ACP medicine, 3rd Edition

Immunology/Allergy

Allergic Rhinitis, Conjunctivitis, and Sinusitis

Raymond G. Slavin MD, MACP1

1Professor of Internal Medicine and Microbiology, and Director, Division of Allergy and Immunology, Saint Louis University School of Medicine

The author has received grants for clinical research from Genentech, Inc., and for educational activities from AstraZeneca Pharmaceuticals LP and has served as a consultant for Dey, Inc., and Aventis.

January 2005

Allergic rhinitis, conjunctivitis, and sinusitis are closely related disorders. Allergic rhinitis and conjunctivitis share the same causes and pathophysiology; sinusitis typically occurs as a complication of allergic rhinitis.

Allergic Rhinitis

Allergic rhinitis is an allergic inflammatory response in the nose. It can be classified as seasonal or perennial, depending on the allergens triggering the reaction.

EPIDEMIOLOGY

Allergic rhinitis is the most common atopic disorder in the United States. It affects about 24 million Americans—an estimated 8% of the population—with an equal distribution between males and females.1 The prevalence of allergic rhinitis varies by age: 32% of patients are 17 years of age or younger, 43% are 18 to 44 years of age, 17% are 45 to 64, and only 8% are 65 years of age or older. The costs of treating allergic rhinitis (and indirect costs of the disorder, such as lowered productivity and time lost from work or school) are substantial. The total direct health care cost of treating allergic rhinitis is estimated at $3.4 billion.1

ETIOLOGY AND PATHOPHYSIOLOGY

The airborne allergens responsible for allergic rhinitis can be divided into seasonal (trees, grass, weeds, and mold) and nonseasonal or perennial (house dust mites, pets, insects).2 These aeroallergens land on the nasal mucosa, are processed by antigen-presenting cells, and are then presented to helper T cells. In genetically predisposed persons, this interaction promotes the generation and release of cytokines that induce B cells to produce antigen-specific IgE. The IgE attaches to receptors on mast cells and basophils, and the patient is thereby sensitized. On subsequent exposure, the allergen bridges IgE molecules, resulting in release of mediators, most notably histamine.3Histamine causes increased epithelial permeability, vasodilatation, and stimulation of a parasympathetic reflex. As a result, acetylcholine is released, resulting in marked hypersecretion of mucus and increased blood flow. Activation of centers in the central nervous system results in sneezing.

DIAGNOSIS

Clinical Manifestations

Symptoms of allergic rhinitis may include paroxysms of sneezing, nasal congestion, clear rhinorrhea, and itching of the nose and palate. Distinct temporal patterns of symptom production may aid diagnosis. For example, seasonal allergic rhinitis symptoms typically appear during a specific time of the year when aeroallergens are abundant in the outside air. Symptoms of rhinitis that occur whenever the patient is exposed to a pet with fur suggest IgE-mediated sensitivity to that species.4 Allergic rhinitis may result in fatigue and significant disability.

Physical Examination

The patient with allergic rhinitis may appear uncomfortable, exhibiting mouth breathing. Children in particular may have so-called allergic shiners (dark rings under the eyes). Allergic shiners develop because the edematous nasal tissue compresses the veins that drain the eyes, leading to pooling of blood under the orbits. On the bridge of the nose, a so-called allergic crease may be present—a result of continued upward rubbing of the tip of the nose (the so-called allergic salute). On nasal examination, the mucosa typically appears pale and swollen, with a bluish-gray appearance when the mucosal edema is severe. Many patients have a normal examination, although they often may be sneezing and have rhinorrhea with mucosal edema. The other physical findings tend to be present in the more severely affected patients.

