Cough is the commonest symptom for which people seek medical advice *(Irwin et al., 1993)*. Lower airway infections are the most common cause of acute cough. Lower airway infections refer to acute tracheobronchitis, acute bronchiolitis and community acquired pneumonia (CAP). Acute tracheobronchitis is mostly viral in origin. Influenza virus, rhinovirus, parainfluenza virus, Respiratory syncytical virus (RSV), adenovirus and coronavirus are the pathogens most commonly associated with acute cough in patients with acute tracheobronchitis. All these viruses have a short incubation period of between one and four days, and all symptoms including cough usually resolves within three weeks *(Pek & Boushey, 2003)*. Many people with viral cough do not seek medical advice, but treat themselves with over the counter products. This means that there is no sufficient statistical data about the extent of acute cough *(Morice, 2003)*. 5-10% of all cases with acute tracheobronchitis are caused by bacteria. Among the most common bacterial pathogens are Bordetella pertussis, Mycoplasma pneumoniae, Streptococcus pneumoniae and Chlamydia pneumoniae. CAP is a common cause of hospitalization and death from infectious disease in adults. The etiological agent is identified in only 50% of all cases. Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus are among the most commonly identified microbial pathogens that cause pneumonia *(Pek & Boushey, 2003)*.

Cough in Allergic Rhinitis 91

cough in adults is subdivided differently. Acute cough duration is of less than 3 weeks, subacute 3-8 weeks and chronic more than 8 weeks *(Pratter el al., 2006; Morice et al., 2007)*. Chronic cough may be classified according to its etiology. By this classification cough is divided into ´expected´ cough, non-specific cough and specific cough; its scientific rationale is discussed elsewhere *(Chang, 2005).* In expected cough, the cough is anticipated, such as after an acute respiratory tract infection. In specific cough the cause is clearly definable by usage of history and examination, where coexisting symptoms and sign often help in diagnosing the etiology. These causes are often serious. Nonspecific cough is a dry cough where neither known aetiology nor any respiratory disease has been identified. Chronic cough in children is most commonly due to an upper respiratory tract infection, asthma,

The cough reflex sensitivity can be assessed by the inhalation cough challenge test. In this test an acid or a non-acid tussive is used to induce cough experimentally. The most common non-acid tussive is capsaicin, while citric and tartaric acids are the most commonly used acid tussives. Before 2007 standardized methods did not exist, making it impossible to compare data in studies obtained from different institutions. The European Respiratory Society (ERS) developed guidelines in 2007 on the standardization of testing with tussive

During the inhalation cough challenge test, the tussives can be administered either by using single-dose or the dose-response method *(Morice et al., 2001)*. In the single-dose method, one concentration of capsaicin or citric acid is administered. In the dose-response method the tussives are administered over a prolonged period. In the dose-response method, variations in respiratory frequency and tidal volume are thought to cause variation in the amount of tussive delivered from individual to individual, and therefore accuracy and reproducibility is poor. The single dose method is the most widely used method, because of the accuracy

The inspiratory flow rate affects the pattern of distribution of the tussives in the airways. Variation in the inspiratory flow rate thus will affect the cough challenge test. The lowering the inspiratory flow rate will increase the cough response to citric acid. Controlling the flow rate ensures that the same amount of tussive is delivered to different individuals *(Barros et al., 1991)*. To control the inspiratory flow rate, ERS currently recommend the use a compressed air-driven nebulizer controlled by a dosimeter modified by an inspiratory

The patient should be told not to suppress any coughs and not to talk immediately after inhalation of the tussive, since talking suppresses the cough response. The cough induced by capsaicin and citric acid occur immediately and only sustain for a short period. Therefore only coughs that occur within 15 sec after the administration of the tussive should be counted. Any cough occurring after this interval should not be counted, since it is not likely to be induced by the tussive agent. In studies the concentration of the selected tussive agent causing two (C2) and five (C5) coughs are reported. C2 is the concentration first resulting in 2 or more coughs, while C5 is the first concentration resulting in 5 or more coughs. In patient with high cough threshold a C5 value may not be possible to obtain, and ERS recommend that these individuals are excluded from the clinical trials *(Morice et al., 2007)*.

gastrointestinal reflux as well as other more uncommon causes.

and reproducibility of the dose delivered *(Morice et al., 2007)*.

regulatory flow regulator valve *(Morice et al., 2007)*.

**3.5 Cough reflex sensitivity assessment**

and non tussive tussives *(Morice et al., 2007)*.

The mechanism of cough in lower airway infection is not completely understood. Possible mechanisms have been suggested by *Pek & Boushey (2003): 1)* Irritation of the nerve endings in the larynx and trachea caused by dripping of secretions containing inflammatory mediators from the nasopharynx into larynx or trachea is one possible mechanism. Exposure of the nerve endings (e.g. RARs) caused by damage and destruction of the airway epithelium is thought to decrease the cough threshold to environmental irritants and inflammatory secretions, thus causing cough. 2) The infection of the airways also leads to accumulation of secretions and debris in the airway lumen. As a result the mechanoreceptors in the bronchial mucosa are activated, triggering cough to clear the airways for the excess secretions and foreign material. 3) Cough may also occur because of stimulation of nerve endings by inflammatory mediators released directly from airway epithelial cells or from inflammatory cells attracted to the site of infection. 4) Neuropeptidases degrade neuropeptides released from adjacent afferent nerve endings. Enhanced effect of neuropeptidases because of decrease in the neutral endopeptidase from epithelial cells is also one possible mechanism triggering cough in lower airway infections.

#### **3.2 Chronic cough in adults**

The three most common causes of chronic cough are asthma bronchiale, GERD and chronic upper airway syndrome (CUAS) – previously postnasal drip syndrome. Other causes of chronic cough include post viral cough, cough in patients with chronic obstructive pulmonary diseases, cough induced by ACE inhibitor therapy and cough in lung cancer patients *(Chung et al., 2003).*

A single cause of cough in a patient is less common than multiple causes of cough. In a study performed by *Palombini et al. (1999)* they found that asthma, CUAS, GERD either alone or in combination, were responsible for 93.6% of the cases of chronic cough. These three conditions were so frequent that they suggested the use of the term "pathogenic triad of chronic cough". 38.5% of the patients investigated had a single cause of cough, while 61.5 % of the patients had two or more causes of cough.

#### **3.3 Acute cough in children**

Some studies of acute cough are old and show systematic reviews on the natural history of the acute cough in children (35-50years). Hay and Wilson (*2002*) did prospective study of the period 1999-2001 of acute cough, which displayed that within 10 days 50% of the children showed recovery, and 90% within 25 days. Also an Australian prospective community study recorded respiratory episodes of 2.2-5.3 year for children aged ≤ 10 years, with results showing a mean duration of 5.5-6.8 days of the episodes *(Leder et al., 2003)*. Thereby indicating that acute cough should be defined as cough less then 14 days of duration.

The most common etiology of acute cough in children is due to an uncomplicated viral acute respiratory tract infection, though one must exclude more serious problems as aspiration of foreign material *(Chang et al., 2006).*

#### **3.4 Chronic cough in children**

Acute cough in children is defined as cough less than 2 weeks, prolonged acute cough (subacute) 2-4 weeks, chronic cough more than 4 weeks *(Chang et al., 2006*). Definition of

The mechanism of cough in lower airway infection is not completely understood. Possible mechanisms have been suggested by *Pek & Boushey (2003): 1)* Irritation of the nerve endings in the larynx and trachea caused by dripping of secretions containing inflammatory mediators from the nasopharynx into larynx or trachea is one possible mechanism. Exposure of the nerve endings (e.g. RARs) caused by damage and destruction of the airway epithelium is thought to decrease the cough threshold to environmental irritants and inflammatory secretions, thus causing cough. 2) The infection of the airways also leads to accumulation of secretions and debris in the airway lumen. As a result the mechanoreceptors in the bronchial mucosa are activated, triggering cough to clear the airways for the excess secretions and foreign material. 3) Cough may also occur because of stimulation of nerve endings by inflammatory mediators released directly from airway epithelial cells or from inflammatory cells attracted to the site of infection. 4) Neuropeptidases degrade neuropeptides released from adjacent afferent nerve endings. Enhanced effect of neuropeptidases because of decrease in the neutral endopeptidase from epithelial cells is also one possible mechanism triggering cough in lower airway infections.

The three most common causes of chronic cough are asthma bronchiale, GERD and chronic upper airway syndrome (CUAS) – previously postnasal drip syndrome. Other causes of chronic cough include post viral cough, cough in patients with chronic obstructive pulmonary diseases, cough induced by ACE inhibitor therapy and cough in lung cancer

A single cause of cough in a patient is less common than multiple causes of cough. In a study performed by *Palombini et al. (1999)* they found that asthma, CUAS, GERD either alone or in combination, were responsible for 93.6% of the cases of chronic cough. These three conditions were so frequent that they suggested the use of the term "pathogenic triad of chronic cough". 38.5% of the patients investigated had a single cause of cough, while 61.5

Some studies of acute cough are old and show systematic reviews on the natural history of the acute cough in children (35-50years). Hay and Wilson (*2002*) did prospective study of the period 1999-2001 of acute cough, which displayed that within 10 days 50% of the children showed recovery, and 90% within 25 days. Also an Australian prospective community study recorded respiratory episodes of 2.2-5.3 year for children aged ≤ 10 years, with results showing a mean duration of 5.5-6.8 days of the episodes *(Leder et al., 2003)*. Thereby indicating that acute cough should be defined as cough less then 14 days of

The most common etiology of acute cough in children is due to an uncomplicated viral acute respiratory tract infection, though one must exclude more serious problems as aspiration of

Acute cough in children is defined as cough less than 2 weeks, prolonged acute cough (subacute) 2-4 weeks, chronic cough more than 4 weeks *(Chang et al., 2006*). Definition of

**3.2 Chronic cough in adults**

patients *(Chung et al., 2003).*

**3.3 Acute cough in children**

foreign material *(Chang et al., 2006).*

**3.4 Chronic cough in children**

duration.

% of the patients had two or more causes of cough.

cough in adults is subdivided differently. Acute cough duration is of less than 3 weeks, subacute 3-8 weeks and chronic more than 8 weeks *(Pratter el al., 2006; Morice et al., 2007)*. Chronic cough may be classified according to its etiology. By this classification cough is divided into ´expected´ cough, non-specific cough and specific cough; its scientific rationale is discussed elsewhere *(Chang, 2005).* In expected cough, the cough is anticipated, such as after an acute respiratory tract infection. In specific cough the cause is clearly definable by usage of history and examination, where coexisting symptoms and sign often help in diagnosing the etiology. These causes are often serious. Nonspecific cough is a dry cough where neither known aetiology nor any respiratory disease has been identified. Chronic cough in children is most commonly due to an upper respiratory tract infection, asthma, gastrointestinal reflux as well as other more uncommon causes.

#### **3.5 Cough reflex sensitivity assessment**

The cough reflex sensitivity can be assessed by the inhalation cough challenge test. In this test an acid or a non-acid tussive is used to induce cough experimentally. The most common non-acid tussive is capsaicin, while citric and tartaric acids are the most commonly used acid tussives. Before 2007 standardized methods did not exist, making it impossible to compare data in studies obtained from different institutions. The European Respiratory Society (ERS) developed guidelines in 2007 on the standardization of testing with tussive and non tussive tussives *(Morice et al., 2007)*.

During the inhalation cough challenge test, the tussives can be administered either by using single-dose or the dose-response method *(Morice et al., 2001)*. In the single-dose method, one concentration of capsaicin or citric acid is administered. In the dose-response method the tussives are administered over a prolonged period. In the dose-response method, variations in respiratory frequency and tidal volume are thought to cause variation in the amount of tussive delivered from individual to individual, and therefore accuracy and reproducibility is poor. The single dose method is the most widely used method, because of the accuracy and reproducibility of the dose delivered *(Morice et al., 2007)*.

The inspiratory flow rate affects the pattern of distribution of the tussives in the airways. Variation in the inspiratory flow rate thus will affect the cough challenge test. The lowering the inspiratory flow rate will increase the cough response to citric acid. Controlling the flow rate ensures that the same amount of tussive is delivered to different individuals *(Barros et al., 1991)*. To control the inspiratory flow rate, ERS currently recommend the use a compressed air-driven nebulizer controlled by a dosimeter modified by an inspiratory regulatory flow regulator valve *(Morice et al., 2007)*.

The patient should be told not to suppress any coughs and not to talk immediately after inhalation of the tussive, since talking suppresses the cough response. The cough induced by capsaicin and citric acid occur immediately and only sustain for a short period. Therefore only coughs that occur within 15 sec after the administration of the tussive should be counted. Any cough occurring after this interval should not be counted, since it is not likely to be induced by the tussive agent. In studies the concentration of the selected tussive agent causing two (C2) and five (C5) coughs are reported. C2 is the concentration first resulting in 2 or more coughs, while C5 is the first concentration resulting in 5 or more coughs. In patient with high cough threshold a C5 value may not be possible to obtain, and ERS recommend that these individuals are excluded from the clinical trials *(Morice et al., 2007)*.

*2006)*.

the cough reflex sensitization (*Pratter, 2006)*.

patient group is lower than in the appropriate reference group.

*1998, O´Connell et al., 1994, O´Connell et al., 1996*).

