nonallergic rhinitis, with a focus on vasomotor rhinitis

Nonallergic Rhinitis, With a Focus on Vasomotor RhinitisClinical Importance, Differential Diagnosis, and Effective

Treatment RecommendationsMark D. Scarupa and Michael A. Kaliner

Abstract: The term Brhinitis[ denotes nasal inammation causing acombination of rhinorrhea, sneezing, congestion, nasal itch, and/orpostnasal drainage. Allergic rhinitis is the most prevalent and mostfrequently recognized form of rhinitis. However, nonallergic rhinitis(NAR) is also very common, affecting millions of people. By con-trast, NAR is less well understood and less often diagnosed. Nonaller-gic rhinitis includes a heterogeneous group of conditions, involvingvarious triggers and distinct pathophysiologies. Nonallergic vasomo-tor rhinitis is the most common form of NAR and will be the primaryfocus of this review. Understanding and recognizing the presence ofNAR in a patient is essential for the correct selection of medicationsand for successful treatment outcomes.

Key Words: nonallergic rhinitis, vasomotor rhinitis,mixed rhinitis, allergic rhinitis

(WAO Journal 2009; 2:20Y25)

Nonallergic rhinitis (NAR) is not a single disease with 1underlying mechanism but is instead a collection of mul-tiple distinct conditions that cause similar nasal symptoms.Nonallergic rhinitis is at times almost indistinguishable fromallergic rhinitis (AR), although typically nasal and palatal itch,sneezing, and conjunctival irritation are less prominent. Non-allergic rhinitis can and frequently does exist simultaneouslywith AR, a condition known as Bmixed rhinitis.[ Themost clini-cally prevalent form of NAR is vasomotor or idiopathic rhinitis,characterized by sporadic or persistent perennial nasal symp-toms that are triggered by environmental conditions, such asstrong smells; cold air; changes in temperature, humidity, andbarometric pressure; strong emotions; ingesting alcoholic bev-erages; and changes in hormone levels. These triggers do notinvolve immunoglobulin E cross-linking or histamine release.

EPIDEMIOLOGY AND IMPACTThe incidence of NAR varies from study to study.

Almost all publications on NAR are found in North Americanand European literature. Thus, it is unclear whether the inci-dence or the age and sex distribution applies to populations notyet studied elsewhere in the world. In 1 survey of US medicalpractices, the classication of patients with rhinitis was 43%

AR, 23% NAR, and 34% mixed rhinitis (rhinitis with both ARand NAR features).1 These data suggest that at least 57% ofrhinitis patients have some contribution from NAR causingtheir rhinitis symptoms. Similar European studies have foundthat approximately 1 in 4 patients complaining of nasal symp-toms has pure NAR.2 Recent estimates suggest that 50 millionEuropeans have NAR, with a total prevalence of greater than200 million worldwide.3 In the United States, there are ap-proximately 60 million patients with AR and 30 million withnonallergic vasomotor rhinitis (VMR).

Nonallergic rhinitis tends to be adult onset, with thetypical age of presentation between 30 and 60 years.4 Oncesymptoms begin, they frequently last a lifetime. If NAR ispresent in pediatric populations, it is more likely to be ana-tomic in nature and to be caused by either adenoid or turbinatehypertrophy, leading to persistent nasal obstruction. In adults,most studies report a clear female predominance, with esti-mates ranging from 58% to 71% of those affected being fe-male. In a Danish study classifying a population of both adultsand adolescents, female predominance held true with ap-proximately double the prevalence of NAR in women.2

The nancial impact of NAR has not been studieddirectly, but numerous studies have looked at the direct andthe indirect costs of AR. It is likely that because most studiesindicate that at least 1 in 4 patients with nasal symptoms havepure NAR, the rough cost of the condition is approximatelyone third of AR. Direct and indirect US medical expendi-tures for AR are in excess of 2.7 billion dollars (1995 dollars).5

When lost productivity due to drowsiness, cognitive/motorimpairment, and missed school and work is considered, thecost estimate increases to $6 billion.6 Thus, although no re-ports of the costs of NAR have been reported, it is likely thatthis disease costs at least US$2 to 3 billion per year.