Laboratory Testing

Although a careful history is the most important step toward the diagnosis of allergic disease, skin testing may be useful in pinpointing the offending allergen [see 6:XI Diagnostic and Therapeutic Principles in Allergy]. The simplicity, ease and rapidity of performance, low cost, and high sensitivity of skin tests make them preferable to in vitro testing.5

DIFFERENTIAL DIAGNOSIS

The two nasal conditions most commonly confused with allergic rhinitis are infectious rhinitis and perennial nonallergic rhinitis (vasomotor rhinitis). Infectious rhinitis is characterized by constitutional symptoms and purulent rhinorrhea. A nasal smear shows a preponderance of neutrophils, whereas in allergic rhinitis, eosinophils predominate. Perennial nonallergic rhinitis is more frequent in women and is precipitated by such nonspecific factors as changes in temperature, humidity, and barometric pressure; strong odors; alcohol; and cigarette smoke. Nasal congestion frequently shifts from side to side and is often alleviated by exercise.6

TREATMENT

Therapy for allergic rhinitis comprises three elements: first, minimizing contact with the allergen (environmental control); second, pharmacotherapy; and third, immunotherapy, which is reserved for selected patients. Together, these treatments ensure an excellent prognosis for allergic rhinitis.

Environmental Control

Reducing or completely avoiding the offending allergen is a vital part of allergy management [see 6:XI Diagnostic and Therapeutic Principles in Allergy]. In the case of seasonal allergies, keeping the doors and windows closed and the air conditioning on will reduce the aeroallergen burden manyfold.7 Measures to avoid house dust mites should focus on the patient's bedroom and include encasing the mattress, box spring, and pillows in occlusive covers; weekly washing of bedding at 130° F or hotter, dehumidification to less than 50%; and removal of reservoirs, such as carpeting. Removal of pets is the optimal approach for pet-sensitive patients. If the patient will not part with the pet, weekly washing of the animal will reduce airborne levels of its allergen.8 Also, patients with allergic rhinitis appear to be more sensitive to nonspecific irritants, such as cigarette smoke.9

Pharmacotherapy

Oral antihistamines are effective in reducing itching, sneezing, and rhinorrhea from allergic rhinitis. A major limitation of the first-generation (classic) antihistamines has been sedation. The second-generation antihistamines—cetirizine (Zyrtec), fexofenadine (Allegra), and loratadine (Claritin) and its metabolite desloratadine (Clarinex)—produce significantly less sedation. In patients with nasal congestion, an antihistamine-decongestant combination can be used.10 An intranasal antihistamine spray (Astelin) has also proved to be efficacious. In severe cases, a short course of oral corticosteroids may be needed.

The most effective medications for controlling symptoms of allergic rhinitis are nasally inhaled corticosteroids.11 They include beclomethasone (Beconase), budesonide (Rhinocort), flunisolide (Flonase), mometasone (Nasonex), and triamcinolone (Nasacort). These agents are generally not associated with significant systemic side effects. Local side effects (e.g., nasal irritation and a burning sensation) are minimized if patients are instructed to direct the spray toward the ear and away from the septum.

Leukotriene receptor antagonists have been approved for use in allergic rhinitis and can be considered as a component of combination therapy, particularly if there is associated asthma.

Omalizumab (Xolair) is a recombinant, humanized, monoclonal anti-IgE antibody for treatment of moderate to severe asthma. It has been shown to significantly reduce serum IgE and to have beneficial effects on allergic rhinitis.12 However, its cost and the present indication by the Food and Drug Administration only for asthma preclude its routine use in allergic rhinitis.

Immunotherapy

Allergen immunotherapy is highly effective in controlling symptoms of allergic rhinitis. It should be considered in patients with severe symptoms that cannot be controlled by other treatment modalities and in those with comorbid conditions such as asthma. Immunotherapy may prevent worsening of asthma or possibly prevent its development.13 The effectiveness of symptomatic medications, particularly intranasal corticosteroids, has made immunotherapy less necessary.

COMPLICATIONS

There is good evidence that poorly managed allergic rhinitis can result in otitis media14 and sinusitis.15 Rhinitis and asthma frequently coexist.16 More than that, rhinitis appears to be a risk factor for development of asthma,17,18 and treatment of rhinitis can improve coexisting asthma.19 Prevention of asthma is an especially important goal in patients with a family history of asthma or atopic disease and early sensitization to aeroallergens.20

Allergic Conjunctivitis

Allergic conjunctivitis is the ocular counterpart of allergic rhinitis, and the two often occur together. Approximately 70% of patients with allergic conjunctivitis have an associated atopic disease, such as allergic rhinitis, asthma, or atopic dermatitis.

