THE DIAGNOSIS AND MANAGEMENT OF CHRONIC RHINOSINUSITIS

Michael Puruckherr, M.D., Ryland Byrd, M.D., Tom Roy, M.D. and Guha Krishnaswamy, M.D.

Address all correspondence to:
Guha Krishnaswamy, M.D.
Department of Medicine
East Tennessee State University
Johnson City, TN 37614-0622
Tel: (423) 439-6282
Fax: (423) 439-6387
e-mail: krishnas@etsu.edu

Key words: Sinusitis, Allergy, immune deficiency, cytokines, antihistamines
Running head: Chronic sinusitis

Funded by NIH grants; AI-43310 and HL-63070, The Rondal Cole Foundation and the Chair of Excellence in Medicine (State of Tennessee grant 20233), Cardiovascular Research Institute, and the Research Development Committee, East Tennessee State University.

INTRODUCTION

Sinusitis is a common health problem that lead to frequent visits to primary care physicians and to ear, nose and throat specialists in the United States and other countries. It contributes to a significant amount of health care expenditure due to direct costs arising from physician visits and antibiotics, as well as indirect costs related to missed days at work and a general loss of productivity due to a decrease in life-quality of those affected (14)(24). The 1996 total direct health care expenditures in the USA attributable to sinusitis were estimated with $ 5.8 billion. Of this number about 58.7% (or $3.5 billion) is probably related to chronic sinusitis alone (17). It is estimated that 13.4 million office visits/year are related to sinusitis and/or its sequelae.
Patients with chronic rhinosinusitis also suffer from a poor quality of life and the disease is often associated with other co-morbid conditions such as asthma, eczema and otitis media. A better understanding of the pathogenesis and etiology of chronic rhinosinusitis is essential in order to develop effective therapies. Recently, there has been an evolving concept of an "one airway disease" as the lower and upper airways, paranasal sinuses and middle ear are related anatomically and functionally. Hence, disease in one portion of the airway is prone to spill over into other parts of the airway. This is extremely important to realize as therapy of the patient with sinusitis may lead to improvements in lung function, for example (20). If gastroesophageal reflux is included, then interactions of the upper and lower airways, and the gastrointestinal tract become clinically relevant. Since the majority of patients with sinusitis also suffer from rhinitis, the term rhinosinusitis may be more appropriate (Figure 1). One fifth of patients with chronic sinusitis also have nasal polyposis and a subset of these patients suffer from the aspirin-sensitivity syndrome often associated with asthma and rhinitis.
There is conflict in the criteria for diagnosis of acute or chronic sinusitis. Patients who have been symptomatic for 3 weeks or less are considered to have acute disease while those having prolonged symptoms lasting longer than 6 weeks or more are referred to as having chronic disease.

CLINICAL PRESENTATION

Patients with sinusitis present with a variety of signs and symptoms. These include purulent discharge anteriorly or posteriorly which are believed to be the one of the most significant findings in the diagnosis of rhinosinusitis. The symptom complex for the clinical evaluation includes major and minor criteria. Major criteria include the above described purulent drainage, headache, facial pain or pressure, nasal congestion/blockage, decreased smelling sensation and fever for acute rhinosinusitis. Minor criteria consist of halitosis, fever (nonacute rhinosinusitis), weakness, dental pain, ear fullness (clicking noises) and pain, cough and in children, irritability (14)(32)(31).
In the case of chronic sinusitis, if two or more of the above mentioned major criteria or one major and two minor criteria are found in the history and exam over a 6-12 week time interval the presence of chronic sinusitis is very likely. Some patients may present with relapsing disease which may include acute rhinosinusitis occurring at least 3-4 times/year and lasting for a minimum of 10 days. Additionally it has been proposed that changes on computerized tomography of the paranasal sinuses which are still present $4 weeks following therapy can be considered chronic (14)(18).

