Sinusitis

From the 16th Annual Educational Meeting of the California Society of Allergy, Asthma, and Immunology

Mark S. Schubert, MD, PhD, Clinical Associate Professor of Medicine, University of Arizona College of Medicine, Phoenix 

Educational Objectives

The goal of this program is to improve diagnosis and management of chronic rhinosinusitis (CRS) and allergic fungal sinusitis (AFS). After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the essential difference between CRS and acute rhinosinusitis.

2.   Compare CRS with and without nasal polyps.

3.   Explain the “fungal conundrum.”

4.   Diagnose AFS.

5.   Plan a treatment strategy for AFS.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Schubert and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Schubert was recorded at A Midsummer Night’s Wheeze, held July 11-13, 2008, in Huntington Beach, CA, and sponsored by the California Society of Allergy, Asthma and Immunology and the Keck School of Medicine of the Uni­versity of Southern California. The Audio-Digest Foundation thanks Dr. Schubert and the sponsors for their coopera­tion in the production of this program.

Acute and Chronic Rhinosinusitis

Background: acute rhinosinusitis distinct clinical condition; chronic rhinosinusitis (CRS) heterogeneous and often overlapping; current research focuses on etiologies, ie, pathogenic pathways that may distinguish different types

Common clinical problems: in study of association between sinusitis-induced pain and findings on  sinus computed tomography (CT), 82% of 200 patients reported facial pain or headache; no difference in CT findings between patients with or without pain; authors concluded  no relationship between symptoms and CT findings (“a real problem clinically for us”); in study of 2000 migraineurs, many reported sinus pressure, pain, nasal congestion, and runny or itchy nose; conclusion  —  sinus symptoms common in headache conditions unrelated to sinusitis

Common causes of nonsinonasal facial pain: mid-facial segment pain (similar to tension headache); atypical facial pain (usually occurs daily; often initiated by facial trauma or surgery and persists for unknown reasons); tension headache; migraine; cluster headache (“histamine headache”); temporomandibular joint (TMJ) dysfunction; tri­geminal neuralgia

Treatment of acute sinusitis: Young et al, Lancet 2008  —meta-analysis of 9 randomized controlled trials (RCTs) in­volving adults with acute rhinosinusitis-like complaints (>2000 patients) found that 15 patients (number needed to treat [NNT]) must be treated with antibiotics to cure 1 patient; NNT of 8 for patients with purulent discharge in posterior pharynx; authors concluded that “common clinical signs and symptoms cannot identify patients with rhi­nosinusitis for whom antibiotic treatment is clearly justified,” and that antibiotic treatment not justified even if symptoms persist longer than 7 to 10 days; nasal challenge with allergen  —double-blind crossover RCT looked at whether antigen placed in nose could lead to inflammation of maxillary sinus; 20 patients allergic to grass or rag­weed; allergen or placebo placed in nose; catheter placed in ipsilateral maxillary sinus; hourly nasal and sinus la­vage examined for inflammatory cells and mediators; no allergen detected in sinus when allergen placed in nose; however, allergen in nose associated with increased numbers of eosinophils, albumen, eosinophil cationic protein, and histamine in ipsilateral maxillary sinus lavage; conclusion  —  allergen challenge induced neural reflex or sys­temic effect that resulted in allergic inflammatory process that may be involved in sinusitis

Chronic rhinosinusitis: defined as symptoms occurring for >12 wk; risk factors include underlying allergic rhinitis, nonallergic rhinitis, deviated nasal septum, anatomic nasal obstruction, nasal polyps, chronic asthma, aspirin-ex­acerbated respiratory disease, rhinitis medicamentosa, diabetes mellitus, immunodeficiency diseases, cystic fi­brosis, gastroesophageal reflux disease, Wegener’s granulomatosis, Churg-Strauss vasculitis, sarcoidosis, ciliary dyskinesia, oral–sinus fistula, maxillary tooth abscess, cocaine abuse, and cigarette smoking