EPIDEMIOLOGY

Seasonal and perennial allergic conjunctivitis are the most prevalent forms of ocular allergy. Most reports agree that allergic conjunctivitis affects up to 20% of the world's population.21

ETIOLOGY AND PATHOGENESIS

Allergic conjunctivitis is triggered by the same aeroallergens and results from the same pathophysiologic processes as allergic rhinitis [seeAllergic Rhinitis, Etiology and Pathophysiology, above].

DIAGNOSIS

Clinical Manifestations

Patients with allergic conjunctivitis present with itching of the eyes, accompanied by tearing and a burning sensation. The reaction is usually bilateral, although unilateral conjunctivitis may occur in a patient who has had direct hand-to-eye contact with an allergen such as dog or cat dander.

The periocular tissues are usually swollen and reddened. The conjunctiva is injected, with mild to moderate chemosis, and there is a ropy mucous discharge in the tear film.

Laboratory Tests

Although examination of the ocular discharge in allergic conjunctivitis typically reveals large numbers of eosinophils, this test is almost never done. Instead, allergic conjunctivitis is generally diagnosed clinically. As with allergic rhinitis, skin testing may be performed to identify the offending allergen or allergens [see Allergic Rhinitis, Laboratory Testing, above].

DIFFERENTIAL DIAGNOSIS

The eye condition that is most likely to be confused with allergic conjunctivitis is infectious conjunctivitis (viral or bacterial). Patients with infectious conjunctivitis complain of matting of the eyelids, with a clear to mucopurulent ocular discharge. The conjunctiva is deeply red, and although a burning sensation is common, itching is not as profound as in allergic conjunctivitis. Vernal conjunctivitis, which may also be confused with allergic conjunctivitis, is a severe, bilateral recurrent condition of the eye often occurring in the spring. It is marked by intense pruritus and a typical cobblestone appearance of the upper eyelid.

TREATMENT

Because allergic conjunctivitis results from the same allergens as allergic rhinitis, environmental control measures and immunotherapy are also the same [see Allergic Rhinitis, Treatment, above].

Drug treatment for allergic conjunctivitis typically begins with a topical over-the-counter antihistamine-decongestant combination such as antazoline-naphazoline (Vasocon-A) or pheniramine-naphazoline (Naphcon-A).21 The next line of therapy would include a selective H1receptor antihistamine, a category that includes ketotifen (Zaditor), epinastine (Elestat), levocabastine (Livostin), azelastine (Optivar), and olopatadine (Patanol). Ketotifen, epinastine, and olopatadine also have mast cell-stabilizing properties. A meta-analysis confirms the benefit of topical mast cell stabilizers and antihistamines over placebo for the treatment of allergic conjunctivitis.22 An additional therapeutic option is a nonsteroidal anti-inflammatory agent such as ketorolac (Acular).21 For the most severe cases of allergic conjunctivitis, the clinician may consider giving corticosteroid eyedrops—loteprednol etabonate (Lotemax) or rimexolone (Vexol)—for 2 to 3 weeks. Long-term use of these agents has been associated with the development of glaucoma, cataracts, and secondary infection and hence should be managed by an ophthalmologist.

Sinusitis

DEFINITION AND CLASSIFICATION

It has been suggested that the term rhinosinusitis may be more accurate than the term sinusitis, for the following reasons: (1) rhinitis typically precedes sinusitis, (2) sinusitis without rhinitis is rare, (3) the mucosa of the nose and sinuses are contiguous, and (4) symptoms of nasal discharge are prominent in sinusitis.23

Rhinosinusitis is classified as acute, recurrent acute, subacute, and chronic. Acute sinusitis is defined as inflammation of the sinuses for less than 4 weeks. Subacute sinusitis, lasting from 4 to 8 weeks, is the development and manifestation of minimal to moderate signs of sinus inflammation without an overt upper respiratory tract infection (URI) or abrupt onset of symptoms. Chronic sinusitis is defined as persistent sinus inflammation for more than 8 weeks. An operational definition of chronic sinusitis is persistent inflammation, documented with imaging techniques, continuing for at least 4 weeks after initiation of appropriate medical therapy in the absence of an intervening acute episode.

