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Rhinitis and sinusitis

  • Mark S. Dykewicz
    Correspondence
    Reprint requests: Mark S. Dykewicz, MD, Center for Human Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157.
    Affiliations
    Allergy and Immunology Unit, Section of Pulmonary, Critical Care Allergy and Immunologic Diseases, Department of Internal Medicine, Center for Human Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC
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  • Daniel L. Hamilos
    Affiliations
    Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital/Harvard Medical School, Boston, Mass
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      Rhinitis and sinusitis are among the most common medical conditions and are frequently associated. In Western societies an estimated 10% to 25% of the population have allergic rhinitis, with 30 to 60 million persons being affected annually in the United States. It is estimated that sinusitis affects 31 million patients annually in the United States. Both rhinitis and sinusitis can significantly decrease quality of life, aggravate comorbid conditions, and require significant direct medical expenditures. Both conditions also create even greater indirect costs to society by causing lost work and school days and reduced workplace productivity and school learning. Management of allergic rhinitis involves avoidance, many pharmacologic options, and, in appropriately selected patients, allergen immunotherapy. Various types of nonallergic rhinitis are treated with avoidance measures and a more limited repertoire of medications. For purposes of this review, sinusitis and rhinosinusitis are synonymous terms. An acute upper respiratory illness of less than approximately 7 days' duration is most commonly caused by viral illness (viral rhinosinusitis), whereas acute bacterial sinusitis becomes more likely beyond 7 to 10 days. Although the mainstay of management of acute bacterial sinusitis is antibiotics, treatment of chronic sinusitis is less straightforward because only some chronic sinusitis cases have an infectious basis. Chronic rhinosinusitis (CRS) has been subdivided into 3 types, namely CRS without nasal polyps, CRS with nasal polyps, and allergic fungal rhinosinusitis. Depending on the type of CRS present, a variety of medical and surgical approaches might be required.

      Key words

      Abbreviations used:

      ABRS (Acute bacterial rhinosinusitis), AERD (Aspirin-exacerbated respiratory disease), AFRS (Allergic fungal rhinosinusitis), AR (Allergic rhinitis), CRS (Chronic rhinosinusitis), CRScNP (Chronic rhinosinusitis with nasal polyposis), CRSsNP (Chronic rhinosinusitis without nasal polyposis), CT (Computed tomography), FDA (US Food and Drug Administration), FESS (Functional endoscopic sinus surgery), INS (Intranasal corticosteroids), LTRA (Leukotriene receptor antagonist), NARES (Nonallergic rhinitis with eosinophilia syndrome), PAR (Perennial allergic rhinitis), PRN (As required), SAR (Seasonal allergic rhinitis), URI (Upper respiratory tract infection)
      Rhinitis and sinusitis are among the most common medical conditions and are frequently associated.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      An estimated 10% to 25% of the population in Western societies has allergic rhinitis.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Sinusitis affects an estimated 31 million persons annually in the United States.
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.
      Both rhinitis and sinusitis can significantly decrease quality of life, aggravate comorbid conditions, and require significant direct medical expenditures. Both conditions also create even greater indirect costs to society by causing lost work and school days, as well as reduced workplace productivity and school learning.
      For the purposes of this review, sinusitis and rhinosinusitis are synonymous terms.

      Rhinitis

       Background

      Although semantically, the term rhinitis implies inflammation of the nasal mucous membranes, inflammatory cell infiltrates are not characteristic of all disorders considered to be rhinitis. As a clinical term, rhinitis refers to a heterogeneous group of nasal disorders characterized by 1 or more of the following symptoms: sneezing, nasal itching, rhinorrhea, and nasal congestion.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Rhinitis can be caused by allergic, nonallergic, infectious, hormonal, occupational, and other factors.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Allergic rhinitis is the most common type of chronic rhinitis, but 30% to 50% of patients with rhinitis have nonallergic triggers. Preliminary data suggest that 44% to 87% of patients with rhinitis might have mixed rhinitis, a combination of allergic and nonallergic rhinitis.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      • Settipane R.A.
      • Charnock D.R.
      Epidemiology of rhinitis: allergic and nonallergic.
      Worldwide, the prevalence of allergic rhinitis continues to increase. Studies suggest that seasonal allergic rhinitis (hay fever) is found in approximately 10% to 20% of the general population,
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      with an even greater prevalence in children. Overall, allergic rhinitis affects 30 to 60 million subjects in the United States annually.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.

      US Census Bureau. Available at: http://www.census.gov/index.html. Accessed October 24, 2009.

      Severe allergic rhinitis has been associated with diminished quality of life, disordered sleep (in as many as 76% of patients), obstructive sleep apnea, and impairment in work performance.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      In addition, rhinitis can contribute to sinusitis (see the section below on Sinusitis, comorbidities, and allergic rhinitis) and is frequently associated with asthma.

       Pathogenesis

       Nasal anatomy and physiology

      The nasal cavity (Fig 1) is divided by the nasal septum, which is composed of bone more proximally and cartilage more distally. The inferior, middle, and superior turbinates in the nasal cavity promote air filtration, humidification, and temperature regulation. The nasal cavity and turbinates are lined with mucosa comprised of pseudostratified columnar ciliated epithelium that overlies a basement membrane and the submucosa (lamina propria). The submucosa consists of serous and seromucous nasal glands, nerves, extensive vasculature, and cellular elements. Overlying the nasal epithelium is a thin layer of mucus that dynamically moves by means of ciliary action to the posterior nasopharynx. Infections (viral or bacterial) and allergic inflammation impair mucociliary clearance. Because nasal tissues are highly vascular, vascular changes can lead to significant nasal obstruction. Vasoconstriction and consequent decreases in nasal airway resistance result from sympathetic nerve stimulation. Parasympathetic nerve stimulation promotes secretion from nasal airway glands and nasal congestion. The nasal mucosa also contains nerves of the nonadrenergic noncholinergic system. Neuropeptides from the latter nerves (substance P, neurokinin A and K, and calcitonin gene–related peptide) are thought to play some role in vasodilatation, mucus secretion, plasma extravasation, neurogenic inflammation, and mast cell nerve interactions, but the relative clinical importance of neuropeptides needs further definition.
      • Rosenwasser L.
      New insights into the pathophysiology of allergic rhinitis.
      Figure thumbnail gr1
      Fig 1Nasal anatomy.
      Reprinted with permission from Dykewicz MS. Rhinitis and sinusitis. In: Rich RR, Fleischer TA, Shearer WT, Schroeder HW Jr, Frew AJ, Weyand CM, editors. Clinical Immunology. 3rd ed. London: Mosby Elsevier; 2008. p. 626-39.

       Allergic rhinitis

       Pathophysiology

      Common allergens causing allergic rhinitis include proteins and glycoproteins in airborne dust mite fecal particles, cockroach residues, animal danders, molds, and pollens. On inhalation, allergen particles are deposited in nasal mucus, with subsequent elution of allergenic proteins and diffusion into nasal tissues. In addition, small-molecular-weight chemicals in occupational agents or drugs can act as haptens that react with self-proteins in the airway to form complete allergens. Evidence extrapolated from asthma studies suggests that once in nasal tissues, common aeroallergens not only undergo antigen processing to elicit allergen-specific allergic responses but also promote development of allergic airway disease through their inherent properties. For example, protease activities of several common aeroallergens can facilitate allergen access to antigen-presenting cells by cleaving tight junctions in the airway epithelium and activation of protease-activated receptors on epithelial cells.
      • Hammad H.
      • Lambrecht B.N.
      Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma.
      Activated epithelial cells then produce cytokines, chemokines, and thymic stromal lymphopoietin, which interact with interepithelial and subepithelial dendritic cells to skew T-cell development and adaptive allergic sensitization. The house dust mite allergen Der p 2 mimics MD-2, the LPS-binding component of the Toll-like receptor 4 signaling complex,
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      and facilitates Toll-like receptor 4 signaling and airway TH2-type inflammation.
      • Trompette A.
      • Divanovic S.
      • Visintin A.
      • Blanchard C.
      • Hegde R.S.
      • Madan R.
      • et al.
      Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein.
      In the nose allergens are processed by antigen- presenting cells (dendritic cells expressing CD1a and CD11c and macrophages) in the nasal epithelial mucosa, with subsequent presentation of allergenic peptides by MHC class II molecules to T-cell receptors on resting CD4+ T lymphocytes in regional lymph nodes. With costimulatory signals, allergen-stimulated T cells proliferate into TH2-biased cells that release IL-3, IL-4, IL-5, IL-13, and other cytokines. These cytokines then lead to a cascade of events that promote B-cell isotype switching with subsequent local and systemic production of allergen-specific IgE antibody production by plasma cells, eosinophilic infiltration into the nasal epithelium and mucosa, and mast cell proliferation and infiltration of airway mucosa.

       Early/immediate allergic response

      Within minutes of inhalation of allergen in sensitized subjects, deposited allergens are recognized by IgE antibody bound to mast cells and basophils, causing degranulation and release of preformed mediators, such as histamine and tryptase, and the rapid de novo generation of mediators, including cysteinyl leukotrienes (leukotrienes C4, D4, and E4) and prostaglandin D2. Mediators cause plasma leakage from blood vessels and dilation of arteriovenous arteriole venule anastomoses, with consequent edema, pooling of blood in the cavernous sinusoids (the principal cause of the congestion of allergic rhinitis), and occlusion of the nasal passages. Mediators also stimulate active secretion of mucus from glandular and goblet cells. Histamine elicits itching, rhinorrhea, and sneezing, whereas other mediators, such as leukotrienes and prostaglandin D2, likely have more important roles in the development of nasal congestion. Stimulation of sensory nerves results in the perception of nasal congestion and itching and can provoke systemic reflexes, such as sneezing paroxysms.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Heppt W.
      • Dinh Q.T.
      • Cryer A.
      • Zweng M.
      • Noga O.
      • Peiser C.
      • et al.
      Phenotypic alteration of neuropeptide-containing nerve fibres in seasonal intermittent allergic rhinitis.

