Fungal Sinusitis: A Call for a Fungal Sinusitis: A Call for a Better UnderstandingBetter Understanding

Hail M. Al-Abdely, MDHail M. Al-Abdely, MDConsultant, Infectious Consultant, Infectious

DiseasesDiseases

What does it mean?What does it mean?

Inflammation of the sinuses due to a Inflammation of the sinuses due to a fungus.fungus.

Direct effect of the fungus Direct effect of the fungus oror indirect. indirect.

What are the clinical forms?What are the clinical forms?

Allergic Fungal ball

Invasive• AcuteAcute

• ChronicChronic - Invasive- Invasive

- Granulomatous- Granulomatous

DeShazo. Arch Otolaryngo Head Nech Surg 1997; 123:1181DeShazo. Arch Otolaryngo Head Nech Surg 1997; 123:1181

Acute invasive

fungal sinusitis

Mucorales, Mucorales, Aspergillus SppAspergillus Spp

Non-specificNon-specific Diabetes, Diabetes, immune-immune-suppressedsuppressed

Diabetes, Diabetes, cancer, iron cancer, iron chelatingchelating

Allergic fungal sinusitis

Aspergillus Aspergillus Spp., Spp., DematiaceousDematiaceous

Humid areasHumid areas Immune-Immune-competentcompetent

Atopy, nasal Atopy, nasal polypspolyps

Sinus

Mycetoma

(fungus ball)

Aspergillus Aspergillus Spp., Spp., DematiaceousDematiaceous

Humid areasHumid areas Immune-Immune-competentcompetent

Chronic Chronic sinusitissinusitis

Chronic

invasive fungal sinusitis

Aspergillus Aspergillus fumigatusfumigatus

Non-specificNon-specific Immune-Immune-suppressedsuppressed

DiabetesDiabetes

Granulomatous

invasive

fungal sinusitis

Aspergillus Aspergillus flavusflavus

Tropical & Tropical & subtropicalsubtropical

Immune-Immune-competentcompetent

NoneNone

SYNDROME COMMON CAUSES

GEOGRAPHIC

DISTRIBUTION

HOST ASSOCIATED

CONDITIONS

FEATURES OF NONINVASIVE AND INVASIVE FUNGAL SINUSITIS

De Shazo: NEJM 337:257. 1997

Allergic Fungal Sinusitis (AFS)Allergic Fungal Sinusitis (AFS)

Allergic Fungal Sinusitis (AFS)Allergic Fungal Sinusitis (AFS)

Most common form of fungal sinusitisMost common form of fungal sinusitis

A recently recognizedA recently recognized– 1976: First described in patients with Allergic 1976: First described in patients with Allergic

broncho-pulmonary aspergillosis broncho-pulmonary aspergillosis (Safirstein. Chest 70: 788)(Safirstein. Chest 70: 788)

– 1983: Few Cases with the histologic triad of necrotic 1983: Few Cases with the histologic triad of necrotic eosinophils, charcot-Leyden crystals and non-invasive eosinophils, charcot-Leyden crystals and non-invasive fungal hyphae and was named fungal hyphae and was named Allergic Aspergillus sinusitis (Katzenstein. J Allergy Clin Immunol 72:89)(Katzenstein. J Allergy Clin Immunol 72:89)

– 1998: English-literature review revealed 263 cases. (Maning. Laryngoscope 108: 1485)(Maning. Laryngoscope 108: 1485)

AFS: How common?AFS: How common?

Chronic rhinosinusitis is the most common chronic Chronic rhinosinusitis is the most common chronic disease in the US affecting disease in the US affecting 37 million37 million ( (14.13%14.13% of of population).population). Vital Health Stat 1995, 10:89Vital Health Stat 1995, 10:89

Incidence of AFS in chronic rhinosinusitis is Incidence of AFS in chronic rhinosinusitis is 7%.7%. (Cody DT. (Cody DT. Laryngoscope.1996; 4:169)Laryngoscope.1996; 4:169)

In a recent prospective cohort from the US, fungi were In a recent prospective cohort from the US, fungi were isolated from isolated from 94%94% of patients with chronic rhinosinusitis. of patients with chronic rhinosinusitis. (Ponikau JU. Mayo Clin Proc.1999; 74:877)(Ponikau JU. Mayo Clin Proc.1999; 74:877)

