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Baroness Karen Christenze von Blixen-Finecke

Germany – Cameroun - 1980

U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Conjunctival and

Corneal Inflammation Uwe Pleyer, FEBO

www 29-2-2020

Inflammation at the ocular surface

Presence!

Outline

Basic mechanisms

Impact on clinical

management (DX, TX)

Conjunctiva, Cornea

Draining

Tearways

(CALT)

Lymphocyte

Recircu-

lation

Tear-

Gland

Lid (margin)

Lacrimal Functional Unit

Neural

Reflex-

Arc

Mod. from Knop E. In: Pleyer U. (Edt.) Entzündliche Augenerkrankungen. Springer, Berlin 2020

Ocular surface „defence system“

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Dermott et al. Exp Eye Res. 2010; 90: 679–687. Mohammed I et al. Human antimicrobial peptides in ocular surface defense. Prog Retin Eye Res. 2017;61:1-22.

Defence – patter recognition - Toll Like Receptors (TLR)

Ocular surface – innate immune response

NF-kB translocation

Association of TLRs with Ocular Surface Diseases

Disease Toll Like Receptor (TLR)

Herpes Simplex keratitis TLR2,3,4,7,9

Pseudomonas keratitis TLR4,5,9

Fungal keratitis TLR2,4

Vernal keratoconjunctivitis TLR4,9

Atopic

Keratoconjunctivitis

TLR2

Sjögren’s syndrome TLR1,2,3,4

Non-Sjögren’s syndrome TLR2,4,5,9

Dermott et al. Exp Eye Res. 90: 679–687 (2010) Kiripolsky J, Kramer JM. Current and Emerging Evidence for Toll-Like Receptor Activation in Sjögren's Syndrome. J Immunol Res (2018)

Ocular surface – innate immune response

Conjunctivitis

Evaporative dry eyeAcute conjunctivitis

Most common eye disease worldwide !

Evaporative dry eyeAcute conjunctivitis Chronic conjunctivitis

Hyperemia

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis Chronic conjunctivitis

Hyperemia

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis Chronic conjunctivitis

Hyperemia

Chemosis

Exsudate

Hyperemia

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis

Hyperemia

Chemosis

ExsudateViruses

Bacteria

Fungi

Chlamydia

Burn

Immunological

Membranous

Pseudo-

membranous

• Incubation 7-12 days

• Contagious: - 2 Weeks

Adenovirus Conjunctivitis

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Hyperemia

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis

Hyperemia

Chemosis

ExsudateViruses

Bacteria

Fungi

Chlamydia

Burn

Immunological

Membranous

Pseudo-

membranous

• Incubation 7-12 days

• Contagious: - 2 Weeks

Adenovirus Conjunctivitis

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeDiagnosis Adenovirus Conjunctivitis

• Clinical course!

• PCR Sensitivity (97%)

Evaporative dry eyeTherapy

• Artifical tears, PVP, Ganciclovir?

• Ciclosporin A

Pepose JS et al. Randomized, Controlled, Phase 2 Trial of Povidone-Iodine/Dexamethasone Ophthalmic Suspension for Treatment of Adenoviral Conjunctivitis.

Am J Ophthalmol. (2018)

Conjunctivitis: TX

Clinical resolution

(PVP-I) 0.6% + Dexa. 0.1%

Adenovirus Conjunctivitis

Conjunctivitis

Kariwa H. et al. Inactivation of SARS Coronavirus Dermatology 2006;212:119–123

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis

Viruses

Bacteria

Fungi

Chlamydia

Burn

Immunological

Membranous

Pseudo-

membranous

Stevens-Johnson-Syndrom

Symblepharon

Viruses

Postinfect.

Allergy

Burn

Immunological

SJS

Pemphigoid

MMP

Limbal stem cell injury

Symblepharon!

Often infection/drug associated

Fever and feeling sick

Large areas of skin damage

Mucosal manifestations

(oral, balanitis, vulvitis/colpitis)

Stevens-Johnson syndrome / toxic epidermal necrolysis

Conjunctivitis

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Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis

Viruses

Bacteria

Fungi

Chlamydia

Burn

Immunological

Membranous

Pseudo-

membranous

Stevens-Johnson-Syndrom

Symblepharon

Viruses

Postinfect.

Allergy

Burn

Immunological

SJS

Pemphigoid

MMP

Saeed H.N., Rashad R. In: Pleyer U. Edt. Entzündliche Augenerkrankungen. Springer, Berlin. (2020)

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeChronic conjunctivitis

Viruses

Bacteria

Fungi

Chlamydia

Burn

Immunological

Membranous

Pseudo-

membranous

Mucous membrane pemphigoid

Symblepharon

Postinfect.

