respiratory symptom during the first few years of life. Later on, the pubertal development seems to play a significant role in changing of the cough threshold during childhood and adolescence resulting in sex-related differences in cough reflex sensitivity in adulthood. Asthma is the major cause of chronic cough in children. Prolonged acute cough is usually related to the long-lasting effects of a previous viral airway infection or to the particular entity called protracted bacterial bronchitis. Cough pointers and type may orient toward specific etiologies, such as barking cough in croup or tracheomalacia, paroxystic whooping cough in Pertussis. Cough is productive in protracted bacterial bronchitis, sinusitis or bronchiectasis. Cough is usually associated with wheeze or dyspnea on exertion in asthma; however, it may be the sole symptom in cough variant asthma. Thus, pediatric cough has particularities differentiating it from adult cough, so the approach and management should be developmentally specific.

Deep Nasal Inspirations Increase the Cough Threshold in Children with Mild Asthma

Asthma is a chronic inflammatory disease characterized by bronchospasms accompanied with frequent coughing, the pathogenesis of which is not clear. In healthy adults deep inspirations (DIs) provide a protective effect against bronchoconstriction triggered by methacholine inhalation, which correlates with the number of accompanying cough efforts. The aim was to study the effect of deep nasal inspirations representing the voluntary equivalent of the sniff-like aspiration reflex on the capsaicin-induced cough in children with mild asthma. The cough reflex sensitivity to capsaicin was determined using a compressed air-driven nebulizer in 21 children (8 girls and 13 boys of median age 13.3 year) suffering from mild asthma (FEV(1)∼80%). The effect of five previous DIs through the nose was examined on the elicitability of two and five or more cough efforts (C2, C5). Under control conditions, the concentration of 20.86 (14.58-29.8) μmol/l of capsaicin provoked two cough efforts (C2). After five DIs similar reaction required significantly higher concentrations of capsaicin: 29.02 (18.88-44.6) μmol/l; P=0.016. Five or more cough efforts (C5) were not significantly changed after previous DIs 161.49 (77.31-337.33) μmol/l and without DIs 141.52 (68.77-291); P=0.54. A series of five deep inspirations decreases the cough reflex sensitivity to evoke two efforts (C2) in children with mild asthma. The inhibitory effect of similar DIs disappeared after repeated applications of increasing doses of capsaicin, aiming to evoke five or more cough efforts, suggesting a reflex character of protective effect of DIs.

Hyperoxia-induced regulation of cough reflex and its effect after antioxidant supplementation

Hyperoxia-induced lung injury is well known in animal and human studies. The respiratory epithelium including sensory nerve endings is a major target for oxidative injury that manifested in lung function changes including cough. On the basis of available information we supposed that hyperoxia alone or in combination with primary lung tissue injury should have a damaging effect on lungs, including the airway nerve endings with the changes in the sensitivity of the central and peripheral neuronal pathways regulating cough. We have previously demonstrated that long-term exposure to 100% oxygen inhibits the cough reflex in cat. This review article summarizes the effect of hyperoxia on the cough reflex in guinea pig model using different concentrations of oxygen and different time of exposure. We also present information on the potential role of antioxidants in reversal of the detrimental effects of hyperoxia on coughing and additional analysis of experiments from previously published studies were obtained and analysed for the cough reflex sensitivity.

Cough and airway defence – Special issue of respiratory physiology and neurobiology