ETIOLOGIES OF CHRONIC RHINOSINUSITIS

TABLE 1 lists the various etiologies that could lead to chronic bacterial rhinosinusitis. Several of these conditions are discussed in further detail below.
The majority of patients with chronic sinusitis have associated rhinitis, either of allergic or infectious origin. On the other hand there is a significant proportion with vasomotor rhinitis, drug induced rhinosinusitis, nonallergic rhinitis with eosinophilia syndrome (NARES), structural rhinitis, neutrophilic rhinosinusitis and some with nasal polyposis, as stated earlier. The term vasomotor rhinosinusitis is used for conditions caused by irritants like air pollutants, smoke or odors, often due to occupational related exposure. In contrast to allergic rhinosinusitis patients with vasomotor rhinosinusitis lack the conjunctival involvement usually found in allergic rhinosinusitis. Rhinitis medicamentosa reflects a condition where repetitive use of nasal decongestants (e.g. oxymetazoline, xylometazoline, etc.) can cause a chronic, progressive and medication-dependant rhinitis. In NARES (nonallergic rhinitis with eosinophilia syndrome) the nasal secretions contain eosinophils as seen in allergic rhinitis but the patient does not suffer from any allergies. This is a steroid-responsive illness and may precede the development of asthma or aspirin sensitivity. Structural rhinitis is usually caused by significant septal deviation or deformities (e.g. after trauma) and can be uni- or bilateral (30). Patients which are sensitive to aspirin and often also to other NSAIDs suffer from severe rhinosinusitis which is frequently accompanied by development of nasal polyps. There is some data to suggest a role for leukotrienes and inflammatory cytokines in eosinophil recruitment and mast cell activation in the aspirin-sensitive syndromes (13)(12).

PATHOGENESIS

The four paired paranasal sinuses (maxillary, ethmoid, frontal and the sphenoid) drain into the nasal cavity. While the frontal, maxillary and anterior ethmoid drain through the osteomeatal complex in the middle turbinate, the posterior ethmoid sinuses and the sphenoids drain via the superior turbinate through the sphenoethmoidal recess. For the maxillary sinus the mucociliary activity must drain against gravity. Messerklinger suggested that recurrent sinusitis is often due to a focus of infection that has remained in a stenotic cleft of the lateral wall (19). These findings let to the understanding that for normal sinus function the patency of the so called "Osteomeatal complex" is critical. Several authors described opacification of the middle meatus and also inflammation in the dependent sinuses in patients with chronic rhinosinusitis (16). The role of allergy, immune deficiency, viral infection and anatomical or structural disease would be to induce osteal obstruction leading to stasis of secretion, secondary infection, inflammatory cytokine synthesis and leukocyte recruitment. This further propagates the inflammatory process, resulting in a vicious cycle, leading to chronicity if untreated or obstruction is unrelieved. A patient with allergic rhinitis can develop sinusitis due to various mechanisms as shown in Figure 2. Increased mucus production, impaired mucociliary clearance and tissue edema can occur with both allergic rhinitis and with sinusitis. This could lead to airway obstruction, stasis and secondary infection, leading to infectious sinusitis. If the patient has other complications, such as structural disease (deviated septum, adenoidal enlargement and nasal polyps or concha bullosa), immune deficiency disease (such as immunoglobulin G or A deficiency), other abnormalities of ventilation such as cystic fibrosis or ciliary dysmotility or viral infectious illness such as coryza which can acutely impair clearance mechanisms, further predispositions to sinusitis are created. Inflammatory response can lead to tissue edema and remodeling, leading to airway obstruction, secondary infection, elaboration of inflammatory cytokines and leukocyte recruitment. This ultimately culminates in infectious sinusitis with all its attendant sequelae.
Mucosal edema, osteal blockage, increased and accumulating viscous mucous secretions or/and decreased mucociliary activity can cause acute, chronic or acute exacerbation of chronic sinusitis (10). Decreased patency or even complete blockage of the sinus ostia decreases gas exchange resulting in hypoxia and hypercapnia. This causes neutrophil activation (increased chemotaxis and degranulation) which leads to more inflammation and also lowers the pH resulting in ciliary dysfunction by lowering ciliary beat frequency. Other causes includes foreign bodies which are in adults often iatrogenic (eg., naso-tracheal or naso-gastric tubes) which produce osteal blockage directly or by inducing mucosal swelling. Infected nasal secretions might also drain back into the sinuses (1). The significance of sinonasal anatomical variations as a cause of chronic rhinosinusitis is controversial. For example Danese et al., found only an association between chronic or recurrent sinusitis in patients with ipsilateral ridges or spurs, unusual deflections of uncinate process and contralateral septal watch glass like deviation but no correlations for other variants like concha bullosa, Haller (infraorbital ethmoidal) cells or accessory maxillary ostium (7). An additional but less recognized factor leading to chronic rhinosinusitis is mucus recirculation. This may occur in a patient who has an accessory sinus ostium of the maxillary sinus where the mucus drains out the usual anatomical way into the middle meatus and then reenters the maxillary sinus through the accessory ostium which is usually located inferior to the osteomeatal complex. Interestingly, nose blowing by propelling nasal secretions into the middle meatus and the maxillary sinus might cause acute sinusitis or recurrent exacerbation of chronic sinusitis and may also worsen chronic sinusitis (9).

