Clinical considerations and recommended diagnostic algorithm for the differential diagnosis of conjunctivitis: a clinical practice review

Introduction

Background

Conjunctivitis refers to inflammation of the conjunctiva, a thin, transparent mucous membrane composed of the palpebral (covering the inner lids) and bulbar (covering the sclera) conjunctiva. Colloquially referred to as “pink eye”, it is characterized by dilated vessels resulting in hyperemia and edema, accompanied by watery, purulent, or mucopurulent discharge (1). While a plethora of conditions can manifest with a red eye, conjunctivitis is one of the most common causes. Conjunctivitis can be categorized by etiology (infectious or non-infectious), chronicity (acute, chronic, or recurrent), and severity (benign to vision-threatening) (2). Etiologic classification serves as a clinically useful approach for diagnosis and management (1,3,4). The differential diagnosis for conjunctivitis is broad and includes conjunctival as well as non-conjunctival conditions.

Rationale and knowledge gap

Conjunctivitis is a common eye condition that affects people of all ages worldwide. In the US, it has been reported to affect 6 million people annually (5) and is the most common ocular condition to present in primary and emergency care settings—constituting one-third of all eye-related encounters in emergency departments (6-8). In 2020, Pepose et al. suggested that indirect costs of viral and bacterial conjunctivitis alone could exceed $1 billion annually (5). A global survey of conjunctivitis experts conducted in 2022 highlighted frequent uncertainty regarding conjunctivitis etiology and the strong potential for misdiagnosis and improper treatment (9). The prevalence and high economic burden associated with conjunctivitis should incentivize clinicians to improve diagnostic accuracy. Given the numerous possible precipitants of conjunctivitis, as well as the non-specific signs and symptoms presented in each condition, diagnosing conjunctivitis properly can be challenging. Prior reviews have summarized causes and ways to assess and diagnose conjunctivitis (3,7,10); however, this article expands on key features and offers clinicians a useful diagnostic algorithm.

Objective

The purpose of this clinical review is to describe different forms of conjunctivitis as well as other ocular conditions that should be included on the conjunctivitis differential, including presentation, pathophysiology, and key diagnostic features. Additionally, we provide a recommended diagnostic algorithm for clinicians.

Conjunctivitis

Conjunctivitis can be divided into infectious and non-infectious causes (Figure 1). Viral conjunctivitis comprises the majority of acute infectious conjunctivitis cases followed by bacterial etiology (Table 1). Non-infectious causes can be divided into allergic and non-allergic groups, the latter of which may be linked to systemic disease, genetic disorders, and mechanic or toxic triggers. Figure 2 presents a diagnostic algorithm for suspected acute conjunctivitis.

Figure 1 Etiologic classification of conjunctivitis into infectious and non-infectious subtypes. C. trachomatis, Chlamydia trachomatis; H. influenzae, Haemophilus influenzae; M. catarrhalis, Moraxella catarrhalis; N. gonorrhoeae, Neisseria gonorrhoeae; S. pneumoniae, Streptococcus pneumoniae.

Figure 2 Recommended diagnostic algorithm for suspected conjunctivitis. AC, anterior chamber; H. influenzae, Haemophilus influenzae; IOP, intraocular pressure; OMMP, ocular mucous membrane pemphigoid; OSJS, ocular Stevens-Johnson syndrome; SLK, superior limbic keratoconjunctivitis; S. pneumoniae, Streptococcus pneumoniae; STD, sexually transmitted disease; URI, upper respiratory infection.

Infectious conjunctivitis

Viral conjunctivitis

Viral conjunctivitis is the most common cause of infectious conjunctivitis. It typically presents in adults unilaterally before progressing bilaterally, with follicular morphology, watery discharge, and preauricular lymphadenopathy (11). Many viruses can present with similar forms of conjunctivitis, and it is not always possible to distinguish one from another.