**4.1 Cough reflex hypersensitivity**

Cough in Allergic Rhinitis 93

patients with chronic cough caused by rhinosinusitis do not experience postnasal drip. Therefore it is unlikely that postnasal drip is the only mechanism responsible for cough in nasal disease *(Tatar et al., 2009)*. Cough reflex sensitization is often observed in patients with chronic cough, including those with nasal diseases. The cough reflex cannot be triggered from the nose, but cough reflex sensitization may occur in nasal diseases. *Tatar et al. (2009)* have suggested that central sensitization of the cough reflex mediated by the nasal trigeminal sensory nerves may be one of the possible mechanisms of chronic cough in patients with nasal diseases. Chronic cough in nasal diseases may also be secondary to aspiration of secretions. The secretions are thought to stimulate the vagal afferents in the lung, thereby mediating cough. However more evidence is needed before this last mentioned mechanism can be accepted as a mechanism of cough in nasal diseases *(Pratter,*

The diseases of the nose and paranasal sinuses are among the most commonly identified causes of chronic cough (*Pratter, 2006*). Depending on the population studied and the variations in diagnostic algorithm, the diseases of nose and sinuses are reported to contribute to coughing in 20–40% of patients with chronic cough who have normal chest radiograph (*Chung & Pavord, 2008*). The mechanisms of chronic cough in rhinosinusitis are incompletely understood. Several mechanisms have been proposed, single or in combination: postnasal drip (PND), direct irritation, inflammation in the lower airways and

Cough reflex hypersensitivity refers to a condition in which the cough reflex is more readily inducible. Cough reflex hypersensitivity can be demonstrated as 1) the lowered intensity of a stimulus required to trigger cough or 2) enhanced coughing in response to a stimulus with the constant intensity. In clinical and laboratory experiments, the cough reflex hypersensitivity is detected by measuring the cough threshold or by evaluating changes in the number of coughs induced by a stimulus with defined intensity. The cough threshold is measured by a controlled inhalation of increasing concentrations of an aerosolized tussigen, commonly capsaicin or acidic solutions (*Morice et al., 1997*) and (*Choudry & Fuller, 1992*). The cough threshold is defined as the lowest concentration of the tussigen required to induce a predetermined number of coughs (typically 2 and 5 coughs, denoted C2 and C5, respectively). The cough reflex hypersensitivity is found when the cough threshold in the

The cough reflex hypersensitivity is often reported in patients with chronic cough attributed to disparate causes including nasal diseases (*McGarvey et al., 1998*). It is implied that the cough reflex hypersensitivity contributes to coughing. In patients with a sensitized cough reflex, the environmental and endogenous stimuli are predicted to be more effective to trigger cough. Thus the cough reflex hypersensitivity results in the amplification of cough, similar to the amplification of pain in hyperalgesia. The observations that the cough sensitivity decreases with the successful treatment or natural resolution of cough also support the notion that the cough sensitization contributes to coughing (*McGarvey et al.,*

There is a consensus that the cough reflex cannot be triggered from the nose. There is the mechanistic question whether the cough reflex can be sensitized from the nose. Based on the general concept that the activation of nasal sensory nerves leads to cough reflex

During the cough challenge test it is also recommended to use placebo inhalations with physiological saline *(Morice et al., 2001)*. The saline solution should be used randomly between the different concentrations of the tussive agent. This is thought to decrease voluntary suppression of cough *(Morice et al., 2007)*.

Tachyphylaxis is the process in which the effect of a drug is reduced during continuous use or by constantly repeated drug administration. In one study that used continuous inhalation over 1 min with capsaicin, the cough frequency was reduced by one third. In continuous inhalation with citric acid, no coughs were evoked after the 1 min period *(Morice et al., 1992)*. The ERS recommends an interval between cough challenge measurements of minimally 1 hour. The optimal interval is set by the ERS to 2 hours.

No serious adverse effect is associated with cough challenge testing using capsacin as tussive agent. The most commonly reported side effect is transient throat irritation *(Morice et al., 2007)*.

Citric acid inhalation may result in a small reduction of forced expiratory volume (FEV), but this is thought to be without clinical significance *(Laude et al., 1993)*. Capsaicin induces bonchoconstriction, but it is not tough to have clinical significance in healthy individuals or in individuals with asthma bronchiale. However, ERS recommend that bronchodilators should be easily available when a cough challenge test is performed *(Morice et al., 2007)*.

#### **4. Cough in rhinosinusitis**

Rhinitis refers to inflammation of the nasal mucosa, while sinusitis means inflammation of the mucosa in one or more of the paranasal sinuses. A continuum exists between rhinitis and sinusitis owing to the anatomical and physiological relationship of the nose and paranasal sinuses. Sinus inflammation generally develops in association with rhinitis and the term rhinosinusitis is applied to these disorders *(Probst et al., 2005)*. Chronic rhinosinusitis is among the commonest causes of chronic cough in adults. In 20-40% of patients with chronic cough who have normal chest x-ray, chronic rhinosinusitis is reported to be the cause of the cough *(Tatar et al., 2009)*.

Chronic rhinosinusitis may be caused by diseases of a chronic inflammatory, allergic, traumatic or neoplastic nature. Chronic rhinosinusitis may also develop as a result of anatomical changes, as seen in e.g. septal deviation or septal spurs. Impaired ventilation of the ostiomeatal unit caused by obstruction or stenosis is the common mechanism for development of rhinosinusistis. The obstruction impairs drainage from the sinus systems. The drainage is further impaired by swelling of the mucosa in the narrow anatomical canal of the ostiomeatal unit. A viscous circle of recurrent acute inflammations that develops into a chronic inflammation is established. In adults the maxillary and ethmoid cells are the sinuses most commonly affected *(Probst et al., 2005)*.

The mechanism of chronic cough in rhinosinusitis is until now not completely understood. Chronic upper cough syndrome, previously postnasal drip, cough reflex hypersensitivity and aspiration of secretions are among the mechanisms thought to be responsible, either alone or in combination *(Tatar et al., 2009)*.

The cough is produced by stimulation of the pharyngeal nerve endings, which are branches of the vagus nerve. The stimulation occur secondary to secretion from the nose and sinuses dripping into the hypopharynx, a process known as postnasal drip *(Palombini & Araujo, 2003)*. However, only some of the patients with postnasal drip complain of cough, and some

During the cough challenge test it is also recommended to use placebo inhalations with physiological saline *(Morice et al., 2001)*. The saline solution should be used randomly between the different concentrations of the tussive agent. This is thought to decrease

Tachyphylaxis is the process in which the effect of a drug is reduced during continuous use or by constantly repeated drug administration. In one study that used continuous inhalation over 1 min with capsaicin, the cough frequency was reduced by one third. In continuous inhalation with citric acid, no coughs were evoked after the 1 min period *(Morice et al., 1992)*. The ERS recommends an interval between cough challenge measurements of minimally 1

No serious adverse effect is associated with cough challenge testing using capsacin as tussive agent. The most commonly reported side effect is transient throat irritation *(Morice et*

Citric acid inhalation may result in a small reduction of forced expiratory volume (FEV), but this is thought to be without clinical significance *(Laude et al., 1993)*. Capsaicin induces bonchoconstriction, but it is not tough to have clinical significance in healthy individuals or in individuals with asthma bronchiale. However, ERS recommend that bronchodilators should be easily available when a cough challenge test is performed *(Morice et al., 2007)*.

Rhinitis refers to inflammation of the nasal mucosa, while sinusitis means inflammation of the mucosa in one or more of the paranasal sinuses. A continuum exists between rhinitis and sinusitis owing to the anatomical and physiological relationship of the nose and paranasal sinuses. Sinus inflammation generally develops in association with rhinitis and the term rhinosinusitis is applied to these disorders *(Probst et al., 2005)*. Chronic rhinosinusitis is among the commonest causes of chronic cough in adults. In 20-40% of patients with chronic cough who have normal chest x-ray, chronic rhinosinusitis is reported

Chronic rhinosinusitis may be caused by diseases of a chronic inflammatory, allergic, traumatic or neoplastic nature. Chronic rhinosinusitis may also develop as a result of anatomical changes, as seen in e.g. septal deviation or septal spurs. Impaired ventilation of the ostiomeatal unit caused by obstruction or stenosis is the common mechanism for development of rhinosinusistis. The obstruction impairs drainage from the sinus systems. The drainage is further impaired by swelling of the mucosa in the narrow anatomical canal of the ostiomeatal unit. A viscous circle of recurrent acute inflammations that develops into a chronic inflammation is established. In adults the maxillary and ethmoid cells are the

The mechanism of chronic cough in rhinosinusitis is until now not completely understood. Chronic upper cough syndrome, previously postnasal drip, cough reflex hypersensitivity and aspiration of secretions are among the mechanisms thought to be responsible, either

The cough is produced by stimulation of the pharyngeal nerve endings, which are branches of the vagus nerve. The stimulation occur secondary to secretion from the nose and sinuses dripping into the hypopharynx, a process known as postnasal drip *(Palombini & Araujo, 2003)*. However, only some of the patients with postnasal drip complain of cough, and some

voluntary suppression of cough *(Morice et al., 2007)*.

hour. The optimal interval is set by the ERS to 2 hours.

*al., 2007)*.

**4. Cough in rhinosinusitis**

to be the cause of the cough *(Tatar et al., 2009)*.

sinuses most commonly affected *(Probst et al., 2005)*.

alone or in combination *(Tatar et al., 2009)*.

patients with chronic cough caused by rhinosinusitis do not experience postnasal drip. Therefore it is unlikely that postnasal drip is the only mechanism responsible for cough in nasal disease *(Tatar et al., 2009)*. Cough reflex sensitization is often observed in patients with chronic cough, including those with nasal diseases. The cough reflex cannot be triggered from the nose, but cough reflex sensitization may occur in nasal diseases. *Tatar et al. (2009)* have suggested that central sensitization of the cough reflex mediated by the nasal trigeminal sensory nerves may be one of the possible mechanisms of chronic cough in patients with nasal diseases. Chronic cough in nasal diseases may also be secondary to aspiration of secretions. The secretions are thought to stimulate the vagal afferents in the lung, thereby mediating cough. However more evidence is needed before this last mentioned mechanism can be accepted as a mechanism of cough in nasal diseases *(Pratter, 2006)*.

The diseases of the nose and paranasal sinuses are among the most commonly identified causes of chronic cough (*Pratter, 2006*). Depending on the population studied and the variations in diagnostic algorithm, the diseases of nose and sinuses are reported to contribute to coughing in 20–40% of patients with chronic cough who have normal chest radiograph (*Chung & Pavord, 2008*). The mechanisms of chronic cough in rhinosinusitis are incompletely understood. Several mechanisms have been proposed, single or in combination: postnasal drip (PND), direct irritation, inflammation in the lower airways and the cough reflex sensitization (*Pratter, 2006)*.

#### **4.1 Cough reflex hypersensitivity**

Cough reflex hypersensitivity refers to a condition in which the cough reflex is more readily inducible. Cough reflex hypersensitivity can be demonstrated as 1) the lowered intensity of a stimulus required to trigger cough or 2) enhanced coughing in response to a stimulus with the constant intensity. In clinical and laboratory experiments, the cough reflex hypersensitivity is detected by measuring the cough threshold or by evaluating changes in the number of coughs induced by a stimulus with defined intensity. The cough threshold is measured by a controlled inhalation of increasing concentrations of an aerosolized tussigen, commonly capsaicin or acidic solutions (*Morice et al., 1997*) and (*Choudry & Fuller, 1992*). The cough threshold is defined as the lowest concentration of the tussigen required to induce a predetermined number of coughs (typically 2 and 5 coughs, denoted C2 and C5, respectively). The cough reflex hypersensitivity is found when the cough threshold in the patient group is lower than in the appropriate reference group.

The cough reflex hypersensitivity is often reported in patients with chronic cough attributed to disparate causes including nasal diseases (*McGarvey et al., 1998*). It is implied that the cough reflex hypersensitivity contributes to coughing. In patients with a sensitized cough reflex, the environmental and endogenous stimuli are predicted to be more effective to trigger cough. Thus the cough reflex hypersensitivity results in the amplification of cough, similar to the amplification of pain in hyperalgesia. The observations that the cough sensitivity decreases with the successful treatment or natural resolution of cough also support the notion that the cough sensitization contributes to coughing (*McGarvey et al., 1998, O´Connell et al., 1994, O´Connell et al., 1996*).

There is a consensus that the cough reflex cannot be triggered from the nose. There is the mechanistic question whether the cough reflex can be sensitized from the nose. Based on the general concept that the activation of nasal sensory nerves leads to cough reflex

*2008*).

inflammation is more active.

not require intact cortical function.

**4.4 Sensitized cough reflex and coughing in humans**

cough associated with rhinosinusitis (*Tatar et al., 2009)*.

Cough in Allergic Rhinitis 95

compared to healthy subjects (measured by the capsaicin C2 cough threshold) (*Pecova et al., 2005*). This finding was reproduced in a separate study in which the capsaicin C5 threshold was evaluated in another groups of patients and healthy subjects (*Pecova et al., 2008*). In this study, the concentrations of capsaicin causing five coughs (C5, geometric mean and 95% CI) were 132.4 (41.3–424.5) μM and 13.1 (6.0–28.6) μM in healthy subjects (5 M/7F, mean age 23 yrs) and patients with allergic rhinitis (5 M/7F, mean age 23 yrs), respectively (*P* < 0.05). We conclude that the cough reflex is sensitized in patients with allergic rhinitis (*Pecova et al.,*

Since the symptoms of allergic rhinitis in pollen-sensitive patients are most prominent during the pollen season, we hypothesized that the sensitization of cough is most pronounced in this period. Fifteen patients were evaluated out of pollen season (January– February) and in the grass pollen season (May–June) in a paired study(*Pecova et al., 2005*). The capsaicin cough C2 threshold was reduced in the pollen season vs. out of the pollen season, 0.11(0.3–0.33) μM vs. 0.84(0.14–5.2) μM, respectively (*P* < 0.05). Thus the cough reflex in patients with allergic rhinitis is further sensitized in the period when the nasal

In a series of studies it was demonstrated that the cough reflex in healthy subjects is sensitized by the intranasal administration of sensory nerve activators (*Plevkova et al., 2004; Plevkova et al., 2006*). These results are consistent with the hypothesis that the activation of nasal sensory nerves sensitizes the cough reflex (*Tatar et al., 2009*). We also show that the cough reflex is sensitized in patients with allergic rhinitis *Pecova et al., 2005; Pecova et al., 2008, Tatar et al., 2009)* and is further sensitized in this group by intranasal sensory activator histamine (*Plevkova et al., 2005*) and during the period of more active nasal inflammation (*Pecova et al., 2005*). Our results may help to explain the mechanisms contributing to chronic

These results are highly indicative that nasal sensory nerves are the neural pathways involved in the sensitization of cough. The wealth of data from the somatosensory (*Jiand & Woolf, 2001*) and vagal (*Mazzone et al., 2005*; *Mazzone & Canning, 2002*) systems allows for an informed speculation that central cough reflex hypersensitivity mediated by nasal sensory nerves underlies the observed cough sensitization. In this scenario the afferent inputs from the nose feed into the central regulatory circuits of the cough reflex in a manner rendering the cough reflex hypersensitive. It has been demonstrated that the cough reflex triggered from trachea is sensitized by the stimulation of sensory nerves innervating distal parts of the respiratory system (lungs) in animal models (*Mazzone and Canning, 2005*), or even from the esophagus in humans (*Javorkova et al., 2008*). The sensitization of cough by the nasal trigeminal sensory pathways is perhaps more complex than the vagally mediated sensitization, since the trigeminal and the cough-triggering vagal sensory nerves terminate in different areas of the brainstem. Interestingly, the sensitization of cough from the nose can be induced even in anaesthetized animals, suggesting that the cough sensitization does

The situation is more complex in patients with allergic rhinitis. Our data discussed thus far predict that the cough reflex hypersensitivity mediated by acute sensory nerve activation occurs in the symptomatic patients. However, in the patients without symptoms (such as the patients with allergic rhinitis out of the allergen season) the absence of the symptoms

hypersensitivity, a series of studies in humans and in animal models were carried out (*Tatar et al., 2009*).