Allergy

Burn

Immunological

SJS

Pemphigoid

(MMP)Rübsam A et al. In: Pleyer U. Edt.

Entzündliche Augenerkrankungen. Springer, Berlin (2020)

Ocular Pemphigoid

Autoimmune disorder

Age: Mean 68 years

20-45% involves other mucosal sites

Diagnosis: Clinical! -> Staging I-IV

Immune histology!

Autoantibodies BP180 AG

Target structure = ß4 Integrin

May correlate with activity

Several mucosa sites: BP180 AG

Yasukochi A et al. Clinical and Immunological Studies of 332 patients.

Acta Derm Venereol. 96:762-7 (2016)

Chronic conjunctivitisMucous membrane pemphigoid

Conjunctivitis

Saw V P J Br J Ophthalmol 2013;97:1364-1367 *Rübsam A, Stefaniak R, Worm M, Pleyer U. Rituximab preserves vision in ocular MMP Expert Opin Biol Ther. (2015)

Kim J M et al. Pediatrics 2013;131:1155-1167

Conjunctivitis

Immune therapy in: Mucous Membrane Pemphigoid

*

PapillarySymblepharon

Viruses

Bacteria

Chlamydia

Parasites

Allergic

Immunological

Foreign body

Granuloma

Viruses

Bacteria

Chlamydia

Immunological

Steven

Johnson

Syndrome

Other

Lignosa

SLK

Allergic

- Seasonal

- Periennial

- Vernal

- Giant

Papillary

Contact

Lens (GPC)

Conjunctivitis

Evaporative dry eyeAcute conjunctivitisEvaporative dry eyeAcute conjunctivitis Chronic conjunctivitis

Mastzelle

Allergen/Antigen

DEGRANULATION

(e.g. Histamin)

Ca2+

Ca2+

Ca2+

(Calcium-Influx)

Granula

IgE-

Antikörper

Seasonal allergic Conjunctivitis (SAC)

Topical Therapy Antihistamines Mast cell stabilizer

Multiple action agents

(Epinastin, Olopatadin, Ketotifen)

AAO Conjunctivitis Preferred Practice Pattern - AAO.org (2018)

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Prevention – Therapy (SAC)

Kim J M et al. Pediatrics 2013;131:1155-1167. Aydogan M et al. Sublingual immunotherapy in children. Respiratory Medicine, 107: 1322 – 1329 (2013)

AAO Conjunctivitis Preferred Practice Pattern - AAO.org (2018)

• Starts in childhood, self limiting, saisonal, boys

• Itching, mucus, photophobia

• Subtarsal: Papillary hypertrophia

• Limbal type: limbal thickening/Tantras´ dots

• Corneal (shield) ulcer can be sight threatening !

Vernal Keratoconjunctivitis

Mast cell stabilisators

Topical Cyclosporine A*; Tacrolimus

(Systemic Cyclosporine A)

Omalizumab (anti-IgE) Biological**

Primary

Therapy

Basic

Therapy

Mast cell stabilisators

Antihistamins (H1,4-Blocker)

Steroids (Hydrocortisone, Dexamethasone)

*Leonardi et al. A Randomized, Controlled Trial of Cyclosporine A Cationic Emulsion in Pediatric Vernal Keratoconjunctivitis:

The VEKTIS Study. Ophthalmology. 126: 671-681 (2019) ** Lau S, Pleyer U, Roßberg S. submitted Allergy, 2020

Vernal Keratoconjunctivitis: Therapy

Galletti JG et al. Mucosal immune tolerance at the ocular surface in health and disease. Immunology (2017)

Yamaguchi T. Inflammatory Response in Dry Eye. Invest Ophthalmol Vis Sci. (2018)

Dry eye syndrome (DES)

Evaporative dry eye Tear deficient dry eyeTear deficient dry eye (10%) Evaporative dry eye

Evaporative dry eyeAcute conjunctivitis Chronic conjunctivitis

Conjunctivitis

Dry eye syndrome (DES)

Evaporative dry eye Tear deficient dry eyeTear deficient dry eye (10%) Evaporative dry eye

Evaporative dry eyeAcute conjunctivitis Chronic conjunctivitis

Prevalence: 8-34%

Conjunctivitis

Report of the TFOS International Dry Eye Workshop II (TFOS DEWS II). Definition and Classification Report The Ocular Surface 15 (2017)

DES: Classification

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• Instability of the tear film

• Tear/ cell hyperosmolarity

• Inflammation

• Neuropathy

DES: Sensitive homeostasis

Adapted from Baudouin et al., J.Fr Opthalmol 2007;30:239-46.

