Keratitis: Clinical Guidelines

List of Abbreviations

AVI — adenoviral infection

AKVK — adenoviral keratoconjunctivitis

AK — Acanthamoeba keratitis

BK — bacterial keratitis

IOP — intraocular pressure

HSV — herpes simplex virus

GK — herpetic keratitis

GrK — fungal keratitis

IK — infectious keratitis

ELISA — enzyme-linked immunosorbent assay

CL — contact lenses

CT — computed tomography

ICD-10 — International Classification of Diseases 10th Revision

NIK — non-infectious keratitis

NK — neurotrophic keratitis

OCT — optical coherence tomography

NSAIDs — non-steroidal anti-inflammatory and antirheumatic drugs

PUK — peripheral ulcerative keratitis

DED — dry eye disease

EKC — epidemic keratoconjunctivitis

** — this symbol indicates a medicinal product used for indications according to its instructions for use

# — this symbol indicates a medicinal product used for indications not included in the instructions for use of the medicinal product.

Terms and Definitions

Keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage.

Infectious keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by the introduction of an infectious agent

Non-infectious keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, developing against the background of various non-infectious pathological conditions.

Bacterial keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by the introduction of a bacterial agent.

Herpetic keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by corneal involvement with the herpes simplex virus (a DNA virus belonging to the human $\alpha$-herpesvirus family).

Adenoviral keratitis (epidemic keratoconjunctivitis, EKC) is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by an adenoviral infection

Fungal keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by the introduction of a fungal infection.

Acanthamoeba keratitis (AK) is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by protozoan infection of the genus Acanthamoeba.

Marginal keratitis (peripheral ulcerative keratitis) is immune-mediated inflammation of the corneal periphery, characterized by thinning and/or ulceration of the peripheral rather than central part of the cornea, spreading along its edge. It may be associated with an underlying local or systemic pro-inflammatory disease, or present in an idiopathic form.

Neurotrophic keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, developing as a result of corneal neurotrophic disorder due to impaired innervation of various origins with decreased/absent sensitivity.

Keratitis in dry eye disease is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, developing as a result of a multifactorial ocular surface disease characterized by loss of tear film homeostasis and accompanied by ophthalmological symptoms, in the development of which instability, tear film hyperosmolarity, inflammation and damage to the ocular surface, as well as neurosensory abnormalities play an etiological role.

Epitheliopathy — isolated punctate defects of the corneal epithelium that stain with fluorescein.

Corneal erosion is a superficial defect of the corneal epithelium of various shapes and areas, staining with fluorescein.

Corneal infiltrate — a local inflammatory focus containing activated keratocytes (corneal fibroblasts), inflammatory cells, inflammatory mediators, and microbes in infectious processes.

Epithelial edema — manifests as the loss of normal corneal luster, small epithelial vesicles may be defined. Bullae form in cases of moderate to severe edema. The cause of edema is usually corneal endothelial decompensation, as well as a sharp rise in IOP.

Hypopyon — accumulation of leukocytes in the inferior angle of the anterior chamber of the eye (may contain elements of an infectious agent).

Anterior synechiae — adhesions between the iris and the cornea.

Posterior synechiae — adhesions between the iris and the anterior lens capsule.

Keratic precipitates — aggregates of inflammatory cells deposited on the corneal endothelium.

Uveitis – an inflammatory disease of the middle coat of the eye (uvea).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Keratitis is corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage [1;2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

By etiology, keratitis is divided into the following groups:

Infectious keratitis (IK):

· Bacterial

· Viral (Herpetic; Adenoviral)

· Fungal

· Acanthamoeba

Non-infectious keratitis (NIK):

· Marginal keratitis (peripheral ulcerative keratitis)

· Neurotrophic

· Keratitis in dry eye disease

Bacterial keratitis (BK) — corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by the introduction of a bacterial agent [2;3;4].

Herpetic keratitis (GK) — corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by corneal involvement with the herpes simplex virus (a DNA virus belonging to the human $\alpha$-herpesvirus family) [2-6].

Adenoviral keratitis (epidemic keratoconjunctivitis, EKC) — corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by adenoviral infection [2-4;7-9].

Fungal keratitis (GrK) - corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by the introduction of a fungal infection [2-4;10-12].

Acanthamoeba keratitis (AK) — corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, initiated by infection with protozoa of the genus Acanthamoeba [2-4;12;13;14].

Marginal keratitis (KK) (peripheral ulcerative keratitis PUK) — immune-mediated inflammation of the corneal periphery, characterized by edema, inflammatory cell infiltration, with or without epithelial damage of the peripheral rather than central part of the cornea and spreading along its edge. It may be associated with an underlying local or systemic pro-inflammatory disease, or present in an idiopathic form [2-4;15;16].

Neurotrophic keratitis — corneal inflammation characterized by corneal edema, inflammatory cell infiltration, developing as a result of a corneal neurotrophic disorder due to impaired innervation of various origins with decreased/absent sensitivity [2-4;17].

Keratitis in dry eye disease (filamentary keratitis) – - corneal inflammation characterized by corneal edema, inflammatory cell infiltration, with or without epithelial damage, developing as a result of a multifactorial ocular surface disease characterized by loss of tear film homeostasis and accompanied by ophthalmological symptoms, in the development of which instability, tear film hyperosmolarity, inflammation and damage to the ocular surface, as well as neurosensory abnormalities play an etiological role [2-4;18-20].

Pathogenesis of bacterial keratitis. The development of BK includes phases of bacterial adhesion, multiplication, penetration into the corneal stroma with the destruction of its architecture and melting of stromal collagen, release of bacterial toxins and lytic enzymes. The release of polymorphonuclear neutrophils from tears and limbal vessels, interleukins and cytokines, as well as free radicals, proteolytic enzymes, and matrix metalloproteinases lead to necrosis of the epithelium, Bowman's membrane, and stroma [1;2;21;22]. The development of BK is associated with the alteration of one or more systems of corneal anti-infective defense.

