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감염성 각막염의 진단, 치료 및 경과 가톨릭 대학교 의과대학 안과 교실 김만수 1
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學 習 目 標 여러 가지 균주에 의한 감염성 각막염의 급성기, 만성기, 회복기, 치료 종료 등 전 과정을 살펴보고 각 과정에서의 주요 병인 및 처치법을 익힌다. 1. Course 2. Risk factors 3. Clinical characteristics 4. Polymicrobial Infection 5. Special treatment : steroid, intrastromal, AC injection
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Stage of Infectious Disease (Keratitis)
Incubation Penetration Reparative stage (Fibrogenesis and Angiogenesis) Acute stage Chronic stage Rehabilitation ; Scar, CL, PPKP
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Collagen formation Thinning and Perforation collagenolysis Synthetic phase : closure of the wound through synthesis of new collagens and proteoglycans by stromal fibroblasts, aided by epithelial cells Herpes ; replication이 빠름 진균 ; 잘 안죽어서 Increase local immunity ; flap. Acute inflammation (Necrosis and collagenolysis) Collagen formation collagenolysis Reparative stage (Fibrogenesis and Angiogenesis)
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Ulcer 후 stroma healing 과정?
Damaged collagen ; - rearranagement - new formed Keratocyte ; myofibroblast Mucopolysaccharides Proteoglycans ; - core protein + glycosaminoglycan chains Cytokines /New vessels - TGF B - TNF a Macrphage
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Initial visit (2007 12 12) Vos : HM
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Infection “Ideal” Mono pathogen Polymicrobial Infection
Bacteria : Gram(+)/Gram (-) Atypical Mycobacterial Infection Virus Fungus Acanthoamoeba Polymicrobial Infection From Contamination From Co-infection From Superinfection
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Monomicrobial Infection
bacteria fungus Inflammation Acanthoamoeba Time Polymicrobial infection Biphasic Pseudo-recurrence ∙ Secretion ∙ Pain ∙ Inflammation ∙ Shape of the infiltration Monophasic/biphasic Transient improvement Monophasic Constant worsening
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Infectious keratitis G (+) (-) Atypical Myco -bacterium HSV VZV
bacteria G (+) (-) Atypical Myco -bacterium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporosis “Ideal” Mono pathogen” infection ∙ Typical clinical presentation / clinical content ∙ Positive result of corneal scrapping ∙ Favorable clinical answer to therapy 1.Well- circumscribed 2.Not grossly exudative 3.Not rapidly ulcerate 4.hypopyon 1.Less well 2.Rapidly progression 3.More 4.Greater ulcerative 5.Ring corneal infiltrates 1.Chronic, indolent 2.Similar with fungal keratitis -Irregular -feathery , -satellite Atypical Myco bacterium
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Infectious keratitis “Ideal” Mono pathogen” infection
bacteria GRAM (+) (-) Atypical Mycobacterium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporosis “Ideal” Mono pathogen” infection ∙ Typical clinical presentation / clinical content ∙ Positive result of corneal scrapping ∙ Favorable clinical answer to therapy Atypical Mycobacterium 1.Epithelial irregularity 2.dendriform pattern 3.Dense stromal infiltrates 4.Ring infiltration HSV 1.Dendritic ulcer 2.Geographic ulcer 3.Marginal ulcer 4.Follicular conjunctivitis VZV 1.Punctate epithelial 2.keratitis 3.Pseudodendrites 4.Anterior stromal infiltrates 5.Disciform keratitis 1.dry rough texture 2.elevated lesion 3.Grey-yellow stromal infiltration 4.Feathery margin 5.Multiple satellite lesion 6.hypopyon 1.More focal 2.Yellow-white infiltrate 3. dense suppuration 4.Similar with bacterial keratitis 5.not feathery 1.Epithelial irregularity 2.dendriform pattern 3.Dense stromal infiltrates 4.Ring infiltration
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Infectious keratitis “Ideal” Mono pathogen” infection
