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Complications of allergic rhinitis

  • David P Skoner
    Correspondence
    Reprint requests: David P. Skoner, MD, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213
    Affiliations
    Department of Allergy and Immunology, Children’s Hospital of Pittsburgh
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      Abstract

      Upper and lower respiratory diseases, including asthma, sinusitis, and otitis media with effusion, frequently complicate allergic rhinitis. The close association of nasal allergies with these conditions has been supported by extensive epidemiologic evidence. Similar models have been proposed to explain the pathophysiologic links between allergic rhinitis and both sinusitis and otitis media with effusion. In these models, inflammation caused by nasal allergy and/or viral infection leads to obstruction, fluid accumulation, bacterial infection, and acute disease. If these diseases are unsuccessfully treated, a chronic state of inflammation, obstruction, and infection develops that can cause mucosal damage and, ultimately, chronic disease. A number of studies have investigated the roles and interactions of viruses and allergens in the development of otitis media with effusion. Diagnosing and prophylactically treating nasal allergies in patients with this condition may help prevent recurrent episodes and improve the response to therapy. (J Allergy Clin Immunol 2000;105:S605-9.)

      Keywords

      Nomenclature

      OME
      Otitis media with effusion
      URTI
      Upper respiratory tract infection
      Approximately 20% of adults and children have seasonal or perennial allergic rhinitis.
      • Settipane GA
      Allergic rhinitis-update.
      Despite its prevalence, the condition is often treated inadequately and becomes chronic. A chronic state of nasal inflammation and obstruction develops, frequently leading to more serious complications in both the upper and the lower airways. Retrospective and prospective epidemiologic surveys have shown that allergic rhinitis is closely associated with, and may be a causative factor in, asthma, sinusitis, and otitis media with effusion (OME).
      Models have been developed to explain the pathogenesis of both sinusitis and OME. The precipitating events in both these models are not bacterial infections but nasal inflammation and obstruction caused by nasal allergy and/or virus infection. With regard to OME, nasal challenges with histamine and allergens have been shown to cause nasal obstruction that results in eustachian tube obstruction. Experimental infection with certain viruses not only causes eustachian tube obstruction but also middle ear under pressure and middle ear disease. Viral upper respiratory tract infection (URTI) in patients with nasal allergy (especially to perennial allergens) may serve to enhance inflammatory responses in the nose and eustachian tube that provoke eustachian tube obstruction and lead to OME.

      EPIDEMIOLOGIC LINKS BETWEEN ALLERGIC RHINITIS AND OTHER AIRWAY DISEASES

      Cross-sectional epidemiologic studies demonstrate that up to 78% of patients with asthma are diagnosed with allergic rhinitis.
      • Pedersen PA
      • Weeke ER
      Asthma and allergic rhinitis in the same patients.
      A more recent study documented that 99% of adults and 93% of adolescents with allergic asthma also have allergic rhinitis.
      • Kapsali T
      • Horowitz E
      • Diemer F
      • Togias A
      Rhinitis is ubiquitous in allergic asthmatics [abstract].
      Conversely, asthma is diagnosed in up to 37% of patients with seasonal rhinitis.
      • Blair H
      Natural history of childhood asthma: 20-year follow-up.
      In patients with both allergic diseases, rhinitis precedes asthma in 43% to 64% of the cases.
      • Kapsali T
      • Horowitz E
      • Diemer F
      • Togias A
      Rhinitis is ubiquitous in allergic asthmatics [abstract].
      A prospective 23-year study reported a 3-fold increase in the incidence of asthma in patients who previously had allergic rhinitis (without apparent asthma) compared with those patients who had not had rhinitis (10.5% compared with 3.6%).
      • Settipane RJ
      • Hagy GW
      • Settipane GA
      Long-term risk factors for developing asthma and allergic rhinitis: a 23-year follow-up study of college students.
      The coexistence of allergic rhinitis and sinusitis has been well documented. An early study demonstrated that 53% of children with allergic rhinitis had abnormal sinus radiographs,
      • Rachelefsky GS
      • Goldberg M
      • Katz RM
      • Boris G
      • Gyepes MT
      • Shapiro MJ
      • et al.
      Sinus disease in children with respiratory allergy.
      whereas, in a more recent study, up to 70% of children with allergy and chronic rhinitis had abnormal findings on sinus radiographs.
      • Shapiro GG
      The role of nasal airway obstruction in sinus disease and facial development.
      Numerous studies of children and adults have documented the prevalence of allergic rhinitis and/or atopy in patients with both acute and chronic sinusitis.
      • Savolainen S
      Allergy in patients with acute maxillary sinusitis.
      • Shapiro GG
      • Virant FS
      • Furukawa CT
      • Pierson WE
      • Bierman CW
      Immunologic defects in patients with refractory sinusitis.
      • Rachelefsky GS
      • Siegel SC
      • Katz RM
      • Spector SL
      • Rohr AS
      Chronic sinusitis in children [abstract].
      In patients with recurrent sinus infections, extensive sinus disease was associated with allergy in 78% of patients.
      • Newman LJ
      • Platts-Mills TAE
      • Phillips CD
      • Hazen KC
      • Gross CW
      Chronic sinusitis: relationship of computed tomographic findings to allergy, asthma, and eosinophilia.
      In children with chronic OME, 40% to 50% have allergic rhinitis confirmed with positive allergy skin tests or increased serum IgE antibodies to specific allergens.
      • Fireman P
      Otitis media and eustachian tube dysfunction: connection to allergic rhinitis.