Pathogenesis of herpetic keratitis. Herpes simplex virus (HSV) is a common DNA virus belonging to the human alphaherpesvirus family. HSV enters the body by contact in early childhood. HSV invades epithelial cells, resulting in primary replication and cell death. Lymphocytes and macrophages migrate to the inflammation site, releasing biologically active substances and damaging capillaries and connective tissue, which leads to the formation of characteristic papules and vesicles. Next, HSV penetrates sensory nerve endings and travels via centripetal nerve fibers to paravertebral ganglia or cranial nerve ganglia. Viral replication occurs in neuronal nuclei. Via efferent nerve fibers, the virus reaches the skin and mucous membranes again, spreading and causing new rashes. Ocular involvement occurs via exogenous (through the epithelium), neurogenic, or hematogenous pathways; HSV actively replicates in corneal epithelial cells, subjecting them to necrosis due to the triggering of cytopathic and dystrophic processes. Afterwards, the virus enters a persistent state and can be detected in the cornea itself or the trigeminal ganglion for a prolonged period [1;2;23-26].

Pathogenesis of adenoviral keratitis (epidemic keratoconjunctivitis, EKC). Adenoviruses are double-stranded DNA viruses ranging from 80 to 110 nm in size, surrounded by a capsid containing group- and type-specific antigens; they are environmentally stable and resistant to many disinfectants. Adenoviral ocular infections are widespread, represent the most frequent cause of viral conjunctivitis, and manifest as simple follicular conjunctivitis, pharyngoconjunctival fever, or epidemic keratoconjunctivitis (EKC) with obligatory corneal involvement, which can become chronic and/or recurrent in ¼–½ of cases. During the development of EKC, infected keratocytes express chemokines that deposit on negatively charged areas of the corneal basement membrane, prompting the formation of subepithelial stromal infiltrates [1;2;9;27].

Pathogenesis of fungal keratitis. The development of FK is based on the infiltration of the corneal stroma by fungal microorganisms with their subsequent proliferation into the corneal thickness, which is accompanied by tissue necrosis and breakdown, resulting in a defect of the epithelium and the superficial and middle layers of the corneal stroma [1;2;28-30].

Pathogenesis of Acanthamoeba keratitis — Acanthamoeba exists as a metabolically active trophozoite or a dormant cyst. Trophozoites move actively using acanthopodia and reproduce by mitosis. The double-walled cyst is usually polygonal or stellate in shape with a wrinkled exocyst and a smooth endocyst. The ability to cause disease depends on the structural and enzymatic properties of Acanthamoeba, the principal one being the ability to form cysts—encystation. The cyst is resistant to extreme temperatures, standard disinfection systems, and radiation, exhibits osmotolerance, and has unlimited viability. Acanthopodia facilitate the binding of Acanthamoeba to biological and inert surfaces, while amoeboid movement, resembling that of macrophages, promotes tissue invasion via a paracellular pathway. Binding to a cell receptor disrupts host intracellular signaling pathways, causing cell cycle arrest and apoptosis, which facilitates phagocytosis and toxin release [1;2;13;31;32].

Pathogenesis of marginal keratitis (peripheral ulcerative keratitis). Conditionally pathogenic microorganisms (S. aureus, Moraxella, Haemophilus, Streptococcus) take part in the development of MK by releasing toxins and leading to immune inflammation of the corneal periphery. Antigen exposure activates the adaptive immune response, the complement system, the production of specific antigen-antibody complexes, and the development of a severe local inflammatory reaction. Complement activation with the release of collagenases, proteases, and various cytokines stimulates keratocytes to produce matrix metalloproteinases and leads to stromal destruction with progressive corneal thinning [1;2;33;34].

Pathogenesis of neurotrophic keratitis. The development of NK is based on impaired corneal innervation, leading to a decrease in sensory and trophic functions, followed by decreased tear film stability, damage to the corneal epithelium and stroma with the formation of non-healing epithelial defects, and damage to Bowman's membrane. Subsequently, against the background of an increase in inflammatory mediators and activation of matrix metalloproteinases, the stroma becomes involved in the process [1;2;17].

Pathogenesis of keratitis in dry eye syndrome (DES). DES is a multifactorial disease of the ocular surface characterized by the loss of tear film homeostasis and accompanied by ophthalmological symptoms, in the development of which the etiological role is played by instability, tear film hyperosmolarity, inflammation and damage to the ocular surface, as well as neurosensory changes. Insufficient tear fluid production and/or increased evaporation leads to altered corneal cell mitosis and impaired epithelial renewal, damage to Bowman's membrane, decreased mechanical protection, increased tear fluid osmolarity, an increase in inflammatory mediators, and activation of matrix metalloproteinases (MMPs) [1;2;19;20].

1.3 Epidemiology of the Disease or Condition

According to Rosstat, 111,506 cases of keratitis were registered in the Russian Federation in 2022, of which 103,653 cases were adult patients.

Bacterial keratitis — the most frequently encountered form of keratitis. In the United States, approximately 71,000 cases of microbial keratitis, including bacterial and fungal infections, are registered annually, which accounts for 12.9% of all corneal pathology. BK most commonly develops upon the introduction of Staphylococcus spp. (especially S. aureus), Streptococcus spp. (including S. pneumoniae and the viridans group), Pseudomonas spp. (P. aeruginosa is the dominant species), Enterobacteriaceae (including Serratia species, Klebsiella species, Citrobacter species, and Proteus species), and gram-negative cocci (including H. influenzae and M. catarrhalis) [21;22;35].

Herpetic keratitis. Globally, 1,000,000 new cases and 9,000,000 recurrent episodes of ocular HSV forms are registered annually. HSV is the cause of visual disability in 1,000,000 people worldwide every year. The incidence of HK in developed countries ranges from 10 to 30 per 100,000 population per year [25;36;37;38].

