Fungal infections of the eye
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Fungal infections of the eye



Fungal infections of the eye

Fungal infections of the eye



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  • Pt of mucorycosis, CT left Mucormycosis of LE, Rt invasive aspergillus eroding Lamina papyracea, Autopsy sphenoid pus which showed

Fungal infections of the eye Fungal infections of the eye Presentation Transcript

  • I See Trees of Green
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  • Prevent trauma Tears : Lysozyme, Lactoferrin, ceruloplasmin,B lysin, Complement & Ig`s Conjunctival follicles & leukocyte defense
  • ANATOMY Rich vascular supply
  • FUNGAL INFECTIONS OF THE EYE Presenter: Dr. Vinaykumar Hallur Moderator: Dr. M.R. Shivaprakash
  •  Periocular Fungal Infections  Mycoses of the Anterior Segment of the Eye  Fungal Endophthalmitis  Laboratory diagnosis  Management  Experimental models
  • KERATOMYCOSIS      First described by Leber (Aspergillus species) in 1879 Major cause of blindness in Asia Incidence low in Britain & North USA 6-53% of all cases of ulcerative keratitis in Asia Can occur alone or coexist with a bacterial infection(14.1%) [Basak et al Indian J Ophthalmol. 2005 Jun;53(2):143]  Earlier phaeoid fungi (Dematiaceous) not considered to be significant but now are important cause of keratomycosis .
  • Rare
  • EPIDEMIOLOGY PREVALENCE North India South India Eastern India Western India North India : Aspergillus40% ,Fusarium 16%, Curvularia 8%, 1994- Chander et al., Aspergillus 35 %, Fusarium 23%, Acremonium 12%, 1993-Chander et al. 82.3% 46.1% 32.0% 38.9% South India : 34.4% fungal keratitis, Fusarium 2007 Bharathi et al, Fusarium 43%, Aspergillus 26%, 30.00% Fungi keratitis in India isDematitiousof 25% 2003 – Bharathi et al Total prevalence of fungal total cases Total prevalence of fungal keratitis in western 8.00% countries IJO Sep 2001
  • PREDISPOSING FACTORS • Trauma vegetable matter metallic foreign body sand/stone • Chronic topical medication • Diabetes Mellitus • Topical or systemic corticosteroids • Extended wear/bandage contact lens • Penetrating keratoplasty • Anterior uveitis • Herpes simplex keratitis
  • ETIOPATHOGENESIS Over 70 genera can cause mycotic keratitis  Fungi of importance in microbial keratitis  Moniliaceae -- Aspergillus (90%) Most common cause in World -- Fusarium(1%)Second most common cause --Paecilomyces. --Penicillium. --Pseudallescheria.  Data in brackets from Dept of ophtahlmology, PGIMER
  • CONTD.. • Dematiaceae. --Curvalaria. (2%) --Alternaria. --Phialophora. --Bipolaris. --Exserohilum. --Cladosporium. -- Colletotrichum • Yeast. --Candida. (2.5%) --Cryptococcus • Dimorphic fungi. --Blastomyces. --Coccidioides. --Histoplasma. --Sporothrix.
  • • PATHOGENESIS -Breach in epithelium -Compromised cornea -Immunocompromised Contact of fungal hyphae with cornea Filamentous Yeast
  • FUNGAL ADHERENCE  Filamentous Fibrinogen receptors on mature conidia of aspergillus and fusarium  Yeast Integrin analogue, Fibronectin receptor, Adhesive mannoprotn, Aspartyl proteinase, Factor 6 , Endo. adhesions.
