Aspergillus sinusitis David W. Denning Wythenshawe Hospital University of Manchester.

Aspergillus sinusitis

David W. DenningWythenshawe Hospital

University of Manchester

Cécile Clercx in www.aspergillus.man.ac.uk

Patient 1Patient 1

Presenting features: 3 month history of sneezing and reverse sneezing, left nasal sanguinopurulent discharge,

2 episodes of epistaxis, ulceration of the external left nare,

hyperkeratosis of the planum nasale


Nasal endoscopyNasal endoscopy

severe turbinate tissue destruction, presence of multiple fungal plaques in the left nasal cavity and in the left frontal sinus


Treatment of canine nasal Treatment of canine nasal aspergillosisaspergillosis

ProductRoute

DoseInterval(hours)

Duration(weeks)

Efficacy(%)

Reference

Thiabendazole

PO* 10 mg / kg 12h 6 to 8 ± 50 Harvey 1984

Ketoconazole PO* 5 mg / kg 12h 6 to 18 ± 50 Sharp 1989Ketoconazole PO* 5 mg / kg 12h 10 ± 60-70 Legendre 1995Fluconazole PO* 2.5 mg / kg 12h 10 ± 60-70 Sharp 1991Enilconazole IN1 10 mg / kg 12h 1 to 2 times ± 80 Sharp 1993

Enilconazole IN2 5 %, 50 - 200 ml

30 - 45 min infusion

1 month interval, 2 to 3 times

100 McCullough 1998

Enilconazole IN2 1% 1 hour infusion1 month interval, 1 to 3 times

up to 80%

Zonderland 2000

Clotrimazole IN1

1%, once, infusion of 1 gm

± 90 Davidson 1997

Clotrimazole IN1 1%, 60 ml/side

1 hour infusion once 80 - 90 Mathews 1998

Clotrimazole IN2 1%, 60 ml/side

1 hour infusion once 80 - 90 Mathews 1998

2% imaverol solution infused during one hour through nonsurgically placed

catheters


Nasal endoscopyNasal endoscopy

severe turbinate tissue destruction, presence of multiple fungal plaques in the left nasal cavity and in the left frontal sinus

After treatment:absence of fungal plaques, cystic appearance of the left nasal and frontal sinus mucosa

Interaction of Aspergillus with the host

A unique microbial-host interaction

Immune dysfunction

Frequency

of a

sperg

illosis

Immune hyperactivity

Frequency

of

asp

erg

illosi

s

Acute invasive sinusitis

Fungus ball of the sinusChronic granulomatous sinusitis

Allergic sinusitis

. www.aspergillus.man.ac.uk

Chronic invasive sinusitis

Hope et al, Med Mycol 2005:43 (Suppl 1):S207

Acute invasive Aspergillus sinusitis

www.aspergillus.man.ac.uk

Myelodysplasia with clinical evidence of sinusitis after

chemotherapy – biopsy showed hyphal invasion of

bone

Pre-treatment 6 months later after initial caspofungin then voriconazole

Management of acute invasive Management of acute invasive Aspergillus sinusitis

Requires both biopsy and preferably culture for Requires both biopsy and preferably culture for diagnosis – differential diagnosis = diagnosis – differential diagnosis =

mucormycosis, mucormycosis, ScedopsporiumScedopsporium//FusariumFusarium infectioninfection

Requires systemic antifungal therapy to Requires systemic antifungal therapy to minimise minimise tissue destruction, including spread tissue destruction, including spread to face, to face, eye, mouth and brain and cureeye, mouth and brain and cure

Herbrecht et al, New Engl J Med 2002; 347:408-15

Antifungal treatment of acute Antifungal treatment of acute invasive invasive Aspergillus sinusitis

Girmenia and the Girmenia group

Antifungal treatment of acute Antifungal treatment of acute invasive invasive Aspergillus sinusitis

First line treatment with voriconazole (n=13)

better responses at day 7 of therapy (62% vs 24%), higher CR + PR, better 3-month survival rate (69% versus 38%) fewer severe side effects

compared to

historical group Rx with amphotericin B or itraconazole (n=21),

with or without combined radical surgery.

