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Nonallergic RhinitisEvaluation and Treatment

Charity C. Fox, M.D.Clinical Assistant Professor

Allergy and ImmunologyDepartment of Internal Medicine

The Ohio State University Medical Center

• A Diagnosis of Exclusion• Candidates have

Negative allergy skin tests or RAST testsNo infectious process

• No definitive diagnostic test • Diagnosis based primarily on clinical

features and associated conditions

Nonallergic Rhinitis

Overlap in Common Causes of Rhinitis

AllergicRhinitis

NonAllergicRhinitis

Infection(Sinusitis)

Three major types of chronic rhinitis

Nonallergic Rhinitis• Little prevalence data for nonallergic

rhinitis syndromes

• 52% of patients seen in an allergy clinic were found to have nonallergic rhinitis

• Female>male in a few studies looking at epidemiology

Mullarkey et al J Allergy Clin Immunol 65: 122, 1980.Sibbald et all. Thorax 6:895, 1991.

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Overlap in Non-Infectious Causes of Rhinitis

Lieberman et al All Asthma Proc 24:95,2003

AllergicRhinitis

NonAllergicRhinitis

Pure Allergic43%

Mixed34%

Pure Nonallergic

23%

CombinedNonallergic

57%

RhinitisNonallergicAllergic

Sneezing Sneezing

Itch Itch

Posterior Rhinorrhea

Eye symptoms Eye symptoms

PressurePressure

Headache Headache

Posterior RhinorrheaCongestion Congestion

Mechanistic Classificationof Rhinitis

Inflammatory(Leukocytes)

Non Inflammatory (No Leukocytes)

Eosinophil Neutrophil Mixed EpithelialDysplasia

Neural Hormonal Structural

Allergy

NARES

CESS

Polyps

NSAIDSensitivity

Allergic FungalSinusitis

BacterialSinusitis

CiliaryDysfunction

ImmuneDeficiency

Dentogenic

Foreign Body

Viral

Vasculitis

Glandular Sinusitis

Atrophic

Sjogrens

Oxidants

Mucosaldisruption

Nociceptive

Parasympathetic

Sympathetic

Olfactory

Thyroid

Pregnancy

Anatomic/Trauma

Tumors

Occupational Meltzer et al. J AllergyClin Immunol114:S155, 2004.

Mechanistic Classification: Nonallergic Noninfectious Rhinitis

• InflammatoryEosinophils• NARES/BENARES• Polyps• NSAID sensitivity

Neutrophils or Mixed• Vasculitis/Autoimmune

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Mechanistic Classification: Nonallergic Noninfectious Rhinitis• Non-Inflammatory

Drug InducedEpithelial dysfunctionOccupational/IrritantHormonalStructuralIdiopathic/Neural/Vasomotor

• Perennial symptoms similar to allergic rhinitis

Sneezing, rhinorrhea, nasal itch, congestion, anosmia

• Eosinophilia on nasal smears• Negative allergy skin tests or RAST

tests• Associated with asthma, aspirin

intolerance and nasal polyps

Nonallergic Rhinitis with Eosinophilia Syndrome

(NARES)

• Good response to intranasal corticosteroids. Budesonide, beclomethasone and fluticasonehave indications for nonallergic rhinitis.

• Oral antihistamines some efficacy in only a few studies.

• Subtypes of the condition with blood eosinophilia(BENARES)

• Patients sometimes describe antigen triggers

Nonallergic Rhinitis with Eosinophilia Syndrome

(NARES)

Purello-D’Ambrosio et al. Clin Exp Allergy 29:1143, 1999.

Positive nasal allergen challenges in patients with

persistent nonallergic rhinitisEvidence for localized allergic response

Rondon et al. J Allergy Clin Immunol 119:899,2007.