In a recent study from Austria, fungi were isolated from In a recent study from Austria, fungi were isolated from 91.3%91.3% from patients with chronic rhinosinusitis. from patients with chronic rhinosinusitis. 75.5%75.5% of of patients had fungal elements on histopathology. patients had fungal elements on histopathology. (Braun H. (Braun H. Laryngoscope.2003; 113:264)Laryngoscope.2003; 113:264)

Subjects224

Chronic Rhinosinusitis

210

Volunteers14

Positive culture100%

Positive culture96%

Fungal Culture

Sinus surgery101

Fungal elements81%

Eosinophilic mucin97%

Fungal Culture

(Ponikau JU. Mayo Clin Proc.1999; 74:877)(Ponikau JU. Mayo Clin Proc.1999; 74:877)

The Mayo Clinic CohortThe Mayo Clinic Cohort

(Ponikau JU. Mayo Clin Proc.1999; 74:877)(Ponikau JU. Mayo Clin Proc.1999; 74:877)

Pathogenesis of AFSPathogenesis of AFS

Exposure

Fungal proliferationAntigen exposure

Inflammatory triggerIgE mediatedT-cell & other

InflammationEosinophilic mediators(MBP, ECP & others)

EdemaObstructionStasisReduced ventilation

Allergic Allergic MucinMucin

Local Factors-Mucostasis-Anatomic anomaly

Enviromental-Fungal exposure

Genetic-Atopy-Unknown

+ +

Marple: Laryngoscope 111:1006. 2001

Which fungus causes AFS?Which fungus causes AFS?

– Aspergillus species.Aspergillus species.– Phaeohyphomycosis:Phaeohyphomycosis:

Bipolaris, Exerohilum, Dreschlera.Bipolaris, Exerohilum, Dreschlera.

Alternaria.Alternaria.

CurvulariaCurvularia

Exophiala.Exophiala.

– Others (rare)Others (rare)Fusarium, Scedosporium (Pseudallescheria).Fusarium, Scedosporium (Pseudallescheria).

Criteria for Diagnosis of AFSCriteria for Diagnosis of AFS

No consensus but several proposals that share:No consensus but several proposals that share:– Presence of allergic mucin on histopathologyPresence of allergic mucin on histopathology– Presence of non-invasive hyphae on histopathology Presence of non-invasive hyphae on histopathology

+/- fungal culture+/- fungal culture– Fungal Ig-E mediated hypersensitivityFungal Ig-E mediated hypersensitivity– Nasal polyposisNasal polyposis– High-signal intensity opacification of sinuses on CT High-signal intensity opacification of sinuses on CT

scanscan

? Associated atopy (65%) with asthma (50%)? Associated atopy (65%) with asthma (50%)

Marple: Laryngoscope 111:1006. 2001

CT and MRI scans in AFSCT and MRI scans in AFS

The sinus filled with high signal intensity soft The sinus filled with high signal intensity soft tissuetissueBone erosions (20% of cases) and extension to Bone erosions (20% of cases) and extension to surrounding structures can happen BUT due to surrounding structures can happen BUT due to pressurepressure and and not invasionnot invasion ((Nussenbaum B,Otolaryngol Head Neck

Surg 001;124:150–154)

Remodeling is commonRemodeling is common

MRI: hypointense central T1 signal, central T2 signal and the presence of increased peripheral T1/T2 enhancement

.

Treatment Goals for AFSTreatment Goals for AFS

Clear current episodeClear current episode

Reduce number of recurrences. Very Reduce number of recurrences. Very common (90% of cases)common (90% of cases)

Improve quality of lifeImprove quality of life

It’s NOT easyIt’s NOT easy

Patient education about the nature of the Patient education about the nature of the diseasedisease

Exposure

Allergic Allergic MucinMucin

Fungal proliferationAntigen exposure

Inflammatory triggerIgE mediatedT-cell & other

InflammationEosinophilic mediators(MBP, ECP & others)

EdemaObstructionStasisReduced ventilation

1. Irrigation2. Antifungals

SteroidsImmunotherapy

Surgery

Therapeutic Strategies for Allergic Fungal SinusitisTherapeutic Strategies for Allergic Fungal Sinusitis

Management of AFSManagement of AFS

Clear current episodeClear current episode– SurgerySurgery

Prevent recurrencePrevent recurrence– SteroidsSteroids– Desensitization to fungal antigensDesensitization to fungal antigens– Antifungal therapyAntifungal therapy– Combination of the aboveCombination of the above

SteroidsSteroids

TopicalTopical– Indicated post-operativeIndicated post-operative– Efficacy is not well established But has the advantage Efficacy is not well established But has the advantage

of lower complicationsof lower complications

SystemicSystemic– success of this strategy in the treatment of ABPA.– Few studies indicated efficacy in reducing Few studies indicated efficacy in reducing

recurrences recurrences ((Schubert MS, J Allergy Clin Immunol 1998;102:395–402.