       Late-phase response

      Mediators and cytokines released during the early phase set off a cascade of events over the ensuing 4 to 8 hours that lead to an inflammatory response called the late response. Although clinical symptoms during the late phase might be clinically similar to those of the immediate reaction, nasal congestion is more prominent. The cysteinyl leukotrienes also play an active role in recruitment of inflammatory cells. Mediators and cytokines released during the early response act on postcapillary endothelial cells to promote expression of adhesion molecules, such as intercellular adhesion molecule 1, E-selectin, and vascular cell adhesion molecule 1, that promote adherence of circulating leukocytes, such as eosinophils, to endothelial cells. Factors with chemoattractant properties, such as IL-5 for eosinophils, promote the infiltration of the superficial lamina propria of the mucosa with many eosinophils, some neutrophils and basophils, and eventually CD4+ (TH2) lymphocytes and macrophages.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      These cells become activated and release more mediators, which in turn activate many of the proinflammatory reactions seen in the immediate response.

       Priming effect

      The amount of allergen necessary to elicit an immediate response becomes less when allergen challenges are given repeatedly, a phenomenon called the priming effect.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Wachs M.
      • Proud D.
      • Lichtenstein L.M.
      • Kagey-Sobotka A.
      • Norman P.S.
      • Naclerio R.M.
      Observations on the pathogenesis of nasal priming.
      During ongoing, prolonged allergen exposure and repeated late-phase/inflammatory responses, the nasal mucosa becomes progressively more inflamed and responsive to allergen. Clinically, the priming effect can explain why patients might have increasing symptoms despite decreasing aeroallergen levels as a season progresses and also provides the rationale for initiating effective anti-inflammatory rhinitis therapies before a pollen season or before other chronic or repetitive aeroallergen exposures. In addition, the priming effect from allergen is also associated with mucosal hyperresponsiveness to nonantigenic triggers, such as strong odors and cigarette smoke.

       Associated nonnasal symptoms

      Allergic rhinitis is often accompanied by allergic conjunctivitis (a complex sometimes referred to as allergic rhinoconjunctivitis) that results in conjunctival injection and chemosis and symptoms of itchy eyes and tearing.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      The prevalence and severity of conjunctival symptoms associated with allergic rhinitis vary with several factors, but one study found allergic conjunctivitis symptoms in more than 75% of patients with seasonal allergic rhinitis.
      • Bousquet J.
      • Knani J.
      • Hejjaoui A.
      • Ferrando R.
      • Cour P.
      • Dhivert H.
      • et al.
      Heterogeneity of atopy. I. Clinical and immunologic characteristics of patients allergic to cypress pollen.
      Sensitivity to pollens is more frequently associated with ocular symptoms than is sensitivity to house dust mites. Itching of the ears and throat can also be associated with allergic rhinitis.

       Association with asthma

      Allergic asthma and rhinitis are comorbid conditions that are associated pathophysiologically and epidemiologically.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Both are airway diseases in which IgE antibody sensitization to aeroallergens is a prominent feature. There is some evidence that systemic trafficking of inflammatory cells from local inflammation in one portion of the respiratory tract can induce inflammatory changes in the other, with one example being that segmental bronchial allergen challenge in patients with allergic rhinitis has been shown to result in both bronchial and nasal inflammatory responses.
      • Braunstahl G.J.
      • Kleinjan A.
      • Overbeek S.E.
      • Prins J.B.
      • Hoogsteden H.C.
      • Fokkens W.J.
      Segmental bronchial provocation induces nasal inflammation in allergic rhinitis patients.
      Treatment with intranasal corticosteroids in patients with allergic asthma and rhinitis has been shown to prevent the seasonal increase in bronchial hyperreactivity and to reduce existing bronchial hyperreactivity.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Corren J.
      • Adinoff A.D.
      • Irvin C.G.
      Changes in bronchial responsiveness following nasal provocation with allergen.
      • Foresi A.
      • Pelucchi A.
      • Gherson G.
      • Mastropasqua B.
      • Chiapparino A.
      • Testi R.
      Once daily intranasal fluticasone propionate (200 micrograms) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis.
      More than 80% of persons with allergic asthma have allergic rhinitis, and allergic rhinitis is a clear risk factor for the eventual development of asthma.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Guidelines recommend that patients with persistent allergic rhinitis should be evaluated for asthma and patients with asthma should be evaluated for rhinitis.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).

       Differential diagnosis, including forms of nonallergic rhinitis

      Some of the classic symptoms of allergic rhinitis (rhinorrhea, nasal congestion, sneezing, and nasal itching) overlap with symptoms associated with forms of nonallergic rhinitis (Table I) and various anatomic abnormalities of the upper airway (Table II), sometimes making it difficult to distinguish between these disorders on the basis of history alone.
      Table ITypes of rhinitis
      Reprinted with permission from Wallace et al.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      I. Allergic rhinitis
      II. Nonallergic rhinitis
       A. Vasomotor rhinitis
        1. Irritant triggered (eg, chlorine)
        2. Cold air
        3. Exercise (eg, running)
        4. Undetermined or poorly defined triggers
       B. Gustatory rhinitis
       C. Infectious
       D. NARES
      III. Occupational rhinitis
       A. Caused by protein and chemical allergens; IgE mediated
       B. Caused by chemical respiratory sensitizers; immune mechanism uncertain
       C. Work-aggravated rhinitis
      IV. Other rhinitis syndromes
       A. Hormonally induced
        1. Pregnancy rhinitis
        2. Menstrual cycle related
       B. Drug induced
        1. Rhinitis medicamentosa
        2. Oral contraceptives
        3. Antihypertensive and cardiovascular agents
        4. Aspirin/NSAIDs
        5. Other drugs
       C. Atrophic rhinitis
       D. Rhinitis associated with inflammatory-immunologic disorders
        1. Granulomatous infections
        2. Wegener granulomatosis
        3. Sarcoidosis
        4. Midline granuloma
        5. Churg-Strauss syndrome
        6. Relapsing polychondritis
        7. Amyloidosis
      NSAIDs, Nonsteroidal anti-inflammatory drugs.
      Table IIDifferential diagnosis of rhinitis: Conditions that might mimic symptoms of rhinitis
      Reprinted with permission from Wallace et al.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      A. Nasal polyps
      B. Structural/mechanical factors
       1. Deviated septum/septal wall anomalies
       2. Adenoidal hypertrophy
       3. Trauma
       4. Foreign bodies
       5. Nasal tumors
        a. Benign
        b. Malignant
       6. Choanal atresia
       7. Cleft palate
       8. Pharyngonasal reflux
       9. Acromegaly (excess growth hormone)
      C. Cerebrospinal fluid rhinorrhea
      D. Ciliary dyskinesia syndrome

       Nonallergic rhinitis without eosinophilia

      Sometimes termed idiopathic rhinitis,
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      this manifests as chronic nasal symptoms not caused by allergic or infectious processes. Symptoms are nasal obstruction, increased secretions, or both, with sneezing and pruritus being less common. This clinical presentation is likely caused by a heterogeneous group of disorders with a pathogenesis that is incompletely understood. Vasomotor rhinitis is a term that is sometimes used synonymously with the term nonallergic rhinitis without eosinophilia but sometimes can more specifically connote nasal symptoms that occur in response to environmental conditions, such as changes in temperature or relative humidity, odors (eg, perfumes or cleaning materials), passive tobacco smoke, alcohol, sexual arousal, and emotional factors. Such hyperreactivity to nonallergic triggers is not mediated by increased neural efferent traffic to the blood vessels supplying the nasal mucosa and can also occur in allergic rhinitis, when the term mixed rhinitis is applied.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).

       Nonallergic rhinitis with eosinophilia syndrome

      Nonallergic rhinitis with eosinophilia syndrome (NARES) is characterized by perennial nasal symptoms (particularly nasal congestion), sneezing paroxysms, profuse watery rhinorrhea, nasal pruritus, and occasional loss of smell.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Nasal smears demonstrate eosinophils (inconsistently defined as >5% to >20%),
      • Ellis A.
      • Keith P.
      Nonallergic rhinitis with eosinophilia syndrome.
      • Schiavino D.
      • Nucera E.
      • Milani A.
      • Della Corte A.M.
      • D'Ambrosio C.
      • Pagliari G.
      • et al.
      Nasal lavage cytometry in the diagnosis of nonallergic rhinitis with eosinophilia syndrome (NARES).
      as in allergic rhinitis, but patients lack evidence of allergic disease based on skin testing or serum levels of IgE to environmental allergens. However, similar to histologic findings in patients with allergic rhinitis, mast cells with bound IgE and increased tryptase levels have been found in nasal mucosal biopsy specimens of patients with NARES. Patients are typically middle-aged adults. The prevalence of NARES in the general population is uncertain, but NARES occurs extremely infrequently in childhood and probably accounts for less than 2% of children with nasal eosinophilia.
      • Rupp G.H.
      • Friedman R.A.
      Eosinophilic nonallergic rhinitis in children.
      It has been proposed that the syndrome might be an early stage of nasal polyposis and aspirin sensitivity.
      • Moneret-Vautrin D.A.
      • Hsieh V.
      • Wayoff M.
      • Guyot J.L.
      • Mouton C.
      • Maria Y.
      Nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: nasal polyposis, intrinsic asthma, and intolerance to aspirin.
      Patients with NARES are at risk for obstructive sleep apnea.
      • Kramer M.F.
      • de la Chaux R.
      • Fintelmann R.
      • Rasp G.
      NARES: a risk factor for obstructive sleep apnea?.