54% of persistent nonallergicrhinitispatients (PNAR) showed positive nasal allergen provocation tests (NAPT) to D. pteronyssinus (DP) dust mite

22% had nasal specific IgE to DP mite in the face of negative skin tests and serum specific IgE to DP

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Nasal Polyps

Photo courtesy of David M. Powell M.D.

© David M Powell MD

Benign polypoidmasses arising from inflamed nasal mucosa.

Contain eosinophils,Lymphocytes, plasma cells and mucin with few nerves.

Nasal PolypsAssociated with• Aspirin intolerance• Sampter’s syndrome

aspirin intolerance,asthma, nasal polyps, sinusitis.

• Cystic Fibrosis• Churg-Strauss syndrome• Chronic sinusitis• Ciliary dyskinesia• Young syndrome• Allergic fungal sinusitis

© David M Powell MD

• Pathophysiology unknown• Recurrent infections contribute• Increased histamine, leukotrienes and

serotonin• Not IgE-mediated• Respond to corticosteroids• Possible role for leukotriene inhibitors

Nasal Polyps

Systemic Autoimmunity/Vasculitis

• Churg-Strauss syndrome• Systemic lupus granulomatosis• Wegener’s granulomatosis

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Systemic Autoimmunity/Vasculitis• Sarcoidosis

Treat underlying conditionTopical corticosteroids

• Sjogren’s syndromeTreatment of xerostomia with nasal saline sprays, moisturizing nasal gels, sialogogues

• Non-Steroidal Anti-Inflammatory Drugs(NSAID Rhinitis, ASA Triad)

• AntihypertensivesACE Inhibitors

Hydralazine

Beta-blockers

Drug Induced Nonallergic Rhinitis

• Rhinitis MedicamentosaTopical decongestants

• Oral Contraceptives/Hormone Replacement Therapy

• Psychotropic agents

Drug Induced Nonallergic Rhinitis

Epithelial DysfunctionAtrophic Rhinitis1) Epistaxis, nasal crusting, stuffiness,

halitosis1) Excessive surgical removal of nasal

mucosa1) Treatment with nasal saline rinses and

moisturizing agents2) Klebsiella infection in elderly

1) Treatment with antibiotics

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Epithelial Dysfunction2) Profuse rhinorrhea in elderly

1) Possible parasympathetic overactivity

1) Treatment with intranasal ipratropium bromide

• Many causative agents in the workplace or home

• Can be inflammatory or non-inflammatory

Immunologic responses

• Comparable to agents of occupational lung disease

Occupational/Irritant

Corrosive effects with epithelial injury

Irritant Rhinitis

• Smoke, paint, air pollution, dust

Physical Stimuli

• Cold dry air, bright lights

Occupational/Irritant

Hormone Induced Nonallergic Rhinitis

• Rhinitis of Pregnancy

• Hormone replacement therapy and oral contraceptive associated rhinitis

• Hypothyroidism

• Acromegaly

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Structural Rhinitis• Septal deviation or other obstructing

abnormality can aggravate rhinitis

• Tumors

• Cerebral Spinal fluid leak

Associated with trauma or surgery

CSF contains glucose and β2-transferrin

• Is the new vasomotor rhinitis

• Corresponds to “neural” or “reflex”rhinitis

• “After having excluded all known causes of chronic rhinitis……”

• Nasal hyperreactivity key feature

Idiopathic Rhinitis

• Exclusion criteriaPositive allergy testSmokingNasal polypsAnatomical abnormalityInfectionPregnancy, lactation, hormone replacementMedications affecting nasal functionBeneficial effect of nasal corticosteroid (NARES)

Idiopathic Rhinitis

Rijswijk et al. Allergy 60:1471, 2005.

• Selection criterionNasal hyperreactivity

• To nonspecific stimuli

–Smoke, spices, strong odors, and other irritants

Idiopathic Rhinitis

Rijswijk et al. Allergy 60:1471, 2005.