– Use is limited by serious long-term complicationsUse is limited by serious long-term complications

ImmunotherapyImmunotherapy

Few and small studiesFew and small studies

Indicate reduction in recurrences up to Indicate reduction in recurrences up to 50% 50% ((Laryngoscope. 1998 Nov;108:1623)

Problems:Problems:– No adequate dataNo adequate data– Long and tedious process 3-5 years.Long and tedious process 3-5 years.– Disease can worsenDisease can worsen

Antifungal TherapyAntifungal Therapy

Prior to Azoles Prior to Azoles – short courses of Amphotericin B were tried short courses of Amphotericin B were tried

mainly because of the concern of invasive mainly because of the concern of invasive diseasedisease

– no success in reducing recurrencesno success in reducing recurrences

Recent data indicate significant success of Recent data indicate significant success of azoles in ABPAazoles in ABPACombining itraconazole with systemic Combining itraconazole with systemic steroids.steroids.

Steroids + itraconazoleSteroids + itraconazole

Retrospective studyRetrospective study139 patients139 patientsAverage F/U 31.4 monthsAverage F/U 31.4 monthsStrategy:Strategy:– Endoscopic surgeryEndoscopic surgery– Itraconazole orally, continuousItraconazole orally, continuous– Topical steroidsTopical steroids– Short courses of low-dose systemic steroidsShort courses of low-dose systemic steroids

Outcome: recurrence of disease in 50% BUT the Outcome: recurrence of disease in 50% BUT the need for surgery was 21%)need for surgery was 21%)

Rains BM. Am J Rhinol. 2003 17(1):1-8.

Topical antifungalTopical antifungal

Ampho B tried as a nasal lavage for 4 Ampho B tried as a nasal lavage for 4 weeks reduced nasal polyps by 39% weeks reduced nasal polyps by 39%

J Laryngol Otol. 2002, 116(4):261-3.J Laryngol Otol. 2002, 116(4):261-3.

Prognosis of AFSPrognosis of AFS

Mortality is rare even with extensive Mortality is rare even with extensive disease and extension to surrounding disease and extension to surrounding structures.structures.

Morbidity is high due to recurrent surgeries Morbidity is high due to recurrent surgeries and nasal blockageand nasal blockage

Visual loss is rareVisual loss is rare

Marple. Otolaryngol Head Neck Surg 2002;127:361-6.

Acute Invasive SinusitisAcute Invasive Sinusitis

Acute Invasive SinusitisAcute Invasive Sinusitis

Relatively uncommonRelatively uncommonLife-threateningLife-threateningTypically in diabetics and the Typically in diabetics and the immunocompromisedimmunocompromisedCaused byCaused by– Mucorales of Zygomycetes (Rizopus, mucor).Mucorales of Zygomycetes (Rizopus, mucor).– Aspergillus species.Aspergillus species.– Fusarium.Fusarium.– Scedosporium (Pseudallescheria boydii).Scedosporium (Pseudallescheria boydii).– Phaeohyphomycosis.Phaeohyphomycosis.

MucormycosisMucormycosis

Mucormycosis is unusual fungal infection caused by fungi of the order Mucormycosis is unusual fungal infection caused by fungi of the order Mucorales from the class Zygomycetes of the phylum Zygomycota.Mucorales from the class Zygomycetes of the phylum Zygomycota.

Rizopus spp. are responsible for about 90% of reported cases.Rizopus spp. are responsible for about 90% of reported cases.

Identified predisposing factors include uncontrolled diabetes with Identified predisposing factors include uncontrolled diabetes with ketoacidosis, cancer, immunosuppressive conditions and dialysis ketoacidosis, cancer, immunosuppressive conditions and dialysis patients on deferoxamine therapypatients on deferoxamine therapy

It affects primarily the sinuses with local destruction extending to the It affects primarily the sinuses with local destruction extending to the orbit and the brain. The lung is the second most common organ.orbit and the brain. The lung is the second most common organ.

