Conjunctivitis
Conjunctivitis, commonly known as pink eye, is an inflammation of the conjunctiva, the thin, transparent membrane that lines the inner surface of the eyelid and covers the white part of the eyeball, often resulting in redness due to dilated blood vessels.[1] This condition is one of the most common and treatable eye disorders, affecting people of all ages, with bimodal incidence peaks in children under 7 years (highest in ages 0-4) and young adults aged 22-28.[2][3] The primary causes of conjunctivitis are divided into infectious and noninfectious categories, with viral infections—particularly adenovirus (which accounts for 65-90% of viral cases)—being the most common cause, responsible for up to 80% of acute cases overall, followed by bacterial pathogens like Staphylococcus aureus and Haemophilus influenzae, and allergic reactions affecting 15-40% of the population.[3] Viral and bacterial forms are highly contagious, spreading through direct contact with infected eye secretions, contaminated surfaces, or respiratory droplets, while allergic conjunctivitis is triggered by environmental allergens such as pollen and is seasonal, peaking in spring and summer.[2][3] Other less common etiologies include chemical irritants, contact lens overuse, foreign bodies, fungi, parasites, or blocked tear ducts in newborns.[1][3] Symptoms typically include redness or pink discoloration of the eye, swollen eyelids, itching, burning, a gritty sensation, increased tearing, and discharge that may crust over the lashes overnight, varying by type—purulent for bacterial, watery for viral or allergic.[2][1] Diagnosis is primarily clinical based on history and physical examination, including discharge characteristics and associated lymphadenopathy, though cultures or rapid antigen tests may be used for severe or recurrent cases.[3] Treatment depends on the cause: supportive care with artificial tears and cold compresses for viral cases, which often resolve in 1-2 weeks; topical antibiotics like fluoroquinolones for bacterial infections; and antihistamines or allergen avoidance for allergic types, with complications such as corneal involvement rare but potentially vision-threatening if untreated.[3] Prevention emphasizes hygiene practices, including frequent handwashing, avoiding eye touching, and not sharing personal items, particularly in contagious forms.[2][1]Overview
Definition
Conjunctivitis, commonly known as pink eye, is an inflammation of the conjunctiva, the thin, transparent mucous membrane that lines the inner surface of the eyelids and covers the anterior portion of the sclera, or white part of the eye.[1][3] This condition arises from various triggers leading to vascular congestion and tissue swelling in the affected area.[3] The term "pink eye" stems from the characteristic redness of the ocular surface, caused by dilation and engorgement of the conjunctival blood vessels.[4] Conjunctivitis affects individuals across all age groups and is generally self-limiting, often resolving spontaneously within one to two weeks, though its potential for contagion depends on the specific etiology.[5][6] In the United States, the condition accounts for an estimated 6 million cases annually.[7]Classification
Conjunctivitis is primarily classified by its etiology into infectious and non-infectious categories, with infectious forms further subdivided into viral and bacterial subtypes, while non-infectious includes allergic, chemical or irritant-induced, and other causes such as autoimmune or neoplastic conditions.[3][8] Viral conjunctivitis, often caused by adenoviruses, represents the most common infectious type, followed by bacterial infections from pathogens like Staphylococcus aureus or Haemophilus influenzae.[9] Non-infectious types encompass allergic reactions mediated by IgE and histamine release, as well as irritant exposures from chemicals or foreign bodies.[1] Other forms, such as those linked to systemic autoimmune diseases like ocular mucous membrane pemphigoid, fall into miscellaneous categories due to their distinct underlying mechanisms.[8] A secondary classification considers the extent of involvement, distinguishing between unilateral (affecting one eye) and bilateral (affecting both eyes) presentations, as well as localized versus diffuse conjunctival inflammation, which aids in differentiating etiologies during clinical assessment.[9] For instance, bacterial conjunctivitis may initially present unilaterally before becoming bilateral, whereas allergic forms typically involve both eyes symmetrically with diffuse involvement.[8] This spatial categorization is crucial for guiding diagnostic approaches, as unilateral cases often prompt evaluation for foreign bodies or focal infections.[1] Conjunctivitis is also categorized by duration and pattern, with acute forms lasting less than 4 weeks, chronic persisting beyond 4 weeks, and recurrent or hyperacute variants indicating severe or repeated episodes.[9][6] Allergic conjunctivitis specifically includes seasonal (triggered by pollen or environmental allergens) and perennial (year-round, often due to indoor irritants) subtypes, reflecting exposure patterns.[10] These temporal distinctions help predict prognosis and management strategies, such as monitoring chronic cases for underlying systemic issues.[8] Neonatal conjunctivitis, also known as ophthalmia neonatorum, forms a distinct subgroup occurring within the first month of life, primarily due to perinatal exposure to bacteria like Chlamydia trachomatis or Neisseria gonorrhoeae during passage through the birth canal, necessitating prompt evaluation to prevent complications like corneal scarring.[11] This category is separated owing to its unique risks and higher potential for severe outcomes compared to adult-onset forms.[1]Pathophysiology