Adenoviral keratitis (epidemic keratoconjunctivitis, EKC). Adenoviral ocular surface disease is considered the most common cause of "red eyes" among the population of various countries worldwide [38]. Adenoviral ocular lesions account for up to 75% of all conjunctivitis cases globally, with approximately 20–30 million people suffering from HAdV-associated conjunctivitis annually [39]. EKC is usually associated with serotypes 8, 19, and 37. The most frequently encountered adenovirus serotypes affecting the ocular surface (in descending order of frequency) are: in Europe — 8, 3, 7, 19/37; in Japan — 8, 81, 4, 19/37, 3; in the USA — 8, 19, and 37 [40;41]. Nosocomial infection is most frequently associated with serotype 8 viruses [42].

Fungal keratitis. There are no exact statistics on the prevalence of fungal keratitis. At the same time, FK occurs in 50% of patients with confirmed bacterial keratitis [44], especially in tropical and subtropical regions. FK is more common in developing countries (China, India) than in developed countries (USA, Australia). According to researchers from India, 1,360 people with culture-confirmed fungal keratitis were monitored over a period of 10 years and 5 months [45]; according to data from China, 654 patients with FK were registered over a 6-year period [44]. At the same time, FK was noted in 56 eyes (56 patients) in Melbourne (Australia) and in 61 eyes (57 patients) in New York (USA) over 8-year and 16-year periods, respectively [44;45].

Acanthamoeba keratitis. AK is considered a rare disease included in the Orphanet database (ORPHA67043), and its prevalence is estimated at 1–9/100,000. The frequency of AK is 1% in India [46], while in countries with significant contact lens use, it is 4–8% [47] and affects approximately 20 patients per 1 million CL users per year [48].

Marginal keratitis (peripheral ulcerative keratitis). Associated with systemic autoimmune diseases — rheumatoid arthritis, systemic collagenoses, vasculitis, etc. The average incidence of MK varies from 0.2 to 3 patients per million population per year [49]. In 25% of cases, the development of MK is the manifestation of a systemic autoimmune disease [15].

Neurotrophic keratitis. Although neurotrophic keratoconjunctivitis (NK) is classified as a rare disease (ORPHA137596) with an estimated prevalence of less than 5 per 10,000 individuals, epidemiological data remain somewhat imprecise. NK develops in an average of 6% of cases following prior herpetic eye infection (prevalence 149 per 100,000) and in 12.8% of cases following H. zoster infection (prevalence 26 per 100,000). Furthermore, 2.8% of patients undergoing surgical procedures for trigeminal neuralgia suffer from NK. Given that the prevalence of trigeminal neuralgia is 1.5 per 10,000, the prevalence of NK as a consequence can be estimated at 0.02 per 10,000. NK frequently occurs secondary to other conditions such as diabetes mellitus, multiple sclerosis, acoustic neuromas, etc. In such cases, statistical data are lacking and unavailable in the literature [17].

Keratitis in dry eye syndrome occurs in 5–35% of the adult population; women are affected more frequently, and the number of patients increases with age. Translating this to the population of Russia, 1.6 million women and 840 thousand men—a total of 2.5 million citizens—should suffer from this pathology. Moreover, dry eye syndrome (DES) affects children and adolescents: in Japan, DES was diagnosed in 4.3% of boys and 8% of girls aged 15–18 years [50].

1.4 Features of Coding the Disease or Condition

H16 – Keratitis

H16.1 – Other superficial keratitis without conjunctivitis

H16.2 – Keratoconjunctivitis (including caused by external agents)

H16.3 – Interstitial (stromal) and deep keratitis

H16.8 – Other forms of keratitis

H16.9 – Keratitis, unspecified

H17.1 – Other central corneal opacities

H17.8 – Other scars and opacities of cornea

H18.2 – Other corneal oedema

H18.3 – Changes in corneal membranes

H18.8 – Other specified disorders of cornea

H19.1* – Herpesviral keratitis and keratoconjunctivitis

1.5 Classification of the disease or condition

There are numerous classifications of keratitis based on etiopathogenesis, severity, localization of the inflammatory process, its depth and extent, clinical forms and phases, as well as the presence of complications such as hypopyon, etc. [17; 23; 51–56]

By etiology:

• Bacterial keratitis.

• Herpetic keratitis.

• Adenoviral (epidemic) keratitis / keratoconjunctivitis.

• Fungal keratitis.

• Acanthamoeba keratitis.

• Autoimmune (allergic) peripheral (marginal) keratitis.

• Neurotrophic keratitis.

• Keratitis in dry eye syndrome.

Herpetic keratitis. By depth of involvement: dendritic — involving the superficial epithelial layer of the cornea; geographic (amoeboid) — involving the superficial epithelial / subepithelial layer of the cornea; disciform — involving the corneal stroma [51; 52; 56].

Neurotrophic keratitis

According to the clinical classification of neurotrophic keratoconjunctivitis (NK) (neurotrophic keratopathy) [17; 57; 58], the development of NK is possible only in mild and moderate stages:

Stage 1 (mild) NK manifests as periodic development of xerosis and epithelial defects of varying severity (ranging from isolated punctate epitheliopathy to total confluent defects), with moderate corneal stromal edema. Prolonged progression of NK can lead to epithelial cell hyperplasia and limbal vessel vascularization.

Stage 2 (moderate) NK is characterized by the formation of more extensive and deeper corneal defects—micro- and macro-erosions, predominantly oval or round in shape, localized paracentrally in the upper half of the cornea. Depending on the depth of the defect, the pathological process may be accompanied by stromal edema and descemetocele.

1.6 Clinical presentation of the disease or condition

Clinical manifestations of keratitis depend on the etiology of the disease [1; 2; 12; 13; 17; 51–56].

Symptoms: Patients with keratitis of any etiology, except neurotrophic keratitis, present with: lacrimation, photophobia, foreign body sensation, pain, redness and swelling of the eyelids, eye redness, and decreased visual acuity.

In neurotrophic keratitis, due to decreased or absent corneal sensitivity, the main complaints presented by the patient are decreased visual acuity and eye redness.

Clinical signs of keratitis:

General nonspecific clinical signs of keratitis:

- discharge of various character (serous, mucous, mucopurulent, purulent)

- eyelid edema and hyperemia

- blepharospasm

- mixed injection of varying severity

- pericorneal injection of varying severity

- corneal stromal infiltration with epithelial defect(s)

- uveal signs

- hypopyon

Specific clinical signs of keratitis:

Infectious keratitis.

