Sinusitis and its Relationship to Asthma

Sinusitis and its Relationship to Asthma
This article first appeared in the January 2, 2001 issue of Sinus News:

Sinusitis and asthma are closely interrelated diseases, and sinusitis often coexists with bronchial hyperresponsiveness. Prompt diagnosis and treatment of sinusitis are essential in the long-term management of chronic asthma.

Primary care physicians frequently encounter inflammatory diseases of the paranasal sinuses. Sinusitis affects an estimated 14% of the US population, and its incidence has increased in recent years (1). In addition, asthma occurs in 5.14% of the population and has resulted in increased morbidity and mortality, with billions of dollars spent each year on treatment (2).

In this article, the relationship of concomitant chronic sinusitis and asthma and the proposed mechanisms responsible for induction of lower airway bronchial hyperresponsiveness are reviewed. As indicated in the medical literature, early recognition and successful management of sinusitis in asthmatic patients positively affect paranasal and lower airway inflammation and encourage favorable outcomes in these patients.

Coexistence of upper and lower airway disease

Scientists have long recognized that diseases coexist in the upper and lower airways. As many as 88% of asthmatic patients exhibit symptoms of rhinitis, and about 50% of rhinitic patients experience acute bronchial hyperresponsiveness (3).

The theory that allergic asthma is a total airway disease was supported when 461 asthmatic adolescents and adults were assessed for symptoms of rhinitis. In this study, investigators concluded that 98.9% of the allergic asthmatic patients had rhinitis, the prevalence of which was significantly less (78.4%) in the non-allergic asthmatic patients (4).

The interrelationship of allergic rhinitis and associated airway diseases is shown in figure 1 (not shown) (5). A spectrum of upper airway diseases, such as acute upper respiratory infection, otitis media with effusion, nasal polyposis, allergic rhinitis, and paranasal sinusitis, can lead to or worsen chronic inflammation of the lower airways (6).

The term "rhinosinusitis" may more accurately reflect the inflammatory process that extends from the sinuses to the contiguous nasal mucosa, causing symptoms of nasal obstruction and nasal discharge--both prominent features of sinusitis (7). Sinusitis can result from nasal, bacterial, or fungal infections or, as in chronic sinusitis, its cause can be noninfectious (eg, allergens, nasal polyposis). The chronological progression of sinusitis has three stages--acute, acute recurrent, and chronic--defined by the duration of signs and symptoms. In acute sinusitis, complete resolution of symptoms may take as long as 12 weeks. By comparison, acute recurrent sinusitis consists of multiple acute episodes between which signs and symptoms resolve. Chronic sinusitis involves low-grade signs and symptoms that persist beyond 12 weeks and that can evolve into acute exacerbations (7).

Most upper airway diseases share common pathogenic mechanisms as well as genetic or environmental influences that predispose patients to the development of a related condition (8). For example, fundamental changes occur in the sinus tissue and airway of patients with intrinsic asthma and nasal polyposis. When those conditions occur concomitantly, asthma often worsens. Most of these patients have no allergies, but 30% to 50% of them exhibit sensitivity to aspirin (9).

Sinopulmonary reflex

The first observation of sinopulmonary reflex dates from the second century, when Galen observed that purging nasal secretions offered relief to persons with pulmonary disease. In 1919, Sluder hypothesized the existence of a sinopulmonary reflex thought to be responsible for that phenomenon (10). In 1928, the French physiologist Kratchmer used noxious agents to stimulate nasal mucosa in animals, and acute bronchial hyperresponsiveness resulted.

In a classic study in rabbits, sinusitis was chemically induced by injecting a modified complement fragment, C5a des arg, directly into the maxillary sinuses. The rabbits exhibited a marked increase in responsiveness to histamine concurrent with the induction of upper airway inflammation. However, bronchial hyperresponsiveness was completely blocked when the animal's head was positioned downward to prevent exudate from draining beyond the pharynx and into the lower airways (11). This effect demonstrates that a neurally mediated pharyngobronchial reflex exists and is activated by cellular inflammatory products acting directly on afferent nerve endings in the sinuses, thereby triggering bronchial hyperresponsiveness.

