1. Fungal Rhinosinusitis
Niyada Teerasuwanajug

2. 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)

3. 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  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

4. 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

5. 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

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

7. 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

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

9. 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

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

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

12. Endoscopic Findings Present During Fungal Infection

13. 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

14. 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

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

16. 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

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

18. Noninvasive Fungal Rhinosinusitis

19. Noninvasive Fungal Rhinosinusitis
Saprophytic colonization
Fungal ball
Allergic fungal rhinosinusitis

20. 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:

21. 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:

22. 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:

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

24. 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:

25. Fungal Ball

26. 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

27. 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 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

28. 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 ปี mean 54, 64 ปี
แต่ female: male 1.5 – 2 : 1 หมด
SIPAC 2003

29. 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

30. 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

31. 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.

32. 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).

33. 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

34. Fungal Ball

35. 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

36. 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)

37. 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

38. 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.

39. 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

40. 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

41. 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

42. 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

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

44. Allergic Fungal Rhinosinusitis
Epidemiology
AR:
63% of AFS patients give Hx of AR  allergy testing  % 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

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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 A
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

53. 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

54. 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

55. 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

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

57. 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.

58. 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

59. 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

60. 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

61. 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

62. 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

63. 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

64. 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:

65. 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: )

66. Allergic Fungal Rhinosinusitis
Natural Course
Frequent recurrence
Reported recurrent rate %
SIPAC 2003

67. 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:

68. 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

69. 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.