Bacterial keratitis: Distinctive symptoms include the presence of purulent or mucopurulent discharge in the conjunctival cavity, moderate to marked pericorneal injection, conjunctival chemosis, pronounced corneal stromal infiltration with epithelial defect(s), and frequently uveal signs and hypopyon. The formation of stromal infiltrate and overlying epithelial defects depends on the causative agent and takes varying amounts of time—from several hours to several days. Infiltrates in bacterial keratitis have a yellowish hue, or a rusty tint in cases of vascularization. The borders of the infiltrate are distinct, with areas of surface ulceration and stromal thinning. When the inflammatory process spreads to deeper structures of the eye, keratoiritis, keratoiridocyclitis, or keratouveitis develops, accompanied by the deposition of precipitates on the posterior surface of the cornea, the appearance of fibrin in the anterior chamber fluid, and hypopyon. In severe cases, a purulent corneal ulcer develops with a risk of perforation and other complications: purulent endophthalmitis, secondary glaucoma, subatrophy of the eyeball, and sympathetic ophthalmia.

Disease progression depends on the virulence of the pathogen and the host's defense capabilities. Thus, Pseudomonas aeruginosa and Neisseria gonorrhoeae cause rapid destruction of the corneal stroma. Other pathogens, such as staphylococci, streptococci, and pneumococci, lead to a slowly developing, localized focus of inflammation [1; 2; 4; 22; 55; 56].

Herpetic keratitis is a progressively developing disease. Examination reveals mild pericorneal and/or conjunctival injection. The cornea exhibits an epithelial defect in the form of dendritic lesions ending in "terminal bulbs," which extend deeper than the basement membrane and coalesce to form geographic lesions. The jagged or geographic borders of the defect distinguish herpetic keratitis from the smooth borders seen in neurotrophic keratitis. In areas of dendritic or geographic epithelial lesions, a decrease in sensitivity is observed in 80% of cases. Intact areas of the cornea retain normal sensitivity. In herpetic keratitis associated with herpes zoster, nearly complete corneal anesthesia is present [5; 6; 23; 24; 26].

Adenoviral (epidemic) keratoconjunctivitis develops against the background of adenoviral conjunctivitis on days 7–10 from disease onset. Examination reveals edema of the plica semilunaris and lacrimal caruncle. Eyelid edema and associated inflammatory ptosis are often observed only in the predominantly affected eye. Serofibrinous, sometimes mucopurulent exudate, redness, and edema (up to chemosis) of the bulbar and palpebral conjunctiva with follicular reaction. Petechiae and subconjunctival hemorrhages are formed. In cases of acute hemorrhagic conjunctivitis, extensive epibulbar and tarsal hemorrhages may be noted. Small epithelial infiltrates form on the cornea, which progress to remain discrete or coalesce into subepithelial "nummular" lesions. Corneal sensitivity remains unaffected, which distinguishes epidemic keratoconjunctivitis from herpetic corneal involvement.

When infiltrates are localized within the visual axis, a decrease in visual acuity is noted. Numular opacities typically regress within a few weeks but can persist for years, causing irregular astigmatism [7–9; 27; 38; 41; 42; 59; 162].

Fungal keratitis

The clinical picture of fungal keratitis depends on the species of the pathogen. Clinical mycology distinguishes two main groups of fungi—molds (hyphal or filamentous) and yeasts. Of these, about 70 species can cause corneal lesions. Among filamentous fungi causing fungal keratitis, representatives of the genera Fusarium, Aspergillus (lightly colored, non-pigmented, or hyalohyphomycetes) and Curvularia (darkly colored, pigmented, or phaeohyphomycetes) are most common. The most frequent genus of yeast-like fungi causing fungal keratitis is Candida. Unlike bacterial keratitis, fungal infection develops slowly. Clinical manifestations are delayed by 10–20 days, during which fungal replication occurs before detection by the host organism. In infections caused by Fusarium species, clinical processes may proceed more rapidly.

At the onset of the disease, the epithelial defect may have a dendritic shape, which requires differential diagnosis with herpetic keratitis. The course of the disease is undulating: against the background of corneal improvement, in the absence of antifungal therapy, a sudden deterioration occurs—the area and depth of the infiltrate increase, and a hypopyon appears and progresses.

The clinical presentation of fungal keratitis depends on the species of fungi, but there are common features characteristic of most fungi: scalloped, serrated edges of the defect; protruding, dry, crumbly, or cheesy structured appearance of infiltrates and necrotic masses (representing fragments of cells, spores, and fungal mycelium); satellite (or shed) infiltrates; changes in the color of the affected area to any color other than white and yellow. Exudate deposits on the endothelium and the formation of immune rings (Wessely ring) in the cornea are less common. The hypopyon is pyramidal or dome-shaped, which can lead to a significant increase in intraocular pressure and the likelihood of further surgical intervention.

In the final stage, the infiltrate (corneal sequester) is rejected by the proliferating fungus. An intense opacity remains at the lesion site [10;11;12;29].

Acanthamoeba keratitis. Acanthamoeba causes keratitis with an undulating course, which, in the absence of early diagnosis and adequate treatment, can lead to severe visual impairment, up to blindness. Almost all patients report pain, eye redness, photophobia, decreased vision, tearing, and a foreign body sensation. Severe pain, disproportionate to the clinical manifestations, is considered characteristic of AK, but its absence does not rule out this diagnosis.

The disease develops in several stages: early stages show changes in the corneal epithelium followed by involvement of the superficial stromal layers, then its deeper layers, and finally, the pathognomonic ring infiltrate. The process takes from several weeks to several months. Clinical manifestations can be diverse; often the early stages of the disease are misdiagnosed as viral keratitis, and the late stages as bacterial or fungal keratitis.

