ALLERGIC FUNGAL RHINOSINUSITIS – CHANGING PARADIGM Dr. (Major)Sapna Nambiar MS(ENT) PGDHHM

AIM OF PRESENTATION AFRS represents a disease of which medical science has recently began to uncover the surface. Controversy – Etiology, Management Evolution in the understanding of this condition

INTRODUCTION AFRS as an entity was recognised 3 decades ago. Safirstein (1976)- First patient with ABPA & features of AFRS Millar Et al (1981)- 5 patients CRS similar to ABPA. Aspergillus Fumigatus isolated. Katzenstein(1983)- Retrospective data.(9/119) – Allergic aspergillus Sinusitis Robson et al (1989) – AFS AFRS – EMRS - EFRS

AFRS / EMRS

INTRODUCTION Fungal sinusitis – Severity of infection : Invasive & Noninvasive Host immune status Allergic reaction to fungal antigen (5 million spores inhaled in a day) Hyper immune individuals are prone to AFRS Chronicity & recurrences (10 to 100%) are the rule. Long term followup essential

PATHOPHYSIOLOGY Exact pathogenesis is uncertain Fungi of Dematiaceous family detected in AFRS Aspergillus, Bipolaris, Alternaria, Fusarium, Rhizopus. Chrzanowski – Panfungal allergen – 18 kD protein. May help in making vaccine.

PATHOPHYSIOLOGY Atopic individual -> Fungal deposit in sinus Type I reaction locally (Ig E) & Specific T- cell HLA receptor expression Mucosal oedema, stasis, inflammatory exudate, osteal block Adjacent sinuses involved – Sinus expansion Bony erosion – demineralization, pressure Type III reaction not demonstrated in AFRS. Invasion of mucosa by fungus has not been found

PATHOPHYSIOLOGY Fungal antigens are immunogenic & alter host responses through T cell and macrophage supression. Ciliary beat supression Disable compliment system Mucous blanket antifungal property – blunted Release of proteolytic enzymes Interferes in phagocytosis & intracellular killing.

DIAGNOSTIC CRITERIA DIAGNOSTIC CRITERIA BENT AND KUHN (1994) MAJOR CRITERIA Type I hypersensitivity Nasal polyps CT Scan findings – Hyperattenuation Positive fungal stain Allergic mucin with fugal elements without tissue invasion MINOR CRITERIA Asthma, Unilateral disease Bone erosion (CT) Serum eosinophilia Charcot – Leyden crystals Fungal culture

PATHOLOGY Mucous – thick, tenaceous, green to black in colour H & E stain – Eosinophils, Charcot – Leyden crystals & fungal hyphae in background of mucinous material Brown – Brenn Stain – C-L crystals Gomori – methenanine – silver stain – fungus Fontana Masson stain – distinguishes dematiaceous family from other septate fungi

KUPFERBERG ENDOSCOPIC MUCOSAL STAGING (1996) Post- treatment mucosal status Stage 0 – Normal mucosa, no mucin Stage 1 – Oedematous mucosa with or without mucin Stage 2 – Polypoidal mucosa with or without mucin Stage 3 – Polyps with fungal mucin/ debris

EPIDEMIOLOGY AFRS in CRS – 5% to 10 % Younger age group (20 – 45 yrs) No gender predilection More common in warm & humid areas.

Symptoms & Signs of Rhino Sinusitis Facial pain / pressure Facial congestion/fullness Nasal obstruction/blockage Nasal discharge/purulence /discoloured posterior drainage Hyposmia /anosmia Purulence on nasal examination Fever ( Acute rhino sinusitis only)  Headache  Fever  Halitosis  Fatigue  Dental pain  Cough  Ear pain / pressure / fullness Major symptomsMinor symptoms * Rhinosinusitis Task Force Definition 2 Major Symptoms or 1 Major 1 Minor

SYMPTOMS & SIGNS Same as CRS patients. History of atopy – skin, bronchus, food Nasal polyposis (100%) – recurrent Thick rhinorrhoea Dark rubbery nasal crusts (70%) Proptosis (more common in children - 50%) Aspirin sensitivity (25%) Bronchial asthma (30 to 50%)

WORKUP Total Eosinophil count Total serum Ig E Antigen specific Ig E – skin tests / invitro tests Nasal endoscopy Microscopic evaluation of mucin evacuated intra-op Fungal culture of mucin removed intra-op

IMAGING Hyperattenuation centrally Represent protinaceous allergic mucin Patterns – star filled sky, ground glass, serpigenous Boneloss – invasion of orbit, ant cranial fossa CT SCAN

RADIOLOGICAL LUND-McKAY GRADING Clear – 0 Partial opacity – 1 Complete opacity -2 6 sites ( 5 sinuses + OMC) Max score of 12 on side.