Common chronic hypertrophic rhinosinusitis: characterized by recurrent cycles of mucosal hypertrophy and hyper­plasia; often associated with nasal polyps; mucosal infiltrate has small lymphocytes, plasma cells, eosinophils, and associated tissue edema (resembles asthma); not associated with mucosal necrosis

Extramucosal allergic mucin: associated with eosinophilic mucin rhinosinusitis (EMRS) and allergic fungal si­nusitis (AFS); mucoid viscoelastic inspissate found within sinus cavity; composed of eosinophils

Prevalence of CRS: >18 million office visits in 2001; most patients 20 to 60 yr of age; sinus CT usually shows sinus mucosal hypertrophy and hyperplasia; intense cellular infiltrate consisting of small lymphocytes, plasma cells, eosinophils, and tissue edema; mucosa often desquamating; asthma has similar histopathologic profile

Allergic fungal sinusitis (AFS): type of CRS; characterized by intense involvement of eosinophils, lymphocytes (type I immediate hypersensitivity); other immu-nologic pathways involved as well; desquamated respiratory epithelium and extramucosal mucin also seen

Nasal polyps: usually attached to mass of sinus tissue; mucosal hypertrophy and hyperplasia results in edematous structure; polyps typical of hypertrophic sinus disease

EMRS: mucosal staining shows intense immunostaining for eotaxin (chemotactic factor for eosinophils); often associated with AFS; deemed EMRS if AFS absent; sinus CT shows hyperattenuated densities in sinus cavities typical of inspissated eosinophil-rich mucin; CT findings similar to those for AFS, but mucin associated with AFS also has fungal hyphae

CRS with nasal polyps: disease more severe on CT than CRS without polyps; polypoid CRS  —  not true polyps; lumpy sinonasal mucosa; intermediate in severity on CT; patients with polyps experience more hyposmia or anos­mia; in one study, facial pain, pressure, and headache commonly reported by patients with CRS, but less frequently by those with CRS and polyps; one investigator has suggested CRS without polyps is different disorder since asso­ciated with fewer eosinophils in mucosal infiltrate, and levels of immune and inflammatory factors lower in CRS with (vs without) polyps; CRS with polyps may be allergic disorder; CRS without polyps more like chronic ob­structive pulmonary disease; patients with CRS and polyps more likely to take oral steroids >3 times/yr; patients also more likely to have AFS, asthma,  history of previous sinus surgery, and dust mite allergy; patients without polyps more likely to have facial pain and headaches, to use antibiotics, and have infectious complications; Staphy­lococcus aureus infections, gastroesophageal reflux disease, pollen allergies, and infection with gram-negative bac­teria common in both groups

Bacterial infection: aerobic pathogens more common among patients with acute rhinosinusitis, while anaerobes more common in patients with CRS; patients with CRS also more likely to have bacterial biofilms on mucosal sur­face; “fungal conundrum”  —  controversial hypothesis that fungal pathogenesis causes virtually all cases of CRS; suggests that CRS be renamed eosinophilic fungal rhinosinusitis

Similarities between CRS and asthma: same histopathologic spectrum; similar patterns of T_H-1, T_H-2 activation and T-regulatory modulation; both have presence of leukotrienes, other shared mediators; often occur together; both ex­acerbated by viral upper respiratory tract infections; both associated with type I immediate hypersensitivity, ele­vated total serum IgE, including anti-staphylococcal superantigen IgE, and peripheral eosinophilia; both associated with aspirin-exacerbated respiratory tract disease (aspirin triad or Samter’s syndrome); both occur in AFS and aller­gic bronchopulmonary aspergillosis (ABPA); both respond to similar treatments

Staphylococcal superantigen: CRS similar to atopic dermatitis; enterotoxins secreted by Staphylococcus aureus act as superantigens that can activate immune and inflammatory cells; enterotoxins secreted by S aureus that may be present on sinus epithelium in CRS; S aureus and staphylococcal enterotoxin B (superantigen) found within epithe­lial cells from patients with CRS; superantigens bypass T-cell specificity for antigens, activating T cell in absence of antigen and resulting in chronic inflammatory response; as level of total serum IgE rises in patients with CRS, IgE to specific staphylococcal superantigens also rises; superantigens may contribute to etiology of CRS