THE ROLE OF ALLERGY IN RHINOSINUSITIS

The prevalence of sinusitis in the United States is almost 15% (37 million persons) and is ranked among the commonest chronic conditions. With improvements in diagnostic capacities, more numbers of patients are being diagnoses with chronic sinusitis in recent years. This has resulted in an increase in the number of surgeries for chronic paranasal sinus disease. Allergic rhinitis is fairly common. In some studies, the total cost to society of allergic rhinitis is estimated at 2.4 billion dollars. This includes not only direct costs associated with physician visits, medications and diagnostic testing but also indirect costs associated with loss of productivity due to days lost at work. When associated costs of caring for asthma and sinusitis are included, the costs involved may exceed $ 10 billion. In total, almost 25-30 million persons may be affected by allergic rhinitis in the U.S. alone (29). Figure 1 shows the relationship between allergy, sinusitis, asthma and reflux. Obviously, all of these disorders may be interactive in a given patient and one needs to individualize approaches to therapy based on the presence of one or more of these processes in a given patient (29). Allergic rhinitis presents in an atopic patient with sneezing, rhinorrhea, nasal congestion, itchy eyes, lacrimation and cough. In some cases, generalized symptoms such as fatigue may be associated complicating features and may be related to the effect of cytokines or impaired sleep in a patient with poorly controlled allergic upper airway disease. Allergic rhinitis can be seasonal or perennial. In the case of the latter, indoor, perennial allergens such as mold, dust mites, cockroach allergen or pet dander can lead to year round symptoms. These allergens especially have been linked to the co-development of asthma. Investigators have shown that aggressive treatment of indoor allergen "burden" by the use of specific filters, mattress and pillow encasings and removal of sources of indoor allergen could lead to improvements in lung function in patients with allergic respiratory disease. Of interest, rhinitis is diagnoses in 28-78% of patients with asthma and asthma is diagnoses in nearly 38% of patients with chronic rhinitis and there is evidence to suggest that allergic rhinosinusitis may present a risk factor for subsequent development of asthma. Moreover, some studies have also shown that antihistamines and aggressive therapy of rhinosinusitis can ameliorate asthma (20). Whether this is an indirect effect due to improvement in rhinitis or due to direct improvements in asthma is unclear.

IMMUNE EVALUATION

The immunological evaluation of a patient with persistent rhinosinusitis is essential as occasionally defects are encountered that could lead to specific therapeutic intervention or immune reconstitution. Table 1 provides a suggested outline for the evaluation of immunological function in a patient with recurrent or chronic rhinosinusitis. Nasal cytology can assist in the detection of eosinophils which would suggest either allergic rhinitis or NARES. Presence of excessive neutrophils in a nasal smear would suggest bacterial rhinosinusitis. Cultures are very essential in the evaluation of bacterial sinusitis since the type of pathogen would determine the nature of immune evaluation. This however may be difficult to pursue as it often involves relatively invasive procedures such as a sinus puncture or antral biopsy. In cases where the sinusitis is poorly responsive to therapy or is progressing, tissue cultures and biopsies are required to exclude fastidious pathogens and fungi where the treatments could be dramatically different. In patients with chronic, recurrent sinusitis, especially if associated with recurring pulmonary infections or infections elsewhere, an immunological evaluation may provide useful information. Defects in humoral immunity are associated with low antibody levels, recurring infections with pyogenic or capsulated pathogens and other complications, including autoimmune disease.