  • PENETRATION  Filamentous fungi: Parallel growth of hyphae to stroma, f/b release of mycotoxins, proteolytic enzymes, soluble fungal antigen  Yeast: Proliferate parallel & perpendicular to corneal stroma f/b release of protease and lipase
  • HOST RESPONSE FILAMENTOUS inablity of PMN,leucocyte cell for phagocytosis destruction of corneal stroma penetrate descement membrane enterAC accumulate around lens seclusion of pupil fungal glaucoma
  • HOST RESPONSE YEAST inability of PMN cell to ingest pseudohyphae and hyphae furstated phagocytosis by PMN destruction of stroma melting of cornea
  • CLINICAL FEATURES • • • • • Signs >> symptoms Manifest within 24 – 48 hours Patient present within 1st week EARLY BI-MICROSCOPIC FINDING Fine or coarse granular infiltrate within the epithelium and anterior stroma • Minimal stromal infiltrate • Epithelial surface is dry rough textured, dirty gray in color
  • CONT……… • Epithelium may be intact or ulcerated. • Pigmented and delicate ,feathery branching hyphae with surrounding infiltrate • Multifocal suppurative microabsscess or satellite lesion
  • CONTD…. • Advanced lesions o Dense fibrinous material adhering to endothelium and iris o Total stromal infiltrate and necrosis
  • CONTD………….. • • • • • • • Other signs White ring (Wessely`s ring) Conjunctival hyperemia AC reaction Hypopyon endothelial plaque Mild iritis
  • YEAST KERATITIS • Risk Fatcors • Previously compromised cornea • SYSTEMIC DISEASE Sjogren’s syndrome Erythema multiforme IgA deficiency HIV Endocrinopathy
  • CLINICAL FEATURE OF CANDIDA INFECTION • Ulcer is small oval with expanding discrete sharply demarcated ,dense yellow –white stromal suppuration • Feathery margins are not seen
  • FUNGAL ENDOPHTHALMITIS  a suppurative inflammation of inner ocular coats and their adjacent structure  with involvement of anterior chamber and vitreous fluid,  caused by various fungal agents
  • FUNGAL ENDOPHTHALMITIS  Clinically two types  Endogenous due to hematogenous spread  Exogenous due to trauma or post operative
  • EPIDEMIOLOGY  The first description of endogenous fungal endophthalmitis was by Dimmer in 1913  Candida endopthalmitis clinical entity in 1958  In U.S.A. compared to previous decades Endophthalmitis Increase from last few decades.  Incidence is increasing because of modern medical practices  USA 30 % candidemia(Last 3 decdes) develop endopthalmitis, now there is a lower incidence because of prophylacyic antifungals CMR, October 2000, p. 662–685
  • PATHOGENESIS ENDOGENOUS  Multifactorial.  It is likely that sustained fungemia with even saprophytic fungi can lead to endopthalmitis Gupte et al -contaminant IV fluids,11 / 72 IV fluid samples culture positive for fungi  At the time of initial infection with some dimorphic, fungi, such as H. capsulatum & C. immitis, unrecognized fungemia occurs and often leads to endophthalmitis.
  • ENDOGENOUS ENDOPHTHALMITIS  Predisposing factors  Systemic debilitating disease  Malignancy  IVDU  Chemotherapy  Systemic antibiotics  Alcoholism &  Diabetes
  • PATHOGENESIS ENDOGENOUS  More common in immunocompromised ie pts on chemo or IV drug abuse  Marked trophism for eye because peculiar blood supply of the eye.
  • PATHOGENESIS: EXOGENOUS  Occurs in immunocompetent people  Direct introduction of the organisms following  Surgery(Catarct removal with placement of IOL mainly Candida spp)  Trauma(Mainly Fusarium spp. )  I/O spread from Fungal keratitis
  • EPIDEMIOLOGY  RACE – no racial preponderance  SEX – Male preponderance (3:1)  AGE – Young and middle age.
  • MORBIDITY  Prognosis     depends upon virulence of organism extent of involvement timing mode of intervention  Prompt therapy following early diagnosis helps to reduce visual loss  Visual outcome of aspergillus endo. is poor d/t macular involvement.
  • AGENTS Endogenous Endotphthalmitis  Candia albicans  Fusarium species  Aspergillus species  Histoplasma capsulatum  Coccidioides immitis  Blastomyces dermatitidis  Cryptococcus neoformnas
  • C. ALBICANS  M.C.C of endogenous endopthalmitis  Infection usually starts from Choroid and then spreads to retina  Non candida albicans fungemia & endopthalmitis is increasing and is concern because of antimicrobial resistance
  • CANDIDIAL ENDOPTHALMITIS Current Eye Research, 1–11, Early Online, 2010
  • ASPERGILLUS ENDOPTHALMITIS  A. flavus second MCC  Spreads from lungs to eye  This is f/b A. fumigatus, A. niger, A. terreus, A. glaucus , & A. nidulans .