The overall mortality rate is approximately 50% to 70% The overall mortality rate is approximately 50% to 70%

Absidia Spp.

Rizomucor Spp.

Rizopus Spp.

Cunninghamella Spp.

Mucormycosis (Zygomycosis) at King Faisal Mucormycosis (Zygomycosis) at King Faisal Specialist Hospital and Research CentreSpecialist Hospital and Research Centre

A retrospective chart review was conducted from A retrospective chart review was conducted from 1985 to 2001. 1985 to 2001. Source for cases identification was medical Source for cases identification was medical RecordsRecordsCases were reviewed for Cases were reviewed for – demographic datademographic data– risk factorsrisk factors– clinical featuresclinical features– relevant laboratory and radiological studies relevant laboratory and radiological studies – fungal cultures and histopathologyfungal cultures and histopathology– Management, complications and outcomeManagement, complications and outcome

Case DefinitionCase Definition

The diagnosis of mucormycosis was defined as:The diagnosis of mucormycosis was defined as:– DefiniteDefinite: if the histopathology was positive for fungal : if the histopathology was positive for fungal

hyphae typical of mucorales and positive culture hyphae typical of mucorales and positive culture – ProbableProbable: if histopathology positive for fungal hyphae : if histopathology positive for fungal hyphae

typical of mucorales or positive culture and typical of mucorales or positive culture and compatible clinical and radiological featurescompatible clinical and radiological features

– PossiblePossible: if sampling was not done or was negative : if sampling was not done or was negative on hisopathology and culture but has compatible on hisopathology and culture but has compatible clinical and radiological featuresclinical and radiological features

ResultsResults

22 cases

4 Wrong diagnosis

18 Cases

0

1

2

3

4

5

6

Ca

se

s

1985-1990 1991-1996 1997-2002

Distribution of Mucormycosis Cases over the YearsDistribution of Mucormycosis Cases over the Years

ResultsResults

# Cases (%)# Cases (%)

MaleMale 13 (72.2)13 (72.2)

FemaleFemale 5 (27.8)5 (27.8)

Age (median)Age (median) 45 (range 4-83)45 (range 4-83)

ClinicalClinical# Cases (%)# Cases (%)

Fever Fever 1111

Facial pain Facial pain 77

Proptosis Proptosis 66

Double vision Double vision 44

Headache Headache 44

Blindness Blindness 55

Palate necrosis Palate necrosis 44

Nasal Blockade Nasal Blockade 33

Diagnosis of MucormycosisDiagnosis of Mucormycosis

0

10

20

30

40

50

60

% C

as

es

Definite Probable Possible

Underlying Conditions in Patients with MucormycosisUnderlying Conditions in Patients with Mucormycosis

0

1

2

3

4

5

6

7

8

9C

as

es

Diabetes HematologyCancer

Chemotherapy CRF Steroids Transplant

Fungal Culture in Patients with MucormycosisFungal Culture in Patients with Mucormycosis

All were Rizopus Spp.

0

1

2

3

4

5

6

7

8

9

10

negative Not done Positive

Ca

se

s

# cases# cases %%

Localized lesion to sinusLocalized lesion to sinus 22 18.218.2

Involvements of sinus +orbit Involvements of sinus +orbit 11 9.19.1

Involvements of sinus +orbit + palateInvolvements of sinus +orbit + palate 11 9.1 9.1

Involvements of sinus +orbit + palate + brainInvolvements of sinus +orbit + palate + brain 77 63.663.6

Extent of Sinus DiseaseExtent of Sinus Disease

Site of Infection Related to Underlying ConditionSite of Infection Related to Underlying Condition

Outcome of Patients with MucormycosisOutcome of Patients with Mucormycosis

Outcome Related to Underlying ConditionOutcome Related to Underlying Condition

5

13

Mortality Related to Type of ManagementMortality Related to Type of Management

P <0.01

0

10

20

30

40

50

60

70

80

% C

as

es

Medical Med+Surgical

Conclusion of the studyConclusion of the study

Mucormycosis is a relatively uncommon but Mucormycosis is a relatively uncommon but aggressive fungal infection associated with high aggressive fungal infection associated with high mortality. mortality. Sinus was the most common site especially in Sinus was the most common site especially in diabeticsdiabeticsAll the culture-positive cases were due to All the culture-positive cases were due to Rizopus Spp.Rizopus Spp.Combined medical and surgical therapy Combined medical and surgical therapy provided the best outcome.provided the best outcome.