bacteria GRAM (+) (-) Atypical Mycobacterium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporosis “Ideal” Mono pathogen” infection ∙ Typical clinical presentation / clinical content ∙ Positive result of corneal scrapping ∙ Favorable clinical answer to therapy 1.Well- circumscribed 2.Not grossly exudative 3.Not rapidly ulcerate 4.hypopyon 1.Less well 2.Rapidly progression ( Serpiginous ) 3.More 4.Greater ulcerative 5.Ring corneal infiltrates 1.Chronic, indolent 2.Similar with fungal keratitis -Irregular -feathery , -satellite Atypical Mycobacterium HSV 1.Dendritic ulcer 2.Geographic ulcer 3.Marginal ulcer 4.Follicular conjunctivitis VZV 1.Punctate epithelial keratitis 2.Pseudodendrites 3.Anterior stromal infiltrates 4.Disciform keratitis 1.dry rough texture 2.elevated lesion 3.Grey-yellow stromal infiltration 4.Feathery margin 5.Multiple satellite lesion 6.hypopyon 1.More focal 2.Yellow-white infiltrate 3. dense suppuration 4.Similar with bacterial keratitis 5.not feathery 1.Epithelial irregularity 2.dendriform pattern 3.Dense stromal infiltrates 4.Ring infiltration
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M/18 Pseudomonas ulcer 4 일 Fortified eyedrop 3’ cephalosporin Amikacin
Vigamox eyedrop Subconjunctival injection 3’ cephalosporin Pseudomonas ulcer 4 일
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Frequency of clinical sign
Trails Fungal Bacterial Central keratitis 57 54 No plaque seen 36 39 Moderately hazy 21 17 Well define 19 20 Hypopyon 16 Irregular/Feathery border 14 4 Minimal haze 11 Prominent haze 7 6 Nonspecific infiltrate Purlunent infiltrate Markdely infiltrate 2 Endothelial plaque 3 1 Ring infiltration Dry appearance Wreath infiltrate Frequency of clinical sign
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Risk Factors Contact lens Trauma Steroid Refractive surgery
Compromized cornea Diabetes
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다음의 risk factor와 각 pathogen을 연결해볼까요?
Infectious keratitis bacteria GRAM (+) (-) Atypical Mycobacterium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporosis Atypical Mycobacterium
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Topical steroid Contact lenses Corneal trauma Risk Factors
Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Topical steroid Contact lenses Compromised cornea ∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea ∙ Atopic keratoconjunctivitis ∙ Ocular cicatricial pemphigoid ∙ Basement membrane dystrophy Corneal trauma Refractive surgery Lasik Intra-corneal ring Cross linking
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Topical steroid Contact lenses Corneal trauma Bandage Contact lenses
Risk Factors Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Topical steroid Contact lenses Compromised cornea ∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea ∙ Atopic keratoconjunctivitis ∙ Ocular cicatricial pemphigoid ∙ Basement membrane dystrophy Corneal trauma Refractive surgery Lasik Intra-corneal ring Cross linking Bandage Contact lenses
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∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea
Risk Factors Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Topical steroid Compromised cornea ∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea ∙ Atopic keratoconjunctivitis ∙ Ocular cicatricial pemphigoid ∙ Basement membrane dystrophy Contact lenses Corneal trauma Refractive surgery Lasik Intra-corneal ring Cross linking Bandage Contact lenses
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Topical steroid Contact lenses Corneal trauma Risk Factors
Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Topical steroid Contact lenses Compromised cornea ∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea ∙ Atopic keratoconjunctivitis ∙ Ocular cicatricial pemphigoid ∙ Basement membrane dystrophy Corneal trauma Refractive surgery Lasik Intra-corneal ring Cross linking
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Topical steroid Contact lenses Corneal trauma Risk Factors
Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Topical steroid Contact lenses Compromised cornea ∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea ∙ Atopic keratoconjunctivitis ∙ Ocular cicatricial pemphigoid ∙ Basement membrane dystrophy Corneal trauma Refractive surgery Lasik Intra-corneal ring Cross linking
