Cough is the most common symptom of respiratory diseases. Under normal conditions cough is beneficial for the organism, however, long lasting non-productive cough considerably reduces the quality of life.
Acute cough is defined as lasting up to 3 or 4 weeks in adults and is usually self-limited. Cough persisting for 8 weeks in adults or 4 weeks in children is defined as chronic cough. Upper and lower airway etiologies of chronic cough are collectively termed upper airway cough syndrome (UACS) and lower airway cough syndrome (LACS), respectively. Other important etiologies include extraoesophageal reflux disease, gastroesophageal reflux disease (GERD)-related cough and laryngeal hyperresponsiveness (LHR), obstructive sleep apnea (OSA), COVID-19, tumors, and drugs (ACE inhibitors, opioids) (1). This review article provides an overview of pathomechanisms causing cough in patients with rhinosinusitis.
Acute and chronic rhinosinusitis are common primary care diagnoses in most of the world. They are caused by mucosal inflammation, which inhibits mucociliary function of the nose and paranasal sinuses (2).
Rhinosinusitis in adults is defined as an inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage / obstruction / congestion or nasal discharge (anterior / posterior nasal drip). Other symptoms include facial pain/pressure, reduction or loss of smell and either endoscopic signs of nasal polyps, mucopurulent discharge primarily from middle meatus, oedema or mucosal obstruction primarily in middle meatus and/or CT changes – mucosal changes within the ostiomeatal complex and sinuses (3). According to the duration of the disease, acute rhinosinusitis lasts for less than 12 weeks. Recurrent acute rhinosinusitis occurs at least 4 times per year with symptom free intervals.
The spectrum of acute rhinosinusitis (ARS) includes the common cold (acute viral rhinosinusitis), post-viral ARS, and acute bacterial rhinosinusitis. Post-viral ARS is defined by an increase of symptoms after 5 days, or a persistence of symptoms after 10 days. It is estimated that less than 2% of episodes of viral upper respiratory tract infections are complicated by bacterial transformation (2).
Chronic rhinosinusitis (CRS) is, characterized by persistent symptomatic inflammation of the nose and paranasal sinus mucosa lasting for more than 12 weeks (3).
The EPOS2020 steering group has chosen to look at CRS in terms of primary and secondary one and to divide each into localized and diffuse disease based on anatomic distribution. In primary CRS, the disease is divided by endotype dominance, either type 2 or non-type 2.
Localized primary CRS is then subdivided into two phenotypes – allergic fungal rhinosinusitis (type 2) or an isolated sinusitis (non - type 2). For diffuse CRS, the clinical phenotypes are predominantly eosinophilic CRS, CRS with nasal polyps (CRSwNP), allergic fungal rhinosinusitis, central compartment allergic disease and non-eosinophilic CRS, determined by the histologic quantification of the numbers of eosinophils.
Among the main causes of secondary chronic rhinosinusitis are cystic fibrosis, Churg-Strauss disease, Wegener’s disease, primary ciliary dyskinesia, selective immunodeficiency, odontogenic sinusitis, tumor of the sinonasal complex, and mycosis.
CRS is a syndrome with a multifactorial etiology resulting from a dysfunctional interaction between various environmental factors and the host immune system. For the vast majority, etiology is uncertain although multiple environmental and host genetic factors have been implicated.
In healthy individuals, the mucosa serves as a relative barrier limiting and regulating environmental interaction with the host immune system. In cases of CRS, the current working hypothesis is that alterred barrier penetration results in a chronic inflammatory response (3).
Some evidence suggests genetic and epigenetic factors, early stage environmental insults including an abnormal microbiome or viral injury, and possibly systemic hormone signaling defects, which could all serve as permissive factors in CRS pathogenesis (4).
