Fungal Rhinosinusitis

1. Fungal Rhinosinusitis Talal Alandejani Department of Otolaryngology University of Ottawa

2. Fungal sinusitis • Overview • Classification. • Allergic Fungal Sinusitis • Classic teaching • Ongoing research and controversies • Further research • Conclusion

3. Fungal sinusitis • Classification: • Acute/Fulminant, Invasive (immunocompromised host) • Chronic/Indolent, Invasive • Fungal Ball • Allergic Fungal Sinusitis (AFS) Bent JP and Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg. 1994.

4. Fungal sinusitis • Classification: • Invasive: • Acute (fulminant) • Chronic ( granulomatous and non-granulomatous ) • Non-invasive: • Saprophytic • Fungus balls ( mycetoma ) • Allergic Fungal Sinusitis ( AFS ) Ferguson BJ. Definitions of fungal rhinosinusitis. Otolaryngol Clin North Am. 2000 Apr;33(2):227-35. Review.

5. Fungal sinusitis • Classification: • Invasive: • Acute Fulminant Invasive Fungal Sinusitis (AFIFS) • Chronic Invasive Fungal Sinusitis (CIFS) • Granulomatous Invasive Fungal Sinusitis (GIFS • Non-invasive: • Saprophytic Fungal Infestation (SFI) • Sinus Fungus Ball (SFB) • Allergic Fungal Sinusitis ( AFS ) Adelson et al. Fungal rhinosinusitis: state-of the-art diagnosis and treatment. J Otolaryngol. 2005

6. Fungal sinusitis • Classification: (Stammberger 2008 AAO-HNS) • Invasive: • Acute Fulminant Invasive Fungal Sinusitis (AFIFS) • Chronic Invasive Fungal Sinusitis (CIFS) • Granulomatous Invasive Fungal Sinusitis (GIFS • Non-invasive: • Saprophytic Fungal Infestation (SFI) • Sinus Fungus Ball (SFB) • Eosinophil Mediated Forms • Allergic Fungal Sinusitis ( AFS ) • Eosinophilic Fungal Rhino-sinusitis (EFRS) • Transitional.

7. Allergic fungal sinusitis • Historical Backround: • 1976 Safirstein ,Chest • First described nasal polyps, crust formation, and sinus cultures showing Aspergillus species in a patient with allergic bronchopulmonary aspergillosis (ABPA). • 1981 Miller ,Thorax • Reports described histologic similarities between sinus mucin from patients with allergic fungal sinusitis and pulmonary secretions from patients with ABPA.

8. Allergic fungal sinusitis • Historical Backround: • 1983 Katzenstein • 7 patients • A distinct mucinous material containing eosinophils, Charcot-Leyden crystals, and fungal hyphae was found in tissue resected from the sinuses • This histologic appearance is identical to mucoid impaction occurring in bronchi in allergic bronchopulmonary aspergillosis

9. Allergic fungal sinusitis • Frequency: • It is estimated that approximately 5-10% of patients affected by chronic rhinosinusitis actually carry a diagnosis of AFS • The (M/F) ratio of AFS equal.

10. Geographic variation • Geographic variation in allergic fungal rhinosinusitis. • 2000 Ferguson et al. • Memphis, Tennessee at 23% • Three other southern practices reporting a frequency of at least 10%. • Northern locations the frequency ranged from 0 to 4%

11. Pathogenic organism • Fungi implicated in AFS are known as the dematiaceous (darkly pigmented) fungi. • Aspergillus spp, • Bipolaris • Curvularia • Alternaria

12. Pathophysiology (Controversial)

13. Pathophysiology (Controversial) • Significance of fungal presence and eosinophilic mucin rhinosinusitis (EMRS)? {BJ Ferguson, 2001} • EMRS = AFS in the absence of fungal hyphae. • EMRS occurs because of dysregulation of immunologic controls involving upper and lower airway eosinophilia, whereas AFS is a localized IgE-mediated reaction to the germinated fungus.

