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Overlap in Common Nonallergic Causes of Rhinitis Three major Evaluation and Treatment Allergic types of Rhinitis Charity C. Fox, M.D. chronic rhinitis Clinical Assistant Professor and Immunology Non Allergic Infection Department of Internal Medicine Rhinitis () The Ohio State University Medical Center

Nonallergic Rhinitis • A Diagnosis of Exclusion • Little prevalence data for nonallergic • Candidates have rhinitis syndromes 9 Negative allergy skin tests or RAST tests • 52% of patients seen in an allergy clinic were found to have nonallergic rhinitis 9 No infectious process • No definitive diagnostic test • Female>male in a few studies looking at epidemiology • Diagnosis based primarily on clinical features and associated conditions Mullarkey et al J Allergy Clin Immunol 65: 122, 1980. Sibbald et all. Thorax 6:895, 1991.

1 Overlap in Non-Infectious Mechanistic Classification of Rhinitis Causes of Rhinitis Inflammatory Non Inflammatory Pure Allergic (Leukocytes) (No Leukocytes) Allergic 43% Neutrophil Mixed Epithelial Neural Hormonal Structural Mixed Rhinitis Dysplasia 34%

Allergy Bacterial Viral Atrophic Nociceptive Thyroid Tumors Combined Sinusitis NARES Para Nonallergic Vasculitis Sjogrens Pregnancy Non Ciliary sympathetic 57% CESS Allergic Dysfunction Anatomic/ Polyps Oxidants Sympathetic Rhinitis Immune Glandular Trauma Deficiency Sinusitis Mucosal Olfactory Pure NSAID Dentogenic disruption Nonallergic Sensitivity 23% Allergic Foreign Occupational Meltzer et al. J Allergy Fungal Body Clin Immunol Lieberman et al All Proc 24:95,2003 Sinusitis 114:S155, 2004.

Mechanistic Classification: Rhinitis Nonallergic Noninfectious Rhinitis Allergic Nonallergic

Sneezing Sneezing • Inflammatory

Itch Itch 9 • NARES/BENARES Eye symptoms Eye symptoms Pressure Pressure • Polyps Headache Headache • NSAID sensitivity 9 Neutrophils or Mixed Posterior Posterior Rhinorrhea • Vasculitis/Autoimmune Congestion Congestion

2 Mechanistic Classification: Nonallergic Rhinitis with Nonallergic Noninfectious Rhinitis Syndrome (NARES) • Non-Inflammatory 9 Induced • Good response to intranasal . Budesonide, beclomethasone and fluticasone 9 Epithelial dysfunction have indications for nonallergic rhinitis. 9 Occupational/Irritant • Oral some efficacy in only a few studies. 9 Hormonal • Subtypes of the condition with blood eosinophilia 9 Structural (BENARES) 9 Idiopathic/Neural/Vasomotor • Patients sometimes describe antigen triggers

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

Nonallergic Rhinitis with Positive nasal allergen Eosinophilia Syndrome challenges in patients with (NARES) persistent nonallergic rhinitis • Perennial symptoms similar to allergic Evidence for localized allergic response rhinitis 54% of persistent nonallergic 9 Sneezing, rhinorrhea, nasal itch, rhinitis patients (PNAR) showed congestion, anosmia positive nasal allergen provocation tests (NAPT) to • Eosinophilia on nasal smears D. pteronyssinus (DP) dust mite

• Negative allergy skin tests or RAST 22% had nasal specific IgE to tests DP mite in the face of negative skin tests and serum • Associated with asthma, aspirin specific IgE to DP intolerance and nasal polyps Rondon et al. J Allergy Clin Immunol 119:899,2007.

3 Nasal Polyps Nasal Polyps • Pathophysiology unknown Benign polypoid masses • Recurrent infections contribute arising from inflamed nasal mucosa. • Increased histamine, and serotonin Contain eosinophils, Lymphocytes, plasma cells • Not IgE-mediated and mucin with few • Respond to corticosteroids © David M Powell MD nerves. • Possible role for inhibitors

Photo courtesy of David M. Powell M.D.