NAR: DIAGNOSIS AND CLASSIFICATIONNonallergic rhinitis denotes a group of heterogeneous

syndromes with distinct underlying pathophysiologies. His-torically, NAR variants have been divided into 2 groupsbased on nasal cytology: NAR with eosinophilia syndrome(NARES) and non-NARES. However, in this era, nasal cy-tology is rarely performed in clinical practice. Thus, it islogical today to classify NAR based solely on symptoms andtriggers. Furthermore, when considering the diagnosis ofNAR, the concomitant presence of AR and/or chronic rhino-sinusitis needs to be considered. Most patients with chronicnasal symptoms appear at the physicians ofce assuming thatthey have AR. As part of the diagnostic steps used to conrmthe diagnosis, most patients undergo specic environmental

REVIEW ARTICLE

20 WAO Journal & March 2009

Received for publication October 21, 2008; accepted December 16, 2008.From the Institute for Asthma & Allergy, Bethesda, MD.Reprints: Michael A. Kaliner, MD, Institute for Asthma & Allergy, 6515

Hillmead Road, Bethesda, MD 20817. E-mail: [email protected] * 2009 by World Allergy Organization

allergy testing either by skin test or by radioallergosorbent test.In the presence of negative allergy skin tests and a history ofrhinitis symptoms, most patients will have some form of NARor rhinosinusitis.

Nonallergic rhinitis can be classied into 9 subtypes(Table 1): drug-induced rhinitis, gustatory rhinitis (rhinorrheaassociated with eating), hormonal-induced rhinitis, infectiousrhinitis, NARES, occupational rhinitis, senile rhinitis, atrophicrhinitis, and VMR (modied from Settipane and Charnock4).Rhinitis of pregnancy is an extremely common conditioneffecting up to 20% to 30% of pregnancies, especially nota-ble during the last trimester.7 It typically resolves spontane-ously within 2 weeks of delivery. As 1 clue to specic causes,Ellegard et al8 have shown that woman with rhinitis of preg-nancy have elevated serum placental growth hormone levelswhen compared with pregnant women without rhinitis. How-ever, it is usually assumed that the rhinitis of pregnancyreects the mucosal engorgement found in the last trimesteras a consequence of progesterone stimulation. Thus, the nasalmucosa also becomes engorged and congestion ensues.

Rhinitis medicamentosa or medication-induced rhinitisis another common NAR variant. The most common cause ofrhinitis medicamentosa is overuse of the topical nasal decon-gestants oxymetazoline or phenylephrine. When used briey(less than 3Y5 days consecutively), these medications providesignicant relief of nasal congestion. However, with chronicuse, rebound nasal congestion can occur and can be quite se-vere. The exact mechanism is poorly understood, but theoriesinvolving recurrent nasal tissue hypoxia and negative neuralfeedback with chronic >-2 receptor agonism exist.9 Rhinitismedicamentosa is treated with topical nasal corticosteroids(NCCSs) and/or oral corticosteroids, and progressive with-drawal of the topical decongestant sprays over a 3- to 7-dayperiod.

More broadly, other medications can cause chronic nasalsymptoms through a host of different mechanisms. Antihy-pertensive medications including A blockers, reserpine, cal-cium channel blockers, and methyldopa frequently cause nasalcongestion.1 Aspirin and nonsteroidal anti-inammatorydrugs also may contribute to congestion especially in patientswith a history of nasal polyposis. Oral contraceptive pills alsocan cause congestion in somewomen. Eye drops can cause rhi-nitis after they pass the nasolacrimal duct into the nose.

Nonallergic rhinitis also is also found with other un-derlying medical conditions, the full range of which is beyondthe scope of this article (Table 2). For example, nasal conges-

tion can be seen in disparate diseases such as hypothyroidismand chronic fatigue syndrome. Baraniuk et al10 found that 46%of patients with chronic fatigue syndrome have NAR and that76% of patients have some nasal complaints. Gastroesopha-geal reux disease or laryngeal-pharyngeal reux can lead tochronic postnasal drip and other throat symptoms and, in se-vere cases, can also cause nasal congestion.

Anatomic anomalies can contribute to NAR. Bothadenoid hypertrophy and turbinate hypertrophy can causesymptoms of chronic nasal congestion with little relief frommedications. Surgical intervention can be curative. Quite dis-similar to the anatomic hypertrophies, senile rhinitis is mostcommon in the elderly and can lead to persistent rhinorrhea,worsened by eating or environmental irritants. Atrophic rhi-nitis is usually seen in patients who have had overzealoussurgeries, with too much mucus-secreting tissues removed.Cerebral spinal uid leak in patients with a history of cra-niofacial trauma or past facial/sinus surgeries must be con-sidered when evaluating persistent rhinorrhea.