14. Pathophysiology (Controversial) • EMRS: • Systemic disease, therefore not unilateral • Higher association with asthma, ASA sensitivity • Increased incidence of IgG1 deficiency • Older patients: avg 50’s • AFS: • Allergic response to fungi • Unilateral or bilateral • Fungal immunotherapy and antifungal agents • Younger patients: avg 30’s • Ferguson BJ: Eosinophilic mucin rhinosinusitis—a distinctive clinicopathological entity. Laryngoscope 2000

15. Clinical presentation • S&S: • Sino nasal. • Ocular. • Complications. • Cranial nerve deficits.

16. Diagnosis of AFS • Five major criteria are: • Evidence of type I hypersensitivity (IgE mediated) by history, skin tests or serology. • Nasal polyposis. • Characteristic computed tomography findings. • Eosinophilic mucus. • Positive fungal stain. Bent JP and Kuhn FA: Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1994

17. Diagnosis of AFS • Six associated criteria are • asthma. (8/15) • unilateral predominance. (13/15) • radiographic bone erosion. (12/15) • fungal culture. (11/15) • Charcot-Leyden crystals. (6/15) • serum eosinophilia. (6/15) Bent JP and Kuhn FA: Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 1994

18. Diagnosis of AFS • Now accepted as the standard criteria for the diagnosis of AFS at most sinus centers. • Nasal polyposis. • Characteristic CT scan. • Eosinophilic mucus.

19. Allergic (Eosinophillic) mucin • The hallmark of AFS • Remains the most reliable indicator of AFS • Grossly, allergic fungal mucin is thick, tenacious, and highly viscous. • Peanut butter .

20. Allergic (Eosinophillic) mucin • Endoscopic findings • Polyps. • Allergic mucin • Thick/Green

21. Endoscopic mucosal staging • Endoscopic mucosal staging system was developed by Kupferberg et al. in 1996 • Stage 0: No mucosal edema or allergic mucin • Stage I: Mucosal edema • Stage II: Polypoid edema • Stage III: Sinus polyps

22. Endoscopic mucosal staging • Mucosal Staging System Stage 0 Stage I

23. Endoscopic mucosal staging • Mucosal Staging System Stage II Stage III

24. Histology • Branching noninvasive fungal hyphae. • Eosinophils and elongated eosinophilic bodies • Charcot-Leyden crystals.

25. IgE levels • Total IgE values generally are elevated in AFS(90%) • Total IgE level traditionally has been used to monitor the clinical activity of allergic bronchopulmonary fungal disease. • IgE levels have been proposed as a useful indicator of AFS clinical activity.

26. Ocular manifestations • 82 patients • Orbital involvement without visual loss was found in 14.6% of the patients and most commonly resulted in • Proptosis (seen in 6.1% of patients) • Telecanthus (seen in 7.3%). • Visual loss from AFS, encountered in 3.7% of patients, was reversible with immediate surgical treatment of the underlying disease. Marple BF, Gibbs SR, Newcomer MT, Mabry RL: Allergic fungal sinusitis-induced visual loss. Am J Rhinol 1999,

27. Imaging- CT • Expansion, remodeling, or thinning of involved sinus wall was common (98%) and was due to the expansile nature of the accumulating mucin. • Signal heterogentiy due to accumulation of heavy metals (eg, iron and manganese) and calcium within inspissated allergic fungal mucin. Mukherji SK, Figueroa R, Ginsbergy LE, Zeifer BA, Marple BF, Alley JG, et al.: Allergic fungal sinusitis: CT findings. Radiology 1998,

28. Imaging- CT • Rail tracks • Very suggestive but not diagnostic by itself.

29. Imaging- MRI • T1- • variable signal intensity • T2- • Hypointensity of signal within involved sinuses • Enhancement of periphery of sinuses invalved (due to mucosal edema)

30. Treatment

31. Treatment • The treatment of AFS requires both medical and surgical treatment. • Aims: • 1) reduce the fungal load in the sinuses. • 2) reestablish physiologic mucous clearance, while preserving normal mucosa. • 3)postoperative access to previously diseased areas to monitor for signs of recurrent AFS, which can often be managed in the office setting

32. Treatment

33. Treatment • Pre-op: • Antibiotics • Steriods : • 1 Week pre-op and at least 4-6Weeks post-op. • 1)shrink the nasal polyps. • 2)reduce mucosal inflammation. • 3)decrease the blood loss.

34. Treatment • Post-op: • F/U • S&S, Endoscopic exam • Monthly total serum IgE • Culture for bacteria and fungi when infected • Total serum IgE parallels mucosal stage: elevates just prior to worsening mucosal stage.

35. Treatment • Corticosteroids are still the best. • BUT? • BD Scans Q2years • Fosamax • Actononel Is there a “steriod sparing” drug (alternative)?