Airway defensive reflexes serve an important role for the respiratory system to fulfil physiological gas exchange at a rate which matches metabolic demands of tissues. These reflexes are specific, spatio-temporally orchestrated motor acts, main purpose of which is to prevent aspiration of liquids or corpuscular material into the airways, or eventually expel mucus and other potentially harmful substances out of the respiratory tract. These motor acts are precisely regulated to provide sufficient airway protection and defence. Decreased performance of these complex neuromuscular behaviours can lead to the aspiration with further consequences, e.g. aspiration pneumonia, which considerably increase respiratory morbidity and mortality in specific populations of patients. Strategies serving to increase effectiveness of these motor acts or to substitute them are of high clinical importance. On the other hand, exaggerated airway defensive reflexes – mainly cough – to otherwise innocuous stimuli lead to intractable coughing, which manifests as hypersensitive cough syndrome. It considerably decreases patient’s quality of life, and may lead to secondary damage of the airway wall. Therapeutic strategies developed in this filed so far are of debatable efficacy. Further research is necessary to understand pathogenesis of this syndrome to find reliable treatment. Both up-regulation and down-regulation of airway defensive reflexes should be studied to develop optimal clinical approaches. In this special issue, Spinou introduces the clinical entity of cough as the continuum with two extremes at its sides. From extremely exaggerated cough, which reduces quality of life to attenuated cough, which represents a risk of aspiration pneumonia. Together with the extensive research of pharmacological strategies, non-pharmacological approaches were developed and validated to help patients with either cough control or cough augmentation. The main direction of these techniques is the support of cough motor output and exercising the cognitive control on coughing. Their article discusses the techniques which can empower patients to increase their supramedullary control of cough or augment the cough motor drive e.g. manual or mechanical hyperinflation, manually assisted cough or respiratory muscles training (Spinou, 2018). Chronic hypersensitivity cough syndrome, which was recently defined as a new clinical entity to embrace all coughers with “unknown” cause of cough but hypersensitivity of airway sensory afferents (Morice, 2013) affects mainly postmenopausal women. Why hypersensitivity develops in this demographic group is not entirely understood, but Kavalcikova-Bogdanova and co-workers threw some light to this field. They showed that sensitivity of airway afferents to the tussive agent capsaicin varies during menstrual cycle and this functional change is not present in women taking contraceptive pills. According their findings the cough sensitivity to capsaicin correlates with ratio of progesterone/oestrogen and relative lack of oestrogen in luteal phase is associated with higher sensitivity to inhaled capsaicin. The ratio of progesterone/oestrogen seems to be the target for further studies to elucidate relationships between hormonal withdrawals in menopause and cough hypersensitivity (Kavalcikova-Bogdanova et al., 2018). Next contribution points to the not entirely understood pathogenesis of cough in sarcoidosis. Cough is a common and significant symptom in sarcoidosis, which is a multisystem disease of unknown aetiology characterized by presence of non-caseating granulomatous inflammation. Objective cough monitoring proved that sarcoidosis patients have significantly higher cough frequency compared to control subjects. Their cough exhibits diurnal variation, it is gender specific and shows racial differences. While it correlates with the presence of the airway inflammation, it shows relationship neither with the X-ray staging, nor the degree of airway obstruction. The most relevant cough triggers interacting with the airway sensory nerves are not only the airway inflammation with its consequences, but also the presence of considerable biomechanical forces in pathologically changed airways (Kovacova et al., 2018). Better understanding of the pathogenesis of cough in sarcoidosis patients may lead to the improvement of their quality of life by application of targeted treatment. Chronic cough is frequently associated with the gastroesophageal reflux (GER). Subjects with reflux have heightened cough sensitivity, and this phenomenon is attributed to the neuroplastic changes of vagal C-fibres innervating the airways and oesophagus, as well. Sensations perceived in reflux patients such as heartburn is however perceived via fibres derived from dorsal root ganglia. Relationship between cough sensitivity measured by inhalation of capsaicin and oesophageal sensitivity measured by intensity of heartburn induced by oesophageal acid infusion was studied by Duricek and his team in patients with symptomatic GER. The measurement was repeated after 3 months on treatment by proton pump inhibitors. This medication substantially reduced oesophageal sensitivity to acid but it did not influence sensitivity of airway afferents to inhaled capsaicin. The results of this group indicate that spinal and vagal afferents are influenced separately in patients with GER (Duricek et al., 2018). Cough and airflow limitation are predominant symptoms and signs in chronic obstructive pulmonary disease (COPD). The natural history of the disease includes progressive development of mentioned problems punctuated by acute exacerbations COPD during which they rapidly