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  • 1. Dr Madan Jr ENT ALLERGIC RHINITIS & VMR AETIOLOGY, PATHOGENESIS, CLINICAL FEATURE TREATMENT AND ROLE OF IMMUNOTHERAPY
  • 2. • ―IgE mediated hypersensitivity disease of mucous membranes of nasal airways characterized by sneezing, watery nasal discharge , itching and nasal obstruction‖ Durham et al.,1999 • Clinically defined : two or more nasal symptom: running blocking itching and sneezing Definition
  • 3. • Important health problem : social life, school performance,and work productivity. • Global health problem • Prevalence : 10-20% • Higher in pediatric age group - 42% - Wright et al .,1994 • AR -> 50% of all allergy cases seen in India • Affecting every 6th person • Peak age - 13 to 14. Approx. 80% - develop symptoms < 20 - Skoner et al., 2001 AR : Epidemiology
  • 4. • Decrease in infectious diseases is causally linked to the increase in the incidence of allergic and autoimmune diseases . Hygiene Hypothesis
  • 5.  Genetic predisposition  Environment changes  Hygiene hypothesis What are the causes?
  • 6. Atopy : • Tendency to develop specific IgE in response to normally innocuous environmental allergens • Eg. allergic rhinoconjunctivitis, asthma, atopic dermatitis & food allergies • Multiple genetic loci on chromosomes 5q, 11q, 12q, • Family history - major risk factor • 13% -/- parent • 29% +/- parent/sibling • 47% +/+ parents Atopy, Risk Factors, and Comorbid Disorders
  • 7. Higher socioeconomic status  Polluted environments Late entry into daycare Kramer et al ., 1999  Heavy maternal smoking during first year of life Risk factors
  • 8. Pathophysiology
  • 9. Pathophysiology
  • 10. From: Immunology a short course, 1996 Pathophysiology
  • 11. Eosinophil • Developed in bone marrow - IL3,IL5, GM-CSF • Half life of 8-18 hrs – blood Half life of several days - peripheral tissue • Eosinophil migration ( into peripheral tissue) • Toxic inflammatory mediators in eosinophil: Major basic protein, eosinophil peroxidase, eosinophil cationic protein • Synthesize and release lipid mediators: leukotriene C4 Pathophysiology
  • 12. Irritation of free nerve endings---- Itching and sneezing Increased mucus production ------ Rhinorrhoea Vasodilation -------- Congestion Increased vascular permeability---- Oedema How are the symptoms caused? Pathophysiology
  • 13. ©
  • 14. Approach to the pt :
  • 15. Approach to the pt :
  • 16. Seasonal Perennial Types of Allergic Rhinitis
  • 17. ARIA Classification:
  • 18. Physical examination
  • 19. Adenoid facies :
  • 20. Lungs Wheezing Persistent coughing Other areas Stigmata of atopic diseases with nasal symptoms • atopic eczema, asthma Others -
  • 21. DIFFERENTIAL DIAGNOSIS Take a moment to consider your differential diagnosis
  • 22. • Nasal Cytology • Skin Prick tests • In vitro tests Allergy Testing
  • 23. •Rapid, efficient & cost effective •Antigens - representative of that patient may encounter & geographically based. Negative result usually requires no additional testing Positive result requires further testing of other antigens in the group or family. Contain multiple antigens, (pollen, mold, weeds, dust mite, animal dander) Skin prick
  • 24. Superficial skin reaction, does not penetrate dermis Highly specific, sensitive, convenient and safe Requires positive (histamine) and negative (saline) control Method Drop of standardized allergen extract-volar aspect of forearm-pricked into skin- lancet Positive control (histamine) ,-ve control (saline or diluent) –innoculated Separate lancet -each test Read -mean wheal diameter -15 mins Reactions ->2 mm - <5 yrs >3 mm- >5 yrs +ve results - 2mm greater than –ve results Skin prick
  • 25. 0.01-0.05 mL - antigen wheal and flare measured after 10-20 min can be used to detect most low-degree atopies does not permit accurate quantitation of sensitivity Causes relatively minimal patient discomfort Disadvantages • higher risk of anaphylaxis • longer time • Possible false positive Intradermal test