General Mechanisms
Conjunctivitis is fundamentally an inflammatory condition of the conjunctiva, where the initial response to injury, infection, or irritation involves vasodilation of the conjunctival blood vessels. This dilation increases blood flow to the area, resulting in the characteristic redness or hyperemia observed clinically. Concurrently, increased vascular permeability allows the leakage of plasma proteins and fluid into the surrounding tissues, leading to conjunctival edema (chemosis) and the production of exudate, which manifests as tearing, discharge, or crusting depending on the severity. These vascular changes are mediated by local release of vasoactive mediators and represent a universal hallmark across all forms of conjunctivitis.[3][6] The inflammatory cascade in conjunctivitis is driven by a complex interplay of signaling molecules, including pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). These cytokines are secreted by activated epithelial cells, resident immune cells, and infiltrating leukocytes, promoting further amplification of inflammation through recruitment of neutrophils, eosinophils, and macrophages to the conjunctival tissues. Histamine, primarily released from degranulated mast cells upon stimulation, exacerbates this process by binding to H1 receptors on endothelial cells, enhancing vasodilation and permeability while contributing to symptoms like itching and irritation. This cascade establishes a self-perpetuating cycle of tissue damage and repair unless resolved.[12][13][14] Conjunctival goblet cells, specialized epithelial cells within the conjunctival mucosa, are integral to the ocular surface defense by secreting gel-forming mucins, primarily MUC5AC, which form a protective layer in the tear film. In the context of inflammation, these cells respond to stimuli by increasing mucin production, which can lead to excessive mucus secretion and contribute to the viscous exudate seen in many cases; conversely, chronic inflammation induced by cytokines like TNF-α can reduce goblet cell density and function, disrupting tear film stability and exacerbating dryness and epithelial damage. This dual role underscores goblet cells' contribution to both protective mucus barriers and pathological responses in conjunctival inflammation.[15][16] The immune response underlying conjunctivitis exhibits variations between innate and adaptive arms, tailored to the underlying trigger. Innate immunity provides rapid, non-specific protection through antimicrobial components in the tear film, such as lysozyme and immunoglobulins, which limit pathogen spread and initiate the inflammatory cascade via pattern recognition receptors on epithelial cells. In contrast, adaptive immunity, predominant in allergic forms, involves antigen-specific T-cell activation and antibody production, leading to sustained lymphocytic infiltration and chronic inflammation. These distinctions highlight how general mechanisms adapt to specific contexts without altering the core vascular and cellular responses.[3][9]Etiology-Specific Pathways
Infectious pathways in conjunctivitis involve pathogen invasion of the conjunctival epithelium, leading to cellular damage and inflammation. For viral causes, such as adenoviruses, which cause up to 90% of viral conjunctivitis cases, the pathogen adheres to epithelial cell receptors via projecting fibers like pentons, facilitating entry and intracellular replication. This replication culminates in epithelial cell lysis, releasing viral particles and inducing superficial punctate keratopathy along with subepithelial infiltrates, particularly in epidemic keratoconjunctivitis caused by serotypes 8, 19, or 37.[17] Bacterial pathogens, including Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus, colonize the ocular surface through direct contact or compromised epithelial barriers, particularly in children, contact lens wearers, and immunocompromised individuals. These bacteria produce toxins and enzymes that exacerbate epithelial disruption, promoting purulent discharge and potential keratitis.[4] Secondary bacterial superinfection frequently complicates viral conjunctivitis, as epithelial lysis weakens local defenses, allowing opportunistic bacterial overgrowth and intensified inflammatory responses.[17] Allergic pathways are characterized by an IgE-mediated type I hypersensitivity reaction, where allergen exposure triggers rapid mast cell degranulation in the conjunctiva. Upon re-exposure, allergens cross-link IgE antibodies bound to high-affinity FcεRI receptors on sensitized mast cells, prompting the release of preformed mediators such as histamine, tryptase, and leukotrienes, alongside newly synthesized cytokines and prostaglandins. This degranulation induces immediate vascular permeability, itching, and chemotaxis of eosinophils and basophils, amplifying ocular surface inflammation.