L. Jones et al. / The Ocular Surface 15 (2017)

Dry Eye Disease Management

Anti Inflammatory TreatmentReport of the TFOS International Dry Eye Workshop II (TFOS DEWS II) (2017)

1. International Dry Eye Workshop. Ocul Surf 2007;5:65–204; 2. Jones L, et al. Ocul Surf 2017;15:575–628.

Treatment Grade 1

Changes in

surroundings/

nutrition

Elimination of

offending

medication

Artificial tears Eyelid therapy

Treatment Grade 2

Anti-

inflammatory

Tetracyclines

(meibomianitis/

rosacea)

Punctal plugs SecretagoguesMoisture chamber

spectacles

Treatment Grade 3

Autologous

serum

Bandage contact

lensesPermanent punctal occlusion

Treatment Grade 4

Systemic anti-inflammatory agents

Surgery

(lid surgery, tarsorrhaphy, mucus membrane, salivary gland, amniotic membrane

translation)

DEWS: Treatment algorithm

Simple meibomian gland obstruction

Rosacea

Cicatricial obstructive meibomian gland disease

Lipid dysfunction

Domenico Ghirlandaio, Ritratto di nonno con nipote (ca. 1490)

Rosacea TX

Azytromycine (top.)

Tetracyclines (syst.)

Lipid dysfunction

Augenklinik, Charité (ca. 2010)

Corneal Inflammation

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KeratitisClassification of acute keratitis

Dart J et al., Am J Ophthalmol. 2009 / Tu E et al. Interstitial Keratitis in Principles and Practice, Jakobiec edited 2007 / Kuo M et al., IOVS 2012

http://www.orpha.net / The Wills Eye Manual (7th Edition) 2017

Non-infectious ("sterile")

Endogenous (for example)

- Immunological origin

- Dermatological diseases

- Hereditary

- Degenerative

- Neuroparalytic

Exogenous

- Toxins

- Traumatic origin

Mixed forms

- Dry eye

Infectious

Bacteria

Viruses

Fungi

Protozoans

Acute infectious keratitis - risk factorsContact lenses

Epithelial defect

• Foreign bodies, recurrent erosion

• Refractive surgery (-> atypical mycobacteria?)

Diseases of the surface of the eye

• Dry eye

• Herpes simplex virus infections

• Metaherpetic healing disorder / neuroparalysis

• Atopy, rosacea, …

• Blepharitis / Blepharokeratoconjunctivitis

• Bullous keratopathy

• Misaligned eyelids -> Exposure keratopathy

General diseases and other risk factors

• Immunosuppressive drugs / Immunocompromised

• Diabetes mellitus

• Vitamin A deficiency

Acute keratitis – Possible pathogens

Bacterial infectionsGram-negative agents

• Pseudomonas• Enterobacteria

• …

• Gram-positive agents• Staphylococci• Streptococci

• ….

Fungal infections• Yeasts

• Candida species (amongothers)

• Filamentous fungi• Fusaria and Aspergillus

(among others)

• Microsporidia

• ...

Protozoal infections• Acanthamoeba

• Onchocerciasis• ...

Special form of bacterial

keratitis

Actinobacteria• Mycobacteriaceae• Nocardiaceae

• Actinomyces

• ...

Viral keratitis• HSV

• VZV• ADV

• [EBV]

• ...

Metaherpetic

stromal

Viral

epithelial

Metaherpetic

epithelial

Viral

endothelialProf. R. Sundmacher

Epithelial Herpes Keratitis – local antiviral therapy

Lokal Standard Medication x/day Duration

Aciclovir (Zovirax®, Acic®, Virupos®, Zoliparin®) 5x 14 Days

Alternativ or when no response

Ganciclovir (VIRGAN®-Gel) 5x 14 Days

Wilhelmus 2015 Cochrane Database

Effectivity •Aciclovir (ACV) / Trifluridin (TFT) > Idoxuridine (IDU)

•GCV = ACV

Kortikosteroids: Contra indicated!

Geographic Lesion: Epithel abrasio to lower viral load

HSV keratitis

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Recurrent Herpes simplex Virus Keratitis

Systemic prophylaxis with a strong tendency to relapse (≥2 relapses / year)

Acyclovir 2x400mg

Valaciclovir (better oral bioavailability) 2x500mg

Brivudine (Zostex®; reserve medication) 1x125mg

High effectiveness of oral prophylactic therapy

Patients without systemic prophylaxis:

Frequent visual impairment

More common complications (perforation, glaucoma, ...)