The microbiota may play a pathogenic role in the development of CRS. Virus and bacterial infection might contribute to the development and exacerbations of CRS. Staphylococcus aureus (SA) is a frequent colonizer in humans, and it is considered to be associated with chronic airway diseases including CRS and asthma (3). The presence of biofilms in CRS patients was first demonstrated in 2004 (5). A biofilm comprises any syntrophic consortium of microorganisms in which cells stick to each other and often also to a surface. Multiple bacterial organisms have been implicated including Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus influenzae, and Moraxella catarrhalis. Of these, SA biofilms have the greatest association with severely recurrent and recalcitrant cases of CRS possibly because of their potential to produce antigens (6). Other possible pathogenic mechanisms are viral and fungal infection, allergy, immunodeficiency, lower airway inflammation, GERD, and exposition to the tobacco smoke and other air pollutants (3).
Remodeling is defined as an abnormal restitution of damaged tissues. In CRS, remodeling also takes place and observed changes include fibrosis, basement membrane thickening (BMT), goblet cell hyperplasia, epithelial barrier abnormalities and polyp formation, osteitis, and angiogenesis (7).
Although patients with CRS do not necessarily have higher rates of specific anatomic variations, it appears that they can affect the progression of the disease (8).
Although rhinosinusitis can constitute up to 20% of adult patients with chronic cough, coughing is not a major feature of CRS, cough aggravation has been associated with presence of bacterial biofilms (1).
Cough is the most common symptom of respiratory diseases. Under normal conditions cough is beneficial for our organism serving the protection of the airways by removing inhaled irritants, particles, and accumulated secretion. However, in specific conditions cough can become damaging (9). In diseases such as asthma, chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease (GERD), and rhinosinusitis, cough may become excessive and harmful to the airway mucosa (10). Cough can also be a mechanism of spreading of the life – threatening respiratory infections (10). Furthermore, persistent coughing can substantially reduce health-related quality of life and is associated with increased levels of depression and anxiety (11).
Cough reflex begins with a deep inspiration, followed by expiration against a closed glottis which produces large increases in intrapulmonary pressures such that the final phase of opening of glottis evokes a large expulsive airflow for clearing the airways (12).
Cough can be induced either reflexively or voluntarily. Reflexive cough is generated on the level of the brainstem, voluntary cough originates from the activation of cortical mechanisms (13).
The respiratory tree and lung parenchyma are densely innervated by heterogeneous populations of sensory receptors that respond to a wide variety of chemical and/ or mechanical stimuli. The majority of the sensory receptors originate in either the jugular (superior) or nodose (inferior) vagal ganglia (14, 15).
The vagal afferents terminate particularly in the nucleus of the solitary tract (nTS) (10), substantial portion of afferent nerve fibers heads to paratrigeminal nucleus (Pa5) (13). Second order neurons project to the respiratory – related neurons in medulla, pons, and spinal cord (16). Cortical mechanisms are responsible for voluntary cough and inhibition of coughing (17).
Cough reflex is modulated by many afferent inputs within and besides the vagus nerve. This modulation significantly contributes to the cough plasticity (18).
Afferent neuronal subtypes can be divided into two classes of sensory receptors.
1. Myelinated mechanoreceptors, which consist of neurons that display limited sensitivity to a wide variety of chemical mediators but are exquisitely responsive to stretch, touch or other mechanical forces (19) and
2. unmyelinated chemoreceptors, (frequently termed nociceptors), characteristically sensitive to the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor agonist capsaicin (15).
C-fibers, the most represented afferent nerves in the airways, mediate the recognition of various chemical substances and endogenous inflammatory mediators (21). Mechano re ceptors can be further subdivided into three functionally unique subgroups; rapidly adapting receptors (RARs), slowly adapting receptors (SARs), and touch sensitive receptors, also known as cough receptors (mechanosensitive Ad fibers) (22).
The cough receptors are localized exclusively in the extrapulmonary airways, RARs and SARs terminate in the intrapulmonary airways (17).
Although C-fibers and the cough receptors serve primary roles in cough initiation, other bronchopulmonary afferent nerve subtypes likely modulate cough pattern and sensitivity to tussive stimuli (17).
Based on its duration cough is defined as acute (less than 4 weeks), subacute (less than 8 weeks), and chronic (more than 8 weeks) (23).