[10] Dominance of Th2 immune responses further sustains the process, with cytokines like IL-4 promoting B-cell class switching to IgE production and IL-13 enhancing goblet cell mucus secretion and epithelial barrier dysfunction. These Th2-skewed signals, including IL-5 for eosinophil recruitment, create a chronic inflammatory milieu in forms like vernal or atopic keratoconjunctivitis.[10][18] Chemical pathways initiate direct toxic injury to the conjunctival epithelium upon exposure to irritants, acids, or alkalis, bypassing immune mediation. Alkalis, such as ammonia or sodium hydroxide, penetrate deeply by saponifying cell membrane lipids, causing liquefactive necrosis and widespread epithelial denudation that extends to stromal layers. Acids, like sulfuric acid, provoke protein coagulation on the surface, limiting deeper invasion but still resulting in ischemic necrosis and sloughing of the epithelium.[19] Irritants, including alcohols or environmental pollutants, induce oxidative stress through reactive oxygen species generation, leading to lipid peroxidation, protein modification, and apoptosis in conjunctival cells. This oxidative damage disrupts tear film stability and triggers secondary inflammatory cascades via cytokine release, such as TNF-α, exacerbating surface toxicity.[19][20] Chronic forms of conjunctivitis arise from persistent antigen exposure, driving progressive fibrosis and tissue remodeling in the conjunctiva. In conditions like vernal or atopic keratoconjunctivitis, ongoing allergen or autoantigen stimulation activates conjunctival fibroblasts and myofibroblasts, marked by α-smooth muscle actin expression, leading to excessive extracellular matrix deposition and subepithelial collagen accumulation. This results in forniceal shortening, symblepharon, and ankyloblepharon, impairing ocular motility and lubrication.[21] Th2-derived cytokines, particularly IL-13 and TGF-β from CD11b+ dendritic cells and T-helper cells, form a feedback loop that sustains fibroblast proliferation and inhibits matrix degradation, culminating in irreversible scarring. In autoimmune variants like ocular mucous membrane pemphigoid, chronic inflammation progresses through phases of injury, proliferation, and fibrosis, with persistent autoantigen-driven responses amplifying remodeling.[21][22]Types of Conjunctivitis
Viral Conjunctivitis
Viral conjunctivitis, the most prevalent form of infectious conjunctivitis in adults, is primarily caused by adenoviruses, which account for approximately 80% of cases, followed by herpes simplex virus and enteroviruses.[23] Adenoviral serotypes such as 3, 4, 7, 8, 19, and 37 are most commonly implicated, often leading to epidemic keratoconjunctivitis (EKC) in outbreaks.[24] Emerging strains, including coxsackievirus A24 variant (CVA24v), have been associated with acute hemorrhagic conjunctivitis outbreaks since 2023, notably in regions like Pakistan, India, Bhutan, and the Indian Ocean islands, with continued outbreaks reported in 2024-2025 in East Africa (e.g., Kenya, Tanzania) and the Indian Ocean (e.g., Madagascar, Mayotte).[25][26][27][28] The pathophysiology involves viral entry and replication within conjunctival and corneal epithelial cells, resulting in cytopathic effects such as cell swelling, lysis, and punctate epithelial erosions.[29] This replication triggers an inflammatory response, including recruitment of immune cells and release of cytokines, which contributes to conjunctival hyperemia and edema.[30] In adenoviral cases, late-phase subepithelial infiltrates in the cornea arise from a hypersensitivity reaction to viral antigens, potentially persisting beyond the acute infection.[23] Characteristic signs and symptoms include unilateral or bilateral ocular redness, watery discharge, foreign body sensation, burning, itching, and photophobia, often with preauricular lymphadenopathy indicating viral etiology.[17] Symptoms typically emerge after a 5- to 12-day incubation period and peak within 3 to 5 days, resolving over 1 to 2 weeks in most cases, though discomfort may linger.[31] Severe adenoviral infections may present with follicular conjunctivitis or, in EKC, corneal involvement manifesting as subepithelial opacities.[32] Diagnosis relies on clinical pattern recognition, including the presence of watery discharge and lymphadenopathy, to differentiate from other forms.[3] In outbreak settings or atypical cases, confirmatory polymerase chain reaction (PCR) testing of conjunctival swabs identifies the specific virus, serving as the gold standard for etiologic confirmation.[33] Rapid antigen tests may aid initial assessment but have lower sensitivity compared to PCR.[34] Treatment is predominantly supportive, emphasizing cold compresses, artificial tears, and vaseline ointment to alleviate symptoms and prevent secondary bacterial infection.[35] For herpetic cases, topical or oral antivirals such as acyclovir are indicated to reduce duration and complications.