Evaluation of these disorders is reviewed in Table 1.

CONDITION	ASSOCIATED SYNDROME	EXAMPLES	EVALUATION
Rhinitis/allergy	Allergic rhinitis Non-allergic rhinitis Iatrogenic Hormonal Rhinitis medicamentosa	Seasonal and perennial Vasomotor rhinitis/NARES Aspirin sensitivity triad Thyroid, pregnancy Antihypertensive, nasal spray	Skin testing, IgE level, RAST, cytology History of aspirin/NSAID use TSH, beta-HCG History
Immunological Disorders	Humoral immune deficiency Complement deficiency Phagocytic disorders T cell defects Ciliary dysfunction	IgA or IgG subclass deficiency CVID Functional antibody deficiency C2/C4 deficiency Chronic granulomatous disease Diabetes mellitus Chemotherapy-induced leukopenia HIV infection Kartageners syndrome Viral infections	IgA or IgG subclass levels, IgG, A, M levels, vaccine response Vaccine response C2/C4 levels Nitroblue tetrazolium test, assay Blood sugars, glycosolated hemoglobin White blood cell count CD4 counts, HIV serology Nasal/lung biopsy Cultures, serology
Structural Disorders	Septal disease Airway occlusive disease Inflammatory obstruction Inspissated mucus	Perforation, deviated nasal septum Neoplasia, polyps, concha bullosa Mucocele Cystic fibrosis	CT or MRI, endoscopy CT or MRI, endoscopy CT or MRI, endoscopy Sweat chloride, CFTR mutation
Inflammatory Disorders	Luminal events Vasculitis Granulomatous disease	Foreign body, endotracheal tube Wegner's granulomatosis Sarcoidosis	History, CT, bronchoscopy ANCA, CT, biopsy for vasculitis ACE level, CT chest, biopsy

TSH=thryoid stimulating hormone, -HCG=beta subunit of human chorionic gonadotropin, CT=computerized tomography, MRI=magnetic resonance imaging, ANCA=antineutrophil cytoplasmic antibody levels, RAST=radioallergosorbent test, NSAID=nonsteroidal antiinflammatory drugs, NARES=nonallergic rhinitis with eosinophilia, ACE=angiotensinogen converting enzyme

DIAGNOSTIC STUDIES IN CHRONIC RHINOSINUSITIS

Allergy and immunological evaluation will provide the role of etiologies in rhinosinusitis and provide guidelines for specific therapy. Imaging studies are crucial to the diagnostic evaluation of chronic rhinosinusitis. Standard radiological studies such as a plain roentgenogram of the sinuses offers little diagnostically as it does not allow visualization of all the sinuses. On the other hand, computerized tomography (CT) and magnetic resonance imaging (MRI) offer excellent diagnostic advantages. A modified or limited CT scan of the sinuses often allows visualization of all the major sinuses and may also permit observation of abnormalities of the osteomeatal complex. Disorders such as nasal polyposis, septal spurs and concha bullosa are readily visible on CT scanning. MRI is more sensitive for fungal sinusitis which produces a low signal intensity and appears black, compared to bacterial or viral sinusitis. On the other hand, a black-appearing MRI may be mistakenly read as being normal when air is present in association with a fungal infection. Neoplasia can also be detected by both MRI and CT scanning. Ultrasonography however, has a poor sensitivity and specificity for sinusitis and is best avoided except in rare situations such as in pregnancy. Fiberoptic rhinoscopy, readily available in an outpatient setting in many offices, provides a means for the physician to directly observe the anatomical structures lining the nasal passages. Nasal polyps, purulent sinusitis, osteomeatal abnormalities and neoplasia can be readily diagnosed by an experienced practitioner skilled in upper airway endoscopy.

MANAGEMENT OF CHRONIC RHINOSINUSITIS

General treatment measures

General treatment measures are employed to provide a favorable nasal environment through moisturization, humidification and reduction of swelling.