Salvage treatment with caspofungin or micafungin in invasive aspergillosis

Maertens et al Clin Infect Dis 2004; 39:1563; Denning et al, J Infect 2006; in press

Favourable response (%) Micafungin

Caspofungin

Management of acute invasive Management of acute invasive Aspergillus sinusitis

Requires both biopsy and preferably culture for Requires both biopsy and preferably culture for diagnosis – differential diagnosis = diagnosis – differential diagnosis =

mucormycosis, mucormycosis, ScedopsporiumScedopsporium//FusariumFusarium infectioninfection

Requires systemic antifungal therapy to Requires systemic antifungal therapy to minimise minimise tissue destruction, including spread tissue destruction, including spread to face, to face, eye, mouth and brain and cureeye, mouth and brain and cure

? Requires surgical removal – and if so early or ? Requires surgical removal – and if so early or latelate

? Requires granulocytes/other immunotherapy ? Requires granulocytes/other immunotherapy


Chronic invasive Aspergillus sinusitis


Chronic invasiveChronic invasive Aspergillus sinusitis

Chronic Aspergillus granulomatous Chronic Aspergillus granulomatous sinusitis = A. flavus

ANITHA, NIZAMUDDIN,PUSHPA, REMADEVI. SIHAM 2006

Diabetic with swelling, nasal obstruction and epistaxis

A. terreus cultured

Aspergillus precipitins

Chakrabarti. Indian J Chest Dis Allied Sci 2000;42:293-304

Probably useful for diagnosis and

monitoring response to

treatment – but limited data


Allergic Aspergillus sinusitisAllergic Aspergillus sinusitis

Clinical features = nasal obstruction, recurrent sinus infections, loss of smell and nasal polyps

Aspergillus precipitins +ve in 85% of original series

Buzina and the Gras group - www.aspergillus.man.ac.uk /laboratory protocols

Surgical handling of specimen Surgical handling of specimen very very importantimportant – mucus versus tissue: – mucus versus tissue:

allergic or chronic invasiveallergic or chronic invasiveAll surgical procedures should be performed without a power microdebrider or the use of suction devices until sample collection is complete.




Mucus should be manually removed, together with inflamed tissue, and placed on a saline-moistened sheet of sterile used x-ray film (approx. 10 x 10 cm) to prevent absorption of the mucus. It should not be placed on a surgical towel or gauze.





Each specimen is then fixed in 10% formalin and embedded in paraffin. Multiple serial sections of different specimens from each patient should be stained with H & E and with GMS.





Each specimen is then fixed in 10% formalin and embedded in paraffin. Multiple serial sections of different specimens from each patient should be stained with H & E and with GMS.

The pathologists should pay special attention to the mucin, focusing on fungal elements and eosinophils.

Chronic invasive Aspergillus sinusitis

Complications:- orbital apex syndrome- generalised proptosis and blindness- cavernous sinus thrombosis- osteomyelitis of the base of the

skull- cerebral aspergillosis


Orbital apex syndromeOrbital apex syndrome

Clinical features = sudden or subacute loss of vision, with ophthalmoplegia on one eye, typically associated with sphenoid sinusitis

Swift & Denning. J Otol Laryngol 1998;112:92-97.

Base of skull osteomyelitisBase of skull osteomyelitis

Clinical features = headache, general ill-health, raised inflammatory markers, sometimes associated sinus features


Sphenoid sinusitis leading to local Sphenoid sinusitis leading to local spread to the brain and cerebral spread to the brain and cerebral

aspergillosisaspergillosis

Sphenoid sinusitis causes a band-like headache over the vertex of the skull, and major deterioration in headache. Nasal symptoms often absent, but loss of smell common.


Non-allergic Aspergillus sinusitis


Saprophytic Aspergillus sinusitisSaprophytic Aspergillus sinusitis

Saprophytic maxillary Aspergillus sinusitis

Often follows upper jaw root canal work, with the Often follows upper jaw root canal work, with the use of zinc materials, and penetration of the use of zinc materials, and penetration of the sinussinus

Presents with ‘chronic’ or ‘recurrent’ sinusitisPresents with ‘chronic’ or ‘recurrent’ sinusitis

Requires removal of fungal ball, and creation of Requires removal of fungal ball, and creation of an antrostomy. Surgical biopsy of the mucosa an antrostomy. Surgical biopsy of the mucosa required to distinguish chronic invasive disease required to distinguish chronic invasive disease from saprophytic. Antifungal therapy not from saprophytic. Antifungal therapy not requiredrequired

ConclusionsThe same spectrum of Aspergillus disease in the The same spectrum of Aspergillus disease in the lung is found in the sinuseslung is found in the sinuses

Bony erosion is consistent with all formsBony erosion is consistent with all forms

The pace/rapidity of the disease is a good guide The pace/rapidity of the disease is a good guide to the severityto the severity

Histology of mucosa and mucous key to Histology of mucosa and mucous key to determining disease classification and determining disease classification and managementmanagement

Precipitating antibodies useful in diagnosisPrecipitating antibodies useful in diagnosis

Treatment depends on the type of diseaseTreatment depends on the type of disease

Aspergillus sinusitis David W. Denning Wythenshawe Hospital University of Manchester.

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