IMAGING : MR Images T-1 weighted : Hypointense areas T-2 weighted : areas of signal void

TREATMENT Surgery – Mainstay Pre-operative medical treatment Post-op steroids : topical and oral (low dose & long term) Post-op antifungals – systemic & topical Post-op immunotherapy Long term follow-up

6/8/2016dept of orlhns,afmc20 Oral Antifungals Topical Antifungal washes Topical CorticosteroidsOral Corticosteroids Endoscopic Sinus Surgery

Treatment Combined surgical &medical approach 1.Symptomatic relief 2. Manage complications 3. Delay recurrence Despite treatment, high recurrence rate

PRE-OPERATIVE TREATMENT Short course of oral steroids (1mg/kg/day for 7 days) Antibiotics – super added infection Saline nasal douching Nasal decongestants – severe nasal block Detailed counselling

SURGERY Conservative, yet complete surgical removal, endoscopically with adjuvant therapy as in ABPA is the standard of care at present Aggressive surgery – Lynch fronto-ethmoidectmies, radical removal of mucosa, open antrostomies were being done. Recidivism was very high.

FOLLOW-UP ENDOSCOPY Monthly endoscopy – 6 months 2 to 3 monthly endoscopy – 2 yrs 6monthly / SOS for 5 yrs

POST-OP TREATMENT Saline nasal douching & suction Steroid nasal spray Low dose oral steroid – ◦ 30mg/day for 2 weeks ◦ 20mg/day for 2 more weeks ◦ Maintenance dose of 10mgs/day for 3 months. Titration of oral steroids Antibiotics

6/8/2016dept of orlhns,afmc26 Allergic Fungal Sinusitis – Our Experience Kuhn FA, Javer AR Protocol for post op steroid ◦ 40 mg/kg/day x 4 days – 30 mg/kg/day x 4 days – 20 mg/kg/day x 1 mnth ◦ 0.2 mg/kg/day x 4 mnth for endoscopic stage 0 – 0.1 mg/kg/day x 2 mnths (including topical steroids) Arch Otolaryngol Head Neck Surg; Vol 124, Oct 1998

6/8/2016dept of orlhns,afmc27 Allergic Aspergillus Sinusitis : Concepts in Diagnosis & Treatment of a new clinical entity. Waxman JE et al Retrospective study, n=15 Therapeutic protocol based on treatment of ABPA. Pts with rapidly & slowly recurrent ds (n=5) - post op prednisone – 0.5mg/kg/day x 2wks, alt day regimen x 3-6 months & maintenance inhalant steroid therapy No recurrence noted during mean follow up period of 14 months in pts treated with steroids Presented at 89 th Annual meeting of the American Laryngological, Rhinological & Otological society, May 7,1990

ANTIFUNGAL TREATMENT Itraconazole 100mgs B.D for 2 to 6 months LFT – monthly Reduces dependence on oral steroids Reduces revision surgeries Topical Successful in in-vitro studies Amphotericin –B, one in 1000 parts used Ketoconazole No evidence to prove efficacy in patients directly or indirectly

6/8/2016dept of orlhns,afmc29 Treatment of AFRS with high-dose itraconazole Rains BM Rains BM Rains BM 12-year retrospective chart review of 139 patients of AFRS Treatment protocol using ESS, itraconazole, oral steroids, and topical steroids No serious adverse effects attributed to itraconazole over the 36,000 doses prescribed Itraconazole, oral steroids, topical steroids, and ESS are safe and clinically effective in management of AFRS. In recurrent AFRS itraconazole may avoid revision surgery Am J Rhinol Jan-Feb;17(1):1-8.