EPIDEMIOLOGY

Rhinosinusitis is the most frequently reported chronic disease in the United States, affecting 16% of the adult population. Chronic rhinosinusitis accounts for 11.6 million physician office visits a year, and the overall direct cost in the United States is estimated to be $4.3 billion annually.24

In one study of patients with rhinosinusitis, a 36-item health survey showed significant worsening in several domains, including bodily pain, general health, vitality, and social functioning. Comparison with other chronic diseases (e.g., chronic obstructive pulmonary disease, heart failure, angina, and back pain) revealed significantly worse bodily pain and social functioning in patients with sinusitis.25

PATHOGENESIS

The paranasal sinuses are composed of the ethmoid, frontal, maxillary, and sphenoid sinuses [see Figure 1]. Microorganisms, pollutants, irritants, and other foreign particles that escape the filtering apparatus of the nose are trapped in the mucus of the sinuses. The steady beating of the cilia that line the sinuses moves mucus out of the sinuses and into the nasal passages via the drainage ostia. This ongoing clearance of the sinuses is important for maintaining health.

 

Figure 1. Drainage of Paranasal Sinuses

The paranasal sinuses drain into the nasal passages via narrow ostia. The ostium through which the maxillary sinus drains is on the superior medial wall of the sinus, and hence the maxillary sinuses drain against the force of gravity. Edema of the nasal mucosa from allergic rhinitis can obstruct the ostia, and the resulting accumulation of mucus within the sinuses promotes bacterial infection.

The key factors that predispose an individual to rhinosinusitis are local [see Table 1]. The most common of these are viral URIs and allergic rhinitis. Edema of the nasal mucosa, which is characteristic of acute infectious or allergic rhinitis, results in obstruction of the ostia, decreased ciliary action in the paranasal sinuses, and increased mucus volume and viscosity. The subsequent accumulation of mucus in the sinus provides an environment for secondary bacterial infection and the conversion of mucus to mucopus.

Table 1 Factors Predisposing to Sinusitis

Upper respiratory infection

Allergic rhinitis
Anatomic variants
   Septal deviation
   Haller cells (infraorbital ethmoid cells)
Hypertrophied adenoids
Nasal polyps, chronic mucosal thickening
Nasal or sinus tumors

Foreign bodies

Cigarette smoke
Swimming and diving; barotraumas
Rhinitis midicamentosa
Cocaine abuse
Nasal intubation
Periapical abscess in a protruding tooth
Dental extraction or injections

Cultures from both adults and children with acute sinusitis grow predominantly aerobic organisms, with the heaviest yield beingStreptococcus pneumoniae, Haemophilus influenzae, and Moraxella (formerly Branhamellacatarrhalis. Although the role of viruses and bacteria in causing acute infectious sinusitis is well established, the role of microbial infection in chronic sinus disease is much less clear. It was once believed that anaerobic organisms were responsible for instances of chronic sinusitis, but aerobes have now been implicated as the major cause. A noninfectious form of chronic rhinosinusitis, sometimes referred to as chronic hyperplastic eosinophilic rhinosinusitis, is marked by a preponderance of eosinophils and mixed mononuclear cells and by a paucity of neutrophils. It is often associated with nasal polyps, asthma, and aspirin sensitivity.26

DIAGNOSIS

Clinical Manifestations

Acute sinusitis

The most important clinical clue to the diagnosis of acute sinusitis is the failure of symptoms to resolve after a typical cold. The previously clear nasal discharge becomes yellow or green. Fever persists and chills may develop. Pain is often felt in the cheek, or it may be referred to the forehead. The discomfort is often worse on bending over or straining. If the ostium of the maxillary sinus is blocked, pain may be severe and felt in the teeth.