       Hormonal rhinitis and rhinitis of pregnancy

      Rhinitis can be caused by hormonal changes of pregnancy or puberty, the use of oral contraceptives or conjugated estrogens, or thyroid disorders. In pregnancy rhinitis de novo nasal congestion develops during pregnancy proposed to occur from hormone-induced nasal vascular pooling resulting from vasodilation and increased blood volume. Symptoms usually disappear within 2 weeks after delivery. However, pre-existing rhinitis is a more common cause of nasal symptoms in pregnant women, with approximately one third of woman with allergic rhinitis having worsened symptoms during pregnancy.
      • Ellegard E.K.
      Pregnancy rhinitis.

       Drug-induced rhinitis

      Rhinitis can be caused by either oral or topical medications. Causal oral medications include angiotensin-converting enzyme inhibitors (which can cause nasal symptoms in the absence of the more common adverse effect of cough), β-blockers, various antihypertensive agents, aspirin, other nonsteroidal anti-inflammatory drugs, and oral contraceptives.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Use of topical α-adrenergic decongestant sprays for more than 5 to 7 days can induce rebound nasal congestion on withdrawal and reduced mucociliary clearance because of loss of ciliated epithelial cells (rhinitis medicamentosa).
      • Knipping S.
      • Holzhausen H.J.
      • Goetze G.
      • Riederer A.
      • Bloching M.B.
      Rhinitis medicamentosa: electron microscopic changes of human nasal mucosa.
      Repeated use of intranasal cocaine and methamphetamine can also result in rebound congestion and, on occasion, septal erosion and perforation.

       Food-induced rhinitis

      Ingested food allergens rarely cause isolated rhinitis on an IgE-mediated basis without involvement of other organ systems.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Ethanol in beer, wine, and other alcoholic drinks can produce symptoms that have been proposed to occur because of pharmacologic nasal vasodilation. Gustatory rhinitis is a cholinergically mediated syndrome of watery rhinorrhea occurring immediately after ingestion of foods, particularly hot and spicy foods.
      • Raphael G.D.
      • Hauptschein-Raphael M.
      • Kaliner M.
      Gustatory rhinitis: a syndrome of food-induced rhinorrhea.
      It can occur as a distinct entity or accompany other types of rhinitis.

       Atrophic rhinitis

      Primary atrophic rhinitis is a chronic condition characterized by progressive atrophy of the nasal mucosa, resorption of underlying bone and turbinates, nasal dryness, and foul-smelling nasal crusts associated with a constant bad smell (ozena).
      • Zohar Y.
      • Talmi Y.P.
      • Strauss M.
      • Finkelstein Y.
      • Shvilli Y.
      Ozena revisited.
      • Moore E.J.
      • Kern E.B.
      Atrophic rhinitis: a review of 242 cases.
      Often associated with sinusitis, it occurs more commonly in young to middle-aged adults and is more prevalent in developing countries with warm climates. The nasal cavities appear abnormally wide on examination, and squamous metaplasia, atrophy of glandular cells, and loss of pseudostratified epithelium are found in nasal biopsy specimens. The dryness and reduction of nasal mucosal tissue with the resultant decreased resistance to airflow is, paradoxically, perceived by patients as severe nasal congestion. An infectious basis has been proposed. Secondary atrophic rhinitis can be less severe and progressive than primary atrophic rhinitis and develops as a direct result of other primary conditions, such as chronic granulomatous nasal infections, chronic sinusitis, excessive nasal surgery, trauma, and irradiation.

       Infectious rhinosinusitis

      Acute viral upper respiratory tract infection (URI) presents with nasal symptoms and constitutional symptoms (fever, myalgias, and malaise). Pruritus is typically absent, and symptoms resolve within 7 to 10 days. Acute and chronic bacterial sinusitis can be difficult to distinguish from rhinitis on the basis of history (see the section on infectious rhinosinusitis).

       Differential considerations other than rhinosinusitis

      For more information on differential considerations other than rhinosinusitis, see Table II. Anatomic abnormalities usually present with prominent obstructive symptoms with less prominent symptoms of rhinorrhea. Septal deviation can cause symptoms of unilateral or bilateral congestion or recurrent sinusitis, although more often it is asymptomatic. Septal deviations can often be diagnosed by seeing the external deviation of the nose or by looking anteriorly with a nasal speculum. Diagnosis might require fiberoptic rhinopharyngoscopy or computed tomographic (CT) scanning. Nasal polyps are benign inflammatory growths that arise from the inflamed mucosa lining the paranasal sinuses. They can cause invariant unilateral or bilateral nasal obstruction and loss of smell or rhinorrhea (see the section on CRS with nasal polyposis [CRScNP]). Polyps are infrequent in children, except for those with cystic fibrosis, in whom polyps with neutrophilic infiltrates are characteristic,
      • Rowe-Jones J.M.
      • Shembekar M.
      • Trendell-Smith N.
      • Mackay I.S.
      Polypoidal rhinosinusitis in cystic fibrosis: a clinical and histopathological study.
      in contrast to eosinophilic infiltrates typical of most nasal polyps. Unilateral nasal polyps should raise consideration of a possible neoplasm.
      Other differential considerations for nasal symptoms include nasal tumors that can be benign or malignant. The most common presentation of tumors is obstruction. Juvenile angiofibromas often present with bleeding in adolescent males. Nasal carcinoma can present with unilateral epistaxis and nasal pain. Young children might place intranasal foreign bodies in their noses (eg, small parts of toys), leading to foul-smelling, purulent discharge and unilateral nasal obstruction that predisposes to sinusitis. Adenoidal hypertrophy in young children causes bilateral nasal obstruction and is often associated with nocturnal mouth breathing and snoring. Wegener granulomatosis can present with nasal and sinus complaints, including purulent rhinorrhea and occasionally septal erosions and perforations. Sjögren syndrome can cause nasal dryness, congestion, and crusting. Sarcoidosis can present with nasal congestion.

       Diagnosis

      Full evaluation of a patient with rhinitis should include assessment of specific symptoms bothersome to the patient (eg, nasal congestion, pruritus, rhinorrhea, and sneezing), the pattern of symptoms (eg, infrequent/intermittent, seasonal, and perennial) that might affect therapeutic choices, identification of precipitating factors that might be avoided, previous response to medications, coexisting conditions, and a detailed environmental history, including home and occupational exposures.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Nasal itching is more suggestive of allergic rhinitis than nonallergic rhinitis. Because allergic rhinitis is frequently associated with allergic conjunctivitis, the presence of eye pruritus and lacrimation is a helpful indication that a patient's rhinitis has an allergic basis. Pollens are generally associated with seasonal allergic rhinitis. In most regions of the United States, trees pollinate in the spring, grasses in the late spring and early summer, and weeds in the late summer and fall. However, in some regions (eg, portions of California) pollens can cause perennial symptoms. Perennial allergens, such as house dust mites, cockroaches, and animals, cause symptoms that vary little between seasons, making it difficult to accurately distinguish between allergic and nonallergic rhinitis on the basis of history alone. Family history is an important clue in making the diagnosis of allergic rhinitis in children. A handheld otoscope or headlamp with nasal speculum permits viewing of the anterior third of the nasal airway, including the anterior tip of the inferior turbinates (and occasionally the anterior tip of the middle turbinates) and portions of the nasal septum. Treatment with a topical decongestant improves visualization of the nasal cavity. However, some nasal polyps, septal deviation, and masses can be missed because of the inability to visualize the posterior and superior nasal airways. Typically, patients with allergic rhinitis have clear discharge, swollen turbinates, and bluish or pale mucosa. Pale or erythematous mucosa can be seen in various types of nonallergic rhinitis. Both allergic and nonallergic rhinitis can cause allergic shiners, infraorbital darkening thought to be caused by chronic venous pooling, or an allergic salute in children who rub their noses upward because of nasal discomfort, sometimes producing a persistent horizontal crease across the nose. In association with rhinitis, physical findings of bilateral conjunctivitis (mild injection with nonpurulent discharge) are suggestive of allergy. Patients with nasal disease require appropriate examination for associated diseases, such as sinusitis and otitis media.
      Determination of specific IgE antibodies to known allergens by means of skin testing or in vitro tests is indicated to provide evidence of an allergic basis for the patient's symptoms, to confirm or exclude suspected causes of the patient's symptoms, or to assess the sensitivity to a specific allergen for avoidance measures, allergen immunotherapy, or both.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Skin testing is preferred for its simplicity, ease, and rapidity of performance; low cost; and high sensitivity.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      In patients with perennial rhinitis, history is usually insufficient for distinguishing allergic from nonallergic rhinitis, and testing is of added importance. Neither total serum IgE levels nor total circulating eosinophil counts are routinely indicated in the diagnosis of rhinitis because they are neither sensitive nor specific for allergic rhinitis.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Nasal cytology might aid in differentiating allergic rhinitis and NARES from other forms of rhinitis, such as vasomotor or infectious rhinitis, if the correct procedure is followed and the appropriate stains are used. However, there is lack of expert consensus about whether nasal cytology should be routinely used in the diagnosis of rhinitis.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      In selected cases special techniques, such as fiberoptic nasal endoscopy, inspiratory peak flow measurements, acoustic rhinometry, or rhinomanometry, to assess airway function might be useful in evaluating patients presenting with rhinitis symptoms.