[36] No specific antiviral therapy is approved for adenoviral conjunctivitis, though Phase 2 trials evaluating IVIEW-1201 were completed in 2024, with Phase 3 studies planned or initiated as of 2025 to explore targeted interventions to shorten viral shedding and symptom resolution.[37][38] Strict hygiene measures, including handwashing and isolation, are essential to curb transmission.[17] Complications are uncommon but may include pseudomembrane formation on the tarsal conjunctiva in severe adenoviral infections, potentially leading to scarring if not managed promptly.[39] Keratitis, manifesting as punctate or geographic epithelial defects, occurs rarely and can impair vision temporarily due to corneal inflammation.[32] Persistent subepithelial infiltrates may require topical corticosteroids in refractory cases, under specialist supervision to avoid exacerbating infection.[17]Bacterial Conjunctivitis
Bacterial conjunctivitis, a common form of infectious conjunctivitis, is particularly prevalent in children and results from bacterial colonization of the conjunctival surface. The primary causative agents include Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, which account for most cases in both children and adults.[40] In neonates, Neisseria gonorrhoeae is a significant pathogen, often acquired through vertical transmission during birth.[41] This condition is more frequent in pediatric populations due to higher exposure in school settings and immature immune responses.[42] The pathophysiology involves bacterial adherence to the compromised conjunctival epithelium, where normal flora such as staphylococci and streptococci overgrow following disruptions in host defenses, such as minor trauma or viral coinfection.[4] Certain bacteria produce toxins that exacerbate inflammation and tissue damage, while biofilm formation by pathogens like S. aureus promotes persistent infection and resistance to clearance, ultimately leading to the accumulation of purulent exudate.[43][44] This inflammatory response causes conjunctival hyperemia and edema, distinguishing it from noninfectious forms. Characteristic signs and symptoms include sticky yellow-green purulent or mucopurulent discharge that often mats the eyelids upon waking, conjunctival injection, and mild ocular discomfort or foreign body sensation.[1][5] Unlike viral or allergic variants, itching is typically absent, and the condition is unilateral at onset but may become bilateral.[4] Most uncomplicated cases resolve spontaneously within 7 to 10 days without intervention, though symptoms can persist longer in the absence of treatment.[6] Diagnosis is primarily clinical, relying on the history of purulent discharge and eyelid crusting in the absence of severe pain or vision changes that might suggest deeper involvement.[45] In mild cases, no further testing is needed, but for severe presentations, neonates, or treatment failures, conjunctival swabs for Gram staining or bacterial culture are recommended to identify the pathogen and guide therapy.[4] Treatment focuses on topical antibiotics to accelerate resolution and reduce contagiousness, with options including erythromycin ointment or fluoroquinolone drops applied four times daily for 5 to 7 days.[46][47] For gonococcal cases, systemic antibiotics such as ceftriaxone are essential alongside topical agents. Emerging therapies, such as the antibiotic-NSAID combination NTC014 (a quinolone with bromfenac), completed Phase II trials in late 2024 (MIRAKLE study), demonstrating non-inferiority to antibiotic monotherapy with faster symptom relief and microbiological eradication.[48] Complications are uncommon in routine cases but can be severe in untreated gonococcal infections, including corneal ulceration, perforation, and potential blindness due to rapid progression.[49][50]Allergic Conjunctivitis
Allergic conjunctivitis is an immune-mediated inflammatory condition of the conjunctiva triggered by environmental allergens, distinguishing it as a non-infectious form of ocular allergy. It affects approximately 15-40% of the global population and is characterized by a type I hypersensitivity reaction. Primary causes include exposure to airborne allergens such as pollen, dust mites, animal dander, and mold spores, often exacerbated by genetic predisposition, atopy, and environmental factors like air pollution.[10][51][52] The condition manifests in several types, with seasonal allergic conjunctivitis (SAC) being the most common, occurring during high-pollen seasons like spring and summer due to tree and grass pollens. Perennial allergic conjunctivitis (PAC) presents year-round with milder symptoms, primarily triggered by indoor allergens such as house dust mites and pet dander, often worsening in autumn. A more severe variant, vernal keratoconjunctivitis (VKC), typically affects young males aged 5-20 in warm, dry climates and involves recurrent episodes linked to allergens and climatic factors.[10][51][52] Pathophysiologically, allergic conjunctivitis involves type I hypersensitivity where allergens cross-link IgE antibodies on sensitized mast cells and basophils, leading to rapid degranulation and release of mediators like histamine, tryptase, and leukotrienes. This initiates an immediate phase of inflammation, characterized by vasodilation and increased vascular permeability. A late-phase response follows, involving recruitment of eosinophils, T cells, and additional inflammatory cells, which perpetuate conjunctival edema and hyperemia through cytokine release.