Disease status and cough to inhaled agents

The cough patterns induced by aerosol products in healthy and diseased people are different. For example, nebulised antibiotics cause more severe coughing and wheezing in non-cystic fibrosis bronchiectasis patients compared to cystic fibrosis patients (Cipolla & Chan, 2013). Patients are pre-treated with bronchodilators to reduce the frequency and severity of these adverse events (Elkins et al., 2006). Drug deposition profile may be affected by the extent of bronchoconstriction, changes in bronchial blood flow, or the presence of excess mucus or oedema. The consequences of reduced airway calibre lead to increased drug deposition in the larger central airways, provoke cough, and lead to insufficient delivery of drug to the target site (Richards, Haas, Simpson, Britten, Renwick & Holgate, 1988; Satia, Badri, Al-Sheklly, Smith & Woodcock, 2016).
Asthma is one of the most common causes of chronic cough in non-smoking adults (Morice, 2004). Moreover, cough as a symptom is more common in patients with severe asthma. Moderate-to-severe asthmatic patients suffer from persistent cough and mucus hypersecretion (de Marco et al., 2006). Cough impacts the quality of life of some asthmatic patients and is a major contributor to poor asthma control (Purokivi, Koskela & Kontra, 2013). The incident rate of cough is significantly higher in asthmatic patients than in healthy subjects (Bonvini & Belvisi, 2017). Cough sensitivity to capsaicin and citrate does not increase in asthma, whereas cough in response to hypertonicity is more pronounced in asthmatic patients (Koskela, Purokivi, Kontra, Taivainen & Tukiainen, 2008). Bronchoconstriction mediators such as methacholine, substantial loss of respiratory heat and water during exercise, and increased ATP levels associated with inflammation may induce cough dyspnoea in asthmatic patients.
Similarly, COPD patients cough due to TRPV1 receptor activation or substantial airway inflammation and subsequent release of inflammatory mediators (e.g., tussive agents such as tachykinins, cough reflex stimulants such as prostaglandins) (Choudry, Fuller & Pride, 1989; Joos, De Swert, Schelfhout & Pauwels, 2003). Anti-cholinergic tiotropium used as bronchodilator activity in patients with asthma can help relieve symptoms and attenuates cough (Birrell et al., 2014). Acrolein and crotonaldehyde in cigarette smoke can also induce cough through stimulating TRPA1 receptors. This suggests a potential role for TRPA1 receptors in coughs induced by cigarette smoke, which is closely linked to COPD development (Mazzone & Undem, 2016). Furthermore, COPD coughs may be induced by increased protease levels stimulating TRPV4 and TRPA1 receptors (Grace et al., 2014), as well as through mechanical stimulation by the excess mucus in the airways (Hogg, 2004).
The frequency of cough in idiopathic pulmonary fibrosis (IPF) is even higher than in asthma or COPD, even though it is a marker of poor prognosis (Ryerson, Abbritti, Ley, Elicker, Jones & Collard, 2011). TRPV1 and ATP (P2X3) receptors may be involved in the generation of cough in IPF patients. Oral inhalation of sodium cromoglicate can reduce the cough frequency of IPF patients by 31% (Birring et al., 2017). Inflammation and mechanical distortion of the lungs may affect nerve fibres and increase cough reflex sensitivity to mechanical stimulation of the chest wall (Bonvini & Belvisi, 2017).
Increased cough response is also observed in patients with viral respiratory infections (Empey, Laitinen, Jacobs, Gold & Nadel, 1976). Viral infection exposes the sensory nerves by damaging the airway epithelial cells, rendering them to higher responsiveness to mechanical and chemical stimuli (Empey, Laitinen, Jacobs, Gold & Nadel, 1976). Cough may also be induced by the production of inflammation-associated mediators that sensitise sensory nerve endings (Fuller & Jackson, 1990). Depending on the respiratory disease status of the patient, cough can be induced by mechanical or chemical stimulation of various ion channels, which activates sensory nerves and the cough reflex. Understanding of the cough pathophysiology has the potential to design drugs that target the receptors of interest and provide quality of life to chronic lung disease patients.