HEDS 1997, HEDS 1998; Young et al. Arch Ophthalmol 2010; Wilhelmus 2015 Cochrane Database

HSV keratitis

Recurrent Herpes KeratitisAciclovir (ACV) – Resistence in HSV

High Prevalence (6.4%) of ACV resistent latent HSV-1 Isolates

Levin et al. 2001, Burrel et al. 2013; van Velzen et al. 2013, Turner 2013, Carter 2016

n = 15 Sequential HH isolates: Tk genes / genotype. Analysis ACV receptivity

ACV susceptibility:

uniform resistant n=4

uniform sensitiv n=2

1. sensitiv – 2. resistant n=6

1. resistent – 2. sensitiv n=3

ACV resistant HSV-1

Establish latency, reactivate

and cause ACV-resistant keratitis

Therapy in ACV-Resistent patients

Ganciclovir or Foscarnet 1.2% (5x/d; Cave: toxic)

HSV keratitis

Bacterial keratitis – Clinical appearanceComplaints

• Redness

• Pain

• Photophobia

• Blurred vision

• Epiphora

• Pus

• …

Clinical course

• Epithelial defect +/- infiltration

• Enlargement of the infiltrate / Epithelial defect

• Eyelid and conjunctival involvement

• Stromal edema, Descemet folds

• Anterior uveitis -> Hypopyon

• Severe ulceration

• Descemetocele

• Corneal perforation (suspicion of pseudomonas)

Epling J., Bacterial keratitis and conjunctivitis. BMJ Clin Evid. 2012 / Cheung N et al., Emerging trends in contact lens-related infections. Curr Opin

Ophthalmol. 2016

Bacterial keratitis – Diagnosis I

Case history

Slit lamp microscopy

• If applicable: Start of empirical therapy (?)

Corneal swab / curettage (if possible before starting therapy)

• Microscopy

• Microbiology

Conjunctival swab

Corneal sensitivity test

Further microbiological examination

• Contact lens / container and cleaning fluid

Microbiology: Smear and resistance testing

Bacterial Viral Allergic

Bacterial keratitis – Diagnosis II

Factors Culture Vital Stain Dyes

Small, peripheral, no stromal melting Culture optional Gram, Giemsa stain optional

Large, central, stromal melting,

chronic, atypical appearance,

sight threatening

Culture Gram, Giemsa stain

Microscopy: After smear and stainingShalchi Z et al., Antibiotic resistance in microbial keratitis: ten-year experience of corneal scrapes in the United Kingdom. Ophthalmology. 2011 Jin, H et al. Evolving risk factors and antibiotic sensitivity patterns for microbial keratitis at a large county hospital. Br J Ophthalmol. 2017; 101: 1483–1487

Bacterial keratitis – Medical therapy

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Bacterial keratitis – Medical therapy

Topical antibiotics

• According to antibiogram – otherwise empirically

• e.g. Ofloxacin (cave: high resistance rate) or

Moxifloxacin + Tobramycin

• Dosage

• According to findings: up to ¼ hourly and over 24 hours

• With intraocular involvement: I.V. dose

Mydriatics

• With intraocular involvement

Steroids (SCUT data)

• Topical administration only when the epithelium is closed

• Minimum amount required to achieve control of inflammation

Bacterial Keratitis Preferred Practice Pattern®; 2019: 126, 1–P55 (2019); Srinivasan, M et al. Steroids for Corneal Ulcers Trial Group.

Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012; 130: 143–150 Papaioannou, L et al. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea. 2016; 35: 62–71

Risks

•Shrinkage of the stroma

•Refraction changes

•Increased scarring

•Perforation

Bacterial keratitis – Surgical therapy I

Cross linking

•in moderate bacterial ulcers

• in more anterior stromal infections

•faster reepithelialization

•can block corneal melting

Foto

Acanthamoeba keratitisClinic

• Young, healthy patients; contact lens

• Mostly one-sided disease / insidious onset

• Severe pain -> (peri-)neuritis

Slit-lamp

Early stage (2 weeks – superficial)

• Dirty epithelium

• (Pseudo-) dendritic changes (HSV-like)

• Limbitis

Middle stage (2-6 weeks – stromal infiltration)

• Spread along the nerve fibers (perineuritis -> pain)

• Spotted/ring -shaped infiltrates

• Without vascularization!