Nonallergic VMRThe most frequent form of NAR observed clinically is

nonallergic VMR or idiopathic rhinitis, characterized by spo-radic or persistent nasal symptoms that are triggered byenvironmental conditions, such as strong smells; exposure tocold air; changes in temperature, humidity, and barometricpressure; strong emotions; ingesting alcoholic beverages; andchanges in hormone levels. The diagnosis of VMR is primarilymade by clinical history. If a patient has appropriate nasalsymptoms (usually rhinorrhea, congestion, postnasal drip,headaches, throat clearing, and coughing) triggered by 1 ormore environmental irritants, then VMR is present. Concomi-tant ocular symptoms tend to be minimal, and the symptomsof nasal and palatal itch as well as sneezing spells are notcommon. Unlike AR, VMR is usually of adult onset and notworsened by exposure to classic allergens such pollen, housedust mite, dog, or cat. A validated questionnaire has beencreated to help identify NAR patients.11 Because VMRmay becaused by shifts in temperature and humidity, patients may

TABLE 1. Specic Syndromes Classied as NAR

Drug-induced rhinitis, including rhinitis medicamentosa

Gustatory rhinitis

Hormonal-induced rhinitis, including the rhinitis of pregnancy

Infectious rhinitis

NARES

Occupational rhinitis

Senile rhinitis

Atrophic rhinitis

Vasomotor or idiopathic rhinitis

TABLE 2. Medical Conditions Associated With or PresentingSimilarly to NAR

Metabolic

Acromegaly

Pregnancy

Hypothyroidism

Autoimmune

Sjogren syndrome

Systemic lupus erythematosus

Relapsing polychondritis

Churg-Straus syndrome

Wegner granulomatosis

Other

Cystic fibrosis

Kartagener syndrome

Sarcoidosis

Immunodeficiency

Adapted from Settipane and Settipane.1

WAO Journal & March 2009 Nonallergic Rhinitis and Vasomotor Rhinitis

* 2009 World Allergy Organization 21

experience seasonal symptoms during spring and fall. Thus,seasonal VMR can easily be confused with Seasonal AllergicRhinitis (SAR).12

The diagnosis of VMR is based solely on the patientshistory of symptoms and their triggers, whereas the diagnosisof AR requires an appropriate history and conrmatory allergytesting, either positive prick skin tests or radioallergosorbenttests. These diseases are not mutually exclusive, and nearly60% of AR patients have a component of VMR participatingin triggering symptoms. In 1 survey of patients with chronicrhinosinusitis, AR was the underlying cause in 65%, whereasVMR was coexistent in 25%.13 Thus, there is an extensiveoverlap between the 3 most common chronic nasal diseases:AR, VMR, and chronic rhinosinusitis.

The exact underlying mechanisms causing VMR are notwell understood. There is evidence that capsaicin-sensitivenociceptors in the nasal mucosa may play a role.14Y16 Otherstudies have shown that in patients with cold-airYinducedNAR, inhalation of cold air into 1 nostril causes contralateralsymptoms that can be blocked by pretreating the challengednostril with lidocaine or repetitively treating the nose withcapsaicin before challenge.17,18 Further evidence of a neu-rologic mechanism driving NAR is a small study suggestingthat endoscopic vidian neurectomy reduces both rhinorrheaand congestion in VMR patients.19 Some studies have alsodemonstrated that topical nasal capsaicin treatment of VMRpatients can induce prolonged symptom relief.15 By contrast,there is some data that mast cells can be activated in cold-airYinduced rhinitis by breathing cold dry air, which caused invivo histamine release in cold-airYinduced rhinitis but not inother forms of VMR.20

The epidemiologic predominance of females experien-cing VMR suggests that female hormones might play somerole, but there is no research explaining this possibility.

TREATMENTAlthough each form of NAR should be treated indi-

vidually, VMR is the most well-studied and clinically im-

portant form of NAR and the only type of NAR for whichclinical studies have led to approved treatments. In the fol-lowing discussion, treatment of NAR will focus on VMR, butsome mention will be made of other forms of NAR whereappropriate. The medications used for treating VMR havebeen studied less extensively than those for AR, but there arestill multiple therapeutic options available (Fig. 1). In Figure 1,the algorithm is based on separation of VMR into 3 clinicalpresentations: congestion predominant, rhinorrhea predomi-nant, and mixed form of VMR where patients experience bothrhinorrhea and congestion.

Nasal CorticosteroidsNasal corticosteroids treat inammatory conditions

regardless of etiology. There is substantial evidence that cor-ticosteroids benet AR, some forms of NAR including VMR,and chronic rhinosinusitis. In a study of 983 patients withNARES and non-NARES, uticasone propionate (FP) at both200 and 400 Kg signicantly improved total nasal symptomsscores when compared with placebo, and no difference wasnoted between the 2 concentrations.21 In the United States, ofall the NCCSs approved by the Food and Drug Authority(FDA) available today, only FP is approved for the treatmentof both AR and NAR.