  • 26. Modified method of IDT Serially diluted antigen extracts used -determine minimal amt of antigen -comparing size of wheal Principle -lowest concentration of antigen -produces - wheal 1. first wheal more than 2 mm larger than negative control wheal 2. followed by second wheal that is at least 2 mm larger than preceding one. Endpoint signifies -safe starting point for immunotherapy Skin Endpoint Titration(SET)
  • 27. Indications Impracticality of skin testing • Skin disorder, drug inhibition, uncooperatvie patients Clarification of skin test results • Bizarre or borderline reactions Prevention of systemic reactions • Prior history of anaphylactic reaction, severe asthma, stinging hypersensitivity In Vitro Testing
  • 28. RAST (radioallergosorbent assay) Allergen-specific IgE antibody testing useful – if percutaneous testing not practical  patients on- - beta-blockers - antihistamines (skin testing is unreliable) - dermatographism, children cannot tolerate skin testing highly specific but not sensitive (Agency for Healthcare Research and Quality,2005 ) In vitro testing
  • 29. • Useful - identifying common allergens (e.g., pet dander, dust mites, pollen, common molds) • less useful - identifying food, venom, or drug allergies. • Allergen coupled to - paper disc and incubated with patients serum • Disc washed and radioactive anti-IgE added • Gamma counters quantitates radioactivity Radioimmunosorbant Assay (RAST)
  • 30. Involves an additional washing procedure in order to reduce non-immunologically bound radioactivity Increased sensitivity to RAST MRT system divided into 5 classes from 1-5, each representing approximately fivefold increase in amount of serum specific IgE antibody present in sample. Class Counts 0.1ml Class 1 751-1600 1:500 Class 2 1601-3600 1:2500 Class 3 3601-8000 1:12500 Class 4 8001-18000 1: 62500 Class 5 18001-40000 1: 312,500 Modified RAST (MRT)
  • 31. Allergen introduced- nose Reaction - measured Rarely necessary Performed when - +ve history & –ive SPT - prior to immunotherapy Allergen –suitable form ( not containing phenol or other irritants) Nasal allergen challenge
  • 32. Initially- Placebo ,diluents 0f allergen –employed Allergen-gradually increasing concentration –monitoring URT & LRT symptoms Subjective –symptom scores, VASs Objective –sneeze count, nasal inspiratory peak flow , rhinomanometry , acousrtic rhinometry , spirometry ,pulmonary peak flow BUT….. Time consuming Excessive lab facilities Trained staff Resuscitation equipment Nasal allergen challenge
  • 33. • Exclusive breast feeding-3 month • Total avoidance of environmental tobacco smoke,passive smoking for children and prgnant women • In infant and pre school children,multifaceted intervention to reduce early life exposure to house dust mites • For indivisuals exposed to occupational agents,specific prevention measures eliminate or reducing occupational exposure. Recommendation for prevention of allergy :: ARIA
  • 34. • In patients with AR and /or asthma sensitive to house dust mite allergens, do not use single chemical or physical preventive methods aimed at reducing exposure to house dust mites or their combination. • In patients with allergy to indoor molds animal dander ,avoid exposure to these allergens at home. • In pts with occupational asthma , immediate and total cessation of exposure to occupational allergen Recommendation for prevention of allergy :: ARIA
  • 35. • Inhibit both early and late phases • Counter effects of other mediators • Fast-acting, to control the early phase • Dosing-od or bd for compliance • No side effects • Manage all symptoms • Intranasal administration Jaci et al.,1999 The “Ideal” Drug For Allergic Rhinitis Should HaveThe Following Features:
  • 36. Single most effective agents Improve all nasal symptoms-nasal congestion, rhinorrhea, itching & sneezing Currently available INS - beclomethasone dipropionate, budesonide fluticasone flunisonide mometasone triamcinolone acetonide. Intranasal corticosteroids