       Treatment

       Avoidance measures

      Avoidance of inciting factors, such as allergens (house dust mites, molds, pets, pollens, and cockroaches), irritants, and medications, can effectively reduce symptoms of rhinitis. In particular, patients allergic to house dust mites should use allergen-impermeable encasings on the bed and all pillows. Pollen exposure can be reduced by keeping windows closed, using an air conditioner, and limiting the amount of time spent outdoors.

       Medications

      Selection of medications should be individualized based on multiple considerations, including patient preference (eg, intranasal vs oral), individual response (which can differ from average responses in the general population), and cost.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Some medications are more effective for treating certain types of rhinitis (eg, allergic vs nonallergic), more severe symptoms, or particular rhinitis symptoms that are more bothersome to a patient (eg, nasal congestion).
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Medications also differ in onset of action, with those having more rapid symptom relief better suited to treating episodic rhinitis (defined by the Joint Task Force as allergic nasal symptoms elicited by sporadic exposures to inhalant aeroallergens that are not usually encountered in the patient's indoor or outdoor environment)
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      or intermittent symptoms (defined by Allergic Rhinitis and Its Impact on Asthma guidelines as present <4 days per week or <4 weeks duration).
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and Its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      Table III reviews principal medication options for rhinitis (both monotherapy and combination regimens), listing therapeutic considerations for treatment of allergic rhinitis and then for nonallergic rhinitis.
      Table IIIPrincipal medication options for rhinitis (listed in alphabetical order)
      Adapted from Wallace et al.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      For AR, both seasonal and perennial
      Therapeutic considerations
      Monotherapy
       Oral agents
        Antihistamines, oral (H1 receptor antagonists)
      • Continuous use is most effective for SAR and PAR but appropriate for PRN use in episodic or intermittent AR because of relatively rapid onset of action.
      • Less effective for nasal congestion than for other nasal symptoms
      • Less effective for AR than INSs, with similar effectiveness to INSs for associated ocular symptoms
      • Because they are generally ineffective for non-AR, other choices are typically better for mixed rhinitis.
      • To avoid sedation (often subjectively unperceived), performance impairment, or anticholinergic effects of first-generation antihistamines, second-generation agents are generally preferred.
      • Of these, fexofenadine, loratadine, and desloratadine without sedation at recommended doses
        Corticosteroids, oral
      • A short course (5-7 days) might be appropriate for very severe nasal symptoms.
      • Preferred to single or recurrent administration of intramuscular corticosteroids
        Decongestants, oral
      • Pseudoephedrine reduces nasal congestion.
      • Side effects include insomnia, irritability, palpitations, and hypertension.
        Leukotriene receptor antagonists (LTRAs)
      • Montelukast is approved for SAR and PAR.
      • The efficacies of LTRAs and oral antihistamines are similar (with loratadine as the usual comparator).
      • Because approved for both rhinitis and asthma, can be considered when both conditions are present.
      • Side effects are minimal.
       Intranasal agents
        Intranasal antihistamines
      • Effectiveness for AR is equal or superior to that of oral second-generation antihistamines with a clinically significant effect on nasal congestion.
      • Generally less effective than INSs for nasal symptoms
      • Clinically significant rapid onset of action (within several hours or less), making them appropriate for PRN use in patients with episodic AR
      • Because azelastine nasal spray is approved for vasomotor rhinitis, appropriate choice for mixed rhinitis
      • Side effects with intranasal azelastine are bitter taste and somnolence.
        Intranasal anticholinergic (ipratropium)
      • Reduces rhinorrhea but not other symptoms of AR.
      • Appropriate for episodic AR because of rapid onset of action
      • Side effects are minimal, but nasal dryness can occur.
        Intranasal corticosteroids (INSs)
      • Most effective monotherapy for AR
      • Effective for all symptoms of SAR and PAR, including nasal congestion
      • The usual onset of action is less rapid than that of oral or intranasal antihistamines, usually occurs within 12 hours, and can start as early as 3-4 hours in some patients.
      • Might be considered for episodic AR
      • PRN use (eg, >50% days use) is effective for SAR.
      • More effective than the combination of an oral antihistamine and LTRA for SAR and PAR
      • Similar effectiveness to oral antihistamines for associated ocular symptoms of AR
      • Appropriate choice for mixed rhinitis because agents in this class are also effective for some cases of non-AR
      • Without significant systemic side effects in adults
      • Growth suppression in children with PAR has not been demonstrated when used at recommended doses.
      • Local side effects are minimal, but nasal bleeding can occur, as well as rare nasal septal perforation.
        Intranasal cromolyn
      • Used for maintenance treatment of AR; onset of action within 4-7 days; full benefit can take weeks.
      • For episodic rhinitis, administration just before allergen exposure protects for 4-8 hours against allergic response.
      • Less effective than nasal corticosteroids, and there are inadequate data for comparison with leukotriene antagonists and antihistamines.
      • Minimal side effects
        Intranasal decongestants
      • Useful for the short-term and possibly for episodic therapy of nasal congestion but inappropriate for daily use because of risk for rhinitis medicamentosa
      Therapeutic considerations
      Combination therapy
       Antihistamine, oral with decongestant, oral
      • Provides more effective relief of nasal congestion than antihistamines alone
       Antihistamine, oral with LTRA, oral
      • Might be more effective than monotherapy with an antihistamine or LTRA
      • Combination is less effective than INSs.
      • Alternative if patients are unresponsive to or not compliant with INSs
       Antihistamine, oral with intranasal antihistamine
      • Combination can be considered, although controlled studies of additive benefit are lacking.
       Antihistamine, oral with INS
      • Combination can be considered, although supporting studies are limited, and many studies are unsupportive of the additive benefit of adding an antihistamine to an intranasal steroid.
       Intranasal anticholinergic with INS
      • Concomitant ipratropium bromide nasal spray with INS is more effective for rhinorrhea than administration of either drug alone.
       Intranasal antihistamine with INS
      • Combination can be considered based on limited data indicating additive benefit.
      • There are inadequate data about the optimal interval between administration of the 2 sprays.
      • For mixed rhinitis, there is a possible added benefit to combination of intranasal antihistamine with INS.
       LTRA, oral with INS
      • Provides subjective additive relief in limited studies; data are inadequate.
      For nonallergic (idiopathic) rhinitis
      Therapeutic considerations (for side effects, see AR table)
      Monotherapy
       Oral agents
        Antihistamines, oral (H1 receptor antagonists)
      • Generally ineffective for non-AR
        Decongestants, oral
      • Pseudoephedrine reduces nasal congestion.
       Intranasal agents
        Intranasal antihistamines
      • Effective for vasomotor rhinitis
        Intranasal anticholinergic (ipratropium)
      • Effective only for rhinorrhea of non-AR syndromes
      • Special role for preventing rhinorrhea of gustatory rhinitis
        INSs
      • Effective for some forms of non-AR, including vasomotor rhinitis and NARES
      Combination therapy
      • There are inadequate data to provide firm recommendations in non-AR.
      AR, Allergic rhinitis; INS, intranasal corticosteroids; LTRA, leukotriene receptor antagonist; PAR, perennial allergic rhinitis; PRN, as required; SAR, seasonal allergic rhinitis.

       Allergen immunotherapy/allergy vaccination

      Subcutaneous allergen immunotherapy can be highly effective in controlling symptoms of allergic rhinitis and favorably modifies the long-term course of the disease.
      Joint Task Force on Practice Parameters; American Academy of Allergy
      Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update.
      Sublingual immunotherapy with single allergens, although part of clinical practice for the treatment of rhinitis in Europe, is undergoing clinical trials in the United States and is not approved by the US Food and Drug Administration (FDA) at the time of this manuscript's submission. Patients with allergic rhinitis should be considered candidates for immunotherapy on the basis of the severity of their symptoms, failure or unacceptability of other treatment modalities, presence of comorbid conditions, and possibly as a means of preventing worsening of the condition or the development of comorbid conditions (eg, asthma and sinusitis).
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Joint Task Force on Practice Parameters; American Academy of Allergy
      Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update.
      Approximately 80% of patients will experience symptomatic improvement after 1 to 2 years of subcutaneous immunotherapy, and guidelines recommend that treatment be continued for a total of 4 to 5 years.
      Joint Task Force on Practice Parameters; American Academy of Allergy
      Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update.
      In many patients the beneficial effects persist for years after injections are stopped. Allergen immunotherapy for allergic rhinitis can reduce the development of asthma in children and possibly in adults.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Joint Task Force on Practice Parameters; American Academy of Allergy
      Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update.
      • Niggemann B.
      • Jacobsen L.
      • Dreborg S.
      • Ferdousi H.A.
      • Halken S.
      • Host A.
      • et al.
      Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children.

       Considerations in select populations

       Children

      Because some, although not all, nasal corticosteroid preparations have been reported to reduce linear growth (at least temporarily),
      • Skoner D.
      • Rachelefsky G.
      • Meltzer E.
      • Chervinsky P.
      • Morris R.
      • Seltzer J.
      • et al.
      Detection of growth suppression in children during treatment with intranasal belcomethasone dipropionate.
      • Agertoft L.
      • Pedersen S.
      Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide.
      • Schenkel E.
      • Skoner D.
      • Bronsky E.
      • Miller S.
      • Pearlman D.
      • Rooklin A.
      • et al.
      Absence of growth retardation in children with perennial allergic rhinitis following 1 year treatment with mometasone furoate aqueous nasal spray.
      growth should be monitored in children receiving these agents.