The most common causes of chronic cough are asthma, gastro-oesophageal reflux disease and extraoesophageal reflux, upper airway cough syndrome, or a combination of these conditions.
The relationships between rhinosinusitis and cough are incompletely understood. Patients with rhinitis suffering from chronic cough report that coughing occurs in response to sensations of airway irritation and an associated urge-to-cough (24). There are many factors that facilitate cough in this group of patients, including direct stimulation of nasal mucosa, post nasal drip syndrome, microaspiration of the inflamed aerosol, nasobronchial reflex, the impact of the unmodified air inhaled through the mouth in patients with nasal obstruction, spreading of the inflammatory process by the systemic circulation and the central and peripheral neuroplasticity (25).
Nasal mucosa is inervated by trigeminal afferents. Direct stimulation of nasal mucosa does not initiate cough (17), however, cough seems to be both up regulated and down regulated by distinct populations of nasal afferents. Signaling from nociceptors may primarily up regu late cough, whereas the activation of other nasal nociceptors may down regulate it (26).
There is a hypothesis that cough reflex is up regulated during the stimulation of nasal afferents in order to minimize the spreading of the pathological process from the nasal cavity to other parts of the respiratory tract (27).
The stimulation of trigeminal terminals in the nose by the TRPV1 agonists (capsaicin and histamine) significantly enhances cough response induced in laboratory animals. Such stimulation also up regulates cough responsiveness in human healthy subjects and patients with allergic rhinitis (28, 29).
These findings suggest cough is enhanced by an increased afferent drive form the nose to the sensory trigeminal nuclei and then by cooperation with the brainstem neuronal circuits modulating cough. Although the primary sensory fibers from the nasal cavity are interpolated to second order neurons mainly in the sensitive nucleus of trigeminal nerve, these afferents have connections to the chemosensitive areas such as the area postrema, and also nTS, which may interfere with modulation of inputs to “cough generator” (27). Hypothetically, the interpolation of nasal trigeminal sensory afferents in the paratrigeminal nucleus and also nTS, which represents the termination of vagal afferents, can feature interactive activity of both afferent nerves (30). Not every activator of nasal sensory nerves will enhance cough reflex. For example, nasal stimulation with water was reported to inhibit cough in anesthetized rabbits (31).
Cold temperatures, menthol, eucalyptol, or camphor activate neurons through gating of TRPM8. Intranasal application of menthol inhibited cough in guinea pigs (32).
Postnasal drip syndrome (PNDS) refers to the sensation of nasal secretions at the back of the throat (or of a ‘drip’), often resulting in the need to clear the throat and is associated with nasal stuffiness or nasal discharge. Patients with PNDS often have features of rhinosinusitis, however, only a small fraction of patients with chronic rhinosinusitis present with cough (33). Nowadays, the term UACS is used instead of PNDS. In 2006, the American College of Chest Physicians (ACCP) defined UACS as one of several critical pathogeneses of chronic cough. In the past, chronic cough from UACS/PNDS was considered to result from postnasal drip-inducing mechano- or chemostimulation of the afferent nerves innervating the pharynx, larynx, or lower airways (34). This includes sensory fibers of the trigeminal nerve and superior laryngeal and pharyngolaryngeal branch of the vagus nerve (35). However, postnasal drip and transport of nose and paranasal sinus mucous secretions to the pharynx or larynx are normal physiological processes (35). Patients with PNDS do not account for a homogeneous group with respect to etiology and PNDS is not a consistent complaint in patients with chronic cough (36). Furthermore, the united airway theory assumes a hematogenous or neural spread of inflammatory mediators between upper and lower airways (35).
UACS can also be influenced by a chronic inflammation in the pharynx or larynx, such as inflammations resulting from allergic pharyngitis and chronic tonsillitis. Such inflammations may result from a long-term contact with nasal or sinus secretions (37). Cough can mechanically damage airway mucosa and either cause or aggravate airway inflammation (38).