On physical examination, thick, purulent, green or deep-yellow secretions are seen in the nose on the side of the diseased sinus. Because the maxillary sinus is most frequently involved, purulent secretions will be seen most often in the middle meatus, which is the drainage site of the maxillary sinus [see 7:XIX Bacterial Infections of the Upper Respiratory Tract]. The middle meatus may be hidden by the middle turbinate, so it may be necessary to shrink the turbinate with a topical decongestant. Once this is accomplished, the nose, particularly the middle meatus, can be examined thoroughly not only for pus but also for underlying problems, such as nasal septal deviation, spurs, and polyps. Frequently, a streak of pus is visible along the lateral wall of the oropharynx. When the diagnosis of sinusitis is in doubt, referring the patient to an otolaryngologist for fiberoptic nasopharyngoscopy can be helpful, because this technique affords a better opportunity for visualization of the drainage ostia of infected sinuses.

Chronic sinusitis

If mucopus is not evacuated, acute sinusitis may enter a subacute or chronic phase. Chronic maxillary sinusitis may exist alone, but it is usually associated with chronic ethmoid and frontal sinusitis. The lack of pain or systemic symptoms makes chronic sinusitis difficult to diagnose on history alone. A patient may complain of dull pressure in the face or head. Chronic sinusitis generally presents as persistent, sometimes unilateral nasal stuffiness, hyposmia, purulent nasal and postnasal secretions, sore throat, fetid breath, and malaise. The secretions often pool in the hypopharynx at night, and the patient complains of increasing postnasal drainage with resultant cough and, sometimes, wheezing. On physical examination, a patient with chronic sinusitis may display an edematous and hyperemic nasal mucosa bathed in mucopus. Nasal polyps may accompany chronic sinusitis.

Nasal Smear and Sinus Culture

Nasal culture does not give an adequate picture of the organisms responsible for sinusitis. Microscopic examination of nasal secretions, however, may be of great diagnostic value. In instances of sinusitis, one sees sheets of polymorphonucleur neutrophils and bacteria. This is unlike viral URIs, in which polymorphonuclear neutrophils are scanty, or allergic rhinitis, in which a high percentage of eosinophils may be seen. Antral puncture provides a true specimen of the microbiology of the sinus cavity and is generally performed by an otolaryngologist when it is important to determine the pathogen (e.g., if fungal infection is suspected).27

Radiology

Two imaging modalities are used for the diagnosis of sinusitis: plain x-rays and computed tomography. In adults, plain films of the sinuses that show mucosal thickening greater than 8 mm, an air-fluid level, or opacification have been shown to correlate with positive bacterial cultures on antral punctures. In children older than 1 year, abnormal findings on maxillary sinus radiographs are generally related to inflammation of the upper airway. Crying has not been shown to be a cause of abnormalities on sinus radiographs in these children.28

The diagnostic value of plain films is controversial. Some authorities advise against plain radiographic studies, particularly for diagnosing chronic sinusitis. Conventional radiographs can depict changes of acute sinusitis in maxillary, ethmoid, frontal, and sphenoid sinuses but cannot delineate the status of individual ethmoid air cells or the osteomeatal complex, nor can they accurately show the extent of inflammatory disease in affected patients. For these reasons, CT is the radiographic modality of choice for examining the paranasal sinuses. Coronal CT scans demonstrate the osteomeatal complex and detect subtle disease that is not shown on plain films. The cost of CT scans used to be prohibitive, but through improved technology and the use of limited slices, the price has been reduced to the point where it is quite close to that of plain films in most centers. A limited four-slice coronal CT scan of the sinuses provides much more information than plain films do, and compared with full CT, four-slice coronal CT provides the increased information at a much reduced radiation dose and cost.29

Transillumination and ultrasonography are used in the diagnosis of sinusitis. Both are subject to great error, however, and cannot be recommended at the present time.

