Fungal Rhinosinusitis Niyada Teerasuwanajug

Cumming otolaryngology head and neck surgery 5th edition Bailey otolaryngology head and neck surgery 4th edition The Otolaryngologic Clinics of North America 2000 SIPAC 2003 Katazenstein ABPA (SIPAC)

Incidence Rare Noninvasive fungal rhinosinusitis is more common. 4-7% of Sx cases for chronic inflammatory sinonasal dis. are AFS. A review by Ferreiro et al. 1984-1994  3.7% of Sx cases for inflammatory sinus dis. were fungal ball. CIFS: very rare in the United States  only case reports & a few small series. More common in region; Sudan & India. CIFS: very rare in the United States  only case reports & a few small series. SIPAC 2003

Incidence Incidence rates of AIFS for leukemia, CA, or bone marrow transplant = 1-2% The incidence of fungal sinus disease seems to be increasing. SIPAC 2003

Factor Contribute to Increase Incidence practitioner awareness. Technical advanced >> mycology, serology , histopathology and radiology. Growth of immunocompromised population. Inappropriate use of anti-bacterial ATBs. incidence of atopic dis. in the United States. 1&2 ทำให้ missed Dx น้อยลง 4. ทำห้มีอาการเปลี่ยน normal nasal flora ช่วยให้ fungal growth ในจมูก + sinus 5. May proliferate AFS

Increased Susceptibility to Invasive Fungal Infections Disease of the sinuses: Dx & Mx. 2001: 180

Classification of Fungal Rhinosinusitis Noninvasive / Extramucosal Saprophytic colonization / Superficial sinonasal mycosis Fungal ball Allergic fungal rhinosinusitis (AFS) Invasive Chronic invasive (indolent) fungal rhinosinusitis (CIFS) Acute invasive (fulminant) fungal rhinosinusitis (AIFS) The simplest form of noninvasive = saprophytic colonization ภาวะนี้มักเกิดตามหลัง Sx ซึ่งมี nasal mucosal drying และปกติมักเป็น asymptomatic บางเล่มจึงไม่รวมอยู่ใน classification AIFS < 4wk บางเล่มแยก CIFS เป็น granulomatous – nongranulomatous form ความแตกต่างทางด้าน clinical ยังไม่ชัดเจน Disease of the sinuses: Dx & Mx. 2001: 179

Am J Surg Pathol Volume 30, Number 6, June 2006

Fungus ball Saprophytic Granulomatous Invasive Fungal sinus dis. manifestations: by host’s immune response & tissue invasion. Non- Invasive Invasive Fungus Ball Chronic Invasive Acute invasive AFRS Hypersensitivity Host response to fungus Immunocompromised SIPAC 2003 Host Defense Atopic Immunocompetent Immunocompromised บางเล่มเรียก non-invasive เป็น extramucosal fungal rhinosinusitis Fungal Form AFRS Fungus ball Saprophytic Granulomatous Invasive Fungal manifestion : by patient’s immunologic status The Otolaryngologic Clinics of North America 2000

Signs & Symptoms Seen with Fungal Infections Disease of the sinuses: Dx & Mx. 2001: 180

Endoscopic Findings Present During Fungal Infection Disease of the sinuses: Dx & Mx. 2001: 180

Endoscopic Findings Present During Fungal Infection

Microbiology Fungal form: 1. Mould 2. Yeast Multicellular colonies Hyphae Cause most fungal rhinosinusitis 2. Yeast Unicellular Most reproduction by asexual budding However, some species >> dimorphic depending upon environmental conditions. SIPAC 2003

Microbiology Common fungi in fungal rhinosinusitis Category Disease Genera Zygomycetes (Mucoraceae) Acute invasive Absidia Cunninghamella Mucor Rhizomucor Rhizopus Hyaline moulds Fungas ball Aspergillus Acute invasive Fusarium Chronic invasive Pseudallescheria Dematiacious moulds Allergic fungal Alternaria Bipolaris Cladosporium Curoularia Exserohilum - Genus bipolaris แต่ก่อนเรียก helminthosporium Hphae ของกลุ่ม aspergillus septate & branchi ทำมุม 45 องศา แต่ zygomycetes branching 90 องศา SIPAC 2003