Similar logic about the existence of a sinopulmonary reflex correlates with the theory that acute bronchial hyperresponsiveness results from sinonasal epithelial damage caused by allergens, irritants, or viruses and leads to stimulation of a trigeminal afferent-vagal efferent neural arc (figure 2: not shown) (10).

Pathophysiologic mechanisms

The pathophysiologic mechanisms that enable the spread of inflammation along the airway and induction of bronchial hyper-responsiveness in asthmatic patients are summarized in table 1. The complex relationships of major pathophysiologic mechanisms include cellular, humoral, and neural pathways.

Cellular pathway

Chronic sinusitis and asthma are characterized by an inflammatory process that is marked histologically by tissue eosinophils. The eosinophil contains major basic protein as well as eosinophilic cationic protein, both of which contribute to inflammation and injury of epithelium of the nose, sinuses, and lungs.

Researchers and clinicians have accepted the theory that inflammation is central to chronic sinusitis and asthma and that the inflammatory process involves many cells, including eosinophils, mast cells, T lymphocytes, macrophages, and epithelial cells (7,12). The rationale for treating the nose in asthmatic patients follows the concept of "united airways," because nasal inflammation can influence the lower airways and intranasal corticosteroids can relieve symptoms of sinusitis and asthma.

Nasal mucosa contains antigen-presenting cells, which are similar to dendritic Langerhans cells. These cells capture and process allergens in nasal mucosa. Immunologic "homing" occurs when T lymphocytes are activated by antigen processing in the paranasal sinuses and migrate to the mucous membranes of adjacent airway mucosa, thereby extending the inflammatory process to the lower airway (13). The release of cytokines recruits other inflammatory mediators to the upper and lower airways, which then perpetuates a chronic inflammatory state.

Humoral pathway

The direct passage of mediators (postnasal drip) produced by activated inflammatory cells from the sinuses exerts a significant effect on bronchial responsiveness (11). Investigators have shown that methacholine administered into the nose of rabbits causes acute bronchial hyperresponsiveness, but this effect is completely blocked in noses that are pretreated with phenylephrine, a selective alpha-adrenergic receptor agonist and potent vasoconstrictor (10).

Neural pathway

The cholinergic parasympathetic nervous system has a key role in maintaining resting bronchial muscle tone and in mediating acute bronchospastic responses (figure 3: not shown) (14). The lungs are innervated by parasympathetic and nonadrenergic, noncholinergic autonomic pathways. Receptors in the nose and pharynx and, presumably, in the paranasal sinuses produce afferent fibers that form part of the trigeminal nerve, which passes to the brain stem and connects with the reticular formation of the dorsal vagal nucleus. From the vagal nucleus, parasympathetic efferent fibers travel in the vagus nerve to the bronchi.

Development of asthma is associated with cholinergic hyperresponsiveness and a postulated partial beta-adrenergic receptor blockade. Sinusitis may be associated with a reversible preexisting partial beta-adrenergic blockade that improves with treatment of upper airway inflammation. The nonadrenergic, noncholinergic nervous system of neuropeptides also contributes to lower airway autonomic function. Neuropeptides trigger smooth-muscle contraction, vasodilation, plasma extravasation, and mucus hypersecretion (15). Stimulation of extrathoracic receptors triggers sustained bronchial hyperresponsiveness, caused by ongoing chronic inflammation of the paranasal sinuses (7,16).

Other associated processes

An interesting mechanism in development of asthma and sinusitis is associated with the depressed nitric oxide concentration that occurs during acute maxillary sinusitis. The nitric oxide level returns to baseline after sinusitis is resolved. A reduction in nitric oxide, which is a potent modulator of bronchial tone, may precipitate acute bronchial hyperresponsiveness (17).

An association between gastroesophageal reflux disease (GERD) and asthma has been documented (9). GERD has a role in inducing the nasal mucosal edema and inflammation that cause obstruction of the sinus ostia, which in turn stimulates the autonomic nervous system. The amount of pharyngeal reflux of gastric acid is greater in patients with chronic sinusitis that does not respond to initial antireflux therapy (18).

Treatment strategies

The effect of treatment of sinusitis on asthma has been documented in the medical literature and by clinical observation. Asthma diminishes when coexistent sinusitis is maximally treated by medical or surgical intervention, such as topical intranasal corticosteroids, sinopulmonary lavage, broad-spectrum antibiotic therapy (when indicated), and decongestants (15).