Moisturization

Saline nasal sprays have been shown to reduce the symptoms of both allergic and nonallergic rhinitis (23) and is helpful in rhinosinusitis as the nasal cavity is moisturized, dryness is reduced, and inspissated or crusty mucus is more easily cleared. Some clinicians recommend that vinegar be added to the saline to establish a more normal pH and others employ hydrogen peroxide to help clean the nose and sinuses.

Humidification

Since mucociliary transport is slowed and mucus becomes thickened in dry environments, humidification may be helpful. This is accomplished with either warm or cool mist. While this modality is used to reduce symptoms, it has not been validated by controlled studies. If excessive humidification is avoided, this adjunctive measure is safe and inexpensive (11).

Specific pharmacotherapy

Mucolytics

The use of mucolytics, such as guaifenesin, should be beneficial in the treatment of rhinosinusitis since they thin mucus and reduce mucus stasis. Demonstration of reduced nasal congestion and improved drainage has been observed in one double-blind, placebo-controlled study (33).

Decongestants

When the alpha-adrenergic receptors in the mucosa of the upper airways are stimulated, there is vasoconstriction of the mucosal capillaries with shrinkage of swollen and edematous mucosa (8). The decrease in nasal swelling and obstruction would be expected to improve ventilation. Topical decongestants (oxymetazoline hydrochloride, xylometolazine, naphazoline, phenylephrine), generally accomplish significant relief of obstruction with minimal systemic effects. Although the patient may benefit symptomatically, it is not clear that the reduction of nasal swelling translates into a positive effect on rhinosinusitis. Some evidence suggests a negative effect attributed to impairment of normal local defense mechanisms by decreasing mucosal blood flow (4). Nevertheless, topical decongestants usually reduce the patient's symptoms and might speed recovery in those with rhinosinusitis. Topical decongestants should probably not be used for longer than 3 days due to rebound congestion. Systemic decongestants (pseudoephedrine, phenyephrine) can be used during the entire course of rhinosinusitis. They can be expected to alleviate symptoms in a similar fashion but must be used with caution in patients who have hypertension, coronary artery disease, diabetes mellitus, hyperthyroidism or require monoamine oxidase inhibitors.

Antihistamines

Antihistamines exert a competitive antagonism of histamine binding to H1 receptors on nerve endings, smooth muscle cells, and glandular cells. They also have anticholinergic antimuscarinic action, local anesthetic and antiserotonin effects. In patients with allergic rhinitis, sneezing and rhinorrhea can be reduced - although the precise mechanism is still unclear (5). Newer antihistamines have unique properties beyond the recognized antihistamine mechanism. Azatadine maleate, azelastine and cetririzine have leukotriene-inhibiting properties in vivo (21). These actions make antihistamines helpful in preventing and treating acute and chronic allergic rhinosinusitis. In particular, antihistamines may decrease the stasis of mucus within the sinuses that sets up conditions conducive to secondary infection. The concern for antihistamines resulting in excessive drying of secretions leading to crust formation is only minor when using the second-generation antihistamines (26).

Ipratropium bromide nasal spray

Topical nasal ipratropium bromide works well in controlling nasal discharge. It also works by blocking mucosal cholinergic receptors. Studies regarding its efficacy in rhinosinusitis are lacking.

Topical Steroids

Topical steroids reduce the sensitivity of the cholinergic receptors, reduce the number of basophils in the nasal epithelium, reduce the number of eosinophils in mucosa and inhibit the ate-phase reaction following antigen exposure (25). These actions translate into decreased secretory response in both allergic and nonallergic rhinitis and chronic sinusitis. Used properly, the topical nasal steroids exert their beneficial action without significant systemic effects. These preparations can be used as an adjunct to antibiotic therapy, improving symptoms and aiding resolution of infectious rhinosinusitis. Topical corticosteroids provide the safest and widest efficacy with negligible side effects (27). And seem to have the best impact on relieving sinus blockage. Several topical steroid sprays are available commercially (fluticasone, triamcinalone, mometasone, flunisolide, beclomethasone etc) (6).