  • 37. Local : nasal burning , stinging, dryness, and epistaxis. ( 5% to 10% ) Local candidiasis, sometimes seen with inhaled corticosteroids rarely seen with nasal corticosteroids.  Systemic side effects :  minimal or no suppression hypothalamic-pituitary-adrenal axis (Wilson et al.,1998)  Osteocalcin – (marker of bone turnover ) - unaffected  no increased likelihood of bone fracture - regardless of dose. (Suissa et al.,2004) Side effects of INS
  • 38. Medication Adult dosage Child dosage Minimum age FDA pregnancy/nursing risk category Beclomethasone (Beclovent) One or two sprays per nostril twice daily One or two sprays per nostril twice daily Six years C Budesonide (Rhinocort) One to four sprays per nostril daily One or two sprays per nostril daily Six years C Ciclesonide (Omnaris) Two sprays per nostril daily NA 12 years C Flunisolide (formerly Nasarel) Two sprays per nostril twice or three times daily Two sprays per nostril twice daily Six years C Fluticasone furoate (Veramyst) Two sprays per nostril daily One spray per nostril daily Two years C Fluticasone propionate (Flonase) Two sprays per nostril daily One or two sprays per nostril daily Four years C Mometasone (Nasonex) Two sprays per nostril daily One spray per nostril daily Two years C Triamcinolone (Nasacort) One or two sprays per nostril daily One or two sprays per nostril daily Six years C
  • 39. • Acts - stabilizing H1- receptor - smooth muscle cells, nerve endings, and glandular cells - reduction in all symptoms • Only modest effect - nasal congestion H1-antihistamines
  • 40. Medication Minimum age Adult dosage Second generation Acrivastine/pseudoephedrine* 12 years 8 mg four times daily Azelastine (Astelin) Five years Two sprays per nostril twice daily Cetirizine* (Zyrtec) Six months 5 to 10 mg daily Desloratadine* (Clarinex) Six months 5 mg daily Fexofenadine* (Allegra) Two years 180 mg daily or 60 mg twice daily Levocetirizine (Xyzal) Six years 5 mg daily Loratadine* (Claritin) Two years 10 mg daily Olopatadine (Patanol) 12 years Two sprays per nostril twice daily First generation Brompheniramine Two years 12 to 24 mg twice daily Chlorpheniramine* Two years 4 mg four times daily Clemastine* (Tavist) Six years 1.34 mg twice or three times daily Cyproheptadine Two years 4 mg three times daily Diphenhydramine (Benadryl) Two years 25 to 50 mg four times daily Hydroxyzine (Vistaril) All ages 25 mg four times daily Promethazine (Phenergan) Two years 25 mg four times daily Triprolidine (Tripohist) Six years 2.5 mg four times daily Oral and Intranasal Antihistamines
  • 41. Topical and oral form. Topical vasoconstrictor: -catecholamine (eg, phenylephrine) -imidazoline (eg, oxymetazoline) oral vasocontrictor- -phenylephrine - pseudoephedrine. Decongestants
  • 42.  action via a1 and a2 adrenoreceptors reduction in blood flow - nasal vasculature - increased nasal patency 5 to 10 mins topically 30 mins - orally. Nasal decongestion - last  8 hours - topical use  24 hours - extended-release oral decongestants nasal congestion only affected (Cohan RH et al.,1972) monotherapy with vasoconstrictors - limited role oral decongestants + antihistamine- all cardinal symptoms of AR - targeted. Decongestants
  • 43. Cysteinyl-leukotrienes (cys-LT) High concentrations LTC4 - in nasal secretions atopic individuals after allergen challenge ( Wang D et al.,1995) LTD4 -increase in nasal mucosal blood flow & nasal airway resistance (Bisgaard Het al.,1986)  Blockage of the LT - 5-lipoxygenase (5-LO) inhibitors -receptor blockade -cys-LT1 receptor Zileuton -blocks the 5-LO pathway.. Antileukotrienes
  • 44. Receptor antagonists- Montelukast & zafirlukast. Zafirlukast performed no better than placebo - seasonal AR ( Pullerits T et al.,1999) Other study - reduction in upper respiratory responses to cat exposure (Phipatanakul W et al.,2000) Montelukast - clinical efficacy seasonal AR (Chervinsky P et al.,2004) Antileukotrienes
  • 45. • Montelukast + loratadine -superior reducing day time nasal symptoms in seasonal AR (Meltzer EO et al.,2000) • Montelukast could be useful as monotherapy and in combination with other classes of drugs Int. Rev. Allergol. Clin. Immunol., 2011 • leukotriene antagonists do not appear more effective than nonsedating antihistamines. • less effective than INS Ratner PH et al.,2003 Useful- concomitant mild persistent asthma and intermittent AR. Antileukotrienes