Although none of the other current NCCS has receivedUS FDA approval for use in NAR, there is some supportivedata for the efcacy of intranasal budesonide and mometasonein some patients with perennial rhinitis.22,23 There is also 1published study demonstrating that there was no benet fromFP in NAR. In that study, NAR patients receiving 200 Kg ofdaily FP showed a reduction in inammatory mediators but noimprovement in symptoms as compared with placebo.14 Bycontrast, clinical experience suggests that all NCCSs havesome effectiveness in treating VMR.

In VMR, the scent of uticasone is sometimes a negativefeature in patients for whom scent is a trigger. However, as aclass, NCCS treats the broadest spectrum of NAR symptomsand seems to have at least some degree of efcacy in all NAR

FIGURE 1. Algorithm for the treatment of nonallergic VMR. Once a patient is categorized as VMR, the predominant symptomcomplex determines initial treatments based on symptom severity. Initial treatments for mildly affected patients use single entities,but patients with more severe disease who have failed monotherapy should be tried on combination therapies. Most patients willultimately respond to the use of combinations of nasal sprays plus an oral medication. Once under control, stepping the therapydown to the lowest effective dose of mediations is suggested.

Scarupa and Kaliner WAO Journal & March 2009


variants, including VMR. Thus, for the treatment of NAR,NCCSs are considered a rst-line therapy.

AntihistaminesIt is quite likely that all NAR patients have tried oral

antihistamines, either in the form of over-the-counter medi-cations or as prescribed by physicians who assume that thesymptoms are caused by allergies. Histamine release has notbeen seen in NAR and is specically not seen in VMR otherthan cold-airYinduced rhinitis.20 Thus, the use of oral antihis-tamines makes little sense, and these medications have rarelybeen studied in VMR. A 1982 study does show that rst-generation antihistamines can improve VMR symptoms whencombined with a decongestant.24

It is predictable that rst-generation antihistaminesmight reduce rhinorrhea through anticholinergic actions,whereas second-generation nonsedating antihistamines haveminimal anticholinergic activity. Typically, second-generationoral antihistamines are of no benet in NAR. Oral antihis-tamines are generally ineffective in reducing congestion inAR and thus would not be expected to work in NAR either.The combination of an antihistamine and a decongestant mighthelp reduce the congestion seen in VMR, but no such indi-cation has been approved by the US FDA. Clinical experiencesuggests that antihistamine/decongestant combinations aresomewhat effective in VMR.

By contrast, intranasal antihistamines are very effectivein treating AR (both azelastine and olopatadine are approvedfor treating SAR). Azelastine is also approved by the FDA fortreatment of nonallergic VMR. Although azelastine is pri-marily an antihistamine, it is unlikely that its efcacy in VMRis due to histamine receptor blockade. Instead, it is probablyazelastines actions as an anti-inammatory and neuroinam-matory blocker that makes this medication useful in treatingVMR or NAR. Azelastine has been shown to deplete inam-matory neuropeptides in the nasal mucosa; to reduce levels ofproinammatory cytokines, leukotrienes, and cell adhesionmolecules; and to inhibit mast cell degranulation.25

In 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials, azelastine showedconsiderable efcacy in the treatment of each of the symptomsof VMR or NAR, including congestion.26 Treatment over 21days caused a signicant reduction in the total VMR symptomscore from baseline when compared with placebo (P = 0.002),and every nasal symptom was effectively reduced. Symptomimprovement was rapid with most patients experiencing reliefwithin 1 week. There were no serious adverse events, althougha bitter taste was experienced by some in the azelastine group.In studies of AR, onset of effect with nasal azelastine is seen in15 to 30 minutes.25

A meta-analysis has suggested that NCCSs are slightlymore effective than azelastine in the treatment of AR, but nosuch analyses exist comparing these products in treatingNAR.27 When NCCS and azelastine were combined in thetreatment of AR, the effects of the combination were additive.In a randomized double-blind trial comparing FP alone versusazelastine alone versus the two in combination for the treat-ment of AR, the combination produced a further 40% reduc-tion in total nasal symptom scores as compared with either FP

or azelastine alone. The combination of FP and azelastinereduced congestion by 48% compared with the individualcomponents.28 The combination has yet to be studied in VMRor NAR, but extensive clinical experience suggests that thiscombination is highly effective in VMR as well. On the basisof both published clinical studies and extensive clinical expe-rience, the use of azelastine (and possibly olopatadine) aloneand in combination with NCCS is a preferred rst-line treat-ment of VMR/NAR as well as AR.