[10][51][52] Clinically, patients experience intense bilateral ocular itching as the hallmark symptom, often accompanied by excessive tearing, conjunctival chemosis (swelling), and injection (redness). Symptoms typically persist or recur with ongoing allergen exposure and may include watery or mucoid discharge; in VKC, additional features like photophobia, thick mucus, and giant papillae on the tarsal conjunctiva are common. These manifestations are usually self-limiting but can significantly impair quality of life during peak exposure periods.[10][51][52] Diagnosis relies primarily on a detailed patient history of allergen exposure and atopic conditions, supplemented by clinical examination revealing characteristic signs like conjunctival hyperemia and chemosis. Conjunctival scrapings or impression cytology can confirm the presence of eosinophils, supporting the allergic etiology, while allergy testing such as skin prick or serum IgE levels may identify specific triggers. Differential diagnosis excludes infectious causes through absence of purulent discharge or lymphadenopathy.[10][51][52] Treatment focuses on symptom relief and inflammation control, beginning with allergen avoidance strategies. Topical antihistamines (e.g., emedastine) and dual-action antihistamine-mast cell stabilizers (e.g., olopatadine) are first-line therapies, providing rapid relief from itching and redness by blocking histamine receptors and preventing mediator release. For severe or refractory cases, particularly VKC, short-term topical corticosteroids (e.g., loteprednol) are used to suppress inflammation, though with caution due to risks like glaucoma. Emerging therapies include reproxalap, a reactive aldehyde species modulator under FDA review as of 2025 for potential use in allergic conjunctivitis to reduce oxidative stress and symptoms. Immunomodulators like cyclosporine may be employed in chronic forms.[10][51][52][53] Complications are rare in mild SAC and PAC but more frequent in VKC, where chronic inflammation can lead to corneal involvement, including superficial punctate keratitis or shield ulcers—raised epithelial defects that occur in 3-20% of cases and risk permanent scarring or vision loss if untreated. Prompt management is essential to prevent these sequelae.[10][51][52]Chemical and Irritant Conjunctivitis
Chemical and irritant conjunctivitis arises from direct exposure to external agents that damage the conjunctival surface without involving infectious or allergic pathways. Primary causes include environmental irritants such as chlorine in swimming pools, tobacco smoke, and airborne pollutants, as well as chemical exposures like acids (e.g., sulfuric acid from battery leaks) and alkalis (e.g., ammonia from cleaning products or lime from construction materials).[54][55] Overuse or improper care of contact lenses, including exposure to contaminated solutions, also commonly triggers this form by causing mechanical irritation and toxic buildup on the ocular surface.[56][57] The pathophysiology involves direct cytotoxicity to the conjunctival epithelium, where irritants disrupt the pH balance, leading to protein denaturation and tissue necrosis. Acids typically cause coagulative necrosis by precipitating proteins, forming a barrier that limits deeper penetration, whereas alkalis induce liquefactive necrosis through saponification of cell membranes and free radical generation, resulting in more severe and penetrating damage.[54] This acute injury provokes an inflammatory response with vasodilation, edema, and release of inflammatory mediators, exacerbating conjunctival hyperemia without the immune-mediated features seen in allergic cases.[3][57] Symptoms manifest immediately upon exposure, characterized by intense burning pain, conjunctival redness, and a foreign body sensation, often accompanied by tearing and mild mucous discharge. Severity varies by agent; for instance, alkali exposures produce more profound symptoms and tissue destruction than acids due to their deeper penetration.[54][1] In cases involving chlorine gas or smoke, patients may experience photophobia and blurred vision from epithelial sloughing, while contact lens-related irritation can lead to discomfort that worsens with prolonged wear.[58][55] Diagnosis relies primarily on a detailed history of recent exposure to confirm the irritant source, supplemented by clinical examination revealing conjunctival injection and edema. Testing the tear film pH with litmus paper is essential for chemical exposures, aiming to neutralize it to 7.0–7.2 to assess the need for further intervention; slit-lamp biomicroscopy may reveal epithelial defects or corneal involvement.[54][3] Unlike infectious forms, routine cultures are unnecessary unless secondary infection is suspected.[57] Treatment prioritizes immediate removal of the irritant through copious irrigation with normal saline or balanced salt solution, ideally for at least 30 minutes or until pH normalizes, to minimize ongoing damage.[54][1] Symptomatic relief includes cycloplegic agents like cyclopentolate to reduce ciliary spasm and pain, along with topical lubricants; antibiotics are reserved for cases with secondary bacterial infection and are not routinely indicated.[3] For milder irritants like smoke or chlorine, artificial tears and avoidance of the trigger often suffice for resolution within hours to days.[58][59] Complications are more likely with severe chemical burns, particularly from alkalis, and can include conjunctival scarring, symblepharon (adhesions between conjunctiva and eyelid), and ischemic damage leading to limbal stem cell deficiency.[54] Untreated exposures may progress to corneal opacification or perforation, necessitating surgical interventions like amniotic membrane transplantation in refractory cases.[57]Other Forms