  • 46. Actions of Various Nasal Preparations in the Treatment of Rhinitis Nasal Preparation Sneezing Itching Rhinorrhoea Congestion Antihistamines +++++ ++++ +++ 0 Anticholinergics 0 0 +++++ 0 Corticosteroids +++++ +++++ +++ +++ Decongestants 0 0 + +++++ Mast cell stabiliser +++++ +++ + 0 Antileukotrienes +++ ++ 0 ++++
  • 47. Medical procedure that uses controlled exposure to known allergens to reduce the severity of allergic disease Disease accepted to be treated by immunotherapy: • Allergic rhinitis • allergic asthma • allergic conjunctivitis • insect sting hypersensitivity Disease not accepted to be treated by immunotherapy: • Food allergy • urticaria • atopic dermatitis Immunotherapy
  • 48. Curtis (1900): immunize people with aqueous extract of whole weeds Dunbar(1903): immunize subjects who had grass-sensitive hay fever with animal derived (horse and goose) grass pollen antisera to subject’s nasal mucosa Besredka and Steinhardt(1907): anaphylactic reaction encountered during immunotherapy is due to immunizing too rapidly or with too large dose of allergen Noon and Cantab: introduced weight units for pollen doses and quantization of individual sensitivity by in vivo testing. Freeman and Koessler(1914): immunotherapy produced long lasting results Cooke(1915): Treatment by pollen immunization of 114 patients with hay fever and asthma. Immunotherapy :History
  • 49. Inclusion criteria: IgE mediated disease Inability to avoid allergen Inadequecy of drug treatment Lilited spectrum of allergen Pts –risk & limitaion of tretment Contraindications: age < 5 yrs use of beta-blockers autoimmune dz. pregnancy uncontrolled asthma FEV1 < 70% Immunotherapy
  • 50. Gradual increase of allergen-specific IgG antibodies -- especially IgG4 subclasses (blocking antibody) • intercept and neutralize allergen before it bound to cell-surface IgE • form IgG-antigen-IgE complex and bind to the IgG receptor resulting co-aggregation with the IgE receptor and inhibition of IgE receptor triggering decreased allergen-specific IgE antibodies increase IgA and IgM antigen-specific B lymphocytes • May limit antigen penetration into the body from mucosa Deviation fromTh2 toTh1 cell Immunotherapy Mechanism:
  • 51. • Durhan et al.: • Randomized, placebo-controlled, double- blind study • Patients (32) with allergy to timothy grass- pollen extract received 3 years of immunotherapy treatment • Patients then randomized to continue with the immunotherapy or to receive placebo • 15 matched patients never received immunotherapy as control group • Presence of symptoms and need for rescue medication were measured after 3 years Long term efficacy of immunotherapy
  • 52. • No significant difference in symptom scores and use of rescue medication between two immunotherapy groups, and were lower than control group • No difference in the late skin responses (size of swelling, number of infiltrating T cells, cells containing IL-4 mRNA) between two immunotherapy groups, and significantly lower than control group • Immunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity Long term efficacy of immunotherapy
  • 53. may prevent progression of rhinitis to asthma in children • Preventive AllergyTreatment Study: • 205 children from 6 pediatric allergy centers in northern Europe aged 6-14 years with grass or birch pollen allergy • randomly assigned either to receive specific immunotherapy for 3 years or to a control group • The children who were treated with immunotherapy had significantly fewer asthma symptoms after 3 years as evaluated by clinical diagnosis may prevent onset of new sensitization in allergic patients Advantage of immunotherapy
  • 54. • Proven allergy with skin test or RAST • With allergic symptoms that are significant to the patient • Attempts to avoid allergens fail or impractical • Treatment with medicine is not fully successful or when medication is not well tolerated. • Young patients without chronic irreversible changes in the upper airways • Patient needs to be motivated and compliant with treatment Patient selection
