1. A Case of Mistaken identity.. MariyamMirfenderesky Registrar Infectious Diseases / Microbiology Tihana Bicanic Consultant Infectious Diseases

2. History • SK 24 yo Sikh female from the Punjab • Arrived in UK October 2010 to study English • Referred to Chest Clinic at a London DGH after an abnormal immigration CXR

4. DGH Chest Clinic October 2010 Hx • Asymptomatic: No SOB, weight loss, fevers, cough • PMH/DH-nil Ix • Mantoux 0 mm (BCG) • HIV negative • Bloods: Normal U&Es, LFTs, Bone profile, • HB 12.2 WCC 6.3 Plt 179 • CRP <4, ESR 95 • CT CAP

5. Mediastinoscopy 12/11/2010 :Right paratracheal lymph node biopsy dPAS x100 • Histology: • Granulomatous lymphadenitis • Microbiology: • AFB smear and culture negative

6. Clinical progress • November 2010 • Watch and wait as asymptomatic • January 2011 • Remained asymptomatic • No interval change in CXR • May 2011 • Non-productive cough 3/12 • Watery right eye 1/12 • 3x sputa smear and culture negative for AFB

7. Bronchoscopy 09/06/2011 • Paratracheal LN, narrowing R main bronchus Biopsy: • Microbiology: Gram NOS, culture negative, AFB smear/ culture negative • Histology: Focal non-necrotising granulomas. ZN negative. • June • Trial of prednisolone 30mg

8. DGH Chest Clinic 01/09/2011 • Progressive non-productive cough • Headaches 2/12 • 5/12 watering R eye • Some difficulty walking O/E • R proptosis • Mild L sided weakness (4+/5) • Emergency admission 1/9/11 • Urgent MRI head / spine

13. Treated empirically for MTB with quadruple therapy and dexamethasone 4 mg qds Transferred to SGH 2/09/2011

14. At SGH • Asked for review of all histology

15. Immunology Ix Fungal Ix Cryptococcal antigen –ve Histoplasma CFT and precipitin –ve Galactomannan –ve (0.08) RAST aspergilllus –ve • IgG 28.6 g/L (6 to 16) • IgA 2.4 g/L ( 0.8 to 2.8) • IgM 1.7 g/L (0.5 to 1.9) • IgE 3730 kU/L (0 to 81) • ANA -ve • RF < 20 iu/ml (0 to 20) • ANCA -ve • B-2 microglobulin 1.9 mg/L • HIV negative

16. Clinical progress • Rapid clinical decline from 2/09/11 to 9/09/11 • Progressive pyramidal weakness • From +4/5 left to 0/5 arm and leg distally • Headache, N&V • Repeat MRI 9/09/11: progression in size of lower medullary lesion with no improvement in size of cerebral lesions

17. 6/9/11 pm phone call.... • …from Consultant histopathologist On review of paratracheal LN biopsy from October 2010 • POSSIBLE FUNGAL ELEMENTS seen

18. Further cuts of LN biopsy Oct 2010 dPAS X100 Grocott x100

19. What we did • Ambisome • Cover • Aspergillus species • Zygomycetes (mucormycosis) • Fusarium • Histoplasma

20. Orbital biopsy 08/09/2011 dPAS x 600 Grocott x 600

21. Orbital biopsy: Culture positive D4 Mycology ref lab Bristol Morphologically confirmed as Aspergillusflavus

22. What we did(Admitted 02/09/2011) MICs • Ambisome 2 R • Voriconazole0.125 S • Caspofungin 0.5 S • Itraconazole <0.03 S • Stopped MTB Tx 7/9/11 • Ambisome 6-22/9/11 • Voriconazole 9/9/11 • Treated with 4/52 combination therapy; echinocandin and azole • Remains on voriconazole for 12 months?

23. Currently • Doing extremely wellDischarged early October 2011 • Complete resolution of hemiparesis and proptosis • Re-imaged at 4 weeks; marked improvement

24. Before After 4/52 tx

25. Before After 4/52 tx

26. Aspergillusflavus • A.flavus is an emerging pathogen in developing countries • Mainly associated with invasive sino–orbital, cerebral and ophthalmic infections without traditional risk factors • Granulomatous reactions are seen in the immunocompetent host • Hyphae are typically scanty

27. Learning points • Granulomas = MTB • Do think about sarcoid, fungal infections and lymphoma • Involve pathologists early: ask for review! • Voriconazole is the drug of choice -excellent CSF penetration and bioavailability but do require drug monitoring to ensure adequate levels

28. Thank you!

29. Voriconazole history • 09/09/11 250mg IV bd (4mg /kg)(level 0.76 mg /L, 13/09) • 14/09/11 300mg IV bd (level 2.12 mg /L ,19/09) • 19/09/11 300mg bd po (level 3.23 mg /L, 26/09) • 02/10/11 Stopped due to↑ LFTs &↓platelets • 04/11/11 200mg bd po (level 1.42 mg/L, 7/10)