Treatment: acute or intermittent RS  —  2005 European Academy of Allergology and Clinical Immunology (EAACI) consensus document recommends antibiotics, with topical corticosteroids as adjunct; CRS  —  for CRS associated with polyps, EAACI recommends topical corticosteroids; evidence inconclusive for use of topical antifungals (Grade D according to Oxford Center for Evidence-Based Medicine); some evidence supports use of oral corti­costeroids for CRS with polyps

Practical approach: speaker recommends history and physical examination; allergy testing; measurement of serum IgE; other work-up as needed; if considering postoperative oral corticosteroid chemoprophylaxis, obtain addi­tional baseline work-up (basic chemistries; complete blood cell count with differential; immunoglobulins; urinal­ysis; delayed hypersensitivity skin test for tuberculosis and Candida; chest x-ray; eye examination; bone density); screening sinus CT; review surgical records and reports of previous sinus CT; coordinate treatment with surgeon; team approach produces best outcomes; intensive medical treatment indicated if results show active dis­ease; treatment typically includes oral antibiotics, nasal corticosteroids, and oral corticosteroids, depending on clinical suspicion; consider antileukotrienes, especially if patient has asthma; endoscopic swab of osteomeatal unit more reliable than office-based transnasal cultures; if patient allergic, institute additional treatment, includ­ing immunotherapy to all relevant aeroallergens; antihistamines; surgery for refractory or highly recurrent dis­ease; restart medical management postoperatively; patient education imperative

Allergic Fungal Sinusitis

Invasive fungal rhinosinusitis: acute necrotizing disease (eg, mucormycosis) very serious, usually fatal; chronic in­vasive (seen mostly in diabetics); granulomatous invasive (indolent; limited to superficial mucosa; well-contained within granulomas)

Noninvasive fungal rhinosinusitis: fungal ball (sinus mycetoma); AFS (6%-9% of all surgically treated CRS)

CT findings typical of AFS: hyperattenuated or increased contrast densities within abnormal hypertrophic sinus lu­men; orbital extension through lamina papyracea, resulting in proptosis; may erode through frontal sinus into cranium, with dural compression

Allergic mucin: characteristic material of AFS; also associated with EMRS, but lacking fungal hyphae; made of compressed eosinophils; forms cast of sinonasal tract; hematoxylin and eosin (H&E) staining reveals extramuco­sal material with eosinophils in massive laminated concretions surrounded by thin mucin; not fungal debris

Mycetoma: mass of compressed fungal hyphae; no eosinophils or allergic mucin present; resembles asthmatic spu­tum inspissate similar to material seen with ABPA

AFS histopathologic findings: intense allergic inflammatory infiltrate on H&E staining; tissue edema; lympho­cytes, eosinophils; desquamated epithelium; thickened basement membrane; extramucosal mucin; findings simi­lar to those associated with chronic severe asthma

Clinical presentation: similar to that seen with CRS with nasal polyps; characteristic allergic mucin seen grossly at surgery, defined further histopathologically; allergic mucin stains positive for sparse scattered fungal hyphae; no fungal elements within mucosa, no granulomatous changes; no evidence of tissue invasion; surgical sinus fungal culture usually positive; sinus CT hyperattenuation caused by allergic mucin; clinically chronic; often surgically recurrent

Pathophysiologic findings: allergic hypersensitivity response to fungi within sinus cavities; all patients atopic, have positive skin test for multiple aeroallergens; all have IgE specific to AFS etiologic fungus; incidence of surgical sinusitis 6% to 9%; endemic in southern, southwestern United States; 75% of patients have nasal casts; asthma common but not severe; patients “uniformly immunocompetent”; associated with histocompatibility leukocyte antigen (HLA) class II; major histocompatibility complex (MHC) class II marker is DQ3; most common causes dematiaceous fungi