AnticholinergicsIpratropium bromide (IB) is a potent intranasal anti-

cholinergic with utility in the treatment of rhinorrhea in ARand NAR. It has been studied in both adults and children.Ipratropium bromide specically treats rhinorrhea and doeslittle to improve congestion. Intranasal anticholinergics workbest for rhinorrhea predominant NAR variants such as cold-airYinduced rhinitis (skiers nose)29 and gustatory and senilerhinitis.30 In 28 patients with cold-airYinduced rhinitis, IBreduced the symptoms and the number of tissues requiredduring and after cold exposure (P = 0.0007 and 0.0023, res-pectively).31 In children with perennial AR or NAR, the effectof IB was superior to placebo and equivocal to beclometha-sone dipropionate (BD) for the treatment of both rhinorrheaand congestion. However, IB was less effective than BD forcontrolling sneezing.32

Similar to the nasal antihistamines, there seems to be anadditive effect when IB is used in conjunction with NCCSs.33

In a study comparing beclomethasone versus IB versus the twocombined, the combination group had better symptom controlof rhinorrhea. Beclomethasone monotherapy was found tobetter treat sneezing and congestion than IB monotherapy.Both medications were very well tolerated.

Oral anticholinergics such as methscopolamine havenot been studied in NAR but likely improve symptoms par-ticularly in rhinorrhea predominant disease or in patients withsignicant postnasal drainage. Many rst-generation antihis-tamines and decongestants also have strong anticholinergicproperties. However, side effects such as dry mouth, sedation,and urinary hesitancy limit the usefulness of these drugs.Clinical experience suggests that oral methscopolamine com-bined with an oral rst-generation antihistamine is helpful intreating patients with postnasal drip and that adding this com-bination to nasal IB, nasal antihistamines, or NCCS is useful.

DecongestantsBoth oral and topical decongestants effectively treat

congestion regardless of cause; however, none have beenstudied for NAR. Oral pseudoephedrine is an effective decon-gestant and can be considered for chronic use. However, sideeffects such as neurogenic and cardiac stimulation, palpita-tions, and insomnia affect a signicant number of patients.Furthermore, the medication is relatively contraindicated inpatients with hypertension. Thus, pseudoephedrine must beused cautiously. Phenylephrine is also an oral decongestant. Ithas been studied far less than pseudoephedrine and is con-sidered a generally less potent medication.

Topical decongestants such as oxymetazoline and phen-ylephrine are fast acting potent local decongestants. These



medications cannot be used chronically because continual usefor more than 3 to 10 days leads to rhinitis medicamentosa. ForNAR patients with intermittent nasal congestion, a topical de-congestant can be used for short-term relief of congestion.

Other NAR TherapiesAlthough NAR effects many patients, very few medica-

tions have been adequately studied for the treatment ofthis condition. In patients who do not adequately respond toNCCSs, intranasal antihistamines, or IB, other agents can beconsidered. There are a few limited studies examining intranasalcapsaicin in NAR. In theory, repetitive capsaicin applicationdepletes certain neuroinammatory chemicals. Van Rijswijket al18 did demonstrate decreased nasal symptoms in VMRpatients treated with capsaicin. Similarly, botulinum toxin Ainjected into the inferior and middle turbinates of patientswith NAR has been shown to decrease congestion, sneezing,rhinorrhea, and nasal itch.34 In patients with congestion-predominant NAR and turbinate hypertrophy, surgical reduc-tion of the inferior turbinates may be of some benet.35 Nasalwashing with isotonic or hypertonic saline has a demonstratedbenet particularly in chronic rhinosinusitis and seems to benetsomeNAR patients.36 Antileukotrienes have not been studied inNAR, but there is at least some theoretical benet in patientswithaspirin sensitivity and/or nasal polyposis. One controlled trialhas demonstrated some efcacy using acupuncture in NAR.37

CONCLUSIONSNonallergic rhinitis is an underrecognized and inade-

quately treated condition affecting many subjects. Diagnosisis dependent on a thorough history and exclusion of otherunderlying conditions, including AR and chronic rhinosinusitis.Nonallergic rhinitis tends to require chronic medical manage-ment, and use of topical NCCSs and nasal antihistamines, usedalone or in combination, is very effective in most patients. Thiscombination is also extremely effective in treating AR. Thus,recognizing that the combination of both NCCSs and nasal anti-histamines effectively treat AR, VMR, and mixed rhinitis, thiscombination of medications seems to be a useful rst-line treat-ment for the overwhelming majority of rhinitis patients.

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nonallergic rhinitis, with a focus on vasomotor rhinitis

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