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Topical steroid Contact lenses Corneal trauma Risk Factors
Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Topical steroid Contact lenses Compromised cornea ∙ Keratoconjunctivitis sicca ∙ Bullous keratopathy ∙ Ocular rosacea ∙ Atopic keratoconjunctivitis ∙ Ocular cicatricial pemphigoid ∙ Basement membrane dystrophy Corneal trauma Refractive surgery Lasik Intra-corneal ring Cross linking
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Risk Factors Infectious keratitis Systemic immunosuppression ∙ HIV
bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Systemic immunosuppression ∙ HIV ∙ Diabetes ∙ Chronic alcoholism(32% polymicrobial infection) Manikandan Petal Facta Univ. 2008 Ray K et al ESCRS abstract Milan 2012 Omerold LD et al. BJO 1988
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Polymicrobial Infection from Contamination
Delayed healing Polymicrobial Infection from Contamination Co-infection/superinfection Drug resistance Delayed response
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Delayed healing 원인과 치료 원인
- Incomplete resolution or stable lesion despite appropriate antibiotic Tx. 원인 Drug toxicity 원인 : Prolonged intensive Tx. (esp. fortified antibiotics) Particularly noted as -Punctate epitheliopathy -Stromal edema -Persistent conjunctival injection -Chemosis Underlying Ocular surface problem Local host factors Endogenous factors (systemic factors) Ocular chemical injury Neurotrophic disease Exposure keratitis Lid /lash malposition Tear insufficiency Stem cell deficiency Bullous keratopathy Previous herpetic disease DM AIDS Malnutrition Alcoholism Other chronic debilitating illnesses Autoimmune disease (RA, Wegener’s granulomatosis, Sjogren syndrome) Immunosuppressive treatments
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Polymicrobial Infection
Recognize Polymicrobial Infection from Contamination ?
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Contamination or Polymicrobial infection ?
20% of polymicrobial infection without exclusion of contaminant Any growth considered isolate Yeh DL et al. Am J Ophthalmol 2006, 20% Bacterial coinfection in fungal keratitis Growth considered an isolate : ∙ Growth on at least one medium AND posivite Smears on corneal scraping ∙ Growth of the same species on 2 OR more mdeia Pate JC et a Br J Ophtalomol 2006, 5~20 % Polymicrobial infection Bacterial Keratitis ∙ Growth on at least one medium AND posivite Smears on corneal scraping ∙ Growth of the same species on 2 OR more mdeia ∙ Confluent growth on 1 solid medium of Staph. Aureus / strep. Pneumoniae OR Pseud Aeruginosa Acanthoamoeba Keratitis ∙ Clinical sign of infection AND Fungal growth in any medium Jones DB. Tr Am
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Rarely, polymicrobial keratitis dysplays
The typical clinical signs from the two different pathogens Acanthoamoeba + G(+)
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Risk Factors Infectious keratitis Systemic immunosuppression ∙ HIV
bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite acanthamoeba microsporisis Systemic immunosuppression ∙ HIV ∙ Diabetes ∙ Chronic alcoholism(32% polymicrobial infection) Manikandan Petal Facta Univ. 2008 Ray K et al ESCRS abstract Milan 2012 Omerold LD et al. BJO 1988
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Dart JI el. Am J Ophthalmol 2009 Oellers et al OMIG 2011
Infectious keratitis Bacteria G(+) G(-) Virus HSV ½ VZV Fungus Filament Spares Parasite acanthamoeba 10 to 25 % cases of AK may be Polymicrobial 70% with Bacteria ∙ 50% gram + cocci (Crystalline Keratitis +++) ∙ 50% Gram negative Rods 2% co-infection with Herpes Virus infection 10 to 25 % cases of AK May be polymicrobial. 20% associated fungal infection 50% co-infection GN prey of AK 50% secondary infection Antiseptic?