  • CRYPTOCOCCAL ENDOPH.  Cryptococci spores survive in pigeons dropping  From lung, fungus – disseminated haematogenesouly and can affect CNS causing fungal meningitis & endophthalmitis in eye  Choroids is the probably first site of ocular infections
  • AGENTS Exogenous Endophthalmitis Aspergillus spp.  C. albicans,C. glabrata, C. tropicalis, C. parapsilosis  Paecilomyces spp.  Fusarium spp.  Acremonium spp.  Curvularia spp. 
  • PRESUMED OCULAR HISTOPLASMOSIS  Occurs in immunocompetent individuals  Recognized by presence of multiple atrophic chorioretinal scars w/o vitreous or aqueous humor inflmn.  Affect 2,000 new individuals a year in areas of endemicity and in some cases may lead to visual loss and blindness  Arises from hematogenous spread  Not detectable in the scars of POH  Strong epidemiological evidence, principally deriving from skin test surveys, linking the scars to histoplasmosis
  • CLINICAL FEATURES Symptoms Visual loss  Pt. may be asymptomatic if the lesion is in the peripheral retina  Red eye.  Photophobia.  Pain.  Floaters.  Scotoma 
  •  Many have a classical appearance with progressive granulomatous uveitis  diffuse retinitis  deep vitreous abscess.   Time to make diag. from onset of symptoms, 3 d to 4 months.
  • PERIOCULAR INFECTIONS Agent  Palpebral Aspergillosis Blastomycosis involvement No of cases in literature 2 12 As a part of generalized or local disease 3 C. albicans  First reported case  1922 case of sporotrichosis 6 Coccidioidomycosis  3 Cryptococcus spp.  Tinea faciale 11 Dermatophyte  Aspergilloma, sporotrichosis  Chalazion 5 Paracoccidioidomycosis 7 Rhinosporidiosis  Blastomycosis, Coccidioidomycosis  Basal cell carcinoma 5 Sporothrix spp.
  • INFECTIONS OF THE LACRIMAL GLAND  Fungi found to account for only 5% of infections .  14% of cases of congenital dacryocystitis  Principally Aspergillus spp. and C. albicans implicated  Epiphora is only clinical finding  Lid edema, conjunctival injection, and swelling in the medial canthus; pressure over the area usually results in a purulent discharge through the lower punctum Thomas, CMR, Oct 2003,
  • FUNGAL INFECTIONS OF ORBIT Proximity of sinuses to orbit, susceptible host & pathogen  Zygomycosis  Rhinoorbitocerebral : one-third to one-half of all cases, Incidence increasing  Major risk factor : uncontrolled diabetes mellitus(70% DKA)  Other predisposing factors        Chronic alcoholism Renal transplantation Hematological malignancies Steroid therapy Breach of skin Starts with symptoms consistent with sinusitis Bloody nasal discharge  Diplopia and loss of vision Chakrabarti et al., 2006
  • INFECTIONS OF ORBIT  Invasive aspergillosis  Increased frequency infection :widespread prophylaxis with fluconazole [VanBurikJH et al. The effect of prophylactic fluconazole on the clinical Spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis.Medicine(Baltimore) 1998;77:246−54.]  Exact prevalence of invasive aspergillosis in India is not known [Chakrabarti et al , Japanese Journal of Medical Microbiology vol 49, 165-72, 2008]
  • INVASIVE ASPERGILLOSIS  Other fungi mimicking aspergillosis Bipolaris spp.  Alternaria spp.  Curvularia spp.  C. immitis  B. dermatitidis  Histoplasma spp.  Penicillium spp.   C/F orbital inflammation & a red proptotic eye with or without associated pain  ophthalmoplegia may develop  Embolization of vessels of the optic nerve, or direct involvement of the nerve may occur 