Ancillary Laboratory Tests

Other laboratory tests may have to be considered in some cases of treatment-resistant sinusitis. Underlying allergy can be determined by appropriate skin testing after a careful history has identified likely allergens. Immunologic testing may be indicated, because patients with refractory sinusitis may have immune dysfunction.30 Associated immunodeficiency is diagnosed by serum immunoglobulin levels and by antibody responses to specific antigens such as pneumococci, diphtheria, and tetanus. Other considerations in medically resistant sinusitis include cystic fibrosis, fungal infection, and anatomic abnormalities.

DIFFERENTIAL DIAGNOSIS

The condition most often misdiagnosed as rhinosinusitis is a viral URI, which is the most important predisposing cause of acute rhinosinusitis. Rhinosinusitis is probably present if the URI symptoms do not resolve in 3 to 6 days; if the secretions, particularly postnasal secretions, turn yellow or green and persist throughout the day; and if the patient notes fullness of the head and discomfort in the face and teeth.

TREATMENT

Concern has been raised about the overdiagnosis of rhinosinusitis and unnecessary treatment with antibiotics of uncomplicated viral upper respiratory infection. More strict criteria for the use of antibiotics are symptoms for 10 to 14 days or severe symptoms, such as fever with purulent nasal discharge, facial pain or tenderness, and periorbital swelling.31,32

The antibiotic of choice for treatment of acute sinusitis is ampicillin or amoxicillin. An appropriate dosage of amoxicillin for acute sinusitis in the adult is 875 mg twice a day for 10 to 14 days. In patients with penicillin sensitivity, trimethoprim-sulfamethoxazole (one double-strength tablet twice a day) is an adequate alternative. More and more cases of β-lactamase-producing organisms are being reported. In penicillin-resistant sinusitis, recommended antibiotics include amoxicillin with clavulanic acid (Augmentin), the quinolones (e.g., levofloxacin [Levaquin]), and telithromycin (Ketek). Antibiotic treatment for chronic sinusitis should be continued for at least 2 weeks. If the patient reports feeling better by the last day of the regimen but still has purulent nasal discharge, the antibiotic can be continued for another 5 to 7 days.

Ancillary treatments for sinusitis, including oral decongestants and mucus thinners, have been advocated, but there are no controlled studies showing their effectiveness. The addition of intranasal corticosteroids may be modestly beneficial in the treatment of patients with recurrent acute or chronic rhinosinusitis.33

In some cases of chronic resistant sinusitis, surgical treatment must be considered. A wide array of surgical procedures are available, but functional endoscopic sinus surgery (FESS) has emerged as the technique of choice.34

COMPLICATIONS

Complications of sinusitis have decreased in incidence since the introduction of antibiotics. The complications most commonly encountered are cellulitis, abscess, and cavernous sinus thrombosis (all involving the orbit); epidural or subdural abscess; mucocele formation; and osteomyelitis.35 It is evident in both children36 and adults37 not only that there is an association between sinusitis and asthma but also that sinusitis is an important trigger for asthma. In a patient who has both sinusitis and asthma, the asthma will be difficult to manage until the sinusitis is brought under control by either medical or surgical means.

PROGNOSIS

The prognosis for patients with sinusitis should be excellent if the diagnosis is made accurately and promptly and an appropriate antibiotic is administered for a sufficient period of time. Consultation with a specialist should be sought in the following situations:

  • If there is a need to clarify the allergic or immunologic basis for sinusitis.
  • If sinusitis is refractory to the usual antibiotic treatment.
  • If sinusitis is recurrent.
  • If sinusitis is associated with unusual opportunistic infections.
  • If sinusitis significantly affects performance and quality of life.

Consultation is also appropriate when concomitant conditions are present that complicate assessment or treatment, including chronic otitis media, bronchial asthma, nasal polyps, recurrent pneumonia, immunodeficiencies, aspirin sensitivity, allergic fungal disease, granulomas, and multiple antibiotic sensitivities.

Acknowledgment

Figure 1 Alice Y. Chen.

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Editors: Dale, David C.; Federman, Daniel D.