Some studies have demonstrated that patients with rhinitis have increased numbers of neurons capable of generating large amounts of neurogenic inflammatory mediators in their nasal mucosa (39). The diseases of the nose and paranasal sinuses have a significant impact on the function of the lower airways.
Patients with UACS showed a remodeling of the airways, characterized by increased sub-ba sement membrane thickness, vascularity, vessel size, and signs of goblet cell hyperplasia (40). Numerous studies have shown that airway inflammation in patients with non –asthmatic chronic cough, including patients with UACS, is mainly due to an infiltration of mast cells, neutrophils, and lymphocytes, which is different from the aetiology associated with cough-variant asthma and eosinophilic bronchitis (41). The mechanical stimulation by repeated cough leads to the epithelial transformation causing an increased cough sensitivity (35).
Lower airway inflammation is commonly associated with chronic cough (35). The main causes of lower airway inflammation resulted in chronic cough are either the postnasal drip or aspiration, mainly in older individuals and patients with cerebrovascular disease, (35).
The term ‘cough hypersensitivity syndrome’ has been used in an attempt to encompass clinical picture of patients suffering from chronic cough and reporting cough in response to a wide range of activities and exposures (42).
Cough reflex sensitization (CHS) can be demonstrated as a decreased intensity of a stimulus required to trigger cough or increased coughing in response to a stimulus with a constant intensity. In patients with sensitized cough reflex, the endogenous and environmental stimuli are expected to be more effective to initiate coughing and thus these patients cough in the situations when their healthy counterparts do not (43). Cough hypersensitivity underlies the aetiology of chronic cough in the majority of patients (44).
Patients with CHS usually present one of three different phenotypes: (1) patients with a predominant phenotype of rhinal symptoms (such as UACS), (2) patients with a Th2-cell dominant phenotype (cough variant asthma or nonasthmatic eosinophilic bronchitis), and (3) patients with a predominant phenotype characterized by acid reflux and heartburn (chronic cough caused by gastroesophageal reflux) (42).
The activation of sensory nerves in the nose and oesophagus leads to an increase in cough reflex sensitivity (43).
Chronic nasal symptoms attributable to sensory nerve activation in patients with rhinitis implicate that the inflammation leads to a repeated activation of sensory nerves. The repeated activation and mediators associated with inflammation in patients with rhinitis can induce sensitization at multiple levels of sensory pathways (25) and may lead to an altered central neural processing in cough control (45).
Stimulation of nasal sensory nerves also affected the urge-to-cough - an irritation or tickle in the back of the neck and is associated with >90% of coughs in patients with chronic cough (46).
Central mechanisms of cough sensitization from the nose are poorly understood. There is some evidence that suggests that the sensitivity of the cough reflex is higher in patients with UACS (34). Inflammatory mediators, neurotrophic factors, and other signals emanating from the nose during symptomatic period could, in theory, initiate long-lasting neural plastic changes in the circuits regulating the cough reflex (25). Allergic rhinitis is connected with the sensitization of the cough reflex, persisting also off pollen season (29,34). It is suggested that allergic rhinitis modulates both distinct types of cough–either cough induced by stimulation of TRPV1-expressing capsaicin-sensitive fibers, or cough initiated by capsaicin- insensitive mechanosensitive A nodose fibers (27).
Cough is a very important defensive reflex, essential for normal function of the airways. Rhinosinusitis represents one of the most common causes of chronic cough. We tried to clarify the most significant factors leading to excessive coughing accompanying rhinosinusitis. Although, direct stimulation of nasal mucosa does not initiate cough, cough is supposed to be up and down regulated by distinct populations of nasal afferents. Postnasal drip induces the stimulation of the afferents in pharynx, larynx, and lower airways, moreover, hematogenous or neural spread of inflammatory mediators between upper and lower airways is possible. Among other important pathomechanisms there are the airway inflammation with remodeling of the airways, epithelial transformation, and cough reflex sensitization. Further studies are needed to recognize the exact mechanism of the connection of these two entities.
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