       Elderly

      Allergy is an uncommon cause of perennial rhinitis in individuals older than 65 years. More commonly, rhinitis in the elderly is due to cholinergic hyperreactivity (associated with profuse watery rhinorrhea, which might be aggravated after eating [ie, gustatory rhinitis]), α-adrenergic hyperactivity (congestion associated with antihypertensive drug therapy), or sinusitis.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Because the elderly might have increased susceptibility to the adverse central nervous system and anticholinergic effects of antihistamines, nonsedating agents are recommended if antihistamines are used for allergic rhinitis. Oral decongestants should be used with caution in this patient subset because of their effects on the central nervous system, heart, and bladder function.

       Pregnancy

      The time for greatest concern about potential congenital malformation caused by medication use is the first trimester, when organogenesis occurs.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      • Gilbert C.
      • Mazzotta P.
      • Loebstein R.
      • Koren G.
      Fetal safety of drugs used in the treatment of allergic rhinitis: a critical review.
      • Schatz M.
      • Zeiger R.S.
      • Harden K.
      • Hoffman C.C.
      • Chilingar L.
      • Petitti D.
      The safety of asthma and allergy medications during pregnancy.
      When selecting medications for treating rhinitis in pregnancy, the clinician might consider the FDA risk categories (category B being more favorable than category C) that are based largely on animal data and limited human studies.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      However, it is also suggested that a clinician consider human cohort and case-control studies, as well as birth registry data.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Bernstein I.L.
      • Blessing-Moore J.
      • Cox L.
      • et al.
      The Joint Force on Practice Parameters, representing the AAAAI, ACAAI, JCAAI. The diagnosis and management of rhinitis: An updated practice parameter.
      Nasal cromolyn has the most reassuring safety profile in pregnancy. Cetirizine, chlorpheniramine, loratadine, and tripelennamine have been rated FDA pregnancy category B, whereas many other antihistamines have a category C rating. Intranasal budesonide has a category B rating, whereas other nasal corticosteroids are rated category C. Oral decongestants are best avoided in the first trimester because of the risk of gastroschisis in the newborn.
      • Werler M.M.
      • Sheehan J.E.
      • Mitchell A.A.
      Maternal medication use and risks of gastroschisis and small intestinal atresia.
      Allergen immunotherapy should not be started or advanced in dose during pregnancy but might be continued at a stable dose.

      Sinusitis (rhinosinusitis)

       Sinus anatomy and physiology

      Normal sinus function requires (1) patency of each sinus ostia, (2) normal mucociliary function, and (3) normal systemic and local immune function. Epithelial cilia in the sinuses normally beat mucus in an ordered fashion toward the ostia that communicate with the nasal cavity. The maxillary, anterior ethmoid, and frontal sinuses drain through a comparatively narrow drainage pathway, the ostiomeatal unit (complex), which communicates into the middle meatus, a space between the inferior and middle turbinates (Fig 2). In 50% of cases, the frontal sinus drains just anterior to this region. The posterior ethmoid and sphenoid sinuses drain through the sphenoethmoidal recess. Sinus ostial obstruction is common in patients with acute rhinosinusitis and CRS. Mucociliary function is grossly abnormal in diseases, such as cystic fibrosis, or in ciliary dysmotility syndrome (Kartagener syndrome). Mucociliary function might be impaired by cigarette smoke, environmental pollutants, or viral URIs.
      • Baroody F.M.
      Mucociliary transport in chronic rhinosinusitis.
      Systemic immune function is impaired by hypogammaglobulinemia, severe T-cell dysfunction, or immune suppression. It has been suggested but not proved that defects in local innate immune function might predispose to sinus infections. Local innate function involves (1) pathogen recognition and signaling through epithelial Toll-like and other innate receptors and (2) secretion of collectins and antimicrobial peptides.
      • Tieu D.D.
      • Kern R.C.
      • Schleimer R.P.
      Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis.
      Defects in either pathway remain largely unstudied in sinusitis.
      Figure thumbnail gr2
      Fig 2The ostiomeatal unit is well visualized on this blow-up of a normal sinus CT scan. The major structures illustrated include the maxillary infundibulum, the ethmoid infundibulum, the uncinate process, and the middle turbinate. The ostiomeatal unit is a 3-dimensional structure made up of these individual components.

       Rationale for rhinosinusitis rather than sinusitis

      The symptoms of rhinitis and sinusitis overlap, and sinusitis rarely occurs in the absence of rhinitis.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      Second, there is an important interrelationship between the middle turbinate and the ethmoid sinus such that cyclic variations in nasal turbinate swelling occurring during the normal nasal cycle can cause mucosal thickening in the ethmoidal infundibulum. This thickening might be interpreted as ethmoid sinusitis.
      • Stringer S.P.
      • Mancuso A.A.
      • Avino A.J.
      Effect of a topical vasoconstrictor on computed tomography of paranasal sinus disease.
      The ethmoid infundibulum and the nose represent contiguous structures sharing vascular, neuronal, and interconnecting anatomic pathways. For these reasons, some expert panels have adopted the term rhinosinusitis rather than sinusitis, emphasizing that sinusitis typically involves the nasal passages and the paranasal sinuses.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      • Lanza D.C.
      • Kennedy D.W.
      Adult rhinosinusitis defined.
      For the purposes of this review, sinusitis and rhinosinusitis are synonymous terms.

       Infectious rhinosinusitis

      Viral rhinosinusitis is defined as acute rhinosinusitis caused by viral infection. Viral rhinosinusitis is often difficult to distinguish from acute bacterial rhinosinusitis (ABRS) and can be accompanied by inflammatory changes in the sinuses.
      • Gwaltney Jr., J.M.
      Acute community-acquired sinusitis.
      ABRS, by definition, is caused by a bacterial pathogen. CRS is an inflammatory condition in which infection plays an important role. Each of these entities is discussed further below.

       The transition from viral rhinosinusitis to ABRS

      The principal inciting event for ABRS is viral rhinosinusitis (also known as a viral URI). The transition from viral rhinosinusitis to ABRS is variable and only occurs in 0.5% to 2% of cases.
      • Gwaltney Jr., J.M.
      Acute community-acquired sinusitis.
      Viral rhinosinusitis is typically accompanied by clear rather than thick or colored secretions. Symptoms can persist up to 14 days or longer. An acute upper respiratory illness of less than approximately 7 days' duration is most commonly caused by viral illness (viral rhinosinusitis), whereas acute bacterial sinusitis becomes more likely beyond 7 to 10 days.
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      Transition from viral URI to ABRS can occur at any time during the viral URI.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.

       Acute and chronic rhinosinusitis: Definitions and symptoms

      Rhinosinusitis is defined as inflammation of the nose and paranasal sinuses. Acute rhinosinusitis is usually infectious, whereas CRS is less clearly infectious and often more inflammatory.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      However, infection still plays an important role in CRS. Acute rhinosinusitis is defined as up to 4 weeks of purulent (not clear) nasal drainage (anterior, posterior, or both) accompanied by nasal obstruction, facial pain-pressure-fullness, or both. Subacute rhinosinusitis is defined in some expert reports
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.
      as rhinosinusitis of between 4 and 8 weeks' duration. CRS is defined as an inflammatory condition involving the paranasal sinuses and nasal passages with a minimum duration of either 8 or 12 weeks despite attempts at medical management.
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      The 4 major symptoms of CRS are (1) anterior, posterior, or both mucopurulent drainage; (2) nasal obstruction or blockage; (3) facial pain, pressure, and/or fullness; and (4) decreased sense of smell. Two or more symptoms must be present to make the diagnosis.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      • Benninger M.S.
      • Ferguson B.J.
      • Hadley J.A.
      • Hamilos D.L.
      • Jacobs M.
      • Kennedy D.W.
      • et al.
      Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology.
      In addition, objective documentation of mucosal inflammation is required.
      The symptoms of CRS do not reliably correlate with specific objective findings nor do they accurately differentiate CRS subtypes (see below).
      Facial pain, pressure, and/or headache are commonly reported symptoms (83% in one series).
      • Bhattacharyya N.
      The economic burden and symptom manifestations of chronic rhinosinusitis.
      The pain is usually described as a dull pain or pressure in the upper cheeks, between the eyes, or in the forehead. Sharp localizing pain is less common. Anterior, posterior, or both nasal drainage of CRS is usually opaque white or light yellow. Thick yellow, green, or brown mucus can occur, although this is more characteristic of recurrent acute rhinosinusitis or AFRS. Nasal congestion can be described as nasal blockage or stuffiness or less commonly as nasal fullness. Disturbance in sense of smell can be partial (hyposmia) or complete (anosmia) and is usually associated with mucosal thickening or opacification in the anterior ethmoid sinuses. Rarely, hyposmia/anosmia is caused by olfactory neuronal degeneration or other diseases. Patients with anosmia often report ageusia, a reduced ability to taste foods.
      There is a poor correlation between the symptoms of CRS and objective findings on imaging of the paranasal sinuses.
      • Bhattacharyya T.
      • Piccirillo J.
      Wippold FJ 2nd. Relationship between patient-based descriptions of sinusitis and paranasal sinus computed tomographic findings.
      • Hopkins C.
      • Browne J.P.
      • Slack R.
      • Lund V.
      • Brown P.
      The Lund-Mackay staging system for chronic rhinosinusitis: How is it used and what does it predict?.