Management of Acute Invasive Fungal Management of Acute Invasive Fungal SinusitisSinusitis

Life-threatening condition with the time Life-threatening condition with the time factor as the main determinant of successfactor as the main determinant of success

Emergency surgery with radical Emergency surgery with radical debridement.debridement.

Adjunctive aggressive antifungal therapyAdjunctive aggressive antifungal therapy– Amphotericin B is the only drug for Amphotericin B is the only drug for

mucormycosismucormycosis

Modify risk factorsModify risk factors

Chronic Invasive Fungal Chronic Invasive Fungal SinusitisSinusitis

Chronic Invasive Fungal SinusitisChronic Invasive Fungal Sinusitis

Poorly described entityPoorly described entityIndolent course with soft-tissue invasion.Indolent course with soft-tissue invasion.Classified into two histological entities Classified into two histological entities (DeShazo. Arch Otolaryngo (DeShazo. Arch Otolaryngo Head Nech Surg 1997; 123:1181)Head Nech Surg 1997; 123:1181)

– Chronic invasiveChronic invasiveInvasion of vesselsInvasion of vesselsImmunocompromised and diabeticsImmunocompromised and diabeticsCaused mainly by Aspergillus fumigatusCaused mainly by Aspergillus fumigatus

– Chronic granulomatous invasiveChronic granulomatous invasiveImmune competent individualsImmune competent individualsNon-caseating granulomatous inflammation, no vessel invasionNon-caseating granulomatous inflammation, no vessel invasionReported mainly in Sudan, India and PakistanReported mainly in Sudan, India and PakistanCaused by Aspergillus flavus and dematiaceous fungiCaused by Aspergillus flavus and dematiaceous fungi

CHRONIC INVASIVE ASPERGILLOSIS OF THE PARANASAL SINUSES INIMMUNOCOMPETENT HOSTS FROM SAUDI ARABIA

Patient selection. – Cases (N 23) involving positive isolates of

Aspergillus from paranasal sinus material between1991 and 1997

– grew Aspergillus and had histopathology showing fungi breaching mucosal barriers and causing tissue necrosis.

Alrajhi et al: A J Trop Med Hyg 65:83. 2001

Alrajhi et al: A J Trop Med Hyg 65:83. 2001

Alrajhi et al: A J Trop Med Hyg 65:83. 2001

Alrajhi et al: A J Trop Med Hyg 65:83. 2001

Granulomata were found in 6 of 23 Granulomata were found in 6 of 23 patientspatients

Fungal organisms:Fungal organisms:– A. flavusA. flavus 15 (65%)15 (65%)– A. fumigatusA. fumigatus 2 (9%)2 (9%)– Aspergillus spp.Aspergillus spp. 6 (26%)6 (26%)

Two cases of visual lossTwo cases of visual loss

No mortalityNo mortality

CHRONIC INVASIVE ASPERGILLOSIS OF THE PARANASAL SINUSES INIMMUNOCOMPETENT HOSTS FROM SAUDI ARABIA

Alrajhi et al: A J Trop Med Hyg 65:83. 2001

Management of Chronic Invasive Management of Chronic Invasive SinusitisSinusitis

SurgerySurgery

Prolonged antifungal therapyProlonged antifungal therapy

ConclusionConclusion

Fungal sinusitis is a relatively Fungal sinusitis is a relatively commoncommon problem problemUnderstandingUnderstanding the nature of the disease the nature of the disease determine the approach to therapydetermine the approach to therapySurgerySurgery is the mainstay treatment for fungal is the mainstay treatment for fungal sinusitissinusitisThe diagnosis of allergic fungal sinusitis could The diagnosis of allergic fungal sinusitis could mean a mean a life-longlife-long relationship with the patient. relationship with the patient.Antifungal therapy is an Antifungal therapy is an absolute indicationabsolute indication in in acute and chronic invasive fungal sinusitis and a acute and chronic invasive fungal sinusitis and a relative indicationrelative indication in allergic fungal sinusitis in allergic fungal sinusitis