Microscopic examination 10% , 20% KOH Light microscopy limit in thick specimen KOH – calcufluor white stain Fluorescence microscope

Microscopic examination Gram stain : not common use H & E (hematoxylin and eosin) GMS (Gomori methenamine silver) PAS (periodic acid schiff) GMS and PAS superior to H&E

Culture identification Media : Sabouraud’ s agar (glucose + beef extract; PH 5 ) Serology specific IgE and IgG  detected by serum radioimmunoassay

Noninvasive Fungal Rhinosinusitis

Noninvasive Fungal Rhinosinusitis Saprophytic colonization Fungal ball Allergic fungal rhinosinusitis

Saprophytic Colonization Extramucosal sinonasal fungi promote inflammation Presence of fungal spores on mucous crusts within nose & paranasal sinus Detected grossly on examination. Perhaps one could consider this an early form of a fungus ball. Common fungal agent: Aspergillus species Disease of the sinuses: Dx & Mx. 2001: 180-182

Saprophytic Colonization Clinical presentation: immunocompetent asymptomatic an odor in nose crusts of debris on nose blowing nasal endoscope: a tuft of fungal material is seen growing on nasal crusts, much like mold growing on old bread Disease of the sinuses: Dx & Mx. 2001: 180-182

Saprophytic Colonization Patient undergone previous endoscopic sinus surgery: disrupt mucocilary transport pathway dry nasal passageways / have some mucus stasis Fungal crusts may appear in areas of high airflow - anterior edge of turbinates , but can also appear in surgical widened sinus cavities. Imaging : not seen on imaging Disease of the sinuses: Dx & Mx. 2001: 180-182

Saprophytic Colonization Treatment: Debridement the involved region  endoscopic cleaning. Disease of the sinuses: Dx & Mx. 2001: 180-182

Saprophytic Colonization Treatment: Saline irrigation if it accumulate. Minimizing overuse of drying agents: antihistamine, topical nasal steriod. Rx underlying bacterial infection. Antifungal agent: not used. Disease of the sinuses: Dx & Mx. 2001: 180-182

Fungal Ball

Fungal Ball Terms: A true mycetoma: Sinus mycetoma Aspergilloma Simple sinus aspergillosis A true mycetoma:  a suppurative & granulomatous subcutaneous fungal infection with draining sinus tracts.  refer to an invasive fungal infection of the feet. Mycetoma เป็น misnomer ปจบ.ใช้ fungal ball แทนแล้ว SIPAC 2003

Fungal Ball Epidemiology: The average age reported in an american 29 cases = 64 yr (28-86 yr). A review by deShazo et al. >> similar age range, the youngest = 18 yr. Common in older No pediatric. Female predominant อายุแต่ละ paper varie แต่ range 18-86 ปี mean 54, 64 ปี แต่ female: male 1.5 – 2 : 1 หมด Fungus ball of paranasal sinus: The Otolaryngologic Clinics of North America 2000

Fungal Ball Often found unexpectedly during Rx of chronic bacterial sinusitis Hx : May be present for months to years. Nonspecific chronic sinusitis symptoms: Nasal obstruction Facial pressure Postnasal drainage **Hx of symptoms refractory to common medical Rx: ATBs Antihistamines Nasal steroids อายุแต่ละ paper varie แต่ range 18-86 ปี mean 54, 64 ปี แต่ female: male 1.5 – 2 : 1 หมด SIPAC 2003

Fungal Ball Diagnosis No evidence of immunocompromise + No incidence of atopy *** A solitory maxillary/ sphenoid sinus May also in frontal & ethmoid sinuses May involve contiguous sinuses In asymptomatic patients  often detect only after imaging for other conditions SIPAC 2003