       Differential considerations other than rhinitis

      Facial pain can be caused by nonrhinogenic conditions, including migraine headaches, tension headaches, cluster headaches, and other poorly understood facial pain syndromes.
      • Jones N.S.
      Midfacial segment pain: implications for rhinitis and sinusitis.
      • Rosbe K.W.
      • Jones K.R.
      Usefulness of patient symptoms and nasal endoscopy in the diagnosis of chronic sinusitis.
      Facial pain, pressure, or both are not reliable for predicting the presence of objective findings of rhinosinusitis.
      • Rosbe K.W.
      • Jones K.R.
      Usefulness of patient symptoms and nasal endoscopy in the diagnosis of chronic sinusitis.
      Focal and sharp facial pain might be a symptom of CRS but is often not associated with radiographic evidence of sinus disease. Pain in the upper teeth, which is suggestive of nerve irritation in adjacent tooth roots, can be a symptom of maxillary sinus infection.
      The differential diagnosis of nasal congestion includes allergic rhinitis, chronic nonallergic (idiopathic) rhinitis, rhinitis associated with medication use, secondary atrophic rhinitis (ie, empty nose syndrome), and cerebrospinal fluid rhinorrhea. Unilateral nasal congestion/blockage raises the question of a local anatomic problem, such as an antral choanal cyst, or tumor, such as an inverted papilloma.

      Kim JH. Available at: http://www.bcm.edu/oto/grand/121792.html. Accessed October 26, 2009.

       Subtypes of CRS

      CRS can be divided into 3 clinical subtypes with distinctive but overlapping clinical features (Table IV).
      • 1.
        CRS without nasal polyposis (CRSsNP) accounts for approximately 60% of CRS cases. It is a heterogeneous condition in which allergic factors, structural abnormalities, and viral and bacterial infection variably contribute to the disease. Facial pain, pressure, and/or fullness are more common in CRSsNP than in CRScNP (see below). Bacterial organisms isolated from diseased sinus cavities can include: Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, coagulase-negative staphylococci, and, less commonly, gram-negative enteric bacteria. The importance of anaerobic bacteria in causing CRS is controversial.
        • Meltzer E.O.
        • Hamilos D.L.
        • Hadley J.A.
        • Lanza D.C.
        • Marple B.F.
        • Nicklas R.A.
        • et al.
        Rhinosinusitis: establishing definitions for clinical research and patient care.
        Sinus ostial blockage is the inciting event, in most cases leading to obstruction of sinus drainage and bacterial infection. As the condition becomes chronic, a chronic inflammatory infiltrate containing neutrophils, mononuclear cells, and some eosinophils is seen. Glandular hyperplasia and submucosal fibrosis are typically present histologically in patients with CRSsNP but absent in patients with CRScNP.
        • Malekzadeh S.
        • Hamburger M.D.
        • Whelan P.J.
        • Biedlingmaier J.F.
        • Baraniuk J.N.
        Density of middle turbinate subepithelial mucous glands in patients with chronic rhinosinusitis.
        • Watelet J.B.
        • Claeys C.
        • Perez-Novo C.
        • Gevaert P.
        • Van Cauwenberge P.
        • Bachert C.
        Transforming growth factor beta1 in nasal remodeling: differences between chronic rhinosinusitis and nasal polyposis.
      • 2.
        CRScNP accounts for 20% to 33% of CRS cases. The symptoms are similar to those of CRSsNP, although hyposmia/anosmia is more common in patients with CRScNP.
        • Hamilos D.L.
        Chronic rhinosinusitis patterns of illness.
        Nasal polyps are typically bilateral in the middle meatus unless they have been previously removed. Unilateral polyps are relatively uncommon and should prompt consideration of other diagnoses, including inverted papilloma or other nasal tumors. CRScNP is more likely than CRSsNP to be associated with asthma and aspirin-exacerbated respiratory disease (AERD). The initial trigger for nasal polyp development is unknown. Polyp tissue typically contains a predominance of eosinophils, high levels of histamine, and high levels of the TH2 cytokines IL-5 and IL-13.
        • Drake-Lee A.B.
        • McLaughlan P.
        Clinical symptoms, free histamine and IgE in patients with nasal polyposis.
        • Hamilos D.L.
        Nasal polyps as immunoreactive tissue.
      • 3.
        AFRS is defined as CRS accompanied by (1) the presence of allergic mucin (thick inspissated mucus that ranges in color from light tan to brown to dark green and that contains degranulated eosinophils), (2) fungal hyphae in the mucin, and (3) evidence of IgE-mediated fungal allergy.
        • Meltzer E.O.
        • Hamilos D.L.
        • Hadley J.A.
        • Lanza D.C.
        • Marple B.F.
        • Nicklas R.A.
        • et al.
        Rhinosinusitis: establishing definitions for clinical research and patient care.
        Allergic mucin is thick inspissated mucus that ranges in color from light tan to brown to dark green and that contains degranulated eosinophils. Sinus surgery is usually required to remove allergic mucin and establish the diagnosis of AFRS. Fungal hyphae are found within the allergic mucin, suggesting fungal colonization. The fungi are strictly noninvasive. Patients with AFRS usually have nasal polyps and are immunocompetent. Symptoms are similar to those of other forms of CRS. Fever is uncommon. Occasionally, AFRS presents dramatically with complete nasal obstruction, gross facial dysmorphia, and/or visual changes.
        • Meltzer E.O.
        • Hamilos D.L.
        • Hadley J.A.
        • Lanza D.C.
        • Marple B.F.
        • Nicklas R.A.
        • et al.
        Rhinosinusitis: establishing definitions for clinical research and patient care.
        The pathophysiology of AFRS is most consistent with chronic, intense allergic inflammation directed against colonizing fungi. Histologically, allergic mucin demonstrates intense eosinophilic degranulation, mucostasis, and inspissations.
        • Schubert M.S.
        • Goetz D.W.
        Evaluation and treatment of allergic fungal sinusitis. I. Demographics and diagnosis.
      Table IVDefinitions of rhinosinusitis based on disease classification
      Recurrent acute rhinosinusitis
       A. Recurrent acute rhinosinusitis >3 times per year
       B. Requires >2 of the following symptoms:
        • Anterior or posterior mucopurulent drainage
        • Nasal congestion
        • Facial pain/pressure
        • Decreased sense of smell
       C. Normal between episodes
      Chronic rhinosinusitis with nasal polyps
       A. Symptoms present for >12 weeks
       B. Requires >2 of the following symptoms
        • Anterior or posterior mucopurulent drainage
        • Nasal congestion
        • Facial pain/pressure
        • Decreased sense of smell
       C. Objective documentation
        • Rhinoscopic examination OR
        • Radiograph (sinus CT scan preferred)
       D. Bilateral nasal polyps in middle meatus
      Chronic rhinosinusitis without nasal polyps
       A. Symptoms present for >12 weeks
       B. Requires >2 of the following symptoms:
        • Anterior or posterior mucopurulent drainage
        • Nasal congestion
        • Facial pain/pressure
        • Decreased sense of smell
       C. Objective documentation
        • Rhinoscopic examination OR
        • Radiography (sinus CT preferred)
      AFRS
       A. Symptoms present for >12 weeks
       B. Requires >2 of the following symptoms
        • Anterior or posterior mucopurulent drainage
        • Nasal congestion
        • Facial pain/pressure
        • Decreased sense of smell
       C. Objective documentation
        • Rhinoscopic examination OR
        • Radiography (sinus CT scan preferred)
       D. AFRS criteria
        • Positive fungal stain or culture of allergic mucin AND
        • IgE-mediated fungal allergy

       Distinct pathologic features of rhinosinusitis

       Allergic mucin

      Allergic mucin is a classic feature of AFRS.
      • Marple B.F.
      • Mabry R.L.
      Comprehensive management of allergic fungal sinusitis.
      • Corey J.P.
      Allergic fungal sinusitis.
      However, allergic mucin is occasionally found in the absence of colonizing fungi in some cases of CRSsNP or CRScNP.

       Hyperdensities on sinus CT scanning

      Opacified sinus cavities might contain inspissated mucus that produces an inhomogeneous hyperdense pattern on sinus CT scanning. Hyperdensities suggest the presence of allergic mucin. They are a classic feature of AFRS (in which case the allergic mucin also contains fungal hyphae), but they can be seen in both CRSsNP and CRScNP.

       A potential role for colonizing fungi in CRS

      Patients with CRS (including those with CRSsNP and CRScNP) have been found to have immune hypersensitivity to fungi, such as Alternaria species, that commonly colonize sinus mucus.
      • Ponikau J.U.
      • Sherris D.A.
      • Kern E.B.
      • Homburger H.A.
      • Frigas E.
      • Gaffey T.A.
      • et al.
      The diagnosis and incidence of allergic fungal sinusitis.
      • Shin S.H.
      • Ponikau J.U.
      • Sherris D.A.
      • Congdon D.
      • Frigas E.
      • Homburger H.A.
      • et al.
      Chronic rhinosinusitis: an enhanced immune response to ubiquitous airborne fungi.
      Although most patients do not produce a classic IgE-mediated response against these fungi, eosinophilic inflammation caused by a TH2-type sensitization is present. The T-cell cytokines involved include IL-5 and IL-13. The eosinophilic inflammation is most intense in the mucus, where the eosinophils physically associate with fungal hyphae.
      • Ponikau J.U.
      • Sherris D.A.
      • Kephart G.M.
      • Adolphson C.
      • Kita H.
      The role of ubiquitous airborne fungi in chronic rhinosinusitis.