      MODEL FOR THE DEVELOPMENT OF SINUSITIS AND OTITIS MEDIA

      A cyclic model has been proposed to explain the progression of sinusitis from an acute to a chronic condition.
      • Reilly JS
      The sinusitis cycle.
      This model assumes that the initial event in sinusitis is not bacterial infection but, rather, the obstruction of the osteomeatal complex, which impedes the normal movement of air and secretions in and out of the sinuses. Nasal inflammation primarily caused by viral URTI and allergic rhinitis contribute to the obstruction of the sinus passages. The results of 1 study showed that approximately one third of subjects who were inoculated with rhinovirus experienced the development of sinus abnormalities and typical sinus disease symptoms.
      • Turner BW
      • Cail WS
      • Hendley JO
      • Hayden FG
      • Doyle WJ
      • Sorrentino JV
      • et al.
      Physiologic abnormalities in the paranasal sinuses during experimental rhinovirus colds.
      In another study, 87% of healthy adult volunteers with self-diagnosed colds had abnormalities of 1 or both maxillary sinuses.
      • Gwaltney Jr, JM
      • Phillips CD
      • Miller RD
      • Riker DK
      Computed tomographic study of the common cold.
      Thickened secretions develop that are unable to pass through narrowed ostia; and the accumulation of these secretions leads to further obstruction, mucosal swelling, and, possibly, thickening of the sinus mucosa. An anaerobic environment develops in the sinus that favors bacterial growth, leading to infection. Impaired ciliary function and an increase in thickened mucus further obstruct drainage. Unless the cycle is broken, obstruction continues to increase and unresolved or new infections flare up, leading to recurrent acute episodes and eventually to chronic disease. This model offers an explanation of why chronic sinusitis is often resistant to treatment with antimicrobials alone and a rationale for treating the cause of inflammation (eg, with antihistamines and corticosteroids).
      A similar model has been developed to explain the pathogenesis of OME. Acute otitis media and OME are the most common childhood illnesses that require physician care.
      • Fireman P
      Otitis media and eustachian tube dysfunction: connection to allergic rhinitis.
      By the time children reach 3 years of age, 83% have had at least 1 episode of acute otitis media.
      • Teele DW
      • Klein JO
      • Rosner B
      • the Greater Boston Otitis Media Study Group
      Epidemiology of otitis media during the first seven years of life in children in Greater Boston: a prospective, cohort study.
      However, acute otitis media also affects a substantial number of adults.
      The OME model hypothesizes that nasal inflammation because of allergens and/or viral URTIs leads to inflammatory swelling and obstruction of the eustachian tube, which in turn leads to increased negative pressure in the middle ear and improper ventilation. Middle ear under pressure allows fluids into the middle ear. Transient eustachian tube opening can occur in the middle ear with an effusion, which results in insufflation or aspiration into the middle ear cavity of nasopharyngeal secretions that contain bacteria, virus, and/or allergens. Bacteria in the middle ear fluid can cause acute bacterial otitis media. Sustained obstruction and dysfunction of the eustachian tube (eg, because of inflammation caused by perennial allergic rhinitis), persistent effusion, and unresolved bacterial infections can lead to chronic OME. This model has been extensively tested because of the accessibility of the middle ear to assessment of function. A number of studies on the pathogenesis of otitis media have described the interactions among viral URTIs, nasal allergic reactions, eustachian tube dysfunction, and middle ear disease.