Fungal Ball PE: A single sinus 40% of patients: purulent d/c from involved sinus 10% of patients: polyps SIPAC 2003 Paper ของ italy 81 patients presenting paranasal fungus ball have been treated (January 1994 to May 2005). 27 men / 54 women (19–91 yr; mean 49.4 yr). 73 patients had a single sinus , but 8 multiple localisations. F. Pagella et al.: Paranasal sinus fungus ball: Dx & Mx. Mycoses (2007), 50, 451–456

Fungal Ball Hx PE Imaging Histopathologic exam. Culture นอกจากมีประวัติ refractory ต่อ standard medical Rx และ PE : พบ lcalized sinusitis ซึ่ง suggest a fungal ball……………………. Histopathology : Fungus balls are extramucosal fungal infestations. No invasion is present. Granulomotous reaction is absent. The fungi usually can be seen on routine hemotoxylin and eosin stains; however, special fungal stains can be confirmatory. Occasionally the fungus ball may not be appreciated without special fungal stains such as Gomori methenamine silver. A tangled mat of hyphae is present. Although morphologic features of the fungi can be seen, such as septations and the 45° angle branching typical of Aspergillus species, the fungi causing the fungus ball usually cannot be determined histologically.

Fungal Ball Unenhanced CT scan Hyperattenuating material filling the Rt. maxillary sinus with central calcific areas of increased attenuation (long arrow). The circumferential thickening of the osseous walls of sinus (short arrows). (13) Mucor fungus ball in a 49-year-old woman with chronic sinus pressure and halitosis. Imaging Features teaching point  Fungus ball appears as a mass within the lumen of a paranasal sinus and is usually limited to one sinus. The maxillary sinus is the most commonly involved sinus (Figs 13, 14). However, sometimes the sphenoid sinus appears to be affected. A fungus ball typically appears hyperattenuating at noncontrast CT due to dense matted fungal hyphae and may demonstrate punctate calcifications (Fig 13).

Fungal Ball Axial unenhanced CT scan The typical hyperattenuating fungus ball with calcific foci in Lt. maxillary sinus (long arrow). The sclerotic thickening of the osseous walls of sinus (short arrows) from chronic sinus inflammation. (14) Aspergillus fungus ball in a 60-year-old woman with mixed connective tissue disorder and a history of cryoglobulinemia and Sjo¨gren syndrome. Complete/ subtotal opacification

Fungal Ball

Fungal Ball Pathology: Gross Lesions: vary from soft, wet-appearing bundles of debris to firm, gritty & crumbly balls Color: white, yellow, green, tan, brown & black

Fungal Ball FIGURE 4. Chronic noninvasive fungal sinusitis. (A) A fungal ball, which appears on low magnification as acellular, eosinophilic material, may be confused with mucin. Mucosal tissue (upper right) is not involved (hematoxylin & eosin). (B) The Gomori methenamine silver (GMS) stain shows that the fungal ball is composed of abundant fungal hyphae. (C) The fungal ball is partially surrounded by inflammatory cells, mostly neutrophils. This finding should not be confused with tissue invasion (hematoxylin and eosin). **ไม่ invade mucosal tissue*** (D) The corresponding GMS stain clearly shows fungal hyphae forming tight clusters in the center and penetrating between inflammatory cells at the periphery. Granville et al: Fungal sinusitis, HUMAN PATHOLOGY Volume 35, No. 4 (April 2004)

Fungal Culture Usually –ve In Klossek's review (109 patients), only 31% of cases had positive cultures. All of these : Aspergillus fumigatus Usual pathogen: Aspergillus species But Pseudallescheria, Alternaria sp, and other species have been reported. Failure of the fungus to grow on fungal culture is common, with only 23% to 50% of cultures resulting in fungal growth. SIPAC 2003

Fungal Ball Pathogenesis Unknown Persistence of fungal spores within nasal cavity into maxillary/ other sinus.  When fungal spore is not cleared. (in warm dark recesses of a sinus)  germination & growth. Saprophytic colonization  obstruct sinus ostium& lead to episodes of acute sinusitis and result in a fungal ball.