Minimum required AFS diagnostic criteria: characteristic allergic mucin seen on surgical sinus histopathology or grossly at surgery; silver stain positive for hyphae within allergic mucin, or positive fungal culture from surgical sampling; H&E staining shows characteristic sinus mucosal inflammatory infiltrate, consisting of small lympho­cytes, plasma cells, and eosinophils, with no necrosis, granulomas, or fungal invasion; exclusion of other fungal diseases; any patient with EMRS potential candidate for AFS, but presence of fungi required for diagnosis of AFS

Comparison of ABPA and AFS: common features  —allergic mucin with noninvasive fungal hyphae; respiratory at­opy; positive fungal skin test; elevated total serum IgE and fungal-specific IgG; change in total serum IgE on fol­low-up prognostic; MHC class II association; favorable clinical response to systemic corticosteroids; differences  —  fungal-specific IgE elevated beyond common atopy, and serum precipitins to fungus seen with ABPA but not AFS; peripheral eosinophilia more common with ABPA than AFS

Treatment of AFS: aggressive sinus surgery; medication for allergy management, including antihistamines and topi­cal nasal corticosteroids; consider antileukotrienes; allergen immunotherapy to control allergic inflammatory dis­ease (reduce inflammatory milieu to decrease risk for AFS relapse); include etiologic mold in immunotherapy mix; postoperative oral corticosteroids, on modified ABPA protocol; close medical-surgical cooperation and follow-up imperative; postoperative monitoring of total serum IgE; systemic antifungals not found effective (topical antifun­gals not studied adequately); consider omalizumab; modified ABPA oral corticosteroid protocol  —  0.5 mg/kg pred­nisone daily beginning immediately postoperatively; after 2 wk, switch to alternate-day schedule for 2 wk; continue tapering on alternate-day regimen until dosage down to 5 to 7.5 mg every other day by 3 mo; continue on this dos­age, with short burst for any acute RS episodes, adding antibiotics as indicated; oral corticosteroids for  ³2 mo clin­ically beneficial for >1 yr, as measured by symptom scores and surgical recurrence rates; if AFS becomes surgically recurrent, begin regimen from time 0; in speaker’s experience, this approach, when combined with ag­gressive postoperative allergy management, significantly reduces RS symptoms and delays need for recurrent sur­gery; observe patient carefully for side effects from corticosteroids; changes in total serum IgE and fungal-specific IgG levels correlated with clinical status; corticosteroid protocol associated with prolonged time to recurrence (10% recurrence by 200 days for patients on protocol, compared to nearly 50% for those not on protocol)

Suggested Reading

Bachert C et al: Role of staphylococcal superantigens in upper airway disease. Curr Opin Allergy Clin Immunol 8:34, 2008; Chakrab­arti A et al: Controversies surrounding the categorization of fungal sinusitis. Med Mycol 29:1, 2008; deShazo RD: The fungal conun­drum. Ann Allergy Immunol 96:256, 2006; Lim M et al: Topical antimicrobials in the management of chronic rhinosinusitis: a systematic review. Am J Rhinol 22:381, 2008; Meltzer EO et al: Rhinosinusitis: developing guidance for clinical trials. J Allergy Clin Immunol 118:S17, 2006; Niederfuhr A et al: Staphylococcus aureus in nasal lavage and biopsy of patients with chronic rhinosinusitis. Allergy 63:1359, 2008; Scadding GK et al: BSACI guidelines for the management of rhinosinusitis and nasal polyposis. Clin Exp Allergy 38:260, 2008; Schubert MS: A superantigen hypothesis for the pathogenesis of chronic hypertrophic rhinosinusitis, allergic fungal si­nusitis, and related disorders. Ann Allergy Asthma Immunol 87:181, 2001; Schubert MS: Allergic fungal sinusitis. Clin Rev Allergy Im­munol 30:205, 2006; Wang M et al: The role of superantigens in chronic rhinosinusitis with nasal polyps. ORL J Otorhinolaryngol Relat Spec 70:97, 2008.