Other forms of conjunctivitis encompass specialized variants such as neonatal infections, chronic infectious conditions like trachoma, drug-induced reactions, and autoimmune-associated cases, which differ from the primary viral, bacterial, allergic, or irritant categories due to their unique etiologies and presentations. Neonatal conjunctivitis, also known as ophthalmia neonatorum, arises from perinatal transmission of pathogens during delivery, with chlamydial and gonococcal infections being prominent causes. Chlamydial neonatal conjunctivitis is caused by Chlamydia trachomatis serovars D-K acquired from maternal genital tract infection, while gonococcal cases stem from Neisseria gonorrhoeae.[60][61] In pathophysiology, chlamydial infection involves intracellular replication of the bacterium in conjunctival epithelial cells, leading to an inflammatory response with inclusion bodies, whereas gonococcal infection triggers a hyperacute purulent reaction due to bacterial endotoxin release. Signs and symptoms of gonococcal neonatal conjunctivitis typically manifest within 24-48 hours of birth, featuring severe eyelid edema, copious purulent discharge, and chemosis, potentially progressing to corneal ulceration if untreated. Chlamydial cases present later, around 5-14 days, with milder mucopurulent discharge, conjunctival injection, and pseudomembrane formation. Diagnosis relies on Gram staining and culture for gonorrhea, revealing gram-negative diplococci, and Giemsa staining or nucleic acid amplification tests (NAATs) for chlamydia to detect intracytoplasmic inclusions. Treatment for gonococcal conjunctivitis requires systemic ceftriaxone (25-50 mg/kg IV single dose) or cefotaxime, alongside saline irrigation to remove discharge, while chlamydial infection is managed with oral erythromycin (50 mg/kg/day for 14 days) or azithromycin (20 mg/kg single dose), evaluating the mother and partner for concurrent infections.[62][63][60] Trachoma represents a chronic form of infectious conjunctivitis endemic in certain regions, caused by repeated ocular exposure to Chlamydia trachomatis serovars A-C, often through direct contact or fly vectors in areas with poor sanitation. The pathophysiology involves persistent follicular hyperplasia in the tarsal conjunctiva from repeated infections, progressing through inflammatory stages to cicatricial scarring, entropion, and trichiasis. Early signs include conjunctival follicles and lymphoid aggregates, evolving to chronic dryness, corneal opacity, and scarring; symptoms encompass irritation, tearing, and photophobia, with late-stage vision loss from corneal abrasion by inturned lashes. Diagnosis is primarily clinical using the WHO simplified grading system, supplemented by PCR detection of C. trachomatis DNA in conjunctival swabs, and Giemsa staining for elementary bodies in resource-limited settings. Treatment follows the SAFE strategy: systemic azithromycin (20 mg/kg single oral dose for children, 1 g for adults) for active infection, surgical correction of trichiasis, facial cleanliness, and environmental improvements to reduce transmission. Complications include irreversible blindness from corneal scarring, making trachoma the leading infectious cause of blindness worldwide, affecting an estimated 1.9 million people.[64][65][66] Drug-induced conjunctivitis can emerge as a hypersensitivity reaction to medications, including recent reports of ocular adverse events from immune checkpoint inhibitors (ICIs) used in cancer immunotherapy, such as pembrolizumab and nivolumab. These agents provoke immune-related adverse events through T-cell activation against self-antigens, leading to conjunctival inflammation in approximately 1% of cases, often manifesting as part of dry eye syndrome. Pathophysiology involves immune-mediated epithelial damage and vascular changes, with symptoms including red eyes, irritation, foreign body sensation, and mild discharge, typically appearing weeks to months after initiation. Diagnosis is clinical, supported by exclusion of other causes via slit-lamp examination and discontinuation trials, with the Naranjo algorithm aiding causality assessment. Management entails prompt discontinuation of the offending drug, artificial tears for mild cases, and topical corticosteroids for persistent inflammation, rarely requiring ICI cessation.