Fungal Ball F. Pagella et al.: Paranasal sinus fungus ball: Dx & Mx. Mycoses (2007), 50, 451–456 F. Pagella et al.: Paranasal sinus fungus ball: Dx & Mx. Mycoses 2007, 50, 451–456

Fungal Ball Treatment The gold  removal of the hyphal mass + re-establishment of drainage from involved sinus. Antifungal Rx : unnecessary เนื่องจาก non-invasive + non-lifethreatening dis…. functional endoscopic sinus surgery is the gold standard for treatment of this pathology, antifungal therapy is unnecessary

Fungal Ball Postoperative care Recurrence  rare Saline irrigation & endoscopic debridements are indicated until complete healing. No further Rx is required & widely aerated sinus should quickly return to normal. Recurrence  rare

Fungal Ball Treatment : Should an asymptomatic patient undergo surgery for an opacified sinus without evidence of bony erosion? This is controversial, and following the patient for symptoms & repeated imaging to assess for progression is also a reasonable path. Fungus ball of paranasal sinus: The Otolaryngologic Clinics of North America 2000

Allergic Fungal Rhinosinusitis Epidemiology The most common form of fungal rhinosinusitis Age: mostly in young adults Average age at Dx >> 23-26 yr. Range 7-62 yr. Sex: Male:Female >> 6:1 SIPAC 2003

Allergic Fungal Rhinosinusitis Epidemiology AR: 63% of AFS patients give Hx of AR  allergy testing  70-90% show evidence of atopy. Asthma: About 50% of patients have asthma. (33-54%) Geography: More common in the warm humid climates of the southern United States and along the Mississippi River. SIPAC 2003

Allergic Fungal Rhinosinusitis Clinical features: Hx Onset: difficult to pintpoint. Symptoms progress slowly (mo./yr. prior to Dx.) Typically presented with prolonged Hx of rhinosinusitis sym.: Nasal congestion & obstruction Anosmia Postnasal drainage SIPAC 2003

Allergic Fungal Rhinosinusitis Clinical features: Hx Despite prolong medical Rx (repeated courses of ATB)  fail to improved. May multiple sinus procedures without benefit if overlooked the Dx. SIPAC 2003

Allergic Fungal Rhinosinusitis Clinical features: PE By the time of Dx >> advanced  PE findings reflect this. GA: nasal widening, proptosis Incidence of proptosis 20% Reversible blindness from sphenoid involved (several case reports) fungal mucocele formation SIPAC 2003

Allergic Fungal Rhinosinusitis Clinical features: PE Intranasal exam. Polyposis predominantly unilateral, maybe bilat. often massive & visible at nasal vestibule ** Allergic mucin -mucin: rubbery -difficult to suction out -often visibly nestle within the polyps รูป 20-4 หน้า 295 SIPAC 2003 Sinus Surgery Endoscopic & Microscopic Approaches, Howard L. Leveine 2005

Allergic Fungal Rhinosinusitis Laboratory May provide evidence of atopy, but not usually required for Dx CBC: peripharal eosinophilia (7-15%) Elevated total IgE level: mean 668 IU/ml (normal= <125 IU/ml) RAST (radioallergosorbent test for quantifying antigen-specific IgE) : +ve to multiple fungi. Skin test: +ve to multiple fungi. Skin test/ RAST (radioallergosorbent test for quantifying antigen-specific IgE) will usually demonstrate IgE-mediated hypersensitivity to multiple fungi and nonfungal antigens SIPAC 2003 Sinus Surgery Endoscopic & Microscopic Approaches, Howard L. Leveine 2005

Allergic Fungal Rhinosinusitis Laboratory Total IgE fluctuates with disease activity. In a review of 67 patients in Arizona, Schubert & Goetz found: Total serum IgE correlated significantly with severity of disease. Importantly, an increase >=10% in total serum IgE during F/U >> strong predictor of recurrence & need for Sx. Schubert MS, Goetz DW. Evaluation & Rx of ARS. J Allergy Clin Immunol. 1998