Early manifestations of the disease include punctate epitheliopathy, epithelial or subepithelial infiltrates, and perineural infiltrates, occurring within a month of disease onset. After 1–2 months, the stroma becomes involved. Limbitis occurs in both early and late stages of the disease. Ulcer, anterior uveitis, hypopyon, endothelial edema, or corneal edema develop in the late stages of the disease [13;14;48].

Non-infectious keratitis.

Marginal keratitis (peripheral ulcerative keratitis)

Clinically, crescent-shaped grey-white infiltrates are recorded, localized at the corneal periphery with the formation of an epithelial defect followed by stromal thinning. The ulceration area increases concentrically. As the clinical condition progresses, the ulceration deepens up to perforation, which may close spontaneously. The formation of several separate foci that merge into a single focus is possible. Associated limbitis, scleritis, iritis, and iridocyclitis may develop. Corneal vascularization develops in the projection of peripheral infiltration with/without stromal involvement. The outcome is marginal corneal opacity with vascularization [15;16;49].

Neurotrophic keratitis

Patients with NK rarely complain of ocular symptoms; the most frequent reason for consulting an ophthalmologist in this group of patients is decreased visual acuity. Lagophthalmos may indicate seventh cranial nerve involvement, leading to corneal xerosis and affecting the clinical progression of NK. Ptosis may indicate third cranial nerve involvement. Clinical signs of conjunctival changes in NK patients are rare, despite the presence of corneal epithelial defects—bulbar conjunctival edema with the formation of parallel conjunctival folds associated with impaired tear production. The presence of a pronounced inflammatory reaction and discharge in the lower fornix may indicate secondary infection.

Corneal epithelial defects, their localization, and extent indicate the severity of NK as well as its progression. Most often, corneal changes are localized in the central zone, progressing from superficial punctate to total epitheliopathy as the condition worsens. Other corneal changes arising during the course of NK, such as neovascularization and opacity formation, may indicate previous acute inflammatory processes. The presence of posterior synechiae may be a sign of prior herpetic uveitis or keratouveitis.

The detection during biomicroscopy of a cellular reaction in the anterior chamber and the presence of fibrin or hypopyon in its aqueous humor may indicate the development of neuroinflammatory iritis, anterior uveitis, and concomitant infection [17;56;57].

Keratitis in dry eye syndrome

A slowly progressive disease, manifested by discomfort and a foreign body sensation, redness, and sometimes photophobia. Conjunctival hyperemia is mild or absent altogether. Punctate epitheliopathy (ranging from single to total) is recorded on the cornea, and micro- and macro-erosions may form. In later stages, filaments composed of dead epithelial cells and mucus form, attached at one end to the cornea and movable with blinking. At the base of the filament, a small epithelial defect staining with fluorescein can be found. Stromal edema and infiltration rarely occur [18;21;54;58].

Complications of keratitis.

The frequency and pattern of keratitis complications depend on the etiological form, duration and severity of the course, and the adequacy of diagnosis and treatment.

Possible complications of keratitis include:

· development of corneal ulcer with perforation/corneal melting;

· formation of anterior synechiae;

· formation of posterior synechiae up to pupillary occlusion;

· formation of prelenticular membranes up to seclusio pupillae;

· rubeosis (neovascularization) of the iris, hyphema;

· secondary ocular hypertension and glaucoma (with pre-angular, angular, pupillary, or malignant block), neovascular glaucoma;

· complicated cataract;

· hypotony and subatrophy of the eye;

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1 Complaints and Anamnesis

Comments:

1. Complaints of tearing, photophobia, foreign body sensation, pain, redness and swelling of the eyelids, eye redness, decreased visual acuity.

2. In infectious keratitis:bacterial keratitis —main complaints of pain, discharge;herpetic keratitis- pain, photophobia, blurred vision, cutting pain in the eye;adenoviral keratitis— foreign body sensation, photophobia, blurred vision;fungal keratitis- decreased visual acuity, photophobia, pain, duration of the course;Acanthamoeba keratitis— severe pain disproportionate to the clinical picture, duration and undulating course.

3. In non-infectious keratitis:marginal keratitis (peripheral ulcerative keratitis- photophobia, tearing;neurotrophic keratitis — due to lack of sensitivity, main complaints of decreased visual acuity, eye redness;keratitis in dry eye syndrome - discomfort, foreign body sensation, sometimes photophobia.

4. When taking the history, attention should be paid to the onset of the disease—acute or gradual; what preceded the onset of the disease: trauma, contact lens wear, ocular surgeries, prolonged use and instillation of medications (especially antibacterials and glucocorticoids), seasonality. Presence of previous eye diseases in the anamnesis—whether the disease is initial or a recurrence. If a recurrence, what treatment was received previously.

5. Presence/absence of surgeries and trauma to the eye.

6. Allergy history. For children — and/or parents' allergy history.

7. The presence of general diseases diagnosed by specialists should be clarified, especially those accompanied by neurotrophic disorders of the eye and its adnexa, immunodeficiency states, and the use of immunosuppressive drugs.

2.2 Physical Examination

Physical examination is not recommended.

Comments: the choice of a specialist profile is determined based on the patient's suspected or confirmed systemic or syndromic disease and the risk of systemic complications.

2.3 Laboratory Diagnostics

Additional laboratory diagnostic tests are prescribed to clarify the diagnosis and to identify systemic and syndromic diseases associated with keratitis, which is important for the patient's further treatment strategy. The decision on the selection and prescription of additional laboratory tests is made following a baseline examination by an ophthalmologist and/or other specialists (rheumatologist, dermatovenereologist, allergist-immunologist, pulmonologist, general practitioner, pediatrician, hematologist, otorhinolaryngologist, urologist, obstetrician-gynecologist).

2.4 Instrumental Diagnostics

At the diagnosis stage and during follow-up examinations:

Comments: the feasibility of refractometry is determined by the location and extent of the corneal lesion, as well as the spread of the infection to deeper structures of the eye.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments:

It is important to remember that the depth of the anterior chamber must be assessed before pharmacological pupil dilation.

Patients with adenoviral keratitis/keratoconjunctivitis are contagious and pose a risk of spreading adenovirus infection.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: Ophthalmodenometry (tonometry) is performed by palpation to minimize traumatic impact on the anterior segment of the eye in keratitis.