      THE ROLE OF ALLERGENS IN MIDDLE EAR DISEASE

      The high prevalence of chronic OME among patients with allergic rhinitis strongly suggests that IgE-mediated allergies are involved in the pathogenesis of middle ear disease. Of the children with allergy, 21% have OME, whereas 50% of children with chronic OME have nasal allergy (Fig 1).
      • Tomonaga K
      • Kurono Y
      • Mogi G
      The role of nasal allergy in otitis media with effusion.
      Figure thumbnail gr1
      Fig. 1.  Nasal allergy and chronic OME in various pediatric populations. *Control group. (Adapted from Tomonaga K, Kurono Y, Mogi G. The role of nasal allergy in otitis media with effusion. Acta Otolaryngol [Stockh] 1988;458[suppl]:41-7. With permission.)
      Several studies have examined the effects of seasonal allergic rhinitis on eustachian tube function and middle ear pressure in subjects with allergic rhinitis. The results of these studies demonstrate that during peak pollen season in untreated pollen-allergic individuals, eustachian tube obstruction increases from 15% at baseline to 60% at peak pollen exposure (Fig 2).
      • Skoner DP
      • Lee L
      • Doyle WJ
      • Boehn S
      • Fireman P
      Nasal physiology and inflammatory mediators during natural pollen exposure.
      In addition, negative middle ear pressure develops in 24% to 48% of pollen-allergic adults during natural peak pollen exposures.
      • Knight LC
      • Eccles R
      • Morris S
      Seasonal allergic rhinitis and its effects on eustachian tube function and middle ear pressure.
      Figure thumbnail gr2
      Fig. 2.  Changes in environment (A ) pollen and (B ) eustachian tube obstruction before (week 1), during (weeks 2 to 9), and after (weeks 10 and 11) grass pollen season. *P < .05 versus baseline. (Modified with permission from Skoner DP, Lee L, Doyle WJ, Boehn S, Fireman P. Nasal physiology and inflammatory mediators during natural pollen exposure. Ann Allergy 1990;65:206-10. Copyright ACAAI.)
      Intranasal pollen challenges in subjects with allergy have been shown to promote nasal symptoms, nasal obstruction, and eustachian tube obstruction.
      • Skoner DP
      • Doyle WJ
      • Boehm S
      • Fireman P
      Priming of the nose and eustachian tube during natural pollen exposure.
      Both early- and late-phase immune reactions in the eustachian tube and the nose have been reported after intranasal challenge with ragweed pollen (Table I).
      • Skoner DP
      • Doyle WJ
      • Boehm S
      • Fireman P
      Late phase eustachian tube and nasal allergic responses associated with inflammatory mediator elaboration.
      Intranasal challenge with a perennial allergen (house-dust mite) also leads to eustachian tube obstruction (Fig 3).
      • Skoner DP
      • Doyle WJ
      • Chamovitz AH
      • Fireman P
      Eustachian tube obstruction after intranasal challenge with house dust mite.
      Fifty-five percent of adults with nasal allergy experienced the development of eustachian tube dysfunction in response to challenge with house-dust mite.
      • Skoner DP
      • Doyle WJ
      • Chamovitz AH
      • Fireman P
      Eustachian tube obstruction after intranasal challenge with house dust mite.
      Eustachian tube obstruction has also been reported to develop more frequently in subjects with allergic rhinitis than subjects without allergy after a single intranasal histamine challenge and at relatively low histamine doses.
      • Skoner DP
      • Doyle WJ
      • Fireman P
      Eustachian tube obstruction (ETO) after histamine nasal provocation-a double-blind dose-response study.
      In allergen-provocation studies, nasal obstruction usually preceded the development of eustachian tube obstruction, which was not the case after histamine challenge.
      • Skoner DP
      • Doyle WJ
      • Fireman P
      Eustachian tube obstruction (ETO) after histamine nasal provocation-a double-blind dose-response study.
      In addition, a variety of potent inflammatory mediators, including histamine, have been detected in middle ear effusions of children with OME.
      • Skoner DP
      • Stillwagon PK
      • Casselbrandt ML
      • Tanner EP
      • Doyle WJ
      • Fireman P
      Inflammatory mediators in chronic otitis media with effusion.
      Table IEarly- and late-phase allergic reactions after intranasal allergen challenge
      ObstructionResponse (n/N)
      EarlyPersistentLate
      Eustachian tube
       Patients7/102/106/10
       Ears12/204/2010/20
      Nasal9/102/107/10
      Bronchial2/100/103/10
      Adapted from Skoner DP, Doyle WJ, Boehm S, Fireman P. Late phase eustachian tube and nasal allergic responses associated with inflammatory mediator elaboration. Am J Rhinol 1988;2:155-61. With permission.
      Figure thumbnail gr3
      Fig. 3.  The distribution of nasal- and eustachian tube–obstructing antigen doses for study subjects. Open bar , nasal obstruction; filled bar , eustachian tube obstruction.(Adapted from Skoner DP, Doyle WJ, Chamovitz AH, Fireman P. Eustachian tube obstruction after intranasal challenge with house dust mite. Arch Otolaryngol Head Neck Surg 1986;112:840-2. Copyright 1986, American Medical Association.)
      It has been proposed that prolonged eustachian tube obstruction, which could result from perennial exposure to an allergen (eg, house-dust mite), could precipitate middle ear disease, if the ″priming” phenomenon occurs in the eustachian tube (ie, the mucosa responds to lower doses of allergen with repeated exposure) as it does in the nose. Seasonal priming has been demonstrated to increase the physiologic responsiveness of the eustachian tube both to ragweed pollen and histamine, with the observed hyperresponsiveness extending beyond the ragweed season.
      • Skoner DP
      • Doyle WJ
      • Boehm S
      • Fireman P
      Late phase eustachian tube and nasal allergic responses associated with inflammatory mediator elaboration.