[67] Autoimmune conjunctivitis, exemplified by keratoconjunctivitis sicca in Sjögren's syndrome, results from systemic autoimmune attack on lacrimal glands, primarily affecting women over 40. The underlying pathophysiology features lymphocytic infiltration and autoimmune epithelitis of exocrine glands, reducing tear production and causing evaporative dry eye with secondary conjunctival inflammation. Signs and symptoms include chronic ocular dryness, grittiness, burning, redness, and filamentary keratitis, often accompanied by xerostomia. Diagnosis involves Schirmer's test for tear quantity (<5 mm/5 min), fluorescein staining for ocular surface damage, and confirmatory salivary gland biopsy showing focal lymphocytic sialadenitis, alongside serologic tests for anti-SSA/Ro and anti-SSB/La antibodies. Treatment focuses on supportive measures like preservative-free artificial tears and punctal occlusion, with anti-inflammatory options such as topical cyclosporine or lifitegrast, and systemic immunosuppressants (e.g., hydroxychloroquine) for severe cases.[68][69]Diagnosis
Clinical Evaluation
The clinical evaluation of suspected conjunctivitis begins with a detailed patient history to identify key features that guide diagnosis and management. Clinicians assess the onset of symptoms, distinguishing acute presentations (typically within days) from chronic ones (lasting weeks to months), as well as whether involvement is unilateral or bilateral, which may suggest infectious versus systemic etiologies.[3] The character of ocular discharge is critical: purulent or mucopurulent discharge often points to bacterial causes, while watery discharge is more common in viral or allergic forms.[6] Symptom differentiation includes evaluating for prominent itching, which strongly suggests allergic conjunctivitis, versus pain or foreign body sensation, which may indicate infectious or irritant processes; photophobia or discomfort in bright light further refines the assessment.[57] Exposures and contacts are probed, including recent upper respiratory infections, close contact with individuals having red eyes, environmental allergens like pollen or animal dander, contact lens use, or chemical irritants, as these can pinpoint transmission routes or triggers.[3] Physical examination follows, starting with measurement of visual acuity to detect any impairment, which is uncommon in uncomplicated conjunctivitis but warrants further investigation if present. External inspection reveals eyelid swelling, crusting, or matting, while slit-lamp biomicroscopy allows detailed evaluation of conjunctival injection—diffuse redness of the bulbar and tarsal conjunctiva—and assessment for corneal involvement such as infiltrates or ulcers.[57] Eversion of the eyelids exposes the superior tarsal conjunctiva to identify follicles (small, avascular elevations typical of viral processes) or papillae (vascularized projections seen in allergic or bacterial cases), aiding in etiological clues.[3] Preauricular or submandibular lymphadenopathy may also be palpated, particularly in viral infections. Type-specific signs, such as preauricular nodes in adenoviral cases, provide additional context but require correlation with history.[6] Red flags during evaluation necessitate urgent ophthalmologic referral to rule out sight-threatening conditions. These include significant vision loss, severe ocular pain disproportionate to findings, hypopyon (pus in the anterior chamber), or profound photophobia, which may signal corneal ulceration, scleritis, or acute angle-closure glaucoma rather than isolated conjunctivitis.[3] In resource-limited settings, basic tools like a penlight can suffice for initial injection assessment, but slit-lamp use is standard for precision.[57] For chronic or recurrent conjunctivitis, emerging evaluation includes analysis of tear biomarkers to differentiate inflammatory subtypes. Tear cytokines, such as interleukin-6 or tumor necrosis factor-alpha, are elevated in inflammatory dry eye-associated conjunctivitis and can help distinguish it from noninflammatory causes.[70] Similarly, oxylipins—lipid-derived inflammatory mediators like hydroxyeicosatetraenoic acids—serve as diagnostic biomarkers in ocular cicatrizing conjunctivitis, a chronic scarring form, with specific profiles aiding in targeted management.[71] These non-invasive tear sampling techniques enhance clinical differentiation when standard history and exam are inconclusive.[72]Laboratory and Imaging Tests
Laboratory tests for conjunctivitis are typically reserved for cases where clinical evaluation is inconclusive, such as severe, recurrent, or atypical presentations, to identify infectious agents or underlying immune responses. Bacterial conjunctivitis diagnosis may involve conjunctival swabs for Gram staining and culture to isolate pathogens like Staphylococcus aureus or Haemophilus influenzae, particularly in neonates or immunocompromised patients where empirical treatment fails.[3] Viral etiologies, especially adenovirus, are confirmed via polymerase chain reaction (PCR) on conjunctival swabs, which offers high sensitivity and specificity compared to traditional viral culture; for instance, real-time PCR detects adenoviral DNA in over 90% of epidemic keratoconjunctivitis cases.[17][73] Point-of-care immunochromatographic assays, such as the AdenoPlus or QuickVue test, provide rapid detection of adenovirus in ocular swabs within 10 minutes; these CLIA-waived tests have a sensitivity of 85-96% and specificity of 96-100% relative to PCR or culture, enabling quick identification of contagious cases in outpatient or emergency settings.