#### **4.2 Sensory nerve activators in the nose sensitize the cough reflex**

The hypothesis that the afferent nerve activators applied into the nose sensitize the cough reflex in humans by using sensory activators histamine and capsaicin was aevaluated. Histamine is a prototypic mediator of nasal inflammation that directly stimulates a subset of nasal sensory nerves (*Taylor-Clark et al., 2005*). The TRPV1 selective agonist capsaicin is also an efficient activator of the nasal sensory nerves (*Taylor-Clark et al., 2005*). A large proportion of the TRPV1-positive trigeminal neurons innervating the nose express a variety of receptors relevant for detection of stimuli associated with inflammation. For example, nasal trigeminal neurons functionally express the histamine H1 receptor, the leukotriene cys-LT1 receptor (*Taylor-Clark et al., 2005*; *Taylor-Clark et al., 2008a, Taylor-Clark et al., 2008b*). Intranasal administration of capsaicin likely stimulates large proportion of nerves that are also stimulated or modulated by nasal inflammation. Local and reflex consequences of the sensory nerves activation with histamine and capsaicin (such as substance P release from peripheral terminals and reflex vasodilation) may generate additional stimuli that further stimulate nasal sensory nerves (*Tani et al., 1990; Petersson et al., 1989*). In addition, direct effects of histamine on the cells other than sensory nerves likely lead to generation of more endogenous sensory stimuli.

Consistent with the extensive data from human studies (*Philip et al., 1994; Secher et al., 1982*) intranasal administration of histamine and capsaicin failed to trigger cough in healthy subjects (*Plevkova et al., 2004; Plevkova et al., 2006*). The effective activation of nasal sensory nerves by histamine and capsaicin was confirmed by the occurrence of sensations and symptoms typically described after intranasal administration of these agents. The cough was induced by inhalation of a tussigen aerosol during the time window of the most pronounced nasal symptoms evaluated by a composite score.

Both histamine and capsaicin applied into the nose caused sensitization of the cough reflex in healthy subjects (*Plevkova et al., 2004; Plevkova et al., 2006*). Following the intranasal administration of capsaicin or histamine, the number of coughs induced by inhalation of a defined dose of capsaicin was increased by 60–80%. Similarly, intranasal histamine did not trigger cough but sensitized the cough reflex in patients with allergic rhinitis (*Plevkova et al., 2005*). These data are consistent with the hypothesis that the activation of nasal sensory nerves sensitizes the cough reflex (*Tatar et al., 2009*).

#### **4.3 Cough reflex is sensitized in patients with allergic rhinitis**

The cough reflex hypersensitivity in patients with allergic rhinitis was evaluated (*Pecova et al., 2005; Pecova et al., 2008*). Chronic nasal symptoms attributable to sensory nerve activation in patients with rhinitis implicate that the inflammation leads to repeated activation of sensory nerves. The repeated activation and mediators associated with inflammation can induce sensitization at multiple levels of sensory pathways. Thus we predicted that the cough reflex is more sensitive in patients with allergic rhinitis than in healthy subjects (*Pecova et al., 2005; Pecova et al., 2008, Tatar et al., 2009).*

The grass pollen-sensitive patients with allergic rhinitis were studied out of pollen season. All patients included in the studies were free of nasal symptoms at the time of investigation. We found that the cough reflex was more sensitive in patients with allergic rhinitis

hypersensitivity, a series of studies in humans and in animal models were carried out (*Tatar*

The hypothesis that the afferent nerve activators applied into the nose sensitize the cough reflex in humans by using sensory activators histamine and capsaicin was aevaluated. Histamine is a prototypic mediator of nasal inflammation that directly stimulates a subset of nasal sensory nerves (*Taylor-Clark et al., 2005*). The TRPV1 selective agonist capsaicin is also an efficient activator of the nasal sensory nerves (*Taylor-Clark et al., 2005*). A large proportion of the TRPV1-positive trigeminal neurons innervating the nose express a variety of receptors relevant for detection of stimuli associated with inflammation. For example, nasal trigeminal neurons functionally express the histamine H1 receptor, the leukotriene cys-LT1 receptor (*Taylor-Clark et al., 2005*; *Taylor-Clark et al., 2008a, Taylor-Clark et al., 2008b*). Intranasal administration of capsaicin likely stimulates large proportion of nerves that are also stimulated or modulated by nasal inflammation. Local and reflex consequences of the sensory nerves activation with histamine and capsaicin (such as substance P release from peripheral terminals and reflex vasodilation) may generate additional stimuli that further stimulate nasal sensory nerves (*Tani et al., 1990; Petersson et al., 1989*). In addition, direct effects of histamine on the cells other than sensory nerves likely lead to generation of more

Consistent with the extensive data from human studies (*Philip et al., 1994; Secher et al., 1982*) intranasal administration of histamine and capsaicin failed to trigger cough in healthy subjects (*Plevkova et al., 2004; Plevkova et al., 2006*). The effective activation of nasal sensory nerves by histamine and capsaicin was confirmed by the occurrence of sensations and symptoms typically described after intranasal administration of these agents. The cough was induced by inhalation of a tussigen aerosol during the time window of the most

Both histamine and capsaicin applied into the nose caused sensitization of the cough reflex in healthy subjects (*Plevkova et al., 2004; Plevkova et al., 2006*). Following the intranasal administration of capsaicin or histamine, the number of coughs induced by inhalation of a defined dose of capsaicin was increased by 60–80%. Similarly, intranasal histamine did not trigger cough but sensitized the cough reflex in patients with allergic rhinitis (*Plevkova et al., 2005*). These data are consistent with the hypothesis that the activation of nasal sensory

The cough reflex hypersensitivity in patients with allergic rhinitis was evaluated (*Pecova et al., 2005; Pecova et al., 2008*). Chronic nasal symptoms attributable to sensory nerve activation in patients with rhinitis implicate that the inflammation leads to repeated activation of sensory nerves. The repeated activation and mediators associated with inflammation can induce sensitization at multiple levels of sensory pathways. Thus we predicted that the cough reflex is more sensitive in patients with allergic rhinitis than in healthy subjects

The grass pollen-sensitive patients with allergic rhinitis were studied out of pollen season. All patients included in the studies were free of nasal symptoms at the time of investigation. We found that the cough reflex was more sensitive in patients with allergic rhinitis

**4.2 Sensory nerve activators in the nose sensitize the cough reflex**

pronounced nasal symptoms evaluated by a composite score.

**4.3 Cough reflex is sensitized in patients with allergic rhinitis**

nerves sensitizes the cough reflex (*Tatar et al., 2009*).

(*Pecova et al., 2005; Pecova et al., 2008, Tatar et al., 2009).*

*et al., 2009*).

endogenous sensory stimuli.

compared to healthy subjects (measured by the capsaicin C2 cough threshold) (*Pecova et al., 2005*). This finding was reproduced in a separate study in which the capsaicin C5 threshold was evaluated in another groups of patients and healthy subjects (*Pecova et al., 2008*). In this study, the concentrations of capsaicin causing five coughs (C5, geometric mean and 95% CI) were 132.4 (41.3–424.5) μM and 13.1 (6.0–28.6) μM in healthy subjects (5 M/7F, mean age 23 yrs) and patients with allergic rhinitis (5 M/7F, mean age 23 yrs), respectively (*P* < 0.05). We conclude that the cough reflex is sensitized in patients with allergic rhinitis (*Pecova et al., 2008*).

Since the symptoms of allergic rhinitis in pollen-sensitive patients are most prominent during the pollen season, we hypothesized that the sensitization of cough is most pronounced in this period. Fifteen patients were evaluated out of pollen season (January– February) and in the grass pollen season (May–June) in a paired study(*Pecova et al., 2005*). The capsaicin cough C2 threshold was reduced in the pollen season vs. out of the pollen season, 0.11(0.3–0.33) μM vs. 0.84(0.14–5.2) μM, respectively (*P* < 0.05). Thus the cough reflex in patients with allergic rhinitis is further sensitized in the period when the nasal inflammation is more active.

#### **4.4 Sensitized cough reflex and coughing in humans**

In a series of studies it was demonstrated that the cough reflex in healthy subjects is sensitized by the intranasal administration of sensory nerve activators (*Plevkova et al., 2004; Plevkova et al., 2006*). These results are consistent with the hypothesis that the activation of nasal sensory nerves sensitizes the cough reflex (*Tatar et al., 2009*). We also show that the cough reflex is sensitized in patients with allergic rhinitis *Pecova et al., 2005; Pecova et al., 2008, Tatar et al., 2009)* and is further sensitized in this group by intranasal sensory activator histamine (*Plevkova et al., 2005*) and during the period of more active nasal inflammation (*Pecova et al., 2005*). Our results may help to explain the mechanisms contributing to chronic cough associated with rhinosinusitis (*Tatar et al., 2009)*.

These results are highly indicative that nasal sensory nerves are the neural pathways involved in the sensitization of cough. The wealth of data from the somatosensory (*Jiand & Woolf, 2001*) and vagal (*Mazzone et al., 2005*; *Mazzone & Canning, 2002*) systems allows for an informed speculation that central cough reflex hypersensitivity mediated by nasal sensory nerves underlies the observed cough sensitization. In this scenario the afferent inputs from the nose feed into the central regulatory circuits of the cough reflex in a manner rendering the cough reflex hypersensitive. It has been demonstrated that the cough reflex triggered from trachea is sensitized by the stimulation of sensory nerves innervating distal parts of the respiratory system (lungs) in animal models (*Mazzone and Canning, 2005*), or even from the esophagus in humans (*Javorkova et al., 2008*). The sensitization of cough by the nasal trigeminal sensory pathways is perhaps more complex than the vagally mediated sensitization, since the trigeminal and the cough-triggering vagal sensory nerves terminate in different areas of the brainstem. Interestingly, the sensitization of cough from the nose can be induced even in anaesthetized animals, suggesting that the cough sensitization does not require intact cortical function.

The situation is more complex in patients with allergic rhinitis. Our data discussed thus far predict that the cough reflex hypersensitivity mediated by acute sensory nerve activation occurs in the symptomatic patients. However, in the patients without symptoms (such as the patients with allergic rhinitis out of the allergen season) the absence of the symptoms

Cough in Allergic Rhinitis 97

chronic cough by amplifying the cough triggered by endogenous and, perhaps less likely, environmental stimuli. While the cough reflex sensitivity is predicted to worsen the cough,

**4.5 Potential mechanisms triggering cough in patients with rhinosinusitis and cough**  The cough reflex hypersensitivity is predicted to amplify cough by increasing the efficiency of endogenous and environmental stimuli to trigger cough but is unlikely to cause chronic coughing by itself. There is an ongoing discussion in the literature whether diseases of the nose actually trigger cough (*Morice, 2004; Sanu & Eccles, 2008*). This confusion is also reflected in the recommendation of the term upper airway cough syndrome (UACS) to be used when discussing cough that is associated with upper airway conditions (*Pratter, 2006*). One proposed mechanism for triggering cough in rhinosinusitis is the postnasal drip (drainage of secretions from the nose or paranasal sinuses into the pharynx). In this scenario the cough-triggering nerves located in the hypopharynx or larynx are stimulated by secretions emanating from the nose and/or sinuses dripping down into these areas (*Irwin et al., 1984*). The arguments against postnasal drip as a sole cause of cough in rhinosinusitis are twofold. Postnasal drip is a common phenomenon, and only a small fraction of patients with the postnasal drip also complain about cough (*O´Hara & Jones, 2006*). Conversely, a proportion (reported ~20%) of patients with chronic cough attributed to rhinosinusitis do not experience postnasal drip. It seems therefore unlikely that postnasal drip is the exclusive mechanism triggering cough. Cough in rhinosinusitis could be also conceivably triggered by aspirated secretions stimulating cough receptors in the lower respiratory tract; however, there are limited data to support this mechanism (*Pratter, 2006*). As is the case with postnasal drip, the aspiration or inhalation of nasal secretions likely occurs also in patients who do not have chronic cough. Enhanced sensitivity to environmental factors has also been

The analysis of the mechanisms triggering cough in rhinitis is further complicated by the fact that rhinosinusitis often coexists with other common causes of chronic cough such as gastroesophageal reflux disease and eosinophilic airway diseases including asthma. Thus the potential cough triggers may be unrelated to the nasal disease (discussed elsewhere in this issue). Rhinitis is also very often part of the asthma presentation (*Togias, 2003*) and chronic sinusitis and postnasal drip can be caused or worsen by gastroesophageal reflux

Treatment aimed at rhinosinusitis improves chronic cough in many patients who also present with other conditions potentially causing chronic cough (i.e. asthma or GERD). That the rhinosinusitis causes cough reflex hypersensitivity may explain the beneficial effect of this therapy. We speculate that the cough reflex hypersensitivity in combination with one or more cough triggers results in some unfortunate individuals in clinically relevant coughing

Advenier, C. *&* Emonds-Alt, X. (1996). Tachykinin receptor antagonists and cough. *Pulm*

Armstrong, D.J. *&* Luck, J.C. (1974). A comparative study of irritant and type J receptors in

it is unlikely to be its only causal mechanism (*Tatar et al., 2009*).

linked to chronic cough in rhinosinusitis (*Millquist & Bende, 2006*).

termed chronic cough associated with rhinitis (*Tatar et al., 2009*).

*Pharmacol*, Vol.9, No 5-6, pp. 329-33.

the cat. *Respir Physiol*, Vol.21, pp. 47-60.

**5. References**

(*Poelmans & Tack, 2005*) introducing even more complexity into the analysis.

indicates limited nasal sensory activity. Yet the cough reflex is strongly sensitized in this group (*Pecova et al., 2005; Pecova et al., 2008, Tatar et al., 2009)*. It seems unlikely that the nasal sensory nerves in patients without symptoms are stimulated in a manner that is sufficient to maintain the cough sensitization but insufficient to trigger the symptoms. Rather, we speculate that the cough sensitization is induced by sensory activation during the period with symptoms and then outlasts the sensory activation. 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 (*Chen et al., 2001; Bonham et al., 2006*). Mechanistic studies are needed to evaluate this speculation.

Nasal provocation with histamine induces significantly stronger sneezing responses in subjects with allergic rhinitis compared with healthy subjects – a sensitized sneezing reflex (*Gerth Van Wijk & Dieges, 1987; Sanico et al., 1999*). We noted that intranasal histamine was more effective in reducing the capsaicin cough threshold in patients with allergic rhinitis than in healthy subjects (*Plevkova et al., 2004; Plevkova et al., 2005*). The simplest explanation is that the nasal sensory nerve pathways are sensitized, resulting in increased sensory feeding into the cough and sneeze regulatory areas. It is noteworthy in this context that nasal inflammation induces lasting changes in expression of molecules predicted to positively regulating activation and excitability in nasal afferent nerves (*O´Hanlon et al., 2007; Keh et al., 2008*). However, a separate sensitization of cough and sneezing at the higher regulatory levels of cough and sneezing reflexes is also a viable option.