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The feasibility of in vivo corneal confocal biomicroscopy depends on the condition of the anterior segment of the eye, the technical equipment of the medical institution, and the availability of a qualified examiner.

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Differential diagnosis

Differential diagnosis is carried out with other visual system disorders characterized by the "red eye" syndrome: acute conjunctivitis, acute glaucoma attack, acute iridocyclitis, as well as with primary corneal dystrophy.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

The goal of treatment is to eliminate the pathogen, relieve active inflammation through local and systemic drug administration, achieve clinical recovery and/or long-term, preferably non-pharmacological remission, and preserve visual functions.

Treatment tactics are determined by the etiology of the inflammatory process, the risk of developing keratitis complications and decreased visual functions, the presence of associated systemic and syndromic pathology, and comorbid conditions.

Treatment of keratitis is carried out by an ophthalmologist; in the presence of an associated systemic or syndromic disease, in close collaboration with relevant specialists (rheumatologist, dermatovenereologist, allergist-immunologist, obstetrician-gynecologist, urologist, etc.).

General practitioners, in accordance with established etiological causes, conduct therapy in accordance with the Federal Clinical Guidelines for the treatment of the underlying disease, monitor the somatic status of patients and adverse events of systemic therapy.

Patients (or patients' parents) must be informed about the benefits and potential side effects of therapy.

Comments: local antibiotic therapy is recommended as etiotropic therapy for the treatment of bacterial, fungal, acanthamoebic keratitis or for suspected/prophylactic secondary bacterial infection in keratitis of other etiology with an antibacterial purpose.

Information on the route of administration, dose, and duration of use of the medicinal product: ofloxacin** 1-2 drops every 4-6 hours, ciprofloxacin** 1-2 drops every 4 hours, levofloxacin** 1-2 drops every 2 hours up to 8 times a day. The course of treatment may last 5-10 days [67-80].

Information on the route of administration, dose, and duration of use of the medicinal product: netilmicin 1-2 drops 3 times a day, tobramycin** 1-2 drops every 4 hours. The course of treatment may last 5-10 days [67-80].

Information on the route of administration dose, and duration of use of the medicinal product: tetracycline**, eye ointment, 0.5-1 cm 2-3 times a day. The course of treatment may last 5-7 days [67-80].

Information on the route of administration erythromycin, eye ointment, dose, and duration of use: 0.5-1 cm from 1 to 3 times a day. The course of treatment may last 5-10 days [67-80].

Information on the route of administration of the medicinal product chloramphenicol, dose, and duration of use: 1 drop every 3-4 times a day. The course of treatment may last 5-10 days [67-80].

Information on the route of administration of the medicinal product colistimethate sodium+ tetracycline+chloramphenicol**, eye ointment, dose, and duration of use: 0.5-1 cm from 3-4 times a day. The course of treatment may last 5-10 days [67-80].

Comments: local antiseptic therapy is recommended as targeted therapy for the treatment of bacterial, fungal, acanthamoeba keratitis, or for suspected/preventive secondary bacterial infection in keratitis of other etiology for antiseptic purposes.

Information on the route of administration, dose, and duration of use of picloxydine: 1 drop 2 to 6 times/day for adults and 1 drop 6 times/day for children. The treatment course may last for 10 days [84-88].

Information on the route of administration, dose, and duration of use of benzyldimethylmyristoylaminopropylammonium: instillations of 1-2 drops 4-6 times/day. The treatment course may last for 5-14 days [84-88].

Comments: local antiviral therapy is recommended as targeted therapy for the treatment of infectious keratitis (herpetic, adenoviral) for antiviral purposes.

Information on the route of administration, dose, and duration of use of interferon alfa-2b + diphenhydramine: 1-2 drops 6-8 times/day. As the inflammatory process resolves, the number of instillations is reduced to 2-3 times/day. The course of treatment lasts until the symptoms of the disease disappear [88-99].

Information on the route of administration, dose, and duration of use of #solanum tuberosum sprouts polysaccharides sum: 2 drops 4 times a day with an interval of 2 hours. The course of treatment is up to 15 days [88-99;162].

Comments: local antiviral therapy is recommended as targeted therapy for patients with infectious keratitis (herpetic) for antiviral purposes.

Information on the route of administration, dose, and duration of use of aciclovir**, eye ointment: for adults and children, 1 cm 5 times a day. The course of treatment is continued until healing + 3 days after healing [102-110].

Comments: Local anti-inflammatory therapy is targeted treatment in patients with peripheral (marginal) keratitis, as well as in pronounced inflammatory response in keratitis of other etiology.

Information on the route of administration, dose, and duration of use of dexamethasone 0.1%: According to the instructions: 1-2 drops 4-5 times a day for 2 days, thereafter the drug is used at 1-2 drops 3-4 times a day for 4-6 days. For children aged 6 to 12 years, 1 drop 2-3 times a day for 7-10 days [113-133].

Information on the route of administration, dose, and duration of use of fluorometholone 0.1%: 1-2 drops 2-4 times a day until inflammation symptoms decrease/disappear. The course of treatment is no more than 3 weeks [113-133].

When using topical glucocorticosteroids, monitoring of intraocular pressure is necessary to prevent its elevation, and monitoring of the anterior segment of the eye (corneal thickness) is required to avoid complications [113-133].

Comments: Information on the route of administration, dose, and duration of use of #diclofenac** 0.1%: 1 drop 4 times/day. The course of treatment may last from 3 to 4 weeks [43;83;100;134;135].

Comments: local NSAID therapy is recommended as symptomatic therapy for the treatment of keratitis with pronounced signs of inflammation.

Information on the route of administration, dose, and duration of use of bromfenac 0.09%: instillations of 1 drop 1-2 times a day for 1 to 2 weeks [134;135].