[74] Allergy testing is indicated when allergic conjunctivitis is suspected based on history of atopy or bilateral symptoms. Skin prick testing (SPT) identifies IgE-mediated sensitization to common aeroallergens like pollen or dust mites by wheal-and-flare response within 15-20 minutes, correlating well with clinical symptoms in seasonal allergic conjunctivitis.[57] Alternatively, serum-specific IgE assays quantify allergen-specific antibodies, providing a non-invasive option for patients on antihistamines that could interfere with SPT, though tear IgE measurement is emerging for direct ocular assessment.[75] Imaging modalities are infrequently required but aid in evaluating corneal complications. Fluorescein staining, applied topically and viewed under cobalt blue light, reveals epithelial defects or ulcers associated with corneal involvement in infectious or chemical conjunctivitis, guiding management to prevent progression.[57] Optical coherence tomography (OCT) of the anterior segment visualizes subepithelial infiltrates in adenoviral cases, measuring corneal thickness and monitoring resolution non-invasively, which is particularly useful in persistent photophobia.[76] Conjunctival biopsy is performed in chronic or suspected autoimmune conjunctivitis to confirm diagnoses like ocular cicatricial pemphigoid. Histopathology and direct immunofluorescence on biopsy specimens detect linear IgG or C3 deposits at the basement membrane, essential for distinguishing cicatrizing conditions from infections. These tests' interpretations align with specific etiologies, such as PCR positivity supporting viral pathways detailed elsewhere.[3]Differential Diagnosis
Conjunctivitis, characterized by diffuse conjunctival injection and often accompanied by discharge, must be differentiated from other causes of red eye to avoid missing vision-threatening conditions. Key mimics include keratitis, which involves corneal inflammation and typically presents with severe pain, photophobia, decreased visual acuity, and fluorescein staining revealing epithelial defects or infiltrates, unlike the usually preserved vision and lack of corneal involvement in conjunctivitis.[77][78] Uveitis, an intraocular inflammation, is distinguished by ciliary flush (perilimbal injection), blurred vision, photophobia, and anterior chamber cells or flare on slit-lamp examination, contrasting with the diffuse redness and absence of pupillary changes or intraocular findings in uncomplicated conjunctivitis.[77][78] Acute angle-closure glaucoma manifests as a painful red eye with marked vision reduction, halos around lights, mid-dilated fixed pupils, and a firm globe due to elevated intraocular pressure, features not seen in conjunctivitis where pain is mild or absent and intraocular pressure remains normal.[77][78] Dry eye syndrome often mimics mild conjunctivitis with bilateral redness, foreign body sensation, and reflex tearing but lacks significant discharge and shows punctate epithelial erosions on staining rather than overt conjunctival inflammation.[77] Episcleritis presents with sectoral redness, mild tenderness, and dilated episcleral vessels that blanch with topical phenylephrine, differing from the diffuse injection and potential discharge of conjunctivitis, with normal vision preserved in both but episcleritis lacking systemic associations common in some conjunctivitis forms.[78][9] In neonates, conjunctivitis differentials include dacryocystitis, a congenital nasolacrimal duct obstruction causing unilateral epiphora, lid swelling, and purulent reflux from the punctum upon medial canthal pressure, unlike the more diffuse bilateral involvement and lack of a palpable mass in infectious neonatal conjunctivitis.[60] Gonococcal conjunctivitis, a severe form, is distinguished by its hyperacute onset with profuse purulent discharge, lid edema, and risk of corneal perforation, often bilateral and requiring urgent Gram staining to identify gram-negative diplococci, contrasting with milder bacterial causes.[60][79] Drug-related conjunctivitis, such as from topical medications or preservatives, typically arises shortly after exposure with watery discharge and unilaterality if unilateral instillation occurred, while infectious forms like viral (watery, preauricular lymphadenopathy) or bacterial (purulent) develop more gradually and may spread bilaterally, aiding distinction based on timing and exposure history.[9][77]| Condition | Key Distinguishing Features | Citation |
|---|---|---|
| Keratitis | Severe pain, photophobia, corneal defects on fluorescein staining, decreased vision | [78] |
| Uveitis | Ciliary flush, anterior chamber inflammation, blurred vision | [78] |
| Glaucoma | Halos, firm globe, elevated IOP, severe pain | [78] |
| Dry Eye Syndrome | Bilateral itching, no discharge, punctate erosions | [77] |
| Episcleritis | Sectoral redness, blanches with phenylephrine, mild discomfort | [78] |
| Neonatal Dacryocystitis | Unilateral mass, reflux on pressure, minimal redness | [60] |
| Gonococcal Conjunctivitis | Hyperacute purulent discharge, lid edema, gram-negative diplococci | [60] |