Another explanation is that the cough reflex is sensitized in patients with allergic rhinitis because of allergic inflammation in the lower airways and lungs. This possibility cannot be excluded. Numerous studies have shown that the inflammation in the lower airways and lungs in patients with allergic rhinitis is in many aspects similar to that in asthmatics (*exemplified by Braunstahl et al., 2003*). However, the studies in asthmatics failed to consistently show lowered capsaicin or citric acid cough thresholds (*Fujimura et al., 1992; Chang et al., 1997; Schmidt et al., 1997*). Since this is in contrast with the dramatic sensitization of cough in allergic rhinitis, this mechanism likely plays only a limited role.

Allergic rhinitis was chosen as a model of a well-defined nasal inflammation allowing for selection of a relatively homogeneous patient population (skin prick test pollen-sensitive patients). Although the cough reflex was sensitized in allergic rhinitis, none of the patients complained about coughing. The increased cough reflex sensitivity is consistently found in patients with chronic cough and the effective treatment of cough is accompanied by normalization of the cough hypersensitivity. These observations advanced the hypothesis that the cough reflex hypersensitivity is the mechanism causing the cough. However, the cough reflex hypersensitivity has been also reported in other groups of patients who do not suffer from chronic cough. For example, the cough reflex sensitivity to capsaicin is increased in the GERD patients who do not complain about cough (*Benini et al., 2000; Ferrari et al., 2005*). Interestingly, the magnitude of the cough threshold reduction in the GERD patients is comparable to that found in chronic coughers, and the cough threshold reduction in allergic rhinitis appears to be even larger. The cough hypersensitivity without cough was also found in other diseases (*Pecova et al., 2003a; Pecova et al., 2003b*).

The observations that the cough reflex hypersensitivity is not always accompanied by cough force the conclusion that the cough reflex hypersensitivity alone is not sufficient for clinical presentation of chronic cough. Rather, the increased cough reflex sensitivity contributes to

indicates limited nasal sensory activity. Yet the cough reflex is strongly sensitized in this group (*Pecova et al., 2005; Pecova et al., 2008, Tatar et al., 2009)*. It seems unlikely that the nasal sensory nerves in patients without symptoms are stimulated in a manner that is sufficient to maintain the cough sensitization but insufficient to trigger the symptoms. Rather, we speculate that the cough sensitization is induced by sensory activation during the period with symptoms and then outlasts the sensory activation. 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 (*Chen et al., 2001; Bonham et al., 2006*). Mechanistic studies are needed to

Nasal provocation with histamine induces significantly stronger sneezing responses in subjects with allergic rhinitis compared with healthy subjects – a sensitized sneezing reflex (*Gerth Van Wijk & Dieges, 1987; Sanico et al., 1999*). We noted that intranasal histamine was more effective in reducing the capsaicin cough threshold in patients with allergic rhinitis than in healthy subjects (*Plevkova et al., 2004; Plevkova et al., 2005*). The simplest explanation is that the nasal sensory nerve pathways are sensitized, resulting in increased sensory feeding into the cough and sneeze regulatory areas. It is noteworthy in this context that nasal inflammation induces lasting changes in expression of molecules predicted to positively regulating activation and excitability in nasal afferent nerves (*O´Hanlon et al., 2007; Keh et al., 2008*). However, a separate sensitization of cough and sneezing at the higher

Another explanation is that the cough reflex is sensitized in patients with allergic rhinitis because of allergic inflammation in the lower airways and lungs. This possibility cannot be excluded. Numerous studies have shown that the inflammation in the lower airways and lungs in patients with allergic rhinitis is in many aspects similar to that in asthmatics (*exemplified by Braunstahl et al., 2003*). However, the studies in asthmatics failed to consistently show lowered capsaicin or citric acid cough thresholds (*Fujimura et al., 1992; Chang et al., 1997; Schmidt et al., 1997*). Since this is in contrast with the dramatic sensitization

Allergic rhinitis was chosen as a model of a well-defined nasal inflammation allowing for selection of a relatively homogeneous patient population (skin prick test pollen-sensitive patients). Although the cough reflex was sensitized in allergic rhinitis, none of the patients complained about coughing. The increased cough reflex sensitivity is consistently found in patients with chronic cough and the effective treatment of cough is accompanied by normalization of the cough hypersensitivity. These observations advanced the hypothesis that the cough reflex hypersensitivity is the mechanism causing the cough. However, the cough reflex hypersensitivity has been also reported in other groups of patients who do not suffer from chronic cough. For example, the cough reflex sensitivity to capsaicin is increased in the GERD patients who do not complain about cough (*Benini et al., 2000; Ferrari et al., 2005*). Interestingly, the magnitude of the cough threshold reduction in the GERD patients is comparable to that found in chronic coughers, and the cough threshold reduction in allergic rhinitis appears to be even larger. The cough hypersensitivity without cough was also found

The observations that the cough reflex hypersensitivity is not always accompanied by cough force the conclusion that the cough reflex hypersensitivity alone is not sufficient for clinical presentation of chronic cough. Rather, the increased cough reflex sensitivity contributes to

regulatory levels of cough and sneezing reflexes is also a viable option.

of cough in allergic rhinitis, this mechanism likely plays only a limited role.

in other diseases (*Pecova et al., 2003a; Pecova et al., 2003b*).

evaluate this speculation.

chronic cough by amplifying the cough triggered by endogenous and, perhaps less likely, environmental stimuli. While the cough reflex sensitivity is predicted to worsen the cough, it is unlikely to be its only causal mechanism (*Tatar et al., 2009*).

#### **4.5 Potential mechanisms triggering cough in patients with rhinosinusitis and cough**

The cough reflex hypersensitivity is predicted to amplify cough by increasing the efficiency of endogenous and environmental stimuli to trigger cough but is unlikely to cause chronic coughing by itself. There is an ongoing discussion in the literature whether diseases of the nose actually trigger cough (*Morice, 2004; Sanu & Eccles, 2008*). This confusion is also reflected in the recommendation of the term upper airway cough syndrome (UACS) to be used when discussing cough that is associated with upper airway conditions (*Pratter, 2006*). One proposed mechanism for triggering cough in rhinosinusitis is the postnasal drip (drainage of secretions from the nose or paranasal sinuses into the pharynx). In this scenario the cough-triggering nerves located in the hypopharynx or larynx are stimulated by secretions emanating from the nose and/or sinuses dripping down into these areas (*Irwin et al., 1984*). The arguments against postnasal drip as a sole cause of cough in rhinosinusitis are twofold. Postnasal drip is a common phenomenon, and only a small fraction of patients with the postnasal drip also complain about cough (*O´Hara & Jones, 2006*). Conversely, a proportion (reported ~20%) of patients with chronic cough attributed to rhinosinusitis do not experience postnasal drip. It seems therefore unlikely that postnasal drip is the exclusive mechanism triggering cough. Cough in rhinosinusitis could be also conceivably triggered by aspirated secretions stimulating cough receptors in the lower respiratory tract; however,

there are limited data to support this mechanism (*Pratter, 2006*). As is the case with postnasal drip, the aspiration or inhalation of nasal secretions likely occurs also in patients who do not have chronic cough. Enhanced sensitivity to environmental factors has also been linked to chronic cough in rhinosinusitis (*Millquist & Bende, 2006*).

The analysis of the mechanisms triggering cough in rhinitis is further complicated by the fact that rhinosinusitis often coexists with other common causes of chronic cough such as gastroesophageal reflux disease and eosinophilic airway diseases including asthma. Thus the potential cough triggers may be unrelated to the nasal disease (discussed elsewhere in this issue). Rhinitis is also very often part of the asthma presentation (*Togias, 2003*) and chronic sinusitis and postnasal drip can be caused or worsen by gastroesophageal reflux (*Poelmans & Tack, 2005*) introducing even more complexity into the analysis.

Treatment aimed at rhinosinusitis improves chronic cough in many patients who also present with other conditions potentially causing chronic cough (i.e. asthma or GERD). That the rhinosinusitis causes cough reflex hypersensitivity may explain the beneficial effect of this therapy. We speculate that the cough reflex hypersensitivity in combination with one or more cough triggers results in some unfortunate individuals in clinically relevant coughing termed chronic cough associated with rhinitis (*Tatar et al., 2009*).

#### **5. References**

Advenier, C. *&* Emonds-Alt, X. (1996). Tachykinin receptor antagonists and cough. *Pulm Pharmacol*, Vol.9, No 5-6, pp. 329-33.

Armstrong, D.J. *&* Luck, J.C. (1974). A comparative study of irritant and type J receptors in the cat. *Respir Physiol*, Vol.21, pp. 47-60.

Cough in Allergic Rhinitis 99

Carr, M.J., Hunter, D.D., Jacoby, D.B. *&* Undem, B.J. (2002). Expression of tachykinin in non-

Caterina, M.J. *&* Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain

Chang, A.B. (2005). Defining the cough spectrum ad reviewing the evidence for treating

Chang, A.B., Landau, L.I., Van Asperen, P.P., Glasgow, N.J., Robertson, C.F., Marchant, J.M.

Chang, A.B., Phelan, P.D., Sawyer, S.M., Del Brocco, S. *&* Robertson, C.F. (1997). Cough

Chen, C.Y., Bonham, A.C., Schelegle, E.S., Gershwin, L.J., Plopper, C.G. *&* Joad, J.P. (2001).

Choudry, N.B., Fuller, R.W. *&* Pride, N.B. (1989). Sensitivity of the human cough reflex:effect

Christian, E.P. *&* Togo, J.A. (1995). Excitable properties and underlying Na+ and K+ currents

Chuang, H.H., Prescott, E.D., Kong, H., Shields, S., Jordt, S.E., Basbaum, A.I. et al. (2001).

Chung, K.F. *&* Pavord, I.D. (2008). Prevalence, pathogenesis, and causes of chronic cough.

Chung, K.F. (2003). Measurment and assessment of cough. In Cough: Causes, mechanisms

Coleridge, J.C. *&* Coleridge, H.M. (1984). Afferent vagal C-fibre innervation of the lungs and

Coryllos, P.N. (1937). Action of the diaphragm in cough. Experimental and clinical study on

Deep, V., Singh, M. *&* Ravi, K. (2001). Role of vagal afferents in the reflex effect of capsaicin

Ferrari, M., Olivieri, M., Sembenini, C., Benini, L., Zuccali, V., Bardelli, E., Bovo, P.,

and lobeline in monkeys. *Respir Physiol*, Vol.125, pp. 155-168.

PtdIns(4,5)P2-mediated inhibition. *Nature*, Vol.411, pp. 957-62.

nucleus tractus solitarius. *J Allergy Clin Immunol*, Vol.108, pp. 557–562. Choudry, N.B. *&* Fuller, R.W. (1992). Sensitivity of the cough reflex in patients with chronic

non-specific cough in children. *Curr Pediatr Rev*; Vol.1, pp. 283-296.

pigs. *Am J Respir Crit Care Med*, Vol.165, pp. 1071-5.

pathway. *Annu Rev Neurosci*, Vol.24, pp. 487-517.

cough. *Eur Respir J*, Vol.5, No.3, pp. 296-300.

Vol.184, pp. 398-403.

*Child*, Vol.77, pp. 331–334.

*Respir Dis*, Vol.140, pp. 137-41.

*Lancet,* Vol. 371, No.9621, pp. 1364-74.

the human. *Am J Med Sci*, Vol,194, pp. 523-35.

Publishing, pp. 39-48.

Vol.151, pp. 557–561.

pp. 75-86.

110.

nociceptive vagal afferent neurons during raspiratory tract viral infection in guinea

*&* Mellis, C.M. (2006). Cough in children: definitions and clinical evaluation, Position statement of the Thoracic Society of Australia and New Zealand. *MJA*,

sensitivity in children with asthma, recurrent cough, and cystic fibrosis. *Arch Dis*

Extended allergen exposure in asthmatic monkeys induces neuroplasticity in

of inflammatory mediators prostaglandin E2, bradykinin, and histamine. *Am Rev*

in neurons from the guinea-pig jugular ganglion. *J Auton Nerv Syst*, Vol.56, No.1-2,

Bradykinin and nerve growth factor release the capsaicin receptor from

and therapy. Edited by: Chung F, Widdicombe J, Boushey H. UK: Blackwell

airways and its functional significance. *Rev Physiol Biochem Pharmacol*, Vol.99, pp. 1-

Cavallini, G., Vantini, I. *&* Lo Cascio, V. (1995). Tussive effect of capsaicin in patients with gastroesophageal reflux without cough. *Am J Respir Crit Care Med*,

Atzori, L., Bannenberg, G., Corriga, A.M., Lou, Y.P., Lundberg, J.M., Ryrfeldt, A. *&*

Barnes P.J. (2001). Neurogenic inflammation in the airways. *Respir Physiol*, Vol.125, pp. 145-

Barros, M.J., Zammattio, S.L. *&* Rees, P.J. (1991) Effect of changes in inspiratory flow rate on cough responses to inhaled capsaicin. *Clin Sci (Lond)*, Vol.81, pp. 539-532. Benini, L., Ferrari, M., Sembenini, C., Olivieri, M., Micciolo, R., Zuccali, V., Bulighin, G.M.,

Bergren, D.R. *&* Sampson, S.R. (1982). Characterization of intrapulmonary, rapidly adapting

Bergren, D.R. (1997). Sensory receptor activation by mediators of defense reflexes in guinea-

Bolser, D.C., DeGennaro, F.C., O´Reilly, S., McLeod, R.L. *&* Hey, J.A. (1997). Central

and SR 48968, in the guinea-pig and cat. *Br J Pharmacol*, Vol.121, pp. 165-70. Bolser, D.C., Hey, J.A. *&* Chapman R.W. (1999) Influence of central antitussive drugs on the

Bonham, A.C., Kott, K.S., Ravi, K., Kappagoda, C.T. *&* Joad, J.P. (1996). Substance P

Bonham,, A.C., Sekizawa, S., Chen, C. *&* Joad, J.P. (2006). Plasticity of brainstem mechanisms

Braunstahl, G.J., Fokkens, W.J., Overbeek, S.E., KleinJan, A., Hoogsteden, H.C. *&* Prins, J.B.

Canning, B.J. *&* Mazzone, S.B. (2005). Afferent pathways regulating the cough reflex. In:

Canning, B.J. (2008). The cough reflex in animals: Relevance to human cough research. *Lung*,

Canning, B.J., Reynolds, S.M. *&* Mazzone, S.B. (2001). Multiple mechanisms of reflex

Canning, B.J., Reynolds, S.M., Meeker, S. *&* Undem, B.J. (2000). Electrophysiological

Carr, M.J. *&* Undem, B.J. (2001). Ion channels in airway afferenet neurons. Respir Physiol,

bronchospasm in guinea pigs. *J Appl Physiol,* Vol.91, pp. 2642-2653.

guniea-pigs(GP). *Am J Respir Crit Care Med*, Vol.161, p. A434.

sensitive activation of sensory nerves. *Respiration*, Vol.59, pp. 272-278. Baluk, P., Nadel, J.A. *&* McDonald, D.M. (1992). Substance P-immunoreactive sensory axons

neurogenetic inflammation. *J Comp Neurol*, Vol.319, pp. 586-598.

receptors of guinea-pigs. *Resp Physiol*, Vol.47, pp. 83-95.

cough motor pattern. *J Appl Physiol*, Vol.86, pp. 1017-24.

of cough. *Respir Physiol Neurobiol*, Vol.152, pp. 312–319.