       Role of bacterial infection

      CRS is a complex inflammatory disorder rather than a simple infectious process. Bacterial infections can complicate all forms of CRS. Bacteria can be involved in the pathogenesis of CRS, in the following ways:
      • ABRS might fail to resolve, leading to a chronic infection in 1 or more sinuses.
      • Bacterial colonization with enterotoxin-producing S aureus is found with increased prevalence in patients with CRScNP and is associated with local production of enterotoxin-specific IgE antibodies.
        • Van Zele T.
        • Gevaert P.
        • Watelet J.B.
        • Claeys G.
        • Haoltappels G.
        • Claeys C.
        • et al.
        Staphylococcus aureus colonization and IgE antibody formation to enterotoxins is increased in nasal polyposis.
        • Bernstein J.M.
        • Kansal R.
        Superantigen hypothesis for the early development of chronic hyperplastic sinusitis with massive nasal polyposis.
        These antibodies can be measured in sinus tissues, although levels in the blood might be undetectable. The enterotoxins act as superantigens and locally activate T lymphocytes.
        • Van Zele T.
        • Gevaert P.
        • Watelet J.B.
        • Claeys G.
        • Haoltappels G.
        • Claeys C.
        • et al.
        Staphylococcus aureus colonization and IgE antibody formation to enterotoxins is increased in nasal polyposis.
        In contrast, patients with CRSsNP do not have an increased prevalence of enterotoxin-specific IgE antibodies.
      • Bacteria can form biofilm on the sinus epithelium. Sequestration of bacteria within biofilms allows the bacteria to resist antibiotic treatment and persist as a low-grade infection within the sinus mucosa.
        • Ramadan H.H.
        Chronic rhinosinusitis and bacterial biofilms.
        • Harvey R.J.
        • Lund V.J.
        Biofilms and chronic rhinosinusitis: systematic review of evidence, current concepts and directions for research.
      • Drug-resistant infection can occur with gram-negative bacteria or methicillin-resistant S aureus.
        • Benninger M.S.
        • Ferguson B.J.
        • Hadley J.A.
        • Hamilos D.L.
        • Jacobs M.
        • Kennedy D.W.
        • et al.
        Adult chronic rhinosinusitis: definitions, diagnosis, epidemiology, and pathophysiology.
      • Acute bacterial infection can lead to osteitis of the underlying bone, although actual invasion of the bone has not been conclusively demonstrated.
        • Lee J.T.
        • Kennedy D.W.
        • Palmer J.N.
        • Feldman M.
        • Chiu A.G.
        The incidence of concurrent osteitis in patients with chronic rhinosinusitis: a clinicopathological study.

       Physical findings

      The diagnosis of ABRS requires the presence of purulent nasal discharge (secretions that are cloudy or colored) and nasal obstruction (congestion, blockage, or stuffiness), facial pain-pressure-fullness, or both.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      Using a positive sinus radiograph as a gold standard for confirmation of disease, this symptom definition only allows for correct diagnosis in approximately 40% to 50% of cases.
      • Hickner J.M.
      • Bartlett J.G.
      • Besser R.E.
      • Gonzales R.
      • Hoffman J.R.
      • Sande M.A.
      • et al.
      Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background.
      Nonetheless, ABRS remains a clinical diagnosis.
      The definitive diagnosis of CRS requires objective confirmation of disease either with nasal endoscopy or sinus CT scanning. Nasal endoscopy might reveal discolored mucus or edema in the middle meatus or sphenoethmoidal recess or similar findings in the sinus cavities of patients who have undergone previous surgery. Typical findings on sinus CT include sinus ostial narrowing or obstruction, sinus mucosal thickening or opacification, and, less commonly, air-fluid levels in the sinuses.

       Diagnostic testing

      Sinus imaging with plain radiography or sinus CT scanning is not recommended in patients with uncomplicated ABRS unless symptoms or signs suggesting extrasinus involvement are present.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      Sinus CT scanning is the imaging study of choice for evaluation of CRS.
      • Meltzer E.O.
      • Hamilos D.L.
      • Hadley J.A.
      • Lanza D.C.
      • Marple B.F.
      • Nicklas R.A.
      • et al.
      Rhinosinusitis: establishing definitions for clinical research and patient care.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      Coronal images are commonly obtained, although multiplanar images are available in many institutions. Nasal endoscopy is sufficient to establish the diagnosis of CRS but is insufficient to establish the extent of sinus involvement unless extensive prior sinus surgery has been performed.
      Because CRS is associated with allergic rhinitis in 60% of adults and 36% to 60% of children, patients with CRS should be evaluated for allergy so that environmental control measures or other interventions appropriate for allergic disease can be implemented.
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.

       Initial treatment of ABRS

      An initial period of watchful waiting without initiation of antibiotics can be considered in adults with uncomplicated ABRS who have mild illness (mild pain and temperature <38.3 °C) and assurance of follow-up.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      Spontaneous resolution has been reported in 62% to 69% of patients in placebo-controlled clinical trials.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      Patients with more severe symptoms should be treated with an antibiotic. The most common bacteria isolated from the maxillary sinuses of patients with ABRS include S pneumoniae, H influenzae, and M catarrhalis, the latter being more common in children.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      If a decision is made to treat with an antibiotic, amoxicillin is considered first-line therapy for most adults. For patients with penicillin allergy, trimethoprim-sulfamethoxazole or macrolide antibiotics are cost-effective alternatives. Several additional antibiotics, including cephalosporins and fluoroquinolones, are FDA approved for treatment of ABRS.
      Intranasal decongestants might relieve nasal congestion but should be limited to 3 days to avoid rebound nasal congestion.
      • Rosenfeld R.M.
      • Andes D.
      • Bhattacharyya N.
      • Cheung D.
      • Eisenberg S.
      • Ganiats T.G.
      • et al.
      Clinical practice guideline: adult sinusitis.
      Intranasal corticosteroid sprays have been studied but are not approved as adjunctive therapy.

       When initial therapy of ABRS fails

      If ABRS does not improve after several days of antibiotics, prescription of an alternative antibiotic for several additional weeks should be considered.
      • Slavin R.G.
      • Spector S.L.
      • Bernstein I.L.
      • Kaliner M.A.
      • Kennedy D.W.
      • Virant F.S.
      • et al.
      The diagnosis and management of sinusitis: a practice parameter update.
      If there is still no response, a sinus CT scan is indicated to confirm the presence of sinusitis and determine whether anatomic abnormalities might be predisposing to sinusitis. Underlying medical conditions should also be considered, including immune deficiency, gastroesophageal reflux disease, or defects in mucociliary clearance (see the section on chronic rhinosinusitis comorbidities). Specialist evaluation is appropriate when sinusitis is refractory to treatment or is recurrent.

       Findings that suggest need for immediate referral

      The following symptoms and signs are suggestive of other conditions that require immediate evaluation: double or reduced vision, proptosis, dramatic periorbital edema, ophthalmoplegia, other focal neurologic signs, severe headache, and meningeal signs.
      • Anon J.
      • Jacobs M.
      • Poole M.
      • Ambrose P.
      • Benninger M.
      • Hadley J.
      • et al.
      Antimicrobial treatment guidelines for acute bacterial rhinosinusitis.
      Extrasinus extension of sinus disease is the most ominous complication of acute rhinosinusitis or CRS. Complications of acute sinusitis include orbital cellulitis, cavernous vein thrombosis, brain abscess, meningitis, localized osteomyelitis, and oral-antral fistula. Complications of chronic sinusitis include localized osteomyelitis, oral-antral fistula, mucocele, and brain abscess.

       Treatment of chronic rhinosinusitis

      Topical corticosteroid nasal sprays are recommended for all forms of CRS.
      • Fokkens W.
      • Lund V.
      • Bachert C.
      • Clement P.
      • Hellings P.
      • Holmstrom W.
      • et al.
      EAACI position paper on rhinosinusitis and nasal polyps executive summary.
      Antihistamines might be helpful in patients with underlying allergic rhinitis.
      • Fokkens W.
      • Lund V.
      • Bachert C.
      • Clement P.
      • Hellings P.
      • Holmstrom W.
      • et al.
      EAACI position paper on rhinosinusitis and nasal polyps executive summary.
      Antibiotics should be used to treat infection if nasal purulence is present, although antibiotics have not been officially approved for use in CRS. Antifungals, including oral terbinafine and topical amphotericin B, have been studied in patients with CRS.
      • Kennedy D.W.
      • Kuhn F.A.
      • Hamilos D.L.
      • Zinreich S.J.
      • Butler D.
      • Warsi G.
      • et al.
      Treatment of chronic rhinosinusitis with high-dose oral terbinafine: a double blind, placebo-controlled study.
      • Ponikau J.U.
      • Sherris D.A.
      • Weaver A.
      • Kita H.
      Treatment of chronic rhinosinusitis with intranasal amphotericin B: a randomized, placebo-controlled, double-blind pilot trial.
      • Ebbens F.A.
      • Scadding G.K.
      • Badia L.
      • Hellings P.W.
      • Jorissen M.
      • Mullol J.
      • et al.
      Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis.
      Most antifungal trials have failed to show efficacy, and antifungal agents are not recommended.

       CRScNP

      Patients might benefit from a brief course (10-15 days) of oral corticosteroids to shrink nasal polyps.
      • Benitez P.
      • Alobid I.
      • de Haro J.
      • Brenguer J.
      • Bernal-Spreckelsen M.
      • Pujols L.
      • et al.
      A short course of oral prednisone followed by intranasal budesonide is an effective treatment of severe nasal polyps.
      Topical corticosteroid nasal sprays are recommended.
      • Small C.B.
      • Hernandez J.
      • Reyes A.
      • Schenkel E.
      • Damiano A.
      • Staudinger H.
      • et al.
      Efficacy and safety of mometasone furoate nasal spray in nasal polyposis.
      In patients with severe polyposis, sinus surgery with debulking of nasal polyps might be necessary. Topical corticosteroid nasal sprays are recommended to prevent recurrence of nasal polyps, although they are not always effective. Antileukotriene agents (eg, zafirlukast, montelukast, and zileuton) have received limited study and are not FDA approved for the treatment of nasal polyps. Patients with nasal polyps who have AERD might benefit from aspirin desensitization and daily aspirin therapy, provided they have no contraindications to aspirin therapy.
      • Fokkens W.
      • Lund V.
      • Bachert C.
      • Clement P.
      • Hellings P.
      • Holmstrom W.
      • et al.
      EAACI position paper on rhinosinusitis and nasal polyps executive summary.