  • FUNGAL CONJUNCTIVITIS     Can occur indepently or with keratomycosis Clinically rare entity Fungi may be present without causing inflammation in~ 25% pts Topical application tetracycline X 4 wks increased prevalence 28.7% [Nema, H.V., O.P. Ahuja, A. Bal and L.N. Mohapatra, Effects of topical corticosteroids and antibiotics on mycotic flora of conjunctiva. Am. J. Ophthal., 1968. 65: p. 747–750].  Topical applications of corticosteroids X 3 wks increase prevalence of fungi 18.8-67% [Mitsui, Y. and J. Hanabusa, Corneal infections after cortisone therapy. Br. J.Ophthal., 1955. 39: p. 244–250.]   C. albicans follows steroid LA  Pseudomembrane Other organisms Aspergillus, Blastomycosis, Sporothrix, Coccidiodomycosis
  • EXPERIMENTAL MODELS FK  Albino, wild rabbit , Dutch belted rabbit  Previously immunocompromised   Fractionated cobalt whole-body radiation  administration of antilymphocyte serum   corticosteroids locally or systemically alloxan-induced diabetes Intra lamellar injection or Superficial inoculation of spore suspension
  • CONTD..  IL inoculation :  C. albicans, C. krusei, C. tropicalis, C. pseudotropicalis, Aspergillus spp., Cephalosporium spp., F. solani, Lasiodiplodia sp.  Superficial inoculation:  C. albicans, C. tropicalis, C. pseudotropicalis, Aspergillus spp., Allescheria boydii, Cephalosporium spp., Geotrichum sp.  Antibacterial prophylaxis & use of characterized strain ensures reproducibilty.  IO penetration of ketokonazole in rabbit has been tried as a therapeutic modaliities
  • OTHERS  Mice BALB/c mice  ip cyclophosphamide 180 mg/kg 1,3, & 5d  Scarified corneas /keratoplasty rat cornea in b/w space  topically inoculated  Easy handling   Rat Wistar rats or Lewis rats  Suitable size & immune response  Size of eyes better surgical manipulation   Pigs   Large size, ease of fitting contact lens Owl monkeys  Not better than Rabbit keratomycosis model
  • ENDOPHTHALMITIS MODELS  Rabbits Both immunocompetent and immunocompromised rabbits are used  Used mainly for endogenous endophthalmitis  0.5 ml of 2 X 107 org/ ml into auricular vein  intravitreal inoculation of 1,000 CFU of susceptible C. albicans  Junko et al Jpn. J. infect. Dis., 60, 33-39, 2007  Mice Fusarium solani in immunocompetent mice  Inocula of 5 x 10(6) conidia  injected into the lateral tail vein  Mayayo et al Med Mycol. 1998 Oct;36(5):249-53
  • DIAGNOSIS  History  Physical examination  Detailed examination of the affected  High risk of suspicion
  • LABORATORY DIAGNOSIS  Sample collection and transport       Biopsy Corneal scraping, corneal button AC tap Vitreous tap Fluids Lens  Swabs not encouraged  Sterile leak proof container ASAP  Delay 4°C with exception of blood and vitreous (30-37°C ) & swab (15%)
  • SAMPLES  Detailed examination of affected eye using slit lamp  Tissues diagnostic material harvested by experienced ophthalmologist after LA or SA Biopsy  Scraping :15 Bard – parker surgical blade from the base & margin(thoroughly) of ulcer aseptically or Kimura’s platinum spatula  Impression smear(Jain et al 2006 – PGIMER, Chandigarh – equally sensitive and specific as Scrappings)  Vitreous tap 300 microL using 23 G needle  Aqeous tap 200 microL using 23 G needle 
  • CONVENTIONAL TECHNIQUES  Direct microscopy Rapid and cost effective  10% KOH preparation  Gram & Geimsa stain  Calcoflour Stain – Easy and fast  H&E, GMS, PAS, cytologic preparation   Culture SDA, Blood agar,  CHROM agar   Susceptibility testing  According to CLSI guidelines
  • CONVENTIONAL  Nonspecific fluorescent stain – {calcoflour white, blankophor, uvitex 2B} –  used in tissue sections and  cytopathologic preparation of rapid diagnosis of mycotic infections.  Chander et al. Sensitivity of Calcofluor white – 95.2% compared to 71.4 % for KOH and culture.  fluorescent microscope  wavelength of 365 nm.  Acridine orange staining – useful in early diagnosis of keratomycosis  PAS (Periodic acid schiff) stain can also use.