Raton, USA, 2005, pp. 25-48 ISBN 978-0-8247-5958-2.

Vol.186 (suppl 1), pp. 23-28.

Vol.125, No.1-2, pp. 83-97.

congestion in rabbits. *J Physiol*, Vol.493, pp. 229-38.

pig lungs. *Respir Physiol*, Vol.108, pp. 195-204.

54.

587.

Vol.46, pp. 762–767.

Moldeus, P. (1992). Sulfur dioxide-induced bronchoconstriction via ruthenium red-

in the rat respiratory tract: a quantitative study of their distribution and role in

Fiorino, F., Ederle, A., Cascio, V.L. *&* Vantini I. (2000). Cough threshold in reflux oesophagitis: influence of acid and of laryngeal and oesophageal damage. *Gut*,

antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, CP-99,994

contributes to rapidly adapting receptor responses to pulmonary venous

(2003). Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways. *Clin Exp Allergy*, Vol.33, pp. 579–

Redington AE, Morice AH(eds). Acute and chronic cough. Taylor & Francis. Boca

identification of tracheal (T) and laryngeal(LX) vagal afferents mediating cough in

Cough in Allergic Rhinitis 101

Jiand, R.R. *&* Woolf, C.J. (2001). Neuronal plasticity and signal transduction in nociceptive

Joad, J.P., Kott, K.S. *&* Bonham, A.C. (1997). Nitric oxide contributes to substance P-induced

Jonzon, A., Pisarri, T.E., Coleridge, J.C. *&* Coleridge, H.M. (1986). Rapidly adapting receptor

Karlsson, J.A. (1996). The role of capsaicin-sensitive C-fibre afferent nerves in the cough

Keh, S.M., Facer, P., Simpson, K.D., Sandhu, G., Saleh, H.A. *&* Anand, P. (2008). Increased

Klesse, L.J. *&* Parada, L,F. (1999). Trks:signal transduction and intracellular pathways.

Kollarik, M., Dinh, Q.T., Fischer, A. *&* Undem, B.J. (2003). Capsaicin-sensitive and -

Korpas, J. *&* Tomori, Z. (1979). *Cough and other respiratory reflexes*, Karger, ISBN 3-8055-3007-

Laude, E.A., Higgins, K.S. *&* Morice, A.H. (1993). A comparative study of the effects of citric

Leder, K., Sinclair, M.I., Mitakakis, T.Z., et al. (2003). A community-based study of

Lee, L.Y. *&* Pisarri, T.E. (2001). Afferent properties and reflex functions of

Lii, Q., Fujimura, M., Tachibi, H., Myou, S., Kasahara, K. *&* Yasui, M. (2001).

Lopshire, J.C. *&* Nocol, G.D. (1998). The cAMP transduction cascade mediates the

Lundberg, J.M., Hokfelt, T., Martling, C.R., Saria, A. *&* Cuello, C. (1984). Substance P-

Ma, Q.P. *&* Woolf, C.J. (1995). Involvement of neurokinin receptors in the induction but not

Matsumoto S. (1988). The activities of lung strech and irritant receptors during cough.

bronchopulmonary C-fibers. *Respir Physiol*, Vol.125, pp. 47-65.

*Neurogastroenterol Motil*, Vol.20, pp. 119–124.

reflex*. Pulm Pharmacol*, Vol.9, pp. 315-21.

rhinitis. *Laryngoscope* , Vol.118, pp. 573–579.

*Microsc Res Tech*, Vol.45, No.4-5, pp. 210-6.

*Pulm Pharmacol*, Vol., No.3, pp. 171-5.

pigs. *Clin Exp Allergy*, Vol.31, No.3, pp. 474-84.

including man. *Cell Tisse Res*, Vol. 235, pp. 251-261.

*Neurobiol Dis*, Vol.8, pp. 1–10.

No.3, pp. 635-43.

1980-7.

pp. 869-879.

399-404.

92.

pp. 769-777.

*Neurosci Lett*, Vol.90, pp. 125-129.

2, Basel, Switzerland.

sensitivity in patients with gastro-oesophageal reflux and chronic cough.

neurons: implications for the initiation and maintenance of pathological pain.

increase in lung rapidly adapting receptor activity in guinea-pigs. *J Physiol*, Vol.503,

activity in dogs is inversely related to lung compliance. *J Appl Physiol*, Vol.61, pp.

nerve fiber expression of sensory sodium channels Nav1.7, Nav1.8, and Nav1.9 in

insensitive vagal bronchopulmonary C-fibers in the mouse. *J Physiol*, Vol.551, No.3,

acid, capsaicin and resiniferatoxin on the cough challenge in guinea-pig and man.

respiratory episodes in Melbourne, Australia. *Aust N Z J Public Health*, Vol. 27, pp.

Characterization of increased cough sensitivity after antigen challenge in guinea

prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: wholecell and single-channel studies. *J Neurosci*, Vol.18, No.16, pp. 6081-

immunoreactive sensory nerves in the lower respiratory tract of various mammales

maintainance of mechanical allodynia in rat flexor motoneurons. *J Physiol*, Vol.486,

Fischer,. A, McGregor, G..P, Saria, A., Philippin,. B. *&* Kummer, W. (1996). Induction of

Fox, A. (2002). Airway nerves: in vitro electrophysiology. Curr Opin Pharmacol, Vol.2, No.3,

Fujimura, M., Sakamoto, S., Kamio, Y. *&* Matsuda, T. (1992). Cough receptor sensitivity and

Gerth Van Wijk, R. *&* Dieges, P.H. (1987). Comparison of nasal responsiveness to histamine,

Gold, M.S., Reichling, D.B., Shuster, M.J. *&* Levine, J.D. (1996). Hyperalgesic agents increase

Hanacek, J. *&* Korpas, J. (1982). Modification of the intensity of the expiration reflex during short-term inflation of the lungs in rabbits. *Physiol Bohemoslov*, Vol.31, pp. 169-174. Hanacek, J., Davis, A. *&* Widdicombe, J.G. (1984). Influence of lung strech receptors on the

Hay, A.D. *&* Wilson, A.D. (2002). The natural history of acute cough in childeren aged 0-4 years in primary care: a systematic review. *Br J Gen Pract*, Vol.52, pp.401-409. Ho, C.Y., Gu, Q., Hong, J.L. *&* Lee, L.Y. (2000). Prostaglandin E(2) enhances chemical and

Ho, C.Y., Gu, Q., Lin, Y.S. *&* Lee, L.Y. (2001). Sensitivity of vagal afferent endings to

Hunter, D.D. *&* Undem, B.J. (1999). Identification and substance P content of vagal afferent

Hunter, D.D., Castranova, V., Stanley, C. *&* Dey, R.D. (1998). Effects of silica exposure on

Hutchings, H.A., Morris, S., Eccles, R. *&* Jawad, M.S. (1993). Voluntary suppression of cough

Irwin, R.S., French, C.L., Curley, F.J., Zawacki, J.K. *&* Bennett, F.M. (1993). Chronic cough

Irwin, R.S., Pratter, M.R., Holland, P.S., Corwin, R.W. *&* Hughes, J.P. (1984). Postnasal drip

Javorkova, N., Varechova, S., Pecova, R., Tatar, M., Balaz, D., Demeter, M., Hyrdel, R. *&*

chemical irritants in the rat lung. *Respir Pysiol*, Vol.127, pp. 113-24.

cough reflex in rabbits. *Respiration*, Vol.45, pp. 161-8.

319-20.

pp. 278-9.

291–295.

*Allergy*, Vol.17, pp. 563–570.

No.3, pp. 1108-12.

Vol.162, pp. 528-533.

No.8, pp. 593-605.

Vol.85, pp. 346–352.

379-382.

*Med,* Vol.159, pp. 1943-1948.

*Chest*, Vol.104, No.5, pp. 1511-7.

tachykinin gene and peptide expression in guinea pig nodose primary afferent neurons by allergic airway inflammation. *J Clin Invest*, Vol.98, No.10, pp. 2284-91. Forsberg,. K. *&* Karlsson, J.A. (1986). Cough induced by the stimulation of capsaicin-

sensitive sensory neurons in counsious guinea-pigs. *Acta Physiol Scand*, Vol.128, pp.

bronchial responsiveness in normal and asthmatic subjects. *Eur Respir J*, Vol.5, pp.

methacholine and phentolamine in allergic rhinitis patients and controls. *Clin*

a tetrodotoxin-resistant Na+current in nociceptors. *Proc Natl Acad Sci USA*, Vol.93,

mechanical sensitivities of pulmonary C fibers in the rat. *Am J Respir Crit Car Med*,

neurons innervating the epithelium of the guinea-pig trachea. *Am J Respir Crit Care*

substance P immunoreactivity and preprotachykinin mRNA expression in trigeminal sensory neurons in Fischer 344 rats. *J Toxicol Environ Health,* Vol*.*53,

induced by inhalation of capsaicin in healthy volunteers. *Respir Med*, Vol.87, pp.

due to gastroesophageal reflux. Clinical, diagnostic, and pathogenetic aspects.

causes cough and is associated with reversible upper airway obstruction. *Chest*,

Kollarik M. (2008). Acidification of the oesophagus acutely increases the cough

sensitivity in patients with gastro-oesophageal reflux and chronic cough. *Neurogastroenterol Motil*, Vol.20, pp. 119–124.

Cough in Allergic Rhinitis 103

O'Connell, F., Thomas, V.E., Pride, N.B. *&* Fuller R.W. (1994). Capsaicin cough sensitivity

O'Connell, F., Thomas, V.E., Studham, J.M., Pride, N.B. *&* Fuller R.W. (1996). Capsaicin

O'Hanlon, S., Facer, P., Simpson, K.D., Sandhu, G., Saleh, H.A. *&* Anand, P. (2007). Neuronal

O'Hara J. *&* Jones N.S. (2006). "Post-nasal drip syndrome": most patients with purulent nasal secretions do not complain of chronic cough. *Rhinology*, Vol.44, pp. 270–273. Pack, A.I. *&* DeLaney, R.G. (1983). Response of pulmonary rapidly adapting receptors

Palombini, B.C. *&* Araujo, E. (2003). Cough in postnasal drip, rhinitis and rhinosinusitis. In

Palombini, B.C., Villanova, C.A., Araujo, E., Gastal, O.L., Alt, D.C., Stolz, D.P. *&* Palombini,

Pecova, R., Frlickova, Z., Pec, J. *&* Tatar M. (2003b). Cough sensitivity in atopic dermatitis.

Pecova, R., Vrlik, M. *&* Tatar M. (2005). Cough sensitivity in allergic rhinitis. *J Physiol*

Pecova, R., Zucha, J., Pec, M., Neuschlova, M., Hanzel, P. *&* Tatar, M. (2008). Cough reflex

Pek, W.Y. *&* Boushey, H.A. (2003). Cough in lower airway infections. In Cough: Causes,

Petersson, G., Malm, L., Ekman, R. *&* Hakanson, R. (1989). Capsaicin evokes secretion of

Philip, G., Baroody, F.M., Proud, D., Naclerio, R.M. *&* Togias, A.G. (1994). The human nasal response to capsaicin. *J Allergy Clin Immunol*, Vol.94, pp. 1035–1045. Plevkova, J., Brozmanova, M., Pecova, R. *&* Tatar M. (2006). The effects of nasal histamine

Plevkova, J., Brozmanova, M., Pecova, R. *&* Tatar M. (2005). Effects of intranasal histamine

Plevkova, J., Brozmanova, M., Pecova, R. *&* Tatar, M. (2004). Effects of intranasal capsaicin

nasal mucosa in the rat. *Br J Pharmacol*, Vol.98, pp. 930–936.

and gastroesophageal reflux disease. *Chest*, Vol.116, No.2, pp. 279-84. Pecova, R., Frlickova, Z., Pec, J. *&* Tatar M. (2003a). Cough sensitivity in localized

during lung inflation. *J Appl Physiol*, Vol.55, pp. 955-963.

Boushey H. UK: Blackwell;2003, pp. 107-114.

*Pulm Pharmacol Ther*, Vol16, pp. 203–206.

*Pharmacol*, Vol.56 (Suppl. 4), pp. 171–178.

*Physiol Pharmacol*, Vol.59(Suppl 6), pp. 557-564.

Vol.54 (Suppl. 1), pp. 25–28.

Blackwell;2003, pp. 83-96.

(Suppl. 4), pp. 185–195.

(Suppl. 3), pp. 101–106.

120–127.

Vol.150, pp. 374–380.

*Laryngoscope*, Vol.117, pp. 1519–1527.

pp. 279–286.

decreases with successful treatment of chronic cough. *Am J Respir Crit Care Med*,

cough sensitivity increases during upper respiratory infection. *Respir Med*, Vol.90,

markers in allergic rhinitis: expression and correlation with sensory testing,

Cough: Causes, mechanisms and therapy. Edited by: Chung F, Widdicombe J,

C.O. (1999). A pathogenic triad in chronic cough: asthma, postnasal drip syndrome,

scleroderma with no clinical symptoms from lower airways. *J Physiol Pharmacol*,

sensitivity testing in seasonal allergic rhinitis patients and healthy volunteers. *J*

mechanisms and therapy. Edited by: Chung F, Widdicombe J, Boushey H. UK:

nasal fluid and depletes substance P and calcitonin gene-related peptide from the

challenge on cough reflex in healthy volunteers. *Pulm Pharmacol Ther*; Vol.19, pp.

on the cough reflex in subjects with allergic rhinitis. *J Physiol Pharmacol,* Vol.56

challenge on cough reflex in healthy human volunteers. *J Physiol Pharmacol*, Vol.55

Mazzone, S.B. *&* Canning, B.J. (2002). Synergistic interactions between airway afferent nerve

Mazzone, S.B., Canning, B.J. *&* Widdicombe, J.G. (2003). Sensory pathways for the cough

Mazzone, S.B., Mori, N. *&* Canning, B.J. (2005). Synergistic interactions between airway

McAlexander, M.A., Myers, A.C. *&* Undem, B.J. (1999). Adaptation of guinea pigs vagal

McGarvey, L.P., Heaney, L.G., Lawson, J.T., Johnston, B.T., Scally, C.M., Ennis, M.,

Michael, G.J. *&* Priestley, J.V. (1999). Differential expression of the mRNA for the vanilloid

Millqvist, E. *&* Bende, M. (2006). Role of the upper airways in patients with chronic cough.