Systemic Nasal Polyps Autoimmunity/Vasculitis Associated with • Aspirin intolerance • Sampter’s syndrome • Churg-Strauss syndrome 9 aspirin intolerance,asthma, nasal polyps, sinusitis. • • Systemic lupus granulomatosis © David M Powell MD • Churg-Strauss syndrome • Wegener’s granulomatosis • Chronic sinusitis • Ciliary dyskinesia • Young syndrome • Allergic fungal sinusitis

4 Systemic Drug Induced Autoimmunity/Vasculitis Nonallergic Rhinitis • • 9Treat underlying condition 9 Topical decongestants 9Topical corticosteroids • Oral Contraceptives/ • Sjogren’s syndrome Replacement Therapy 9Treatment of xerostomia with nasal • Psychotropic agents saline sprays, moisturizing nasal gels, sialogogues

Drug Induced Epithelial Dysfunction Nonallergic Rhinitis Atrophic Rhinitis • Non-Steroidal Anti-Inflammatory 1) Epistaxis, nasal crusting, stuffiness, 9 (NSAID Rhinitis, ASA Triad) halitosis • Antihypertensives 1) Excessive surgical removal of nasal mucosa 9 ACE Inhibitors 1) Treatment with nasal saline rinses and 9 Hydralazine moisturizing agents 9 Beta-blockers 2) Klebsiella infection in elderly 1) Treatment with antibiotics

5 Epithelial Dysfunction Occupational/Irritant

2) Profuse rhinorrhea in elderly 9 Corrosive effects with epithelial injury 9 Irritant Rhinitis 1) Possible parasympathetic overactivity • Smoke, paint, air pollution, dust 9 Physical Stimuli 1) Treatment with intranasal • Cold dry air, bright lights

Hormone Induced Occupational/Irritant Nonallergic Rhinitis • Many causative agents in the workplace or home • Rhinitis of Pregnancy • Can be inflammatory or non- • Hormone replacement therapy and inflammatory oral contraceptive associated rhinitis 9 Immunologic responses • Hypothyroidism • Comparable to agents of occupational lung disease • Acromegaly

6 Structural Rhinitis Idiopathic Rhinitis • Exclusion criteria • Septal deviation or other obstructing abnormality can aggravate rhinitis 9 Positive allergy test 9 Smoking • Tumors 9 Nasal polyps 9 Anatomical abnormality • Cerebral Spinal fluid leak 9 Infection 9 Associated with trauma or surgery 9 Pregnancy, lactation, hormone replacement 9 Medications affecting nasal function 9 CSF contains glucose and β -transferrin 2 9 Beneficial effect of nasal (NARES) Rijswijk et al. Allergy 60:1471, 2005.

Idiopathic Rhinitis Idiopathic Rhinitis

• Is the new vasomotor rhinitis • Selection criterion • Corresponds to “neural” or “reflex” 9 Nasal hyperreactivity rhinitis • To nonspecific stimuli • “After having excluded all known causes of chronic rhinitis……” –Smoke, spices, strong odors, and other irritants • Nasal hyperreactivity key feature

Rijswijk et al. Allergy 60:1471, 2005.

7 Summary: Treatment of Idiopathic Rhinitis Nonallergic Rhinitis Inflammatory Non Inflammatory Importance of neurologic vascular control Eliminate triggers and treat identifiable causes

• Hyperactive parasympathetic system Rhinorrhea Nasal corticosteroid Pruritis Sneezing • Hypoactive sympathetic system Congestion Add Rhinorrhea Ipratropium • Overactivity of C-fibers of the Oral or Congestion nonadrenergic noncholinergic system Azelastine (Esp Gustatory Or Atrophic 9 Enhanced release of substance p and (Leukotriene Rhinitis) nasal corticosteroid azelastine inhibitors other neuropeptides Proposed) With or without nasal saline rinses

Consider ipratropium or cromoglycate

Efficacy of topical antihistamine in idiopathic : rhinitis Initial Diagnosis and Azelastine Treatment effective for the David W. Hauswirth, M.D. treatment of Clinical Assistant Professor Idiopathic Allergy and Immunology, (vasomotor) Internal Medicine and Pediatrics rhinitis in two The Ohio State University Medical Center DBPC trials. Nationwide Children’s Hospital

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

8 Chief Complaint Age Matters • Sneezing • Runny Nose • Adolescents and Adults • 9Allergic Rhinitis • Facial Pressure 9Non-Allergic Rhinitis/Vasomotor Rhinitis • Headache • Facial Pain 9Infection (viral URI or sinusitis) • Ear Pressure/fullness 9Obstructing polyps, septal deviation • Eyes water or itch

Chief Complaint Age Matters • Decreased Smell • Children • Decreased Taste 9Infection • Bad Breath 9Allergic Rhinitis (generally >2 y/o) • Cough 9Non-Allergic Rhinitis/Vasomotor • Sore Throat Rhinitis • Throat Clearing –Irritant (esp. tobacco smoke) • Throat Drainage 9Obstruction ( hypertrophy, • Sinus Infections foreign body)