30 Management protocol for Allergic Fungal Sinusitis. Gupta RP et al. Dept of ORL-HNS, AIIMS n = 34 Group A (n=11) – Systemic Itraconazole (200 mg BD) + nasal alkaline douches for 2 months Group B (n=12) – Topical steroids + nasal alkaline douches for 4 months Group C (n=11) - Nasal alkaline douches 6 months Assessed at 6 month post op using Kupferberg grading system, grade 3 mucosal ds = recurrence Better outcome with post-op systemic itraconazole Indian Journal of Otolaryngology & Head & Neck Surgery Vol 59, No 1, Jan – Mar 2006 : 35-40

ANTIFUNGAL TREATMENT Michael Weschta et al (2006) 60 CRS patients Amphotericin B & saline – 8 wks Fungal elements, Eosinophilic cationic protein, tryptase levels before & after treatment Cultures PCR assays Fluorescent enzyme immuno assays Pre Rx: No correlation between fungus & cell activation markers After Rx: No effect on markers even when fungus got eradicated

6/8/2016dept of orlhns,afmc32 Adverse effects Oral Corticosteroids ◦ Cushing’s habitus ◦ Hyperglycemia ◦ Susceptibility to infection ◦ Peptic ulceration ◦ Osteoporosis ◦ Cataract ◦ Psychiatric disturbances ◦ Suppression of hypothalamo-pituitary adrenal axis Oral Itraconazole ◦ Gastric intolerance ◦ Pruritis ◦ Headache ◦ Hypokalemia (Lowest toxicity in azole group)

IMMUNOTHERAPY Decreases nasal crusting, polyposis Decreases need for steroids Should be given after surgery (4 -6 wks) Subcutaneous doses of antigens given Fungal antigens alone given for first 6 months. Non fungal antigens added later Antigens are given in increasing doses

UNANSWERED ISSUES Aetiopathogenesis is still not well understood Is it a autoimmune disorder? Rather than a hypersensitivity disorder Cell mediated activity – present or not Early diagnostic criteria Curative treatment Refinement of Immunotherapy Does gene therapy has a role?

CONCLUSIONS AFRS is a definite entity Hyperimmune status has a role CT evaluation, Endoscopic biopsy as early as 2 to 3 wks, in patients with atopy, will help in early diagnosis. ESS followed by oral steroids & meticulous follow-up are the main stay of management

CONCLUSIONS Oral antifungals – to be added if steroids are not effective or causing side effects Immunotherapy can be given in multiple recurrences and also in clinical research setting Is this an end result of over using or abusing antibiotics / other medications

THANK YOU

6/8/2016dept of orlhns,afmc38 Systemic corticosteroids for AFRS and chronic rhinosinusitis with nasal polyposis: A Comparative study. Landsberg R et al Landsberg R Landsberg R Effect of preop systemic corticosteroids in 8 AFRS & 10 CRSwNP pts Comparison between CT scan( Lund-Mcay scoring system) / endoscopic findings with preop 1 mg/kg prednisone for 10 days. AFRS group ◦ Better radiologic scores. ◦ Normal Endoscopic appearance of sinus mucosa Otolaryngol Head Neck Surg Feb;136(2):252-7

6/8/2016dept of orlhns,afmc39 Azoles for Allergic Bronchopulmonary Aspergillosis associated with Asthma. Wark, P et al. (2001). Cochrane review 3 Prospective randomised and controlled trials Number of exacerbations requiring oral corticosteroids was reduced with itraconazole ITRACONAZOLE modifies the immunologic activation associated with ABPA and improves clinical outcome in ABPA at least over the period of 16 weeks.

6/8/2016dept of orlhns,afmc 40 Antifungal activity against allergic fungal sinusitis organisms. Bent JP, Kuhn FA Review of 50 AFRS patients Role of topical antifungal therapy in lowering fungal antigen loads via postoperative irrigations Identification of antifungal drug for postoperative irrigations in AFRS patients. Fungal cultures grown from AFRS patients studied for in vitro susceptibility to five common antifungal drugs : Ketoconazole, Amphotericin B, Itraconazole, Nystatin, and Fluconazole Ketoconazole and Amphotericin B most effective Clinical trials are indicated to evaluate the efficacy of these drugs as a supplement to current AFRS treatment.

ESS - STANDARD

ESS - POWERED Ant ethmoid Posterior ethmoid

PREVENTING COMPLICATIONS

REVISION ESS

Treatment Combined surgical and medical approach 1. Symptomatic relief 2. Manage complications 3. Delay recurrence Despite treatment, high recurrence rate