Comments: Information on the route of administration, dose, and duration of use of #amphotericin B** (0.15% solution) for adults and children: #amphotericin B** solution (1.5–3.0 mg per 1 ml of aqueous solution), into the conjunctival sac, 1 drop 4–6 times/day, 10–15 days. Topical drug administration is combined with subconjunctival injection of antifungal agents (prepared ex tempore): #amphotericin B** solution (0.1–0.5 mg in 0.5 ml of water for injections), subconjunctivally 1 time/day, 10–15 days [136-143, 177].

Comments: Information on the route of administration, dose, and duration of use of #fluconazole** (0.2% solution) for adults and children: instillations of #fluconazole** 0.2% solution into the conjunctival sac, 1 drop 4–6 times/day, 10–15 days [136-143, 174-176].

Comments: in the absence of a manufactured ophthalmic form, it is prepared ex tempore by diluting a 0.05% aqueous solution of #chlorhexidine** to a 0.02% solution (with saline in a 2:3 ratio) [136-143, 178].

Information on the route of administration of the drug #chlorhexidine** (0.02% solution), dose, and duration of use: eye instillations of #chlorhexidine** 0.02% solution, 1 drop 5–6 times/day, 10–20 days [136-143, 178].

Comments: Instillations of sulfated glycosaminoglycan are prescribed to accelerate the epithelialization of corneal defects [144-145].

Information on the route of administration, dose, and duration of use of sulfated glycosaminoglycan: eye drops – instillations of 1-2 drops 4-5 times a day for 1 month.

Comments: Instillations of dexpanthenol are prescribed to accelerate the epithelialization of corneal defects [150-151].

Information on the route of administration, dose, and duration of use of dexpanthenol: eye drops – instillations of 1 drop 4 times a day, as well as 1 drop at bedtime [144-145].

Comments: Instillations of hypromellose** are prescribed for replacement of the precorneal tear film and to accelerate epithelialization of corneal defects [144-145].

Information on the method of administration, dose, and duration of treatment with the medicinal product hypromellose**: eye drops — instill 1 or 2 drops 4–8 times a day into the lower conjunctival sac, or 1 or 2 drops every hour if necessary. Treatment duration is at least 2–3 weeks [144-145]. In children under 18 years of age, the drug should be used only if the expected benefit outweighs the potential risk.

Comments: Cyclosporine instillations are prescribed as targeted therapy for non-infectious keratitis (keratitis in dry eye syndrome) when tear replacement therapy is ineffective [18;21;54;58].

Information on the method of administration, dose, and duration of treatment with the medicinal product cyclosporine: eye drops — instill 1 drop 1–2 times/day. Treatment duration is at least 2 months [18;21;54;58].

Comments: All drugs are prescribed taking into account age restrictions according to the instructions.

Comments: Information on the method of administration, dose, and duration of treatment with the medicinal product phenylephrine: phenylephrine is used in keratitis with iridocyclitis to prevent the development and rupture of already formed posterior synechiae and to reduce exudation into the anterior chamber of the eye as instillations of 1 drop 2–3 times a day; in case of insufficient efficacy in adults — #subconjunctivally 1% solution, 0.2 ml once [152-155;172;173]. Phenylephrine is contraindicated in children.

Information onстю the method of administration of the medicinal product phenylephrine: #subconjunctivally administered 0.1% phenylephrine solution 0.2 ml once.

Information on the method of administration, dose, and duration of treatment with the medicinal product atropine**: in patients over 7 years of age, #subconjunctivally 0.1% solution is administered at a dose of 0.2–0.5 ml [172;173]. Instillations of a 1% solution in patients over 7 years of age are performed 1–2 drops 2–3 times with a 6-hour interval.

Comments: local therapy is prescribed as monotherapy or, in case of insufficient efficacy, as drug combinations. Drugs of choice are carbonic anhydrase inhibitors (#brinzolamide 1%, dorzolamide** 2%), beta-blockers (timolol** 0.25%, 0.5%, #betaxolol 0.5%), sympathomimetics for glaucoma treatment (brimonidine 0.15%, 0.2%).

Information on the method of administration, dose, and duration of treatment with the medicinal product #brinzolamide 1% (contraindicated in children), dorzolamide** 2%: 1 drop into the affected eye(s) 3 times a day, duration not exceeding 1–2 months.

Information on the method of administration, dose, and duration of treatment with the medicinal product brimonidine 0.15%, 0.2%: 1 drop 3 times a day with an interval of about 8 hours between administrations. According to the instructions, it is used in children from 2 years of age and weighing more than 20 kg.

Information on the method of administration, dose, and duration of treatment with the medicinal product #betaxolol 0.5%: in patients over 18 years of age, 1–2 drops 2 times a day, duration not exceeding 1–2 months.

Systemic antibacterial therapy (ATX group J01) may be prescribed to adults and children (according to the instructions) to resolve the bacterial process in keratitis [2;141;142].

Level of Evidence CGrade of Recommendation 5Level of Recommendation C (Grade of Evidence – 5)

Systemic NSAID therapy may be prescribed to adults and children (according to the instructions) to relieve inflammation and pain in keratitis [154-159].

Patients receiving NSAIDs require monitoring for potential adverse events: gastrointestinal tract lesions, nephrotoxicity, allergic reactions, hepatotoxicity, hematotoxicity, and others.

Comments: systemic antifungal therapy cannot be considered as monotherapy in the treatment of fungal keratitis due to low concentrations achieved in corneal tissues.

With prolonged systemic therapy, monitoring for potential side effects is necessary due to the potential nephro- and hepatotoxicity of these drugs.

# in the Russian Federation, most systemic antifungals lack official package insert indications for the treatment of ophthalmic mycoses. Prescribing these drugs is recommended for deep corneal stromal involvement and severe disease course [136-143].

3.2 Surgical Treatment

An indication for surgical treatment of keratitis is a long-standing non-healing ulcer refractory to medical therapy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

6. Organization of Medical Care

Emergency medical care is provided in outpatient and inpatient settings.

Stages of medical care delivery

1. First medical aid

2. Outpatient

3. Inpatient

Medical indications for hospitalization in a medical organization

Elective hospitalization is carried out when conservative therapy under the constant supervision of an ophthalmologist is required, when there is a threat of complications, when outpatient treatment is not feasible, and for surgical treatment of keratitis.