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Importance of neurologic vascular control• Hyperactive parasympathetic system

• Hypoactive sympathetic system

• Overactivity of C-fibers of the nonadrenergic noncholinergic system

Enhanced release of substance p and other neuropeptides

Idiopathic Rhinitis

Efficacy of topical antihistamine in idiopathic

rhinitisAzelastineeffective for thetreatment ofIdiopathic(vasomotor)rhinitis in twoDBPC trials.

From Gehanno et al. ORL J Otorhinolaryngol Relat Spec 63:76, 2001.

Summary: Treatment of Nonallergic Rhinitis

Inflammatory Non Inflammatory

PruritisSneezingCongestionRhinorrheaCongestion

Eliminate triggers and treat identifiable causes

azelastine

Consider ipratropium or cromoglycate

nasal corticosteroid

Nasal corticosteroid

AddAntihistamine

Oral or Azelastine

(Leukotrieneinhibitors Proposed)

Rhinorrhea

Ipratropium

(EspGustatory Or Atrophic

Rhinitis)

Azelastine

With or without nasal saline rinses

Allergic Rhinitis:Initial Diagnosis and

TreatmentDavid W. Hauswirth, M.D.

Clinical Assistant ProfessorAllergy and Immunology,

Internal Medicine and PediatricsThe Ohio State University Medical Center

Nationwide Children’s Hospital

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• Sneezing• Runny Nose• Nasal Congestion• Facial Pressure• Headache• Facial Pain• Ear Pressure/fullness• Eyes water or itch

Chief Complaint

• Decreased Smell• Decreased Taste• Bad Breath• Cough• Sore Throat• Throat Clearing• Throat Drainage• Sinus Infections

Chief Complaint

• Adolescents and AdultsAllergic RhinitisNon-Allergic Rhinitis/Vasomotor RhinitisInfection (viral URI or sinusitis)Obstructing polyps, septaldeviation

Age Matters

• ChildrenInfection Allergic Rhinitis (generally >2 y/o)Non-Allergic Rhinitis/Vasomotor Rhinitis

–Irritant (esp. tobacco smoke)Obstruction (Adenoid hypertrophy, foreign body)

Age Matters

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Exam Pearls• Edema and venous sinusoid congestion

leads to swollen pale or blue turbinates

• Clear middle ear fluid is common with significant congestion

• The eyes are important (redness, swelling, shiners, Dennie’s lines)

• Other sign of atopy--asthma, eczema

• Testing should be to relevant local antigens

• Pollen seasons and indoor allergen patterns help interpret history

–Spring-Trees; Summer-Grass; Fall-Weeds

Skin Testing

• History dictates what antigens are to be tested

• Interpreted only in the context of the clinical history

Skin Testing

Population Data

J Allergy Clin Immunol 2005;116:377-83.

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• A number describing the amount of allergen specific IgE

• Should be interpreted in context of total IgE, symptoms

• No defined level for each antigen to predict clinical symptoms

RAST Testing

• Can be used to qualify a patient for anti-IgE therapy

• Not all antigens have defined cutoff values

• Longer turn around time, cost ($35-45+ per antigen)

RAST Testing

Test Performance-Cat Allergy

J Allergy Clin Immunol 1999;103:773-9.

86.4 (+7.1)87.2(+6.9)

87.1 (+6.0)93.6 (+4.3) 90.1 (+5.3)

91.1 (+5.9)

ARIA ClassificationIntermittent

Less that 4 days/week OR less than 4 weeks/year

PersistentMore than 4 days/week AND

more than 4 weeks/year

Mild

No Sleep Disturbance

No Impairment of school, work or desired activities

No “Troublesome” symptoms

Moderate-Severe

Sleep Disturbance

Impairment of school, work or desired activities

“Troublesome” symptoms

Bousquet J. Et al. JACI 2001; 108(suppl) S147-334.

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Treat the early and late phase symptoms

Bousquet J. Et al. JACI 2001; 108(suppl) S147-334.