9 Exam Pearls Skin Testing • and venous sinusoid congestion leads to swollen pale or blue turbinates • History dictates what antigens are to be tested • Clear middle ear fluid is common with significant congestion • Interpreted only in the context of • The eyes are important (redness, the clinical history swelling, shiners, Dennie’s lines)

• Other sign of atopy--asthma, eczema

Skin Testing Population Data • Testing should be to relevant local antigens • Pollen seasons and indoor allergen patterns help interpret history –Spring-Trees; Summer-Grass; Fall-Weeds

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

10 Test Performance- RAST Testing Cat Allergy • A number describing the amount of allergen specific IgE 93.6 (+4.3) 90.1 (+5.3) 87.1 (+6.0) • Should be interpreted in context of total IgE, symptoms

• No defined level for each antigen 87.2(+6.9) 91.1 (+5.9) 86.4 (+7.1) to predict clinical symptoms

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

RAST Testing ARIA Classification

• Can be used to qualify a patient Intermittent Persistent Less that 4 days/week OR More than 4 days/week AND for anti-IgE therapy less than 4 weeks/year more than 4 weeks/year • Not all antigens have defined cutoff values Mild Moderate-Severe No Sleep Disturbance Sleep Disturbance No Impairment of school, work Impairment of school, work or • Longer turn around time, cost or desired activities desired activities ($35-45+ per antigen) No “Troublesome” symptoms “Troublesome” symptoms

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

11 Treat the Stepwise treatment-- early and Allergic late phase symptoms Step 1: Antihistamine or Nasal Corticosteroid

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

Stepwise treatment-- Stepwise treatment-- Allergic Allergic

Step 1: Antihistamine or Nasal Corticosteroid

Step 2: Nasal Corticosteroid AND Antihistamine or Leukotriene modifier

12 Stepwise treatment-- Stepwise treatment-- Allergic Allergic

Step 1: Antihistamine or Nasal Corticosteroid Step 1: Antihistamine or Nasal Corticosteroid

Step 2: Nasal Corticosteroid AND Saline Irrigation/ Step 2: Nasal Corticosteroid AND Allergen Antihistamine or Leukotriene modifier Lavage Antihistamine or Leukotriene modifier Immunotherapy

Step 3: Nasal Steroid/Antihistamine/Leukotriene modifier Step 3: Nasal Steroid/Antihistamine/Leukotriene modifier

Referral for testing at any stage

Stepwise treatment-- Allergic Treat the Symptoms • Primarily — Itch, Sneeze,

Step 1: Antihistamine or Nasal Corticosteroid Rhinorrhea • Antihistamine (oral or intranasal) Step 2: Nasal Corticosteroid AND Allergen Antihistamine or Leukotriene modifier Immunotherapy • Weekend symptoms

Step 3: Nasal Steroid/Antihistamine/Leukotriene modifier

Referral for testing at any stage

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

13 Long-Term Clinical Efficacy of Treat the Symptoms Grass-Pollen Immunotherapy Initial Placebo Trial Current Trial ) • Primarily Congestion 3 (grains/m

• First line should be nasal Pollen Count corticosteroid

Study group Immunotherapy Immunotherapy Maintenance • Leukotriene modifier Placebo Discontinuation None (control) Score • Decongestant Symptom May June July Aug May June July Aug May June July Aug May June July Aug 1989. 1993. 1994. 1995 .

J Allergy Clin Immunol 2006;118:985-96. Durham SR et al N Engl J Med 1999; 341: 468-475

Indications for Immunotherapy SLIT • Failure of medical treatment • Sublingual Immunotherapy--a future alternative to subcutaneous IT • Desire to decrease long term • Multiple dosing forms exist (extract, medication use tablet) • Intolerance to medication of side • Increased safety profile effects • Can be done at home • Allergic rhinitis and asthma (or possible prevention of asthma) • Dose varies by antigen, not established yet for US extracts • Venom anaphylaxis

14 SLIT ISS Conjugated • Currently undergoing clinic trials in the Proteins US • Amb a 1-ISS has shown benefit in • Similar immunologic changes to ragweed allergic patients Subcutaneous immunotherapy • Administered as six escalating • Increased Treg cells doses before 2001 pollen season • Blunted seasonal rise in IgE, increased antigen specific IgG4 • Followed for 2001 and 2002

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

ISS Conjugated Ragweed Results 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 Creticos, PS et al. NEJM 2006;355:1445-1455

15 Allergic Rhinitis--Summary • 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

Treatment 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

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