Late stage (> 6 weeks – deep)

• Hypopyon (-> Superinfection)

• Secondary glaucoma

Acanthamoeba keratitis

Diagnosis

Confocal microscopy

• Cave: Interpretation difficult

• No sure proof

PCR

• Contact lens PCR can be positive ->

No sure proof for a Corneal infection

Histology

• Conclusive proof

Therapy

• Polyhexanid (Polyhexamethylenbiguanid / PHMB 0,02% / Lavasept®)

• (Dibromo-)Propamidine Isoethionate (Brolene® 0,1%)

• Polymyxin B + Neomycin + Gramicidin (Polyspectran®)

• Moxifloxacin (Vigamox® -> for bacterial superinfection)

• Voriconazol (VFend® 1% -> Special product)

• Hexamidin (Desomedin®, approved in Switzerland)

Patel, D et al., 2013/09/01

Papaioannou, L et al. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea. 2016; 35: 62–71

Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, Aureobasidium pullulans, Alternaria alternata, Cladosporium oxysporum, Cylindrocorpon

tonkinensis,Curvularialunata,Curvulariageniculata,Curvularia pallescens, Curvularia senegalensis,

Curvularia verruculosa, Cladorrhinum spp., Drechslera spp., Drechslera rostrata, Drechslera spicifera, Lasidiplodia theobromae, Phialophora verrucosa, Phoma oculohominis, Pleospora

infectoria, Botryodiplodia spp., Tetraploa spp., Rhizoctonia spp., Macrophoma spp., Trichosporon

spp., Ustilago spp., Scopulariopsis spp., Pseudallescheria (Syn. Allescheria) boydii, Sporothrix

schenckii, Verticillium spp., Acremonium spp., Fusidium spp., Sterigmatocystis nigra, Paecilomyces lilacinus, Periconia keratitidis, Neurospora spp., Volutella spp., Glenospora spp., Penicillium spp.,

Penicillium citrinum, Penicillium spinulosum, Graphium spp., Fusarium solani, Fusarium nivale,

Fusarium oxysporum, Candida albicans, Candida guilliermondii, Candida viswanathii, Candida krusei, Rhodotorula spp., Colletotrichum state of Glomerella cingulata, Acrophialophora fusispora,

Phaeotrichoconis crotalariae, Helminthosporium, Neosartorya fischeri var. fischeri, Arthrobotrys

oligospora, Trichophyton mentagrophyte

Hintergrund: Fungal Spp… Keratomycosis

Mojon`s Manual of Medicine

by Springer

Keratomycosis

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Clinical appearance – Keratomycosis

Mycotic keratitis Acanthamoeba keratitis

Mycotic keratitis Mycotic keratitis

Dalmon C et al. The clinical differentiation of bacterial and fungal keratitis. Invest Ophthalmol Vis Sci., 2012

Preserved epithelium

Subepithelial spread

Prominent Infiltrate (s)

Geographical extent

"Deep" keratitis

Satellites

Hypopion

Clinical appearance – Keratomycosis

Befunde

Preserved epithelium

Subepithelial spread

Prominent Infiltrate (s)

Geographical extent

"Deep" keratitis

Satellites

Hypopion

Clinical appearance – Keratomycosis

• Preserved epithelium

• Subepithelial spread

• Prominent Infiltrate (s)

• Geographical extent

• "Deep" keratitis

• Satellites

• Hypopion

Befunde Clinical appearance – Keratomycosis

• Preserved epithelium

• Subepithelial spread

• Prominent Infiltrate (s)

• Geographical extent

• "Deep" keratitis

• Satellites

• Hypopion

Befunde Clinical appearance – Keratomycosis Befunde

Preserved epithelium

Subepithelial spread

Prominent Infiltrate (s)

Geographical extent

"Deep" keratitis

Satellites

Hypopion (inverse)

Clinical appearance – Keratomycosis

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Directe confirmation

Confocal microscopy

Histopathology/EM

Multi-Photon microscopy

Smear/Culture

PCR, MALDI-TOF…

Diagnostik Keratomycosis - Diagnosis

Conjunctivitis – Keratitis

• Broad spectrum of ethiologies –

acute/chronic presentation

• Very heterogenous clinical pictures

History

• Disease onset?

• Systemic disoders? (Skin – rheumatological)

• Trauma - Contact lens use?

Diagnosis

• Based on the clinical findings -> as targeted as possible

• A lack of pathogen detection does not rule out infection

Therapeutic regimen

• Check closely and adjust accordingly

Conclusion: Inflammation at ocular surface

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