      THE ROLE OF VIRUS INFECTION IN MIDDLE EAR DISEASE

      Epidemiologic studies show that one half of all new episodes of otitis media are diagnosed immediately after or concurrent with a viral URTI.
      • Fireman P
      Otitis media and eustachian tube dysfunction: connection to allergic rhinitis.
      In the past, viruses have been isolated rarely from middle ear effusions in patients with otitis media with the use of standard culture techniques. However, recent studies with PCR-based molecular analysis have shown that 53% of middle ear effusions are positive for viruses.
      • Buchman CA
      • Doyle WJ
      • Skoner DP
      • Post JC
      • Alper CM
      • Seroky JT
      • et al.
      Influenza A virus–induced acute otitis media.
      Experimental infection with rhinovirus-39 in humans has shown substantial increases in eustachian tube dysfunction in most subjects and abnormal middle ear pressures in approximately 30% of infected subjects, but the development of otitis media was rare (0% to 3%).
      • Doyle WJ
      • Skoner DP
      • Hayden F
      • Buchman CA
      • Seroky JT
      • Fireman P
      Nasal and otologic effects of experimental influenza A virus infection.
      However, in a study of intranasal inoculation with influenza A virus, 59% of subjects experienced the development of middle ear under pressure, and 25% of subjects experienced the development of otitis media.
      • Buchman CA
      • Doyle WJ
      • Skoner DP
      • Post JC
      • Alper CM
      • Seroky JT
      • et al.
      Influenza A virus–induced acute otitis media.
      This study was unique because 1 subject experience the development of middle ear under pressure followed by purulent otitis media. PCR analysis of the patient’s middle ear effusion was positive for both influenza A and Streptococcus pneumoniae .
      • Buchman CA
      • Doyle WJ
      • Skoner DP
      • Post JC
      • Alper CM
      • Seroky JT
      • et al.
      Influenza A virus–induced acute otitis media.
      More than 80% of infected subjects experienced the development of eustachian tube dysfunction, and approximately 80% had middle ear under pressure.
      • Doyle WJ
      • Skoner DP
      • Hayden F
      • Buchman CA
      • Seroky JT
      • Fireman P
      Nasal and otologic effects of experimental influenza A virus infection.
      Five of 21 infected subjects had otoscopic evidence of OME beginning as early as 4 days after viral exposure. One subject experienced symptoms of dizziness and vertigo, which suggested transient inner ear involvement.
      • Doyle WJ
      • Skoner DP
      • Hayden F
      • Buchman CA
      • Seroky JT
      • Fireman P
      Nasal and otologic effects of experimental influenza A virus infection.
      This supports a causal role for viral URTIs in the pathogenesis of otitis media through the early development of eustachian tube obstruction and abnormal middle ear pressure.
      In a recently published study of children with acute otitis media, investigators isolated micro-organisms from the fluids in their subjects’ middle ears.
      • Heikkinen T
      • Thint M
      • Chonmaitree T
      Prevalence of various respiratory viruses in the middle ear during acute otitis media.
      Sixty-five percent of the fluid samples contained both bacteria and viruses. Of these samples, 100% of those samples that were infected with influenza virus also contained S pneumoniae, 25% contained Haemophilus influenzae, and 38% Moraxella catarrhalis (Table II).
      • Heikkinen T
      • Thint M
      • Chonmaitree T
      Prevalence of various respiratory viruses in the middle ear during acute otitis media.
      These results suggest the possibility that virus infection sets the stage for bacterial infection.
      Table IISpecific micro-organisms in the 43 samples of middle ear fluid that contained both bacteria and viruses*
      Table available in print only.
      *More than 1 bacterial species was identified in samples from 8 ears.
      Pseudomonas aeruginosa was cultured in 2 ears with enteroviruses.
      P = .003 for the comparison with respiratory syncytial virus and P < .001 for the comparison with parainfluenza viruses (by Fisher’s exact test).
      Adapted from Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340:260-4. Copyright 1999, Massachusetts Medical Society. All rights reserved.