Allergic Fungal Rhinosinusitis Pathology Gross - The distinctive pathology of AFS >> tenacious inspissated mucin / “peanut butter-like” - Thick yellow, brown, or green debris fills the involved sinuses.  similar to fungal ball grossly Mucin เหนียว ๆ หนา ๆ ลักษณะคล้าย peanut butter

Allergic Fungal Rhinosinusitis Histopathology Microscope: - Within allergic mucin : “onionskin lamination” / cluster of necrotic & degranulation of eosinophil - Charcot-Leyden crystal. Hyphal fragments scattered No fungal tissue invasion Microscope: this mucin reveals necrotic eosinophils,, frequently in wavelike concentric layers. รูป 291 20-2A สิ่งสำคัญในการdx hyphal fragment scattered + eosinophilli mucin (ซี่งใน mucin นี้มี necrotic eos. + charcot-leyden crystal) Small hexagonal & bipyramidal crystal in this mucin ซึ่งเป็นผลมาจาก eos. degranulation Sinus Surgery Endoscopic & Microscopic Approaches, Howard L. Leveine 2005

Allergic Fungal Rhinosinusitis Histopathology 20-2B dense inflammatory cell *** no fungal tissue invasion *** +++++++++++++ Histo ที่ว่ามาทั้งหมด สำคัญในการ Dx ++++++++++ Special stains for fungus: GMS >> hyphae Sinus Surgery Endoscopic & Microscopic Approaches, Howard L. Leveine 2005

Histopathology GMS >> scatter hyphae Periodic acid-Schiff, ×520 Allergic fungal sinusitis. (A) So-called allergic mucin characterized by large accumulations of eosinophils forming a characteristic wavelike pattern, embedded in mucin, which appears eosinophilic by hematoxylin & eosin stain. (B) Eosinophils within the eosinophilic mucin with adjacent Charcot-Leyden crystals (arrows). GMS : scatter hyphae GMS >> scatter hyphae Periodic acid-Schiff, ×520

Allergic Fungal Rhinosinusitis Fungal culture Positive 70-80% of patients diagnosed with AFS. Dematiaceous fungi : the most common based on C/S data  84% of the total positive C/S The most common fungi = Bipolaris species

Allergic Fungal Rhinosinusitis Fungal culture Aspergillus species 13% of all fungal C/S

Allergic Fungal Rhinosinusitis Fungal culture Appear to be geographic variability in incidence of AFS & in fungal organism Dematiaceous fungi : most common in the United states Aspergillus species : most cases reported in the Middle East.

Allergic Fungal Rhinosinusitis Staging System Kupferberg et al. >> F/U patients: recurrent following surgery. They found : these physical findings appear before return of subjective clinical symptoms Stage 3 หรือมี allergin mucin ด้วย

Allergic Fungal Rhinosinusitis Imaging CT: Initial study of choice An important roadmap before Sx >> Multiple opacified sinuses Predominantly unilateral, possibly bilateral Expanded sinuses Bone erosion into orbit, cranium, or soft tissue of face. Focal areas within sinuses: hyperattenuation = fungal allergic mucin  irregular, speckled, or serpiginous Allergic mucin : Ca, Mg , or iron within mucin , or high protein and low water content SIPAC 2003

Allergic Fungal Rhinosinusitis Coronal sinus CT Axial sinus CT Absent bone between cranial & ethmoid มี bone erosion Same patient : hyperattenuation of mucin in central cavity of maxillary sinus. รอบ ๆ mucin >> low-attenuation soft tissue density ของ hyperplastic mucosa lining sinuses+ nasal polyps Sinus Surgery Endoscopic & Microscopic Approaches, Howard L. Leveine 2005

Allergic Fungal Rhinosinusitis Imaging MRI Sinus contents >> low T2 & isointense/hypointense T1 signal Peripheral mucosa & polyps >> hyperintense on both T1 & T2 ตรงข้ามกับ CT ใน high attenuated area ตรง central sinus  MRI diminish signal ทั้ง T1 & T2