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Infectious Keratitis Bacteria Fungus Yeast Filament 20%
Gram+; 82% Cocci 50% Coag Neg Stoph ++ Rods 32% Propiono bacteria corynebacteria Gram- 18% Rods Pseudomonas Klebsiella Fungus Yeast Filament 20% Fungal-Bacterial Co-infection Yeast-Bacteria co-infection 3X more frequent than Filament-Bacteria co-infection Gram positive bacteria co-infection With Yeast = Flament Gram positive Rods with filaments ++ Pate JC al.Br J Opthalmol 2006;
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Co-infection/superinfection
∙ In case of co-infection: - Clinical picture is severe and atypical. - Common risk factors for multiple infectious agents ∙ Treat with combine therapies after microbial investigations ∙ Reevaluate every hours ∙ In case of superinfection: - Appearance of new clinical signs/symptoms - Inflammatory acutization ∙ Scrapping/HRT cornea/biopsy - Add New antimicrobial agent - Reevaluate hours, +/- Therapeutic pause
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Treatment
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Fortified antibiotics
Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite Acanthamoeba Antimicrobial Agents Broad spectrum Antibiotherapy Targeting Gram+ and – +/- Fortified antibiotics Antiviral therapy Polyene Imid/triazole Fortified drops Biguanide (PHMB) Diamidine (Propamidine) Aminolycosides Imidazoles Azythromicine Ciprofloxacine Amikacine Vancomycine
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Fortified antibiotics
Infectious keratitis bacteria G(+) G(-) Atypical Mycobac-terium virus HSV VZV fungus filament yeast parasite Acanthamoeba Antimicrobial Agents Broad spectrum Antibiotherapy Targeting Gram+ and – +/- Fortified antibiotics Antiviral therapy Polyene Imid/triazole Fortified drops Biguanide (PHMB) Diamidine (Propamidine) Aminolycosides Imidazoles Azythromicine Ciprofloxacine Amikacine Vancomycine Imid/triazole Aminoglycosides
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Anti-microbial intrastromal injections
∙ Voriconazole (Fungal-Acanthamoeba) ∙ Amphotericin B (Fungus) ∙ Cefuroxim (GN and GP bacteria) ∙ Vancomycin (GP bacteria) 30 G Needle ∙ voriconazole (50μg in 0.1 ml) ∙ amphotericin B (5 mg per 0.1 ml) ∙ Vancomycine (5 mg per 0.1 ml) 그림 Haddad RS et al. MEAJO 2012, 19(2): Prakash G et al. Am J Ophthalmol Jul;146(1):56-59 Khan lJ et al. Cornea Oct;29(10);1186-8
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Anti-microbial anterior chamber injections
∙ Voriconazole (Fungal-Acanthamoeba) ∙ Amphotericin B (Fungus) ∙ Cefuroxim (GN and GP bacteria) ∙ Vancomycin (GP bacteria) 30 G Needle ∙ voriconazole (50μg in 0.1 ml) ∙ amphotericin B (5 mg per 0.1 ml) ∙ Vancomycine (5 mg per 0.1 ml) 그림 Haddad RS et al. MEAJO 2012, 19(2): Prakash G et al. Am J Ophthalmol Jul;146(1):56-59 Khan lJ et al. Cornea Oct;29(10);1186-8
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Steroid Use in The Management of Corneal Ulcer
Rationale - suppression of inflammation - reducing of scar - prevention of neovascularization Complications - local immunosuppression – impairment of phacocytosis - collagen synthesis inhibition - 2ndary glaucoma - cataract 3. Contraindications - corneal thinning, impending perforation - deepithelized cornea 4. Indications - vision threatening in central area - arising to neovascularization 5. Use - with antibiotics - tapering is essential
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Take Home Massage Stage of Infectious Disease (Keratitis)
“Ideal” Mono pathogen” infection 3. Polymicrobial infection ; Co-infection/ Superinfection Contamination 4. Steroid Use in The Management of Corneal Ulcer
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