An exhaustive review of the therapy for sinusitis and asthma is beyond the scope of this article. However, the fundamental role of medication in treatment of these conditions is to reduce chronic inflammation associated with asthma and coexisting paranasal sinus disease. Antihistamines effectively block H1 receptors and function as anti-inflammatory agents because they downregulate the intercellular adhesion molecule-1 involved in eosinophil recruitment at dermal and respiratory mucosal sites (19). Decongestants can significantly affect ostial blockage that causes decreased aeration of the sinus and stagnation and thickening of mucus, which predispose the person to secondary bacterial infection. Clinical and research observations have demonstrated that treatment of nasal inflammation with topical intranasal corticosteroids has a profound effect on reducing tissue edema and inflammation in the sinuses, which in turn reduces lower airway inflammation (15).

Careful history taking and physical examination of the patient are highly recommended. The osteomeatal complex should be assessed using flexible rhinolaryngoscopy or coronal sinus computed tomography, both of which reveal pertinent signs and symptoms of systemic disease in patients with acute recurrent or chronic sinusitis. In patients with bacterial sinusitis who do not improve with treatment or who continue to have chronic sinusitis and worsening asthma, long-term antibiotic therapy of 3 to 6 weeks, guided by cultures obtained by otolaryngologic evaluation, is warranted (2).

Evaluation of noninfectious causes of chronic sinusitis should include investigation for an underlying primary immunodeficiency. This evaluation should include testing for levels of quantitative immunoglobulins (eg, IgG, IgA, IgM) and prevaccination and 4-week postvaccination titers to polysaccharide (eg, pneumococcal and influenza vaccines) and protein antigens (eg, diphtheria tetanus vaccine). A complete evaluation should also include assessment of T-cell delayed hypersensitivity by intradermal skin testing with purified protein derivative, Trichophyton, streptokinase, and mumps antigen. Comorbid conditions, such as common variable immunodeficiency, allergic fungal sinusitis, cystic fibrosis, Wegener's granulomatosis, and allergic or nonallergic rhinitis, should be excluded by clinical assessment and the judicious use of laboratory studies.

In cases where maximal medical therapy fails, surgical intervention by functional endoscopic sinus surgery (FESS) is recommended to provide adequate sinus drainage. The effect of FESS on asthma has been studied by Senior and associates (20), who monitored 125 rhinosinusitis patients for an average of 6.5 years after FESS was performed. About 90% of patients with concomitant asthma reported improved asthma symptoms, and the benefits lasted over time: 49% of patients reported benefit at 1.1 years after FESS, and 65% maintained an improved asthma status 6.5 years after FESS (20). Benefit was demonstrated by less frequent use of a beta-agonist inhaler in 50% of patients and by the need for fewer oral corticosteroid bursts to control acute asthma exacerbations in 66% of patients. Current evidence indicates improved sinus and asthma symptoms, improved peak flow, and decreased corticosteroid use in asthmatic patients with chronic sinusitis who have undergone FESS (21,5).

Conclusion

Considerable clinical and research evidence substantiates the interrelationship between sinusitis and asthma. Optimal treatment of asthma depends on aggressive management of acute inflammation in the paranasal sinuses and on identification of underlying sinusitis.

Data support the theory that endogenous pathways trigger and maintain acute bronchial hyperresponsiveness when sinusitis develops. Primary pathophysiologic pathways include a sinopulmonary reflex that facilitates triggering of a neural arc by the spread of inflammation in the lower airways from the paranasal sinuses, and vice versa. Cellular, humoral, neural, and immunologic factors also contribute to sinopulmonary reflexes that perpetuate lower airway hyperresponsiveness.

Comorbidity associated with acute sinusitis and asthma is best managed by accurate and timely diagnosis, judicious treatment with antibiotics, and use of topical nasal corticosteroids, decongestants, and sinus lavage to maintain adequate mucociliary clearance. Proper management results in a dramatic reduction in acute-care outpatient visits, emergency department treatment, hospitalizations, and the exponential costs associated with treatment of sinusitis and asthma.