Mohammed, S.P., Higenbottam, T.W. *&* Adcock, J.J. (1993). Effects of aerosol-applied

Morice, A.H. (2003). Epidemiology of cough. In Cough: Causes, mechanisms and therapy. Edited by: Chung F, Widdicombe J, Boushey H. UK: Blackwell;2003, pp. 11-16. Morice, A.H. (2004). Post-nasal drip syndrome–a symptom to be sniffed at?. *Pulm Pharmacol*

Morice, A.H., Fontana, G.A., Belvisi, M.G., Birring, S.S. et al. (2007). ERS guidelines on the

Morice, A.H., Higgins, K.S. *&* Yeo, W.W. (1992). Adaptation of cough reflex with different

Morice, A.H., Kastelik, J.A. *&* Thompson, R. (2001). Cough challenge in the assessment of

Myers, A.C., Kajekar, R. *&* Undem, B.J. (2002). Allergic inflammations-induced

Neumann, S., Doubell, T.P., Leslie, T. *&* Woolf, C.J. (1996). Inflammatory pain

Nishino, T., Sugimori, K., Hiraga, K. *&* Hond, Y. (1989). Influence of CPAP on reflex

Nishino, T., Tagaito, Y. *&* Isono, S. (1996). Cough and the reflexes on irritation of airway

neuropeptide production in rapidly adapting afferent nerves in guniea pig airways.

hypersensitivity mediated by phenotypic switch in myelinated primary sensory

responses to tracheal irritation in anesthetized humans. *J Appl Physiol*, Vol.67,

downregulation by axotomy. *J Neurosci*, Vol.19, No.5, pp. 1844-54.

*Curr Opin Allergy Clin Immunol*, Vol.6, pp. 7–11.

anaesthetized cats. *J Physio,l* Vol.469, pp. 51-66.

assessment of cough. *Eur Respir J*, Vol.29, pp. 1256-1276.

types of stimulation. *Eur Respir J*, Vol.5, No.7, pp. 841-7.

*Am J Physiol Lung Cell Mol Physiol*, Vol.282, pp. L775-L781.

cough reflex. *Br J Clin Pharmacol*, Vol.52, pp. 365-375.

mucosa in man. *Pulm Pharmacol*, Vol.9, pp. 485-493.

Mechanisms ans Therapy. Oxford: Blackwell Publishing. pp. 161-171. Mazzone, S.B., Mori, N. *&* Canning, B.J. (2002). Bradykinin-induced cough in counscious

guinea-pigs. *Am J Respir Crit Care Med*, Vol.165, p. A773.

*Comp Physiol*, Vol.283, No.1, pp. R86-R98.

Vol.569, pp. 559–573.

Vol.53, pp. 738–743.

*Ther*, Vol.17, pp. 343–345.

neurons. *Nature*, Vol.384, pp.360-4.

pp.954-958.

subtypes mediating reflex bronchospasm in guinea pigs. Am J *Physiol Regul Integr*

reflex,. In: Chung, F., Widdicombe, J. *&* Boushey, H. (eds) Cough: Causes,

afferent nerve subtypes regulating the cough reflex in guinea-pigs. *J Physiol*,

airway afferent neurones to mechanical stimulation. *J Physiol*, Vol.521, pp. 239-247.

Shepherd, D.R. *&* MacMahon, J. (1998). Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. *Thorax*,

receptors subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its

capsaicin, histamine and prostaglandin E2 on airway sensory receptors in

Cough in Allergic Rhinitis 105

Shannon, R., Baekey, D.M., Morris, K.F. *&* Lindsey, B.G. (1998). Ventrolateral medullary

Shannon, R., Baekey, D.M., Morris, K.F., Li, Z. *&* Lindsey, B.G. (2000). Functional

Shannon, R., Bolser, D.C. *&* Lindsey, B.G. (1996). Neural control of coughing ans sneezing.

Shin, J., Cho, H., Hwang, S.W., Jung, J., Shin, C.Y., Lee, S.Y. et al. (2002). Bradykinin-12-

Stead, R.H. (1992). Nerve remodelling during intestinal inflammation. *Ann N Y Acad Sci*,

Tani, E., Senba, E., Kokumai, S., Masuyama, K., Ishikawa, T. *&* Tohyama M. (1990).

Tatar, M., Webber, S.E. *&* Widdicombe, J.G. (1988). Lung C-fibre receptor activation and defensive reflexes in anaethetized cats. *J Physiol*, Vol.402, pp. 411-420. Taylor-Clark, T.E., Kollarik, M., MacGlashan, D.W. Jr. *&* Undem B.J. (2005). Nasal sensory

Taylor-Clark, T.E., Nassenstein, C. *&* Undem B.J. (2008a). Leukotriene D4 increases the

Taylor-Clark, T.E., Undem, B.J., Macglashan, D.W. Jr., Ghatta, S., Carr, M.J. *&* McAlexander,

Togias, A. (2003). Rhinitis and asthma: evidence for respiratory system integration. *J Allergy*

Tomaki, M., Ichinose, M., Miura, M., Hirayama, Y., Yamauchi, H., Nakajima, N. et al. (1995).

allergen provocation. *Am J Respir Crit Care Med*, Vol.158, No.6, pp. 2002-5. Wang, A.L., Blackford, T.L. *&* Lee, L.Y. (1996). Vagal bronchopulmonary C-fibers and acute ventilatory response to inhaled irritants. *Respir Physiol*, Vol.104, pp. 231-239.

morphological study in the guinea pig. *Neurosci Lett*, Vol.112, pp. 1–6. Tatar, M., Plevkova, J., Brozmanova, M., Pecova, R. *&* Kollarik, M. (2009). Mechanisms of the cough associated with rhinosinusitis. *Pulm Pharmacol Ther*, Vol.22, pp. 121-6. Tatar, M., Sant´Ambrogio, G. *&* Sant´Ambrogio, F.B. (1994). Laryngeal and tracheobronchial

cough in anesthetized dogs. *J Appl Physiol*, Vol.76, pp. 2672-2679.

during fictive cough in the cat. *J Physiol*, Vol.525, pp. 207-24.

Vol.84, pp. 2020-2035.

Vol.664, pp. 443-55.

Vol.116, pp. 1282–1288

274–281.

stimuli. *Br J Pharmacol*, Vol.154, pp. 1359–1368.

*Clin Immunol*, Vol.111, pp. 1171–1183.

Raton: CRC Press, 1996, pp. 215-24.

*Sci USA*, Vol.99, No.15, pp. 10150-5

respiratory network and a model of cough motor pattern generation. *J Appl Physio*l,

connectivity among ventrolateral medullary respiratory neurons and responses

In: Miller AD, Bianchi AL, Bishop BP, eds. Neural Control of Breathing. Boca

lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. *Proc Natl Aced*

Histamine application to the nasal mucosa induces release of calcitonin generelated peptide and substance P from peripheral terminals of trigeminal ganglion: a

nerve populations responding to histamine and capsaicin. *J Allergy Clin Immunol,*

excitability of capsaicin-sensitive nasal sensory nerves to electrical and chemical

M.A. (2008b). Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1). Mol *Pharmacol,* Vol.73, pp.

Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. *Am J Respir Crit Care Med*, Vol.151, pp. 613-7. Undem, B.J., Oh, E.J., Lee, M. *&* Weinreich, D. (2003). Subtypes of vagal nociceptive C-fibers in guinea pig lungs. *Am J Respir Crit Care Med*, Vol.167, Suppl., p. A708. Virchow, J.C., Julius, P., Lommatzsch, M., Luttmann, W., Renz, H. *&* Braun, A. (1998).

Neurotrophins are increased in bronchoalveolar lavage fluid after segemental

Poelmans, J. *&* Tack, J. (2005). Extraoesophageal manifestations of gastro-oesophageal

Pounsford, J.C., Birch, M.J. *&* Saunders, K.S. (1985). Effect of bronchodilators on the cough

Pratter, M.R. (2006). Chronic upper airway cough syndrome secondary to rhinosinus

Premkumar, L.S. *&* Ahern, G.P. (2000). Induction of vanilloid receptor channel activity by

Probst, R., Grevers, G. *&* Iro, H. (2005). Basic Otorhinolaryngology: A Step-by-Step Learning

Riccio, M.M., Kummer, W., Biglari, B., Myers, A.C. *&* Undem, B.J. (1996c). Interganglionic

Riccio, M.M., Kummer, W., Biglari, B., Myers, A.C., Undem, B.J., Pride, N.B. *&* Fuller, R.W.

Riccio, M.M., Myers, A.C. *&* Undem, B.J. (1996a). Immunomodulation of afferent neurons in

Roberts, A.M., Kaufman, M.P., Baker, N.G., Brown, J.K., Coleridge, H.M. *&* Coleridge, J.C.

Sanico, A.M., Koliatsos, V.E., Stanisz, A.M., Bienenstock, J. *&* Togias, A. (1999). Neural

Sant´Ambrogio, G. *&* Widdicombe, J.G. (2001). Reflexes from airway rapidly adapting

Sant´Ambrogio, G., Sant´Ambrogio, F.B. *&* Davis, A. (1984). Airways receptors in cough.

Sanu, A. *&* Eccles, R. (2008). Postnasal drip syndrome.  An overview of the anatomy and physiology of slowly

Schmidt, D., Jorres, R.A. *&* Magnussen, H. (1997). Citric acid-induced cough thresholds in

Secher, C., Kirkegaard, J., Borum, P., Maansson, A., Osterhammel, P. *&* Mygind, N. (1982).

normal subjects, patients with bronchial asthma, and smokers. *Eur J Med Res*, Vol.2,

Significance of H1 and H2 receptors in the human nose: rationale for topical use of combined antihistamine preparations. *J Allergy Clin Immunol*, Vol. 70, pp. 211–218. Shannon, R., Baekey, D.M., Morris, K.F. *&* Lindsey, B.G. (1997). Brainstem respiratory

adapting pulmonary strech receptors. *Respir Physiol*, 125, pp. 17-31.

guinea-pig isolated airways. *J Physiol*, Vol.491, No.2, pp. 499-509.

based clinical practice guidelines. *Chest*, Vol.129(Suppl 1), pp. S63-71. Pratter, M.R., Brightling, C.E., Boulet, L.P. *&* Irwin, R.S. (2006). An empiric integration

response to inhaled citric aid in normal and asthmatic subjects. *Thorax*, Vol.5, pp.

diseases (previously referred to as postnasal drip syndrome): ACCP evidence-

approach to the management of cough: ACCP evidence-based clinical practice

segregation of distinct vagal afferent fibre phenotypes in guinea-pig airway. J

(1996b). Interganglionic segregation of distingct agal afferent fibre phenotypes in

(1981). Reflex tracheal contraction induced by stimulation of bronchial C-fibers in

hyperresponsiveness and nerve growth factor in allergic rhinitis. *Int Arch Allergy*

reflux. *Gut*, Vol.54, pp. 1492–1499.

guidelines. *Chest,* 129, pp. 222-231.

*Physiol*, Vol.496, pp. 521-530.

protein kinase C. *Nature*, Vol.408, pp. 985-90.

guinea-pig airways. *J Physiol*, Vol.496, No.2, pp. 521-30.

Guide. 1st edition. Thieme; 2005, 430 p.

dogs*. J Appl Physiol*, Vol.51, pp. 485-93.

receptors. *Respir Physiol*, Vol.125, pp. 33-45.

*Bull Eur Physiopathol Respir*, Vol.20, pp. 43-47.

between UK and USA. Rhinology, Vol.46, pp. 86–91.

networks and cough. *Pulm Pharmacol*, Vol.9, pp. 343-7.

*Immunol*, Vol.118, pp. 154–158.

pp. 384–388.

296-300.

**7**

*1Australia 2Sweden*

J. Rimmer1 and J. Hellgren2

**Allergic Rhinitis and Its Impact on Sleep**

*1Woolcock Institute and University of Sydney, Department of ENT, Sydney*

Allergic rhinitis affects a fifth of the population in industrialised countries and sleep disturbance has emerged as one of the major impacts of allergic rhinitis on patients. Sleep disturbances and its consequences on daytime sleepiness and fatigue affects the health related quality of life negatively and contributes significantly to patients'suffering and major health economic costs. Experimental studies have shown that sleep disturbances are induced when the nose is blocked with adhesive tape or petroleum jelly during sleep in healthy individuals. Nasal obstruction is the most commonly reported symptom by patients with allergic rhinitis and it causes an increased number of microarousals (short awakenings). Nasal obstruction is believed to be the most important mechanism behind poor sleep and daytime sleepiness in allergic rhinitis. Relieving nasal obstruction with nasal steroids significantly improves subjective sleep compared to placebo. Allergic rhinitis is present in a majority of patients with asthma. Identifying and treating allergic rhinitis improves sleep and the health related quality of life which reduces patient suffering and potentially saves significant health economic health costs. The present chapter reviews the current literature of

The prevalence of allergic rhinitis has steadily increased in developed countries since the industrial revolution and now affects 20-40% of the population (1,2). Studies suggest that allergic rhinitis and conjunctivitis are rare in infants but are estimated to affect around one in six children aged 6-7 years, one in ten children aged 13-14 years, 18% of those aged 15-34 years and 10% of older adults aged 35-54 years. AR is more common than asthma and chronic rhinosinusitis. Symptoms generally persist for at least ten years, often longer (3). Sleep disordered breathing has been recorded in 68% of PAR patients and 48% with SAR (4).

allergic rhinitis and its impact on sleep and the health related quality of life.

**1. Introduction**

**1.1 Abbreviations**  AR: allergic rhinitis

**1.2 Prevalence**

PAR: perennial allergic rhinitis SAR: seasonal allergic rhinitis SDB: sleep disordered breathing RDS: rhinitis disturbed sleep

*2Head & Neck Surgery, Sahlgrenska Academy, Göteborg*

### **Allergic Rhinitis and Its Impact on Sleep**

#### J. Rimmer1 and J. Hellgren2

*1Woolcock Institute and University of Sydney, Department of ENT, Sydney 2Head & Neck Surgery, Sahlgrenska Academy, Göteborg 1Australia 2Sweden*

#### **1. Introduction**

106 Allergic Rhinitis

Widdicombe, J.G. (1974). Pathophysiology of lung reflexes. *Bull Physiopathol Respir (Nancy),*

Widdicombe, J.G. (2003). Overview of neural pathways in allergy and asthma. *Pulm*

Woolf, C.J. *&* Salter, M.W. (2000). Neuronal plasticity: increasing the gain in pain. *Science*,

Widdicombe, J.G. (2001). Airways receptors. *Respir Physiol*, Vol.125, pp. 3-15.

Vol.10, No.1, pp. 65-9.

Vol.288, pp. 1765-9.