Stepwise treatment--Allergic

Stepwise treatment--Allergic

Step 1: Antihistamine or Nasal Corticosteroid

Stepwise treatment--Allergic

Step 1: Antihistamine or Nasal Corticosteroid

Step 2: Nasal Corticosteroid AND Antihistamine or Leukotriene modifier

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Stepwise treatment--Allergic

Step 1: Antihistamine or Nasal Corticosteroid

Step 2: Nasal Corticosteroid AND Antihistamine or Leukotriene modifier

Step 3: Nasal Steroid/Antihistamine/Leukotriene modifier

Stepwise treatment--Allergic

Step 1: Antihistamine or Nasal Corticosteroid

Step 2: Nasal Corticosteroid AND Antihistamine or Leukotriene modifier

Step 3: Nasal Steroid/Antihistamine/Leukotriene modifier

AllergenImmunotherapy

Referral for testing at any stage

Stepwise treatment--Allergic

Step 1: Antihistamine or Nasal Corticosteroid

Step 2: Nasal Corticosteroid AND Antihistamine or Leukotriene modifier

Step 3: Nasal Steroid/Antihistamine/Leukotriene modifier

Saline Irrigation/Lavage

AllergenImmunotherapy

Referral for testing at any stage

• Primarily — Itch, Sneeze, Rhinorrhea

• Antihistamine (oral or intranasal)

• Weekend symptoms

Treat the Symptoms

J Allergy Clin Immunol 2006;118:985-96.

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• Primarily Congestion

• First line should be nasal corticosteroid

• Leukotriene modifier

• Decongestant

Treat the Symptoms

J Allergy Clin Immunol 2006;118:985-96.

• Failure of medical treatment

• Desire to decrease long term medication use

• Intolerance to medication of side effects

• Allergic rhinitis and asthma (or possible prevention of asthma)

• Venom anaphylaxis

Indications for Immunotherapy

Long-Term Clinical Efficacy of Grass-Pollen Immunotherapy

Durham SR et al N Engl J Med 1999; 341: 468-475

Initial Placebo Trial Current Trial

Polle

n C

ount

(gra

ins/

m3 )

Sym

ptom

Scor

e

May June July Aug.

May June July Aug.

May June July Aug.

May June July Aug.1989 1993 1994 1995

Study groupImmunotherapyPlacebo

ImmunotherapyMaintenanceDiscontinuationNone (control)

SLIT• Sublingual Immunotherapy--a future

alternative to subcutaneous IT

• Multiple dosing forms exist (extract, tablet)

• Increased safety profile

• Can be done at home

• Dose varies by antigen, not established yet for US extracts

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SLIT• Currently undergoing clinic trials in the

US

• Similar immunologic changes to Subcutaneous immunotherapy

• Increased Treg cells

• Blunted seasonal rise in IgE, increased antigen specific IgG4

ISS Conjugated Proteins

• ISS is unmethylated CpG DNA, a strong immune stimulus

• Stimulate TLR-9

• Published use in ragweed allergy

Creticos, PS et al. NEJM 2006;355:1445-1455

ISS Conjugated Proteins

• Amb a 1-ISS has shown benefit in ragweed allergic patients

• Administered as six escalating doses before 2001 pollen season

• Followed for 2001 and 2002Creticos, PS et al. NEJM 2006;355:1445-1455

Ragweed Results

Creticos, PS et al. NEJM 2006;355:1445-1455

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• Treat the patient’s symptoms and pick the treatment to fit the symptoms

• Discover and remove triggers

• Diagnosis—History/Exam will exclude likely causes

• Re-evaluate if symptoms don’t respond

• Patients often have multiple causes

Allergic Rhinitis--Summary

• Often a combination of medication is necessary—stepwise approach to treatment aids decision making

• Immunotherapy has multiple indications

• Multiple new administration methods and preparations in future

Treatment Summary