36. Treatment • Antifungal: • The benefit of systemic antifungal agents is unclear in the literature. • Amphotericin B, ketoconazole, itraconazole, and fluconazole have all been evaluated. • Mixed results have been reported; the drugs are expensive and sometimes dangerous • Regular evaluation of their LFT.

37. Treatment • 2000 Chan et al. Pilot study: itraconazole in the management of refractory AFRS • 32 patients AFRS refractory to treatment. • Sporanox X 3months • Subjectively by RSOM-31 • 9(28%) significant improvement. • 9(28%) moderate improvement. • 14(44%)little or no change. • Endoscopically • 12 improvement. • 15 no change. • 5 worse.

38. Treatment • 2000 Chan et al. Pilot study: itraconazole in the management of refractory AFRS • LFT • 6 (19%) had increase in LFTD/C drug. • 1 chemical hepatitis with jaundice. • All LFT returned to normal.

39. Treatment • Antifungal irrigations: • The role and efficacy of antifungal irrigations is also unclear. • Amphotericin B has been advocated strongly as the answer to maintenance therapy

40. Treatment • Immunotherapy: • Reoperation rates of 33% in patients not receiving immunotherapy (n = 24) compared with 11.1% in those receiving immunotherapy (n = 36). • Mabry's warn that immunotherapy can worsen patients' symptoms if therapy is started before a significant antigenic load is removed. • He specifically sites Ferguson's report of five patients whose AFS worsened when immunotherapy was started prior to surgery. • Bassichis BA, Marple BF, Mabry RL, et al.: Use of immunotherapy and previously treated patients with allergic fungal sinusitis. Otolaryngol Head Neck Surg 2001

41. AFS- Controversies • Questions? To be answered: • Is AFS immunologic or infectious? • If it is immunologic, why does it occur unilateral? • Why only 30-40% have elevated IgE? • Why do some have IgE mediated allergy to a fungus and have it growing in the nose, but don’t have AFS?

42. CRS and fungi • 54 patients with CRS • 54 (100%) of 54 specimens stained fungi using the fluorescein-labeled chitinase. • Only 41 (76%) of 54 of the specimens stained with the Grocott methanamine silver stain technique demonstrated fungi Taylor MJ, Ponikau JU. Detection of fungal organisms in eosinophilic mucin using a fluorescein-labeled chitin-specific binding protein. Otolaryngol Head Neck Surg. 2002 Nov;127(5):377-83.

43. CRS and fungi • Fungi in (93%) patients undergoing surgery for any form of chronic rhinosinusitis. • Of note, the presence of fungi was also identified within 100% of the control subjects used for comparison.!! • Allergy only present in half of patients, therefore: “AFRS” should be replaced with “EFRS”. Ponikau et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 1999.

44. Significance of fungi? • Common airborne fungi is everywhere. • Can culture fungi from everybody – 2.7 species (Ave) per person. • 40 different genera Ponikau et al. The diagnosis and incidence of allergic fungal sinusitis. Mayo Clin Proc 1999.

45. Significance of Fungi? • When does fungal manifestation start? • 30 neonates Lackner A, Stammberger H et al. Fungi: a normal content of human nasal mucus. Am J Rhinol. 2005 Mar-Apr;19(2):125-9.

46. Significance of Fungi? • Question? • If everybody has fungi, why only certain people develop AFS?

47. AFS- Controversies • Ponikau et al. • CRS- no sufficient evedense to show bacterial cause (resistance to antibiotics). • CRS not explained by IgE mediated hypersensitivity: • Only 40-60% have positive allergy tests • Eosinophil content is independent of IgE levels • Symptoms are different from those of pateints IgE mediated allergies (sneezing, itching) • Allergic rhinitis occurs as a comorbid disease

48. AFS- Controversies • Ponikau et al. • A prominent IgE independent and cytokine driven inflammation has been found. • IL-5, IL-13 and IFN-gamma are present in CRS and absent healthy controls. • IL-5: eosinophil migration • IL-13 eosinophil activation

49. AFS- Controversies • Pathophysiology: • Inhale spores • Antigen recognition +react • Lymphocyte T-cells secrete • IL-5 and IL-13 • Activate eosinophils • Travel through tissue towards sinus cavity and mucus

50. AFS- Controversies • Pathophysiology (c’td) • Eosinophils attack germinating spores of hyphae (not the hyphae themselves) • Eosinophils release major basic protein (MBP) • Toxic to epithelium (3000x) • Epithelial damage • Entry port for bacteria causing recurent-ABRS