*Pharmacol Ther*, Vol.16, No.1, pp. 23-30.

Allergic rhinitis affects a fifth of the population in industrialised countries and sleep disturbance has emerged as one of the major impacts of allergic rhinitis on patients. Sleep disturbances and its consequences on daytime sleepiness and fatigue affects the health related quality of life negatively and contributes significantly to patients'suffering and major health economic costs. Experimental studies have shown that sleep disturbances are induced when the nose is blocked with adhesive tape or petroleum jelly during sleep in healthy individuals. Nasal obstruction is the most commonly reported symptom by patients with allergic rhinitis and it causes an increased number of microarousals (short awakenings). Nasal obstruction is believed to be the most important mechanism behind poor sleep and daytime sleepiness in allergic rhinitis. Relieving nasal obstruction with nasal steroids significantly improves subjective sleep compared to placebo. Allergic rhinitis is present in a majority of patients with asthma. Identifying and treating allergic rhinitis improves sleep and the health related quality of life which reduces patient suffering and potentially saves significant health economic health costs. The present chapter reviews the current literature of allergic rhinitis and its impact on sleep and the health related quality of life.

#### **1.1 Abbreviations**

AR: allergic rhinitis PAR: perennial allergic rhinitis SAR: seasonal allergic rhinitis SDB: sleep disordered breathing RDS: rhinitis disturbed sleep

#### **1.2 Prevalence**

The prevalence of allergic rhinitis has steadily increased in developed countries since the industrial revolution and now affects 20-40% of the population (1,2). Studies suggest that allergic rhinitis and conjunctivitis are rare in infants but are estimated to affect around one in six children aged 6-7 years, one in ten children aged 13-14 years, 18% of those aged 15-34 years and 10% of older adults aged 35-54 years. AR is more common than asthma and chronic rhinosinusitis. Symptoms generally persist for at least ten years, often longer (3). Sleep disordered breathing has been recorded in 68% of PAR patients and 48% with SAR (4).

Allergic Rhinitis and Its Impact on Sleep 109

effects of cytokine changes on sleep (see below).Eczema may also contribute to SDB with

Sleep impairment in AR has been demonstrated by means of questionnaires, actigraphy

The presence of abnormal sleep in association with AR categorises the disease as moderate to severe according to the ARIA classification of AR (Allergic Rhinitis and its Impact on

**Intermittent symptoms Persistent symptoms**

 <4 days per week >4 days per week Or < 4 weeks And > 4 weeks

**Mild Moderate – severe (≥ 1 item)** Normal sleep Abnormal sleep Normal daily activities Impairment of daily

Normal work and school Problems caused at school

No troublesome symptoms Troublesome symptoms

The average sleep duration of healthy adults is about 7 hours but surveys show that a significant % of the population (43%) achieve less than this (23) and that these subjects felt tired, performed inefficiently and reported feeling drowsy while driving. It has been estimated that 20% of all traffic accidents in industrialised societies are related to sleep

Sleep disorders refers to a range of disorders including insomnia, OSAS, narcolepsy and idiopathic hypersomnolance, periodic limb disorders of sleep and restless leg syndrome. All of these primary sleep disorders are associated with excess daytime fatigue. SBD in AR includes insomnia and OSAS although recently a separate classification of RDS (rhinitis

Insomnia is a subjective perception of the amount or quality of sleep. It can comprise delayed initiation of sleep, difficulty with sleep maintenance and early awakening. It is associated with impaired QOL as demonstrated by reduced daytime alertness, lethargy, reduced cognitive functioning and altered emotional states. The 2008 NSF Sleep in America Poll found that 11% of the population described insomnia (26% difficulty falling asleep, 42% waking during the night, 29% woken early and unable to return to sleep)(25). Subjects with

OSAS in the general population is estimated at 2-4% and results in snoring, severe daytime sleepiness and increased risk of traffic accidents. The risk of RTA for OSAS is 12 times greater than controls and also higher than insomniacs. There is a direct relationship between

However despite the documented impaired cognition and presence of SDB in AR no studies

insomnia have a higher rate of traffic accidents: 5% versus 2% of normal sleepers.

activities, sport, leisure

or work

symptoms of pruritis often worse at night (18).

(19,20) and polysomnography (17, 21)

Asthma) guidelines (Fig 1) (22 )

Fig. 1. ARIA classification of AR

disturbed sleep) has been postulated (24).

the apnoea-hypopnoea index and crash risk.

of driving crash risk have been performed.

disorders.

#### **1.3 Costs**

More than \$6 billion was spent on prescription medications for AR in 2000 (5) in the USA. A specifically commissioned report in Australia estimated the total costs costs of Allergic disease (not asthma) including prescription medication to be \$349 million in Australia in 2007 (3).

#### **1.4 Symptoms**

Symptoms of AR include nasal blockage or congestion occurring in up to 85%, and this tends to be the dominant symptom in children (5). It is generally most troublesome in the early morning on waking which may relate to the circadian rhythm for cortisol although the peak in symptoms is delayed compared to that of nocturnal asthma (6am versus 4am) (6). Nasal obstruction is the symptom that relates most to impaired quality of life (7). In addition there is a direct relationship between sleep impairment and symptom severity ( 5, 8). Nasal obstruction has been shown to be an independent risk factor for OSAS (obstructive sleep apnoea syndrome) (9). Other symptoms include sneezing, pruritis, anterior rhinorrhoea, post nasal drip and these may also contribute to SDB.

Numerous studies have shown that AR results in impaired QOL and affects numerous activities eg work productivity and attendance, physical activity, exam performance. How much of this is due to the disease itself or the accompanying SDB or both is unclear.

Interestingly many patients report dissatisfaction with the effectiveness of therapy (10).

#### **1.5 Children and AR**

SDB is well documented to occur in children and adolescents with AR (5, 11) The most common symptom is nasal obstruction. In children there are typical appearances associated with AR including mouth breathing, allergic shiners, allergic crease, allergic facies and these may be reversed by treatment of the rhinitis. Rhinitis has frequently been considered to be a benign condition in children and one that does not need treating. However more recent data indicates that in addition to symptoms there may be deleterious effects of the condition on their performance. Specifically in children studies have shown reduced examination performance in the spring season and reduced participation in skill based, social and informal activities (12, 13). Habitual snoring is increased in children with AR (14)

#### **2. Sleep problems in AR**

Sleep disordered breathing is reported by subjects with allergic rhinitis versus controls including difficulty getting to sleep (24% versus 8%), waking during the night (31% versus 13%) and poor sleep (26% versus 11%) (5, 15) Leger et al additionally noted early wakening in 29% of AR , feeling of lack of sleep in 63%, snoring 40%, insomnia 36%, OSAS 4% and also that there was a greater use of sedatives in the AR group (16). Poor sleep is associated with negative effects on mood, cognition and motor performance. A large epidemiological study of over 4900 subjects showed that AR subjects who reported nocturnal nasal congestion ≥ 5 nights/month were more likely to be habitual snorers, experience excess daytime sleepiness or nonrestorative sleep (17). SDB is felt to relate to nasal obstruction but can also be caused by other symptoms eg rhinorrhea, pruritis and sneezing occurring during the night and also by the effects of inflammatory mediators. In addition commonly co-existing diseases such as asthma in which nocturnal asthma can be a significant symptom can disturb sleep. Nocturnal asthma is attributed to a circadian variation in airway physiology as well as the

More than \$6 billion was spent on prescription medications for AR in 2000 (5) in the USA. A specifically commissioned report in Australia estimated the total costs costs of Allergic disease (not asthma) including prescription medication to be \$349 million in Australia in

Symptoms of AR include nasal blockage or congestion occurring in up to 85%, and this tends to be the dominant symptom in children (5). It is generally most troublesome in the early morning on waking which may relate to the circadian rhythm for cortisol although the peak in symptoms is delayed compared to that of nocturnal asthma (6am versus 4am) (6). Nasal obstruction is the symptom that relates most to impaired quality of life (7). In addition there is a direct relationship between sleep impairment and symptom severity ( 5, 8). Nasal obstruction has been shown to be an independent risk factor for OSAS (obstructive sleep apnoea syndrome) (9). Other symptoms include sneezing, pruritis, anterior rhinorrhoea,

Numerous studies have shown that AR results in impaired QOL and affects numerous activities eg work productivity and attendance, physical activity, exam performance. How

SDB is well documented to occur in children and adolescents with AR (5, 11) The most common symptom is nasal obstruction. In children there are typical appearances associated with AR including mouth breathing, allergic shiners, allergic crease, allergic facies and these may be reversed by treatment of the rhinitis. Rhinitis has frequently been considered to be a benign condition in children and one that does not need treating. However more recent data indicates that in addition to symptoms there may be deleterious effects of the condition on their performance. Specifically in children studies have shown reduced examination performance in the spring season and reduced participation in skill based, social and

Sleep disordered breathing is reported by subjects with allergic rhinitis versus controls including difficulty getting to sleep (24% versus 8%), waking during the night (31% versus 13%) and poor sleep (26% versus 11%) (5, 15) Leger et al additionally noted early wakening in 29% of AR , feeling of lack of sleep in 63%, snoring 40%, insomnia 36%, OSAS 4% and also that there was a greater use of sedatives in the AR group (16). Poor sleep is associated with negative effects on mood, cognition and motor performance. A large epidemiological study of over 4900 subjects showed that AR subjects who reported nocturnal nasal congestion ≥ 5 nights/month were more likely to be habitual snorers, experience excess daytime sleepiness or nonrestorative sleep (17). SDB is felt to relate to nasal obstruction but can also be caused by other symptoms eg rhinorrhea, pruritis and sneezing occurring during the night and also by the effects of inflammatory mediators. In addition commonly co-existing diseases such as asthma in which nocturnal asthma can be a significant symptom can disturb sleep. Nocturnal asthma is attributed to a circadian variation in airway physiology as well as the

much of this is due to the disease itself or the accompanying SDB or both is unclear. Interestingly many patients report dissatisfaction with the effectiveness of therapy (10).

informal activities (12, 13). Habitual snoring is increased in children with AR (14)

**1.3 Costs**

2007 (3).

**1.4 Symptoms**

**1.5 Children and AR**

**2. Sleep problems in AR**

post nasal drip and these may also contribute to SDB.

effects of cytokine changes on sleep (see below).Eczema may also contribute to SDB with symptoms of pruritis often worse at night (18).

Sleep impairment in AR has been demonstrated by means of questionnaires, actigraphy (19,20) and polysomnography (17, 21)

The presence of abnormal sleep in association with AR categorises the disease as moderate to severe according to the ARIA classification of AR (Allergic Rhinitis and its Impact on Asthma) guidelines (Fig 1) (22 )

Fig. 1. ARIA classification of AR

The average sleep duration of healthy adults is about 7 hours but surveys show that a significant % of the population (43%) achieve less than this (23) and that these subjects felt tired, performed inefficiently and reported feeling drowsy while driving. It has been estimated that 20% of all traffic accidents in industrialised societies are related to sleep disorders.

Sleep disorders refers to a range of disorders including insomnia, OSAS, narcolepsy and idiopathic hypersomnolance, periodic limb disorders of sleep and restless leg syndrome. All of these primary sleep disorders are associated with excess daytime fatigue. SBD in AR includes insomnia and OSAS although recently a separate classification of RDS (rhinitis disturbed sleep) has been postulated (24).

Insomnia is a subjective perception of the amount or quality of sleep. It can comprise delayed initiation of sleep, difficulty with sleep maintenance and early awakening. It is associated with impaired QOL as demonstrated by reduced daytime alertness, lethargy, reduced cognitive functioning and altered emotional states. The 2008 NSF Sleep in America Poll found that 11% of the population described insomnia (26% difficulty falling asleep, 42% waking during the night, 29% woken early and unable to return to sleep)(25). Subjects with insomnia have a higher rate of traffic accidents: 5% versus 2% of normal sleepers.

OSAS in the general population is estimated at 2-4% and results in snoring, severe daytime sleepiness and increased risk of traffic accidents. The risk of RTA for OSAS is 12 times greater than controls and also higher than insomniacs. There is a direct relationship between the apnoea-hypopnoea index and crash risk.

However despite the documented impaired cognition and presence of SDB in AR no studies of driving crash risk have been performed.

Allergic Rhinitis and Its Impact on Sleep 111

inflammatory nasal disease. An activation of muscles in the anterior part of the nose help to counteract this tendency to collapse. When air is passed through the narrow isthmus with a high flow rate into the much larger nasal cavity where the flow rate is lower, the air flow becomes turbulent and disperses in a similar fashion to when water is expelled through a garden hose spray nozzle. Through this design the contact area between the air and the walls of the nasal cavity increases and enables the nose to effectively condition the inhaled air. The nasal cavities: The contact surface between the inhaled air and the mucous membrane is further enhanced by the folded structures on the lateral wall of the nasal cavity called the turbinates. There are three sets of turbinates in each nasal cavity. Most of the nasal cavity is encased in the skull bone and from an anterior view it is pyramid shaped. The inferior turbinates protrude into the airway at the base of the pyramid and an increase in the swelling of the mucosa covering the inferior turbinate can thus effectively obstruct the main

The nasal mucosa: The nasal respiratory mucosa replaces the skin starting at the head of the inferior turbinate and goes all the way to the nasopharynx. The nasal mucosa has major similarities with the respiratory mucosa of the bronchi and is today considered to be a linked functional organ with the lower respiratory tract which becomes evident in asthma and allergic inflammatory disease. The main difference is the presence of smooth muscle in the bronchi and the presence of sinusoids in the nose. Smooth muscle contraction can cause airway narrowing in the lungs which can be relieved with βagonists, but these drugs have no effect in the nose. Nasal patency is mainly regulated by variation of blood content in the erectile capacitance vessels called the sinusoids located in the sub mucosa. The regulation of nasal patency in the sinusoids is mediated through a neurovascular mechanism with different triggers such as air temperature, posture and physical exercise (27). Blood can be shifted in and out of the sinusoids through a rich capillary network equipped with artery-venous shunts. Nasal patency is maintained by a continuous sympathetic tone that can be up or down regulated. Increased sympathic activity during physical exercise or addition of adrenergic agonists increase nasal patency while a decrease in sympathetic activity decrease nasal patency as in Horner´s syndrome. In a third of the population "the nasal cycle" causes an alternating congestion and decongestion of the two nasal cavities going from one side to the other, a few hours apart. Nasal patency can also be changed by the application of pressure to the body surface. Unilateral pressure to the axillary region in the sitting position results in nasal congestion on the ipsilateral side and decongestion on the contralateral side, mediated via pressure sensitive receptors in the skin (28). A change in body position from sitting to supine also changes nasal patency, which may be important in regulating nasal patency during sleep

Nasal function: Breathing through the nose conditions the inhaled air which increases in humidity and temperature. Particles are cleared and the immune system is activated against inhaled bacteria and viruses to protect the lungs. Nitric oxide from the nasal and sinus mucosa is added to the inhaled air which promotes the gas exchange in the lungs by enhancing the ventilator-perfusion ratio. During nasal exhalation humidity and energy is effectively recovered from the air compared to the oral route (29). Nasal function also includes the sense of smell and a loss of this function has a marked effect on both the ability to smell and taste. Nasal breathing is the preferred breathing route at rest for most people,

nasal air flow like a cork seals a bottle neck.

as will be discussed in detail further down.

