1. Aspergillosis 2007.2.8 case of the week reivew Prof. 이미숙 /R3 양병혁

2. Mycology Ubiquitous environmental, opportunistic molds Hypae : septate, acute angle-dichotomous branching Aspergillosis genus comprises 180 species, of which 33 have been associated with human disease A. fumigatus (56%) A. flavus(18.7%) A. terreus(16%) : poor prognosis A. niger(8%) A. versicolor(1.3%) A. nidulans Infect Dis Clin N Am20(2006)

3. Pathogenesis Conidia formed by asexual production 2~10μm in diameter hydrophobic Aerosolization Inhalation Uncontrolled germination in hyphae β – glucans interact with Toll-like receptors and Dectin on macrphage Proinflammatory cytokines Neutrophil response Lymphocytic infiltrate Infect Dis Clin N Am20(2006)

4. Clinical syndromes Allergy : CD4 Th-2 response Asthma : Aspergillus spp as a cause of severe asthma Allergic sinusitis Allergic bronchopulmonary aspergillosis Local saprophytic disease Mycelial ball w/o allergy or invasion Lung and sinuses Semi-invasive disease Mycelial ball, progressive fibrosis & minimal fungal invasion Three disease entities Chronic cavitary pulmonary aspergillosis(CCPA) Chronic fibrosing pulmonary aspergillosis(CFPA) Progressive enlargement of a single cavity Diabetes, corticosteroid use Infect Dis Clin N Am20(2006)

5. Clinical Infectious Diseases 2006; 43

7. Directs techniques Wet mounts, potassium hydroxide preparations, and use of routine stains Fluorescent techniques Calcofluor white, Uvitex 2B, Blankophor Binding to beta-glycosidically linked polysaccharides Not specific for Aspergillosis, but high sensitivity Fungal stain GMS PAS Lancet Infect Dis 2005;5

8. Other diagnostic tests Culture Antifungal drug-resistant non fumigatus Aspergillosis Other molds causing invasive disease Histologic examination Imaging Anti-Aspergillosis Ab Galactomannan(GM) assay GM : polysaccharide component cell wall Double-sandwich ELISA(EIA) Sensitivity : 65 % Specificity : 87.5 % Beta-glucan assay Sensitivity : 62 % Specificity : 94 % PCR Lancet Infect Dis 2005;5

10. Treatment

12. Clinical Infectious Diseases 2006; 43

13. Voriconazole 2 new azole agents in 1900s Fluconazole Limited spectrum of antifungal activity Resistance Itraconazole – absorption problem 2 nd generation azole – voriconazole Synthetic derivative of fluconazole Replacement of one of the triazole rings with a fluorinated pyrimidine and the addition of an α-methyl group Clinical Infectious Diseases 2006; 43

15. Side effects of voriconazole Side effects Reversible disturbance of vision(photopsia) :~30% altered color discrimination, blurred vision, the appearance of bright spots, wavy lines, photophobia. During the first week of therapy Self limited in spite of continued therapy Skin rashes, Steven-Johnson syndrome, TEN, photosensitivity Hepatitis Ass. with increased voriconazole level LFT performed prior to therapy, within the first 2 weeks after the initiation of therapy, and then every 2–4 weeks throughout therapy. Clinical Infectious Diseases 2006; 43

17. Caspofungin Echinocandin antifungals were identified in 1974 and named the pneumocandins, owing to their activity against Pneumocystis. Semisynthetic derivative of pneumocandin B derived from Glarea lozoyensis Inhibitors of the UDP-glucose (1,3)- D -glucan- (3)- D -glucosyltransferase, commonly referred to as - (1,3)-glucan synthase Pharmacology 2006;78

18. Clinical Infectious Diseases 2006; 43

19. Side effects of caspofungin Hepatic effects Elevations in ASAT, ALAT and AP < 5 times UNL m/c laboratory abnormality Renal effects and effects on creatinine levels Increase of serum creatinine in 1.2–3.7% Hematologic effects Decreases in hemoglobin concentrations and hematocrit Pharmacology 2006;78

20. voriconazole 제제 ( 품명 : 브이펜드주사, 브이펜드정 ) 아래와 같은 기준으로 투여시 요양급여를 인정하며, 허가사항 범위이 지만 동 인정기준 이외에 투여한 경우에는 약값의 100 분의 100 을 본 인부담토록 함 ( 보건복지부 고시 제 2004-61 호 ) - 아 래 - - 주사제의 경우 : 기존 항진균제 (conventional amphotericin B) 로 치료 에 실패하였거나, 투여가 불가능한 경우 요양급여를 인정 - 정제의 경우 : 주사용 항진균제 사용 후 동 경구제로 전환할 필요성이 있을 때 인정 caspofungin acetate 주사제 ( 품명 : 칸시다스주 ) 기존 유사 항진균제 치료에 실패하였거나 투여가 불가능한 경우 요양급 여를 인정하며, 허가사항 범위이지만 동 인정기준 이외에 투여한 경우에 는 약값의 100 분의 100 을 본인부담토록 함.( 보건복지부 고시 제 2004- 38 호 )

21. Infect Dis Clin N Am20(2006)

22. Invasive Sinus Aspergillosis in Apparently Immunocompetent Hosts C. J. Clancy and M. H. Nguyen Joun~aI of Infection (1998) 37, 229-240

23. Demographics and underlying disease Median age : 44 (range : 21~81) Female : 62% No underlying medical condition Corticosteroid Immunosuppression 34 % prior history of sinus surgery 14 % nasal polyps

24. Clinical manifestations The median time from the onset of symptoms to the initiation of a diagnostic evaluation was 6 months (range:1 month to 10 years). Presenting symptoms Headache (62%) Proptosis (52%) Nasal obstruction(45%) Decreased visual acuity(31%) Retro-orbital pain(24%) Epitaxis(24%) Diplopia(21%) Sinus or facial tenderness(14%) Nausea, ophthalmoplegia, rhinorrhea, post-nasal drip, decreased level of consciousness

25. Sites of infection Multiple sinuses in 83 %, single sinus in 11 % Ethmoid(83%), Sphenoid(79%) Maxillary(48%) Frontal(10%) In 10% of cases, infection extended only into the sinus walls or nasal cavity. In 31% of cases, infection extended locally into the orbit, cribiform plate, anterior skull base, or sella turcica/ pituitary. In the remaining 59%, extension into the dura or meninges, brain, cavernous sinus, or blood vessels of the head occurred.

26. Complications Sites of complications : 83% Cranial nerves I~IV(41%) Eye(41%) Dura(34%) Vascular invasion(24%) Internal jugular vein Basilar artery Internal carotid artery Middle cerebral artery Cerebral abscess(17%)

27. Risk factors for mortality Extent of infection Sinonasal or cranial extension Intracranial extension Histopathological pattern of disease Invasive form : central nervous system, vascular structure Granulomatous form Onset of symptoms > 6 months after onset of symptoms

28. Conclusions Invasive sinus aspergillosis carries high morbidity and mortality, even in immunocompetent hosts. To improve outcome, the diagnosis must be recognized early, before the organism can invade the central nervous system or vascular structures. Aggressive surgical resection of the infected areas is of utmost importance in the management of this infection.