  • CULTURE  Corneal scraping inoculated on agar plate as a ‘C’ or ‘S’ shaped streak incubated at 25 & 37°C X 4wks  Fungal growth in the form of the streak ensure that the growth is from the inoculum / specimen rather than a laboratory contaminant.  Two sets of SDA with antibiotic, inoculated and incubated at 250 C & 370C separately x 4 wks. Keeping a possibility of dimorphic fungi
  • CULTURE  Vitreous fluid inoculated on routine fungal culture media .  Vitreous sample should be concentrate either by   centrifugation Millipore filtration
  • CULTURE  All the culture checked everyday during first week and  twice a week during next 3 week weeks.   Positive culture are more convincing  when growth is obtained on more than one occasion.
  • CONVENTIONAL TECHNIQUES  Serological techniques  Diagnosis of Histoplasmosis, Blastomycosis
  • MOLECULAR TECHNIQUES  PCR based detection methods  PCR Rapid molecular identification of fungal pathogens in corneal samples from suspected keratomycosis cases. J Med Microbiol. 2006 Nov;55(Pt 11):1505-9.  PCR - SSCP Sensitive and rapid polymerase chain reaction based diagnosis of mycotic keratitis through single stranded conformation polymorphism. Am J Ophthalmol. 2005 Nov;140(5):851-857.  Nested PCR Comparative study of Gram stain, potassium hydroxide smear, culture and nested PCR in the diagnosis of fungal keratitis. Ophthalmic Res. 2010;44(4):251-6.
  • MOLECULAR TECHNIQUES  PCR-RFLP Diagnosis of Aspergillus fumigatus endophthalmitis from formalin fixed paraffinembedded tissue by polymerase chain reaction-based restriction fragment length polymorphism Indian J Ophthalmol. 2008 Jan-Feb;56(1):65-6.  Real time quantitative PCR Detection and quantification of pathogenic bacteria and fungi using real-time polymerase chain reaction by cycling probe in patients with corneal ulcer. Arch Ophthalmol. 2010 May;128(5):535-40.
  • PRINCIPLES OF TREATMENT  As with any other fungal infection , look & treat for any predisposing illness  Confirm lab diagnosis  Look for and treat any superadded infection  Remember  Poor penetration of antifungal drugs  Corticosteroids are contraindicated  Use both surgical and medical approach whenever needed  Close follow up is required
  • FUNGAL KERATITIS  Superficial (early keratitis): Topical natamycin (5%) (hyphae)  Topical 0.15% amphotericin B or topical fluconazole (yeasts)  Debridment of the epithelium   Deeper and larger lesions: Subconjunctival or intravenous miconazole  Ketoconazole, itraconazole, fluconazole or voriconazole (p.o.)  Intracameral amphotericin B   Surgical treatment: Cyanoacrylate tissue adhesive  Amniotic membrane transplantation  Penetrating keratoplasty 
  • ENDOGENOUS ENDOPHTHALMITIS  Systemic antifungal agents: Fluconazole, voriconazole (azole compounds)  Systemic antifungal agents: Amphotericin B: Parenteral ± intravitreal  Pars plana vitrectomy
  • EXOGENOUS ENDOPHTHALMITIS    Intraocular (intracameral ± intravitreal) amphotericin B Intravitreal voriconazole or miconazole Subconjunctival antifungal agents: when associated with keratitis  Systemic antifungal agents: fluconazole, ketoconazole, voriconazole, itraconazole, m iconazole, and amphotericin B: important in immunocompromised patients  Pars plana vitrectomy
  • MUCORMYCOSIS  Radical surgery+ antifungal therapy + correcting underlying conditions  Amphotericin B Ist DOC(Amphotericin B given IV at a daily dose of 1.0-1.5 mg/kg infused during 2-4 hr for a total of 1-4 g)  Lipid formulations of amphotericin B alternative Ferri: Practical Guide to the Care of the Medical Patient, 8th ed
  • INVASIVE ASPERGILLOSIS  Voriconazole 6 mg/kg IV q12h for 2 doses, then 4 mg/kg q12h PO Rx for adults is 200 mg bid or 4 mg/kg bid.  Caspofungin in pts who fail to respond to or are unable to tolerate other antifungal drugs. The recommended dosage is 70 mg on the first day and 50 mg qd thereafter given as a single dose IV over 1 hr. Ferri: Practical Guide to the Care of the Medical Patient, 8th ed
  • Even though we cannot live forever, let our eyes live and give sight for the needy! I have pledged my eyes, you can do that too..