RDS is a term that has been suggested to separate the effects of nasal obstruction and pharyngeal obstruction on SDB (24). It has frequently been observed by ourselves and others that the effect of INCS improves nasal related symptoms more consistently and effectively than sleep related objective measures such as the apnoea-hyponoea index and actigraphy measurements (unpublished data,20,24). Therefore effects of INCS on nasal inflammation may result in improvements in subjective sleep indices without improvements in objective sleep measures, supporting the concept of two co-existing conditions. One study undertook polysomnography pre and post pollen season in 25 subjects SAR and 25 normals Subjects with SAR showed a significant increase in symptoms (overall symptoms score 1.08 ± 2.7 at baseline compared with 21.3±13.1 in season) and also subjective increases in daytime sleepiness which only occurred in the moderate and severe SAR subjects. Objective sleep parameters showed an increase in objective sleep abnormalities, but the differences occurred within the normal range and were not felt to be of clinical relevance (26). This study tends to support the fact that RDS may be more significant in AR than other causes of SDB such as OSAS and insomnia.

#### **3. Mechanisms of sleep impairment in AR**

#### **3.1 Nasal anatomy and physiology**

Introduction: The nose is an integrated part of the combined upper and lower airways both in function and inflammatory airways disease such as allergic rhinitis and asthma. There has been an increased focus on the significance of nasal breathing and it´s effect on health related quality of life and sleep during the last decade. Though easily accessible for examination, still little is known about how the regulation of nasal function is disturbed during inflammatory nasal disease.

 Respiratory function during sleep is a dynamic process involving changes in respiratory drive, airway patency and in airway muscular tone during REM and non REM sleep which makes the relationship between nasal function and poor sleep complex and difficult to assess. Most studies addressing nasal patency in inflammatory airways disease have been performed in awake subjects sitting in the upright position. In reality the nasal mucosa is highly reactive and responds almost instantly to changes in temperature, humidity and a change in body position. In the evaluation of patients with sleep disturbances and allergic rhinitis several aspects of nasal anatomy and physiology thus have to be taken into account.

External nose: The external nose protrudes from the bone aperture and is mainly composed of cartilage, muscle and subcutaneous fat apart from the two nasal bones at the top. The inside of the nasal openings and the anterior part of the nose is covered with skin and thus unaffected by nasal inflammation. The isthmus, is the narrow opening on the inside of the nose corresponding to the insertion of the nasal wings (alae) and the naso labial crest on the outside. More than half of the airway resistance is under normal conditions located here. During inspiration, the nasal openings tends to collapse as the passage of air through the narrow isthmus area put a suction force on the airway walls, the so called Bernouille effect. Patients with narrow nasal openings and weak alae are more prone to alar collapse especially when it combines with other abnormalities such as a septal deviation, turbinate hypertrophy or

RDS is a term that has been suggested to separate the effects of nasal obstruction and pharyngeal obstruction on SDB (24). It has frequently been observed by ourselves and others that the effect of INCS improves nasal related symptoms more consistently and effectively than sleep related objective measures such as the apnoea-hyponoea index and actigraphy measurements (unpublished data,20,24). Therefore effects of INCS on nasal inflammation may result in improvements in subjective sleep indices without improvements in objective sleep measures, supporting the concept of two co-existing conditions. One study undertook polysomnography pre and post pollen season in 25 subjects SAR and 25 normals Subjects with SAR showed a significant increase in symptoms (overall symptoms score 1.08 ± 2.7 at baseline compared with 21.3±13.1 in season) and also subjective increases in daytime sleepiness which only occurred in the moderate and severe SAR subjects. Objective sleep parameters showed an increase in objective sleep abnormalities, but the differences occurred within the normal range and were not felt to be of clinical relevance (26). This study tends to support the fact that RDS may be more significant in AR than other causes of SDB such as

Introduction: The nose is an integrated part of the combined upper and lower airways both in function and inflammatory airways disease such as allergic rhinitis and asthma. There has been an increased focus on the significance of nasal breathing and it´s effect on health related quality of life and sleep during the last decade.  Respiratory function during sleep is a dynamic process involving changes in respiratory drive, airway patency and in airway muscular tone during REM and non REM sleep which makes the relationship between nasal function and poor sleep complex and difficult to assess. Most studies addressing nasal patency in inflammatory airways disease have been performed in awake subjects sitting in the upright position. In reality the nasal mucosa is highly reactive and responds almost instantly to changes in temperature, humidity and a change in body position. In the evaluation of patients with sleep disturbances and allergic rhinitis several aspects of nasal anatomy and

External nose: The external nose protrudes from the bone aperture and is mainly composed of cartilage, muscle and subcutaneous fat apart from the two nasal bones at the top. The inside of the nasal openings and the anterior part of the nose is covered with skin and thus unaffected by nasal inflammation. The isthmus, is the narrow opening on the inside of the nose corresponding to the insertion of the nasal wings (alae) and the naso labial crest on the outside. More than half of the airway resistance is under normal conditions located here. During inspiration, the nasal openings tends to collapse as the passage of air through the narrow isthmus area put a suction force on the airway walls, the so called Bernouille effect. Patients with narrow nasal openings and weak alae are more prone to alar collapse especially when it combines with other abnormalities such as a septal deviation, turbinate hypertrophy or

OSAS and insomnia.

**3. Mechanisms of sleep impairment in AR**

**3.1 Nasal anatomy and physiology**

during inflammatory nasal disease.

physiology thus have to be taken into account.

inflammatory nasal disease. An activation of muscles in the anterior part of the nose help to counteract this tendency to collapse. When air is passed through the narrow isthmus with a high flow rate into the much larger nasal cavity where the flow rate is lower, the air flow becomes turbulent and disperses in a similar fashion to when water is expelled through a garden hose spray nozzle. Through this design the contact area between the air and the walls of the nasal cavity increases and enables the nose to effectively condition the inhaled air.

The nasal cavities: The contact surface between the inhaled air and the mucous membrane is further enhanced by the folded structures on the lateral wall of the nasal cavity called the turbinates. There are three sets of turbinates in each nasal cavity. Most of the nasal cavity is encased in the skull bone and from an anterior view it is pyramid shaped. The inferior turbinates protrude into the airway at the base of the pyramid and an increase in the swelling of the mucosa covering the inferior turbinate can thus effectively obstruct the main nasal air flow like a cork seals a bottle neck.

The nasal mucosa: The nasal respiratory mucosa replaces the skin starting at the head of the inferior turbinate and goes all the way to the nasopharynx. The nasal mucosa has major similarities with the respiratory mucosa of the bronchi and is today considered to be a linked functional organ with the lower respiratory tract which becomes evident in asthma and allergic inflammatory disease. The main difference is the presence of smooth muscle in the bronchi and the presence of sinusoids in the nose. Smooth muscle contraction can cause airway narrowing in the lungs which can be relieved with βagonists, but these drugs have no effect in the nose. Nasal patency is mainly regulated by variation of blood content in the erectile capacitance vessels called the sinusoids located in the sub mucosa. The regulation of nasal patency in the sinusoids is mediated through a neurovascular mechanism with different triggers such as air temperature, posture and physical exercise (27). Blood can be shifted in and out of the sinusoids through a rich capillary network equipped with artery-venous shunts. Nasal patency is maintained by a continuous sympathetic tone that can be up or down regulated. Increased sympathic activity during physical exercise or addition of adrenergic agonists increase nasal patency while a decrease in sympathetic activity decrease nasal patency as in Horner´s syndrome. In a third of the population "the nasal cycle" causes an alternating congestion and decongestion of the two nasal cavities going from one side to the other, a few hours apart. Nasal patency can also be changed by the application of pressure to the body surface. Unilateral pressure to the axillary region in the sitting position results in nasal congestion on the ipsilateral side and decongestion on the contralateral side, mediated via pressure sensitive receptors in the skin (28). A change in body position from sitting to supine also changes nasal patency, which may be important in regulating nasal patency during sleep as will be discussed in detail further down.

Nasal function: Breathing through the nose conditions the inhaled air which increases in humidity and temperature. Particles are cleared and the immune system is activated against inhaled bacteria and viruses to protect the lungs. Nitric oxide from the nasal and sinus mucosa is added to the inhaled air which promotes the gas exchange in the lungs by enhancing the ventilator-perfusion ratio. During nasal exhalation humidity and energy is effectively recovered from the air compared to the oral route (29). Nasal function also includes the sense of smell and a loss of this function has a marked effect on both the ability to smell and taste. Nasal breathing is the preferred breathing route at rest for most people,

Allergic Rhinitis and Its Impact on Sleep 113

subjects with oro pharyngeal narrowing in the awake situation and not in all patients with nasal obstruction, underlining that nasal obstruction is a co-factor affecting sleep in a complex way (37). With regard to the neurovascular regulation of the nasal mucosa, interesting data have emerged recently. Objective measurements of nasal patency during sleep are difficult to obtain without interfering with the sleep pattern. Lebowitz has described a study on 10 subjects doing consecutive acoustic rhinometry measurements during sleep while monitoring sleep stage. The results showed that nasal patency varies with sleep stage exhibiting a marked congestion during REM-sleep and decongestion during non-REM sleep (38). Variable nasal obstruction has been found to play a greater role in the pathophysiology of obstructive sleep apnea syndrome, than conditions associated with a fixed obstruction (39). In healthy subjects the nasal patency is typically reduced when going from sitting to supine body position measured with acoustic rhinometry (40). It has been suggested that this alteration of nasal patency supine is due to an increased hydrostatic pressure in the nasal vasculature supine and thus a passive mechanism (41). Ko measured heart rate variability as a measure of activity in the autonomic nervous system simultaneously with rhinomanometry between sitting and supine in 12 healthy subjects and found a significant correlation between decreased sympathetic activity supine followed by decreased nasal patency indicating an active regulation of nasal patency supine (42). In studies of patients with snoring and OSAS without rhinitis nasal geometry changes less or remain unchanged supine compared to healthy controls (43, 44). This could be related to an increased sympathic activity seen in this patient group (45). In fact an increased nasal obstruction or symptoms of nasal obstruction when lying down has been observed in patients with seasonal allergic rhinitis compared to controls, indicating an inflammatory up regulation of the neurovascular

We recently found no response with acoustic rhinometry to a change between sitting and supine in 19 patients with asthma and allergic rhinitis at inclusion, but a normalized reaction (with significantly decreased nasal patency supine) after 6 weeks treatment with a nasal steroid compared to placebo (unpublished data). Disturbances in the neurovascular control of the nasal mucosa supine is thus present in allergic rhinitis along with nasal obstruction and could interfere with nasal function during sleep but this has to evaluated

**4. Is there a definite relationship between nasal congestion and SDB?**

OSAS such as obesity, craniofacial abnormalities and male sex.

The relationship between subjective and objective measures of nasal obstruction are often poor which can confound studies in this area. Nasal obstruction is an independent risk factor for OSAS (9) but this is not confirmed in all studies. In normal subjects occlusion of the nose during the night causes an increase in sleep apnoea and transient arousals (50) suggesting that nasal obstruction irrespective of cause is an important cause of OSAS. In AR there is a general relationship between the presence and degree of nasal obstruction and obstructive sleep apnoea (8,50,51). This has also been confirmed in population studies (17). Anatomical deformities such as nasal septal deviation, adenoidal hypertrophy, nasal polyps are associated with SDB. However there are also other important predisposing factors for

control of the nasal mucosa (46 47).

further.

but there is a shift to oral breathing at some point when developing nasal obstruction that varies individually. Oral breathing, apart from being less effective than the nose in air conditioning, also promotes airway collapse in oropharynx due to increased upper airway resistance (30).

Assessing nasal patency: Objective measurements of changes in nasal patency can be obtained either as alterations in nasal air flow and resistance or as changes in intranasal diameter and volume. Rhinomanometry, nasal peak flow and nasal spirometry are examples of methods that give a good perception of the overall nasal air flow resistance but are less reliable to predict specific changes in the mucosa. Acoustic rhinometry or rhinostereometry are preferred when studying the variations in the nasal cavity dimensions due to swelling and decongestion at specific sites in the nasal cavity. For instance it has been shown that the minimal cross sectional area at 4 cm from the nostril is where the nasal mucosa decongests the most (31). Acoustic rhinometry, introduced by Hilberg in the 1980`s is by far the most widely used of the 2 methods and is quick to perform (32). Audible sound is lead into the nasal cavity and reflected back to generate a description of nasal cross sectional areas and volumes at different levels. Attempts have been made to correlate intranasal dimensions in healthy subjects to the subjective sensation of nasal patency, age, gender, BMI and head circumference without success. When used to compare changes in the same individual before and after an intervention, acoustic rhinometry has, however, proven accurate with a high reproducibility (33). In a recent review, Eccles found evidence for the benefit of septoplasty in studies using acoustic rhinometry, before and after surgery (34).

#### **3.2 Nasal function and sleep**

Nasal obstruction is considered the most important factor that links nasal inflammation to poor sleep but other factors such as the presence of inflammatory mediators affecting the CNS may also contribute. Nasal obstruction due to nasal inflammation is probably multi factorial including altered neurovascular control of the sinusoids, formation of sub mucous edema, secretion of excessive nasal secretions and cicardian changes following the serum cortisol cycle with a peak of nasal congestion in the morning. How these factors interact in nasal obstruction and how it affects sleep still remains unclear. This was recently reviewed by Craig and in summary, most studies showing a relationship between allergic rhinitis and poor sleep have focused on symptoms of nasal congestion rather than objective measurements of nasal patency during sleep (21). In a large north European multicentre study study we also found rhinitis to be an independent risk factor for sleep disturbances in asthma specifically in subjects reporting nasal symptoms every day (35). Studies looking at objective measures of nasal function are rare but Lavie et al found a an increased number of micro arousals during sleep in patients with allergic rhinitis during sleep (36)

When regarding nasal congestion as a cause to poor sleep, one has to consider several options. If the nasal congestion is severe enough it leads to a shift into oral breathing and thus the effect on sleep is due to a change in breathing route. Effects of oral breathing on airway collapse and it´s relationship to OSAS goes beyond the focus of this chapter and will not be discussed here. If, however, nasal breathing is maintained during recumbent body position and sleep, it is necessary to consider both an increased airway resistance and changes to the neurovascular control of the nasal mucosa in relation to nasal inflammation. A relationship between nasal obstruction and sleep disordered breathing has been observed mainly on