  • 55. Subcutaneous immunotherapy - only approved route of administration in USA Subcutaneous immunotherapy - involves a weekly subcutaneous injection of an extract of the allergen, in solution, in increasing doses until a standard maintenance dose is reached. This dose is then injected subcutaneously on a regular basis (at intervals of approximately 20 days) for not less than 3 years for perennial allergens. Short term immunotherapy does not affect the cytokine profile and do not have long-term efficacy after discontinuation start at an earlier age, so that adverse changes to the immune system can be prevented before they become irreversible Immunotherapy
  • 56. Considerations in writing an allergy extract (vaccine) prescription are: • decision as to which allergen extracts to include • maintenance doses which have been proven to be clinically effective • potency of the allergen extracts available • patterns of cross-reactivity and • deleterious effects of some allergen extracts on others with which they may be mixed. Writing an allergen extract (vaccine) prescription
  • 57. Clinical experience indicates that the 1:1000 v/v dilution of the maintenance vial is generally a safe starting concentration Skin endpoint titration can also be used to determine starting dose, based on dilution which elicited positive reaction Patients may also be prick skin tested with each dilution of extract mix and immunotherapy commenced with the most dilute concentration that yields a positive prick skin test. Starting Concentration
  • 58. Wilson et al.: • systemic review of literature in Cochrane library • 22 clinical studies, a total of 979 patients • double-blinded, placebo-controlled, parallel-group studies • highly significant reduction in symptoms as well as definite decrease in medicine intake for symptoms • whether sublingual therapy equals the efficacy of subcutaneous immunotherapy is not clear Sublingual immunotherapy widely used and investigated in Europe since late 1980’s keep the extract under the tongue for a couple of minutes and then swallow it dose of allergen is greater than subcutaneous immunotherapy (about 3-300 times higher) Efficacy of sublingual immunotherapy
  • 59. Updosing phase- weekly inj -8 to 16 wks Maintainance phase- 4- 8 wkly intervals-3-5yrs Hospital basis Observation -60 min Protocols
  • 60. Double blind placebo-controlled study of ragweed immunotherapy Observed that SCIT alone induced allergen- specific IgG4 that partially blocked binding of allergen-IgE complexes to cells This binding was completely blocked with the addition of omalizumab Immunotherapy with Omalizumab Klunker S, Saggar LR, et al. Combination treatment with omalizumab and rush immunotherapy for ragweed induced allergic rhinitis: inhibition of IgE facilitated allegen binding. J AllergyClin Immunol 2007; 120:688-695.
  • 61. Constant symptoms of profuse , clear rhinorrhea , nasal congestion without correlation to specific antigen exposure or signs of atopy. • ALSO CALLED noninfectious nonallergic rhinitis or idiopathic rhinitis , is a chronic nasal dysfunction characterized by nasal hyperreactivity, i.e., nasal blockage, rhinorrhea, and sneezing in response to nonallergic stimuli such as •emotional factors • exposure to cold air • sudden temperature change •humidity • tobacco smoke • or irritating body sprays and cosmetics •Segal et al., in a recent report, studied previous nasal trauma as a causative factor. VASOMOTOR RHINITIS
  • 62. Several mechanisms have been postulated to explain the pathophysiology of idiopathic rhinitis (i) increased permeability of the nasal epithelium (ii) non-IgE-mediated inflammatory responses; (iii) neurogenic responses are the most plausible The classical theory is that vasomotor rhinitis is caused by autonomic imbalance: • Underactivity of the sympathetic nervous system Overactivity of the parasympathetic nervous system (singer et al). Mechanisms of vasomotor rhinitis
  • 63. Other theories increase in vasoactive peptides released from mast cells. • histamine, • leukotrienes, • prostaglandins, • vasoactive intestinal polypeptide, • kinins but release of these peptides is non-IgE mediated, as it is in allergic rhinitis Mechanisms of vasomotor rhinitis