Allergic Fungal Rhinosinusitis Imaging Bony remodeling / erosion is common (90%)  from atrophy / the release of inflammatory mediators that dissolve bone, not due to fungal invasion While definitive Dx requires histological verification, the imaging findings are almost pathognomonic & facilitate pre-op planning. SIPAC 2003

Allergic Fungal Rhinosinusitis Diagnostic Criteria Several criteria have been proposed for the Dx. Kartzenstein 1983 Manning 1989 Ence 1990 Bent 1994 deShazo 1995 Kuferupferberg 1996 Schubert 1998 Ponikau 1999 Schubert 2000 McCann 2002 Meltzer 2004 Singhal D et al. Medical interventions for post-surgical Mx of AFRS: The Cochrane Library 2008

Allergic Fungal Rhinosinusitis Diagnostic Criteria Presence of allergic mucin: fundamental criterion for the dis. Bent & Kuhn diagnostic criteria for allergic fungal rhinosinusitis Type I hypersensitivity confirmed by Hx, skin test, or serology Nasal polyposis Characteristic CT scan findings +ve fungal strain of sinus contents Eosinophilic mucus without fungal invasion into sinus tissue อันแรก >> Bent& Kuhn reviwe series of 15 patients AFS หา common feature : widest acceptance  ทุก case พบว่าที 5 องค์ประกอบด้วยกัน Bent JP III, Kuhn FA: Dx of AFS. Otolaryngol Head Neck Surg 1994; 111: 580-588.

Eosophillic inflammation Pathophysiology & Natural Course Local Mucostasis Anatomic anomaly Environmental Fungal exposure Genetic Atopy T-lym susceptibility Exposure Fungal proliferation Antigen exposure Anatomic factors Edema Obstruction Stasis Decreased ventilation Inflammatory trigger Gell & Coombs I/III T-cell Other Allergic mucin คิดว่าน่าจะเกิดจาก immune hypersensitivity ต่อ fungus เหมือน pathogenesis ของ allergic bornchopulmonary aspergillosis (ABPA) Evidence of this theory >> series of AFS (Bipolaris) หลาย series >> ทำ RAST & enz.-linked immunosorbent assay testing: elevated specific IgE & IgG, +ve immediate skin reactivity to bipolaris extract in all case Bacterial infection Inflammation Eosophillic inflammation (MBP, ECP, etc) The UT Southwestern model of AFS pathogenesis. Local tissue, environ., & immunologic factors converge in pathogenesis of this disease. (Laryngoscope 2001; 111: 1006-1019)

Allergic Fungal Rhinosinusitis Natural Course Frequent recurrence Reported recurrent rate 10-100% SIPAC 2003

Allergic Fungal Rhinosinusitis Treatment : Surgical Required in almost all cases. Goal: removing fungal mucin + widely marsupialize the involved sinuses. Occasionally, the fungal mucin is so difficult to clear from the maxillary sinus & frontal sinus >> external approach / frontal sinus trephination may be necessary. Comprehensive approach to Mx depend on complete removal of all fungal mucin (Sx) + long term prevention of recurrence ทั้ง immunomodulation ได้แก่ immunoRx/ steroids และ antifungal agents Widen เปิด sinus cavities Marple BF: AFRS: Current theories & Mx strategies. Laryngscope 2001; 111: 1006-1019

Allergic Fungal Rhinosinusitis Surgical Dis. may distort normal intranasal landmarks & erode important bony barriers to orbit/cranium.  CT prior Sx. Sx alone isn’t sufficient Rx for AFS, it is a crucial first step in Mx. SIPAC 2003

Allergic Fungal Rhinosinusitis Surgical Goal : same as primary Sx; allergic mucin, nasal polyps & other sinus obstruction should be removed. Complete Sx to removed all fungal mucin is critical to reduce risk of recurrence. บางครั้ง allergic mucin สามารถ completel suction ได้ in the office + intensive medical Rx can reduce polyp volume, massive polyposis & outflow tract obstruction. อาจไม่ response ต่อ medication เนื่องจากมี antigenic load of allergic mucin within sinuses.