      VIRAL/ALLERGEN INTERACTION

      The relationship between viral infection and nasal allergens in provoking OME is not clearly understood. However, there is evidence that their interaction enhances certain immune responses. Infection with rhinovirus-39 induces significant increases from baseline (P = .000008) in serum IgE antibodies in subjects with allergic rhinitis.
      • Skoner D
      • Doyle WJ
      • Tanner EP
      • Kiss J
      • Fireman P
      Effect of rhinovirus 39 (RV-39) infection on immune and inflammatory parameters in allergic and non-allergic subjects.
      URTI also intensifies the release of a variety of inflammatory substances, some of which have been shown to provoke eustachian tube obstruction. For example, experimental infection with influenza A increases the release of histamine from peripheral blood basophils of patients with allergic rhinitis.
      • Fireman P
      Otitis media and eustachian tube dysfunction: connection to allergic rhinitis.
      It has been reported that patients with allergic rhinitis and rhinovirus URTI have enhanced lower airway responsiveness and basophil histamine release to ragweed challenge,
      • Busse W
      Respiratory infections and bronchial hyperreactivity.
      which suggests that patients with allergic rhinitis may be hyperresponsive to inflammatory mediators elaborated during a viral URTI, which can be potentiated by the priming of a preceding allergy season or URTI.

      SUMMARY

      Numerous studies have supported the involvement and interaction of virus infection and allergic rhinitis in the pathogenesis of OME. Further clarification of the nature of the interactions between viruses and allergens in middle ear disease may help describe populations at risk for OME that would benefit from preventative therapies (eg, influenza inoculations, allergen avoidance, antihistamines). A small study investigated the prevention of eustachian tube obstruction by pretreatment with an antihistamine plus decongestant in a group of subjects who were ragweed-sensitive and who underwent nasal provocation with allergen. As the dose of ragweed was increased, actively treated patients showed a substantially lower incidence of eustachian tube obstruction (Fig 4).
      • Stillwagon PK
      • Doyle WJ
      • Fireman P
      Effect of an antihistamine/decongestant on nasal and eustachian tube function following intranasal pollen challenge.
      Figure thumbnail gr4
      Fig. 4.  Incidence of eustachian tube obstruction in patients who were sensitized to ragweed and who were challenged with antigen after pretreatment with either placebo or antihistamine plus decongestant. (Modified with permission from Stillwagon PK, Doyle WJ, Fireman P. Effect of an antihistamine/decongestant on nasal and eustachian tube function following intranasal pollen challenge. Ann Allergy 1987;58:442-6. Copyright ACAAI.).

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        Late phase eustachian tube and nasal allergic responses associated with inflammatory mediator elaboration.
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        Effect of an antihistamine/decongestant on nasal and eustachian tube function following intranasal pollen challenge.
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