  • 64.  variable presentation.  Most patients - older sometimes -seasonal pattern. Patients present with rhinorrhea (thick or scanty) frontal headaches congested turbinates but usually no pruritis. Rates of anxiety and depression are higher in women with vasomotor rhinitis than in healthy women without rhinitis (Addolorato G et al) Clinical presentation :
  • 65. Vasomotor rhinitis - a diagnosis of exclusion i.e., absence of • Infection • Exposure to drugs, • Significant anatomical disorder of the nose • Hormonal change • Negative response to skin prick test, • Normal serum specific Ig Lal D and Corey JP. Vasomotor rhinitis update. The rhinomanometric exercise test Acta Otorhinolaryngology Diagnostic approach
  • 66. If the irritant is known, the best treatment is prevention, Pharmacological: Surgical Antihistamines Triamcinoline injection Ant-cholinergic agents Electrical cautrey Topical steroids Cryosurgery Decongestants Laser Vidian neurectomy Treatment
  • 67. • Topical anticholinergics should be used for rhinorrhea caused by vasomotor rhinitis. • Azelastine (Astelin) may be used for vasomotor rhinitis associated with rhinorrhea, sneezing, postnasal drip, and nasal congestion. • Topical corticosteroids may be used for vasomotor rhinitis associated with nasal obstruction and congestion. • Cromolyn sodium (Intal) may be used for vasomotor rhinitis associated with sneezing and congestion in patients older than two years. A = consistent, good-quality, patient-oriented evidence; B = inconsistent or limited-quality, patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series American Family Physician
  • 68. The effect of intranasal injection of botulinum toxin A on the symptoms of vasomotor rhinitis Intranasal injection of BTX-A is a highly effective, safe, and simple treatment modality with a long-lasting effect for patients with VMR. Botulinum toxin A may be a good alternative especially for the treatment of resistant VMR cases. Cengiz O zcan, et al
  • 69. Vidius (1509) 1st –identified Sectioning of GSPN as a treatment for VMR -1st proposed by Zeilgelmann . VIDIAN NERVE
  • 70. CRYOSURGERY ON POSTGANGLIONIC FIBERS (POSTERIOR NASAL BRANCHES) OF THE PTERYGOPALATINE GANGLION FOR VASOMOTOR RHINITIS Operative technique
  • 71. • Incision –hard palate • Mucoperiosteal dissected till palatal aponeurosis is visible • Soft palate incised from post end of hard palate-nasopharynx • L Shaped incision long limb-just above the tubal elevation, short limb- b/w post. & lat. Wall of nasopharynx • Mucosal elevation-exposed med pterygoid plate-drilled-canal opened-nerve cut & cauterized Transpalatal approach
  • 72. • Using operative microscope • Incision-sup surface of inf turbinate-post end of middle turbinate • Mucoperiosteum elevated • Ethmoidal creast identified • Exposing sphenopalatine foramen-ptergoid canal identified • Nerve cauterized. Transnasal approach
  • 73. Step1 –lateralization of middle turbinate Step2-perforation of ant wall of sphenoid sinus(using elevator)- opening over the ant. Face of sphenoidal sinus is widened till vidian canal is identified. Step3-wall of vidian canal is perforated –nerve is severed. Endoscopic intrasphenoidal
  • 74. • Incision –curved incision given in middle meatus(post end of sup margin of inf turbinate to horizontal part of ground lamella) • Mucoperiosteal elevated • The sphenopalatine foramen and sup portion of perpendicular plate of palatine bone - exposed • Post. Sup. And post. Inf. Nasal nerve identified and sectioned. Endoscopic post. Nasal neurectomy
  • 75. • Palpate the lateral nasal wall behind the uncinate and above the insertion of the inf turbinate • Identify the soft membranous part of post frontanelle • Identified palatine bone • C shaped incision • Mucoperiosteal flap raised • Dissection is continued till the ant. Face of sphenoid sinus • Post. Rim of sphenopalatine foramen widened • Vidian canal identified—nerve exposed--cut Endoscopic vidian neurectomy