Criteria for patient discharge from a medical organization: completion of the specialized medical care phase in an inpatient or day-hospital setting.

7. Additional Information

Currently, thanks to early detection and modern methods of medical and surgical treatment, the prognosis for keratitis is favorable in the majority of patients. The prognosis is largely determined by the etiopathogenetic form of the disease.

Predictors of a good functional prognosis are a mild course of the inflammatory process in the eye, as well as timely administration of local and systemic therapy.

Predictors of a poor functional prognosis are: a severe or persistent course of inflammation, development of keratitis complications, resistance to ongoing therapy, and a prolonged disease course.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Arestova N.N., MD, Leading Researcher, Department of Pediatric Eye Pathology, National Medical Research Center of Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

2. Brzheskiy V.V., MD, Professor, Head of the Department of Ophthalmology, Saint Petersburg State Pediatric Medical University, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

3. Grishina E.E., MD, Professor, Professor at the Department of Ophthalmology and Optometry, Faculty of Advanced Medical Training, M.F. Vladimirskiy Moscow Regional Research Clinical Institute (MONIKI), member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

4. Drozdova E.A., MD, Associate Professor, Professor at the Department of Eye Diseases, South Ural State Medical University of the Russian Ministry of Health, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

5. Kasparova E.A., PhD, Leading Researcher, Department of Pathology of Optical Media of the Eye, Research Institute of Eye Diseases, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

6. Lebedev O.I., MD, Professor, Head of the Department of Ophthalmology, Omsk State Medical Academy, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

7. Maychuk D.Yu., MD, Head of the Department of Therapeutic Ophthalmology, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health.

8. Markova E.Yu., MD, Head of the Department of Microsurgery and Functional Rehabilitation of the Eye in Children, S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

9. Obrubov A.S., PhD, Associate Professor at the Department of Ophthalmology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health; ophthalmologist at the inpatient unit of the Moscow City Ophthalmological Center, S.P. Botkin City Clinical Hospital, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

10. Panova I.E., MD, Professor, Deputy Director for Research, St. Petersburg Branch of the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

11. Polovinkina G.V., ophthalmologist of the highest qualification category, ophthalmologist at the fee-for-service ophthalmology department, City Diagnostic Center No. 7; expert in quality control of medical care provided to patients by the physicians of Department No. 1 (Pathology of the Anterior Segment of the Eye), member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

12. Riks I.A., PhD, Head of the Ophthalmology Department, Nashe Zdorovye Multidisciplinary Clinic, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

13. Saydasheva E.I., MD, Professor at the Department of Ophthalmology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Chief Pediatric Ophthalmologist of the Russian Ministry of Health in the North-Western Federal District, member of the Presidium of the Association of Ophthalmologists, member of the Russian Ophthalmological Society, Honored Doctor of the Russian Federation.

14. Safonova T.N., PhD, Leading Researcher, M.M. Krasnov Research Institute of Eye Diseases, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

15. Slonimskiy A.Yu., MD, Professor, Moscow Eye Clinic, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

16. Trufanov S.V., MD, Deputy Director for Research, Nashe Zdorovye Multidisciplinary Clinic, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

17. Chernakova G.M., PhD, Associate Professor, Head of the Consultation Department, Moscow City Ophthalmological Center, S.P. Botkin City Clinical Hospital, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

18. Chekhova T.A., PhD, Head of the Therapeutic Department, Novosibirsk Branch of the S.N. Fyodorov Eye Microsurgery Federal State Institution of the Russian Ministry of Health, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

19. Yani E.V., PhD, Head of the Department of Infectious and Allergic Eye Diseases, National Medical Research Center of Eye Diseases named after Helmholtz of the Russian Ministry of Health, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

20. Yanchenko S.V., MD, Associate Professor, Professor at the Department of Ophthalmology, Kuban State Medical University, ophthalmologist of the highest qualification category, member of the Association of Ophthalmologists, member of the Russian Ophthalmological Society.

    Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

· Ophthalmologists;

· General practitioners (family physicians)

Methods used for collecting/selecting evidence: search in electronic databases, analysis of current scientific developments on the problem of keratitis in Russia and abroad; synthesis of practical experience of Russian and foreign specialists; library resources. Description of methods used for collecting/selecting evidence: the evidence base for the guidelines includes publications included in the Cochrane Library, EMBASE and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on the subject. The search depth was 10 years. Methods used for assessing the quality and strength of evidence: expert consensus, assessment of significance in accordance with the rating scale.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Current instructions for the medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru

2. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). World Health Organization.

3. Nomenclature of Medical Services. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

4. Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

5. Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, its Adnexa, and Orbit. Order of the Ministry of Health of the Russian Federation No. 902n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, its Adnexa, and Orbit."

6. List of Vital and Essential Drugs for Medical Use for 2020. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on April 26, 2020), "On Approval of the List of Vital and Essential Drugs for 2020, as well as Lists of Drugs for Medical Use and the Minimum Assortment of Drugs Required for the Provision of Medical Care."

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Keratitis is inflammation of the cornea with/without disruption of its integrity; in the absence of timely diagnosis and treatment, it can lead to the risk of losing the eye, as well as a significant decrease in visual acuity, up to blindness.

Keratitis is a polymorphic process caused by bacteria, viruses, allergic agents, as well as non-infectious processes.

The patient must be informed about the possible symptoms of keratitis and its complications, and the need for urgent consultation with an ophthalmologist upon their appearance. Immediate medical attention from an ophthalmologist is required if any of the following symptoms occur: photophobia, pain, decreased and/or blurred vision, change in iris color, pupil size and shape.

Strict adherence to all prescriptions of the ophthalmologist and related specialists (rheumatologist, dermatologist, general practitioner, pediatrician, urologist, gynecologist, etc.) is required.

The patient must be aware of the potential side effects of therapy and the need to seek immediate medical attention from an ophthalmologist (or related specialists) if they develop.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Rating scales, questionnaires, and other patient status assessment tools are not used.