Topical cromolyn sodium

Cromolyn sodium stabilizes mast cell membranes and its topical use has been an alternative to steroids in patients with chronic rhinosinusitis and atopy. However, its 4 to 5 times per day dosing schedule is cumbersome and decreases compliance. It remains a useful prophylactic treatment before an anticipated exposure to a known allergen.

Systemic steroids

Oral steroids have been effective in allergic rhinosinusitis. Their major action is in the reduction of tissue edema by inhibiting the production of the mediators of inflammation such as prostaglandins, lymphokines, leukotrienes, bradykinins, serotonin, and interferon (22). We now know that glucocorticoids work by modulating the expression and activation of transcription factors such as nuclear factor kappaB (3). Systemic steroids can have significant troublesome side effects and since there are less risky medications available, they are not routinely used in acute rhinosinusitis. When used in more chronic situations, the clinician must monitor the patient for both short and long-term complications.

Antibiotics

Acute viral rhinosinusitis and most cases of bacterial infection improve spontaneously. In more severe bacterial infections antibiotics are generally prescribed. Typically this is empiric therapy that utilizes broad-spectrum antibiotics such as amoxycillin, erythromycin, or cefadroxil used for 5-10 day courses. Failure to respond should suggest bacterial resistance or raise doubts about the accuracy of diagnosis. Referral to an ENT specialist at this point may be important especially if symptoms are progressive or suggestive of an orbital or intracranial complication. In this situation drainage, culture of the organism and parenteral antibiotics may be necessary.
In chronic infectious, oral antibiotic therapy is directed against coagulase-positive and coagulase-negative staphylococcus species and streptococcus species. There is no consensus as to whether anaerobic coverage is necessary. In addition to antibiotic selection, it must be recognized that tissue penetration varies. Treatment is typically carried out for a longer period of time, usually 4 to 6 weeks.
Although direct aspiration for culture is not needed as a routine measure in acute rhinosinusitis, cultures should be obtained in all immunocompromised patients and in patients whose symptoms persist during therapy. The culture specimen can be obtained from the middle meatus under direct endoscopic guidance. The information regarding the pathogen and its drug sensitivities can then help guide specific antibiotic selection.

Surgical therapy

Surgical intervention is most commonly used in patients with chronic rhinosinusitis who are refractory to an appropriate medical therapy and patients with recurrent acute rhinosinusitis in which an obstruction to sinus drainage can be identified (2). Limited surgery in the area of the ostiomeatal complex, that area into which the anterior ethmoids, maxillary, and frontal sinuses drain, is often sufficient to improve the drainage of these dependent sinuses without the more radical extirpation of sinus mucosa required in the past. Surgery on the nasal septum and turbinates is less often required as experience in the last decade has indicated that extrasinus infections can usually be addressed with a transnasal drainage of the affected sinus into the nasal cavity. An external approach is indicated when an extrasinus infection progresses beyond cellulitis to abscess formation. Case series indicate that 80-90% of patients who have functional endoscopic surgery enjoy complete to moderate relief of symptoms. In experienced hands the rate of significant complication is less than 2% (15).

Immunotherapy

Immunotherapy is perceived by many investigators as helpful in controlling allergies and preventing the recurrence of rhinosinusitis. There are, however, no studies to support the benefits of immunotherapy. This may reflect the observation that allergy may not play a significant role in 50% of patients with chronic rhinosinusitis (28). Nevertheless, if allergy evaluation suggests a significant role for inhalant sensitivity in a given patient, immunotherapy ,may be indicated. Moreover, the interrelationship of allergy and chronic rhinosinusitis is accepted in many patients. Selected individuals with an allergic component may benefit from immunotherapy as allergen-specific immunoglobulin G-blocking antibodies are stimulated. Other advantages of immunotherapy include, but are not limited to, a drop in the allergen-specific immunoglobulin E antibodies, a decrease in the release of basophil histamine in response to allergen challenge,, an increase in allergen-specific suppressor T cells, and a decrease in the lymphocyte-cytokine response to an allergen challenge (5). Immunotherapy should be considered in patients who fail to respond to a combination of environmental control measures and medications, who experience significant side effects from medications, who have symptoms for a significant portion of the year that require daily therapy, or who prefer long-term modulation of their allergic symptoms (6).

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