       AFRS

      Sinus surgery is almost always required to establish the diagnosis of AFRS, remove inspissated mucus, and restore sinus patency. Nearly all patients with AFRS have nasal polyps. After surgery, oral corticosteroids are recommended at 0.5 mg/kg daily, with gradual tapering of the dose to the lowest possible dose necessary to maintain control of sinus symptoms. Topical corticosteroid nasal sprays are also recommended to control inflammation and prevent recurrence of nasal polyps.

       Indications for sinus surgery

      Functional endoscopic sinus surgery (FESS) is the procedure of choice for surgical management of refractory CRS. FESS is predicated on the observation that CRS “usually starts in the nose and spreads through the ethmoidal prechambers to the frontal and maxillary sinuses, with infections of these latter sinuses thus usually being of secondary nature.”
      • Stammberger H.
      • Posawetz W.
      Functional endoscopic sinus surgery. Concept, indications and results of the Messerklinger technique.
      The principal goal of FESS is to restore patency to the ostiomeatal unit, the key anatomic area of drainage of the maxillary and anterior ethmoid sinuses (Fig 2). A typical FESS procedure includes (on each side) removal of the uncinate process, creation of a widened maxillary antrostomy, an ethmoidectomy, and (in some cases) a sphenoidotomy. Additional goals of FESS might include correction of septal deformities, removal of severe concha bullosa deformity (enlarged middle turbinate containing an air cell), and restoration of patency to the frontal sinus. Several studies have reported a high success rate for FESS in improving the symptoms of CRS.
      • Chambers D.W.
      • Davis W.E.
      • Cook P.R.
      • Nishioka G.J.
      • Rudman D.T.
      Long-term outcome analysis of functional endoscopic sinus surgery: correlation of symptoms with endoscopic examination findings and potential prognostic variables.
      • Senior B.A.
      • Kennedy D.W.
      • Tanabodee J.
      • Kroger H.
      • Hassab M.
      • Lanza D.
      Long-term results of functional endoscopic sinus surgery.
      • Jakobsen J.
      • Svendstrup F.
      Functional endoscopic sinus surgery in chronic sinusitis—a series of 237 consecutively operated patients.
      The classic indications for FESS include (1) persistence of CRS symptoms despite medical therapy, (2) correction of anatomic deformities believed to be contributing to persistence of disease, and (3) debulking of advanced nasal polyposis.

       Comorbidities

       Allergic rhinitis

      IgE-mediated allergy to environmental allergens is found in 60% of patients with CRS (including CRSsNP and CRScNP) compared with 30% to 40% for the general population.
      • Berrettini S.
      • Carabelli A.
      • Sellari-Franceschini S.
      • Bruschini L.
      • Abruzesse A.
      • Quartieri F.
      • et al.
      Perennial allergic rhinitis and chronic sinusitis: correlation with rhinologic risk factors.
      Patients with CRS are typically sensitized to perennial rather than seasonal (ie, pollen) allergens.
      • Berrettini S.
      • Carabelli A.
      • Sellari-Franceschini S.
      • Bruschini L.
      • Abruzesse A.
      • Quartieri F.
      • et al.
      Perennial allergic rhinitis and chronic sinusitis: correlation with rhinologic risk factors.
      By definition, all patients with AFRS have IgE-mediated allergy to fungi. Fungal spores can germinate in sinus mucus, thereby increasing the allergenic stimulus.
      Histopathologic studies of ethmoidal tissue from patients with CRSsNP and nasal polyps from patients with CRScNP have shown that patients with CRS with associated allergies have mucosal TH2 cell infiltration with production of classic TH2 cytokines, including IL-4, IL-5, and IL-13.
      • Hamilos D.L.
      • Leung D.Y.
      • Wood R.
      • Cunningham L.
      • Bean D.K.
      • Yasruel Z.
      • et al.
      Evidence for distinct cytokine expression in allergic versus nonallergic chronic sinusitis.
      • al Ghamdi K.
      • Ghaffar O.
      • Small P.
      • Frenkiel S.
      • Hamid Q.
      IL-4 and IL-13 expression in chronic sinusitis: relationship with cellular infiltrate and effect of topical corticosteroid treatment.
      This suggests that allergens contribute to chronic allergic sinus inflammation.

       Immunodeficiency

      Deficient antibody production in response to vaccination or hypogammaglobulinemia is found in approximately 12% of adults with CRSsNP.
      • Hamilos D.L.
      Chronic rhinosinusitis patterns of illness.
      Immunodeficiency is rare in patients with CRScNP or AFRS. Most patients with deficient antibody production or hypogammaglobulinemia have a pattern of recurrent acute episodes of purulent infection. They might also have a history of concomitant pulmonary infections or recurrent otitis media. Although the nasal and sinus epithelium expresses Toll-like and other innate receptors and produces a variety of antimicrobial proteins, such as lactoferrin, lysozyme, defensins, collectins, and cathelicidins, there are limited data about CRS risk in patients with defects in innate immunity.
      • Psaltis A.J.
      • Bruhn M.A.
      • Ooi E.H.
      • Tan L.W.
      • Wormald P.J.
      Nasal mucosa expression of lactoferrin in patients with chronic rhinosinusitis.

       Gastroesophageal reflux disease

      Sinusitis is considered a possible extraesophageal manifestation of gastroesophageal reflux disease. The mechanism is believed to be due to direct reflux of gastric acid into the pharynx and nasopharynx, causing inflammation of the sinus ostium and leading to sinusitis.
      • Barbero G.J.
      Gastroesophageal reflux and upper airway disease.
      • Schreiber S.
      • Garten D.
      • Sudhoff H.
      Pathophysiological mechanisms of extraesophageal reflux in otolaryngeal disorders.

       Defects in mucociliary clearance

      Defects in mucociliary clearance, such as those found in patients with cystic fibrosis and primary ciliary dyskinesia, dramatically increase the risk of CRS.

       Viral infections

      In a small number of cases, patients appear to have CRS after a period of repeated exposure to viral URIs. This is characteristically seen in patients exposed to health care settings, day care centers, schools, or homes with small children. However, data clearly implicating viral agents in the pathogenesis of CRS are scarce,
      • Jang Y.J.
      • Kwon H.J.
      • Park H.W.
      • Lee B.J.
      Detection of rhinovirus in turbinate epithelial cells of chronic sinusitis.
      and the role of viral infection in patients with CRS is controversial.

       Systemic diseases

      CRS might be the presenting feature of an underlying systemic illness, such as Wegener granulomatosis or Churg-Strauss vasculitis
      • Lohrmann C.
      • Uhl M.
      • Warnatz K.
      • Kotter E.
      • Ghanem N.
      • Langer M.
      Sinonasal computed tomography in patients with Wegener's granulomatosis.
      • Alobid I.
      • Guilemany J.M.
      • Mullol J.
      Nasal manifestations of systemic illnesses.
      or, less commonly, sarcoidosis.
      • Kay D.J.
      • Har-El G.
      The role of endoscopic sinus surgery in chronic sinonasal sarcoidosis.

       Anatomic abnormalities

      Several common anatomic variants can be seen in patients with CRS, including nasal septal deviation, concha bullosa deformity, Haller cells, agar nasi cells, and paradoxical curvature of the middle turbinate. However, these abnormalities are also seen in otherwise healthy subjects and are not clearly epidemiologically linked to an increased risk of sinusitis.
      • Lusk R.P.
      • McAlister B.
      • el Fouley A.
      Anatomic variation in pediatric chronic sinusitis: a CT study.
      • Bolger W.E.
      • Butzin C.A.
      • Parsons D.S.
      Paranasal sinus bony anatomic variations and mucosal abnormalities: CT analysis for endoscopic sinus surgery.
      • Jones N.S.
      • Strobl A.
      • Holland I.
      A study of the CT findings in 100 patients with rhinosinusitis and 100 controls.
      • Danese M.
      • Duvoisin B.
      • Agrifoglio A.
      • Cherpillod J.
      • Krayenbuhl M.
      Influence of naso-sinusal anatomic variants on recurrent, persistent or chronic sinusitis. X-ray computed tomographic evaluation in 112 patients.

       Associated conditions

      Both asthma and AERD are associated with CRS. Approximately 20% of patients with CRS have concomitant asthma. Conversely, approximately two thirds of asthmatic subjects, including both children and adults, have evidence of chronic sinus mucosal thickening or sinus opacification in cross-sectional studies.
      • Jani A.L.
      • Hamilos D.L.
      Current thinking on the relationship between rhinosinusitis and asthma.
      The combination of aspirin sensitivity, asthma, and nasal polyposis is referred to as triad asthma, Samter syndrome, or AERD.
      • Samter M.
      • Beers Jr., R.F.
      Intolerance to aspirin. Clinical studies and consideration of its pathogenesis.
      • Berges-Gimeno M.P.
      • Simon R.A.
      • Stevenson D.D.
      The natural history and clinical characteristics of aspirin-exacerbated respiratory disease.

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