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

2. Patient 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
Cécile Clercx in

3. Nasal endoscopy
severe turbinate tissue destruction, presence of multiple fungal plaques in the left nasal cavity and in the left frontal sinus
Cécile Clercx in

4. Treatment of canine nasal aspergillosis
Product
Route
Dose
Interval (hours)
Duration (weeks)
Efficacy (%)
Reference
Thiabendazole
PO*
10 mg / kg
12h
6 to 8
± 50
Harvey 1984
Ketoconazole
5 mg / kg
6 to 18
Sharp 1989 10
± 60-70
Legendre 1995
Fluconazole
2.5 mg / kg
Sharp 1991
Enilconazole
IN1
1 to 2 times
± 80
Sharp 1993
IN2
5 %, ml
min infusion
1 month interval, 2 to 3 times
100
McCullough 1998 1%
1 hour infusion
1 month interval, 1 to 3 times
up to 80%
Zonderland 2000
Clotrimazole
1%, once, infusion of 1 gm
± 90
Davidson 1997
1%, 60 ml/side
once
Mathews 1998
2% imaverol solution infused during one hour through nonsurgically placed catheters
Cécile Clercx in

5. Nasal 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
Cécile Clercx in

6. Interaction of Aspergillus with the host A unique microbial-host interaction
Acute invasive sinusitis
Allergic sinusitis
Frequency of aspergillosis
Frequency of aspergillosis
Chronic invasive sinusitis
Fungus ball of the sinus
Chronic granulomatous sinusitis
Immune dysfunction
Immune hyperactivity .

7. Acute invasive Aspergillus sinusitis
Hope et al, Med Mycol 2005:43 (Suppl 1):S207

8. biopsy showed hyphal invasion of bone
Myelodysplasia with clinical evidence of sinusitis after chemotherapy –
biopsy showed hyphal invasion of bone
6 months later after initial caspofungin then voriconazole
Pre-treatment

9. Management of acute invasive Aspergillus sinusitis
Requires both biopsy and preferably culture for diagnosis – differential diagnosis = mucormycosis, Scedopsporium/Fusarium infection Requires systemic antifungal therapy to minimise tissue destruction, including spread to face, eye, mouth and brain and cure

10. Antifungal treatment of acute invasive Aspergillus sinusitis
Herbrecht et al, New Engl J Med 2002; 347:408-15

11. Antifungal treatment of acute 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.
Girmenia and the Girmenia group

12. Favourable response (%)
Salvage treatment with caspofungin or micafungin in invasive aspergillosis
Caspofungin
Favourable response (%)
Micafungin
Maertens et al Clin Infect Dis 2004; 39:1563; Denning et al, J Infect 2006; in press

13. Management of acute invasive Aspergillus sinusitis
Requires both biopsy and preferably culture for diagnosis – differential diagnosis = mucormycosis, Scedopsporium/Fusarium infection Requires systemic antifungal therapy to minimise tissue destruction, including spread to face, eye, mouth and brain and cure ? Requires surgical removal – and if so early or late ? Requires granulocytes/other immunotherapy

14. Chronic invasive Aspergillus sinusitis
Hope et al, Med Mycol 2005:43 (Suppl 1):S207

15. Chronic invasive Aspergillus sinusitis
Chronic Aspergillus granulomatous sinusitis = A. flavus
Hope et al, Med Mycol 2005:43 (Suppl 1):S207

16. Diabetic with swelling, nasal obstruction and epistaxis
A. terreus cultured
ANITHA, NIZAMUDDIN,PUSHPA, REMADEVI. SIHAM 2006

17. Aspergillus precipitins
Probably useful for diagnosis and monitoring response to treatment – but limited data
Chakrabarti. Indian J Chest Dis Allied Sci 2000;42:

18. Allergic Aspergillus sinusitis
Clinical features = nasal obstruction, recurrent sinus infections, loss of smell and nasal polyps
Aspergillus precipitins +ve in 85% of original series

19. Surgical handling of specimen very important – mucus versus tissue:
allergic or chronic invasive
All surgical procedures should be performed without a power microdebrider or the use of suction devices until sample collection is complete.
Buzina and the Gras group - /laboratory protocols

20. Surgical handling of specimen very important – mucus versus tissue:
allergic or chronic invasive
All 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.
Buzina and the Gras group - /laboratory protocols

21. Surgical handling of specimen very important – mucus versus tissue:
allergic or chronic invasive
All 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.
Buzina and the Gras group - /laboratory protocols

22. Surgical handling of specimen very important – mucus versus tissue:
allergic or chronic invasive
All 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.
The pathologists should pay special attention to the mucin, focusing on fungal elements and eosinophils.
Buzina and the Gras group - /laboratory protocols

23. Chronic invasive Aspergillus sinusitis
Complications: - orbital apex syndrome - generalised proptosis and blindness - cavernous sinus thrombosis - osteomyelitis of the base of the skull - cerebral aspergillosis

24. Orbital apex syndrome
Clinical features = sudden or subacute loss of vision, with ophthalmoplegia on one eye, typically associated with sphenoid sinusitis

25. Base of skull osteomyelitis
Clinical features = headache, general ill-health, raised inflammatory markers, sometimes associated sinus features
Swift & Denning. J Otol Laryngol 1998;112:92-97.

26. Sphenoid sinusitis leading to local spread to the brain and cerebral aspergillosis
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.

27. Non-allergic Aspergillus sinusitis
Hope et al, Med Mycol 2005:43 (Suppl 1):S207

28. Saprophytic Aspergillus sinusitis

29. Saprophytic maxillary Aspergillus sinusitis
Often follows upper jaw root canal work, with the use of zinc materials, and penetration of the sinus Presents with ‘chronic’ or ‘recurrent’ sinusitis Requires removal of fungal ball, and creation of an antrostomy. Surgical biopsy of the mucosa required to distinguish chronic invasive disease from saprophytic. Antifungal therapy not required

30. Conclusions
The same spectrum of Aspergillus disease in the lung is found in the sinuses Bony erosion is consistent with all forms The pace/rapidity of the disease is a good guide to the severity Histology of mucosa and mucous key to determining disease classification and management Precipitating antibodies useful in diagnosis Treatment depends on the type of disease