Adenoviruses are responsible for most cases of viral conjunctivitis manifesting in three major clinical forms. Serotypes 1–11 cause a nonspecific follicular conjunctivitis. Serotypes 3, 5, 7, and 11 can additionally cause pharyngoconjunctival fever (PCF), characterized by an acute high fever, pharyngitis, bilateral conjunctivitis at onset, and mild keratitis in 30% of cases (11,12). Epidemic keratoconjunctivitis (EKC) has been associated with serotypes 8, 19, 37, and 54 (13,14). EKC typically starts as a unilateral follicular conjunctivitis, with chemosis, watering, and ipsilateral lymphadenopathy, and progresses to bilateral keratoconjunctivitis within 1 week. It constitutes the most severe form of ocular adenoviral infection, with moderate to severe keratitis occurring in 80% of cases (11). Keratopathy is a key distinguishing feature of EKC, and photophobia is often a chief complaint (15). Severe cases may also present with pseudomembranes, symblepharon, and vision-impairing subepithelial infiltrates (SEIs) (4,12,15). Adenovirus infection is highly contagious, and history of close contact with an individual who has had recent conjunctivitis or flu-like symptoms can point to adenoviral etiology. Concurrent systemic events such as gastroenteritis, cystitis, myocarditis, and pneumonia may also indicate an adenoviral infection (16-18). Rarely, adenoviral conjunctivitis can become chronic. This diagnosis might be challenging, as conjunctival papillae begin to predominate over the more common follicles (14). While lab tests are rarely necessary to ascertain an acute infection, viral cultures, immunochromatography, and serology testing can be of greater benefit in the setting of atypical or chronic conjunctivitis with suspected infectious etiology (11).

Viral cultures and polymerase chain reaction (PCR) have been cited as gold standards for diagnosing adenoviral conjunctivitis (19), but their role in the acute setting is debated. Viral cultures can take 1–2 weeks to result, limiting their clinical utility. While PCR testing can provide results in hours, it is expensive, requiring access to specialized laboratory testing and personnel (20-22). Despite these limitations, some have argued PCR can be cost effective by reducing productivity loss due to widespread employee furloughs based on clinical diagnosis alone (20).

QuickVue Adenoviral conjunctivitis test, an antigen-based immunoassay, is the only Food and Drug Administration (FDA)-approved point-of-care test for acute adenoviral conjunctivitis, which can yield results in minutes (23). The test’s clinical utility is debated due to variability in diagnostic accuracy with sensitivities ranging from 40% to 93% and specificities ranging from 81% to 98% (24-27).

Given its self-limited course, the standard of care for acute adenovirus conjunctivitis is symptom relief with artificial tears, lid scrubs, and cool compresses; however, other modalities have been explored, which provide further incentive to optimize diagnostic accuracy.

Topical corticosteroid use for pseudomembranes and persistent SEIs secondary to adenoviral keratoconjunctivitis is a subject of debate (28). Although steroids may suppress SEIs, they can prolong adenoviral shedding and increase the risk of elevated intraocular pressure (IOP), glaucoma, and cataracts (29). SEIs tend to have a high recurrence rate, complicating the approach to steroid tapering (28). Recent studies have shown that milder steroids, such as loteprednol, may share similar efficacy in managing SEIs with fewer ocular side effects (30).

Immunotherapies have been investigated as potential alternatives. Both 0.05% and 1% topical cyclosporine have been shown to effectively treat SEIs (31,32). Topical tacrolimus 0.03% use has been found to reduce SEI formation and improve vision compared with dexamethasone 0.05% alone, although burning and foreign body sensation have been noted (33-35). Combination therapy with prednisolone showed a faster recovery rate but risk of elevated IOP (34).

Povidone-iodine (PVP-I) is a broad-spectrum antimicrobial agent that has been used off-label for adenoviral conjunctivitis (36-40). Studies have shown decreased viral load and severity of signs and symptoms compared with artificial tears alone with no associated ocular discomfort (41). Others have found shorter resolution times, lower risk of corneal haze and SEIs, reduced conjunctival injection, discharge, and swelling, and decreased pseudomembrane formation (39,40). While results are promising, confirmatory studies with larger sample sizes, long term follow-up assessments, and direct comparison with other treatment modalities are warranted.

Herpes simplex virus (HSV) and varicella zoster virus (VZV) infections can impact any part of the eye, including the conjunctiva. Both HSV and VZV typically present with unilateral follicular conjunctivitis and preauricular lymphadenopathy. Primary HSV infection typically involves a pruritic vesicular rash on or around the ocular adnexa, causing blepharoconjunctivitis. While HSV is known to cause keratitis, the absence of keratitis should not exclude HSV as a potential cause of conjunctivitis. Herpes zoster ophthalmicus (HZO) results from reactivation of a latent VZV infection along the ophthalmic division of the trigeminal nerve. Adults over 50 years of age and immunocompromised individuals are at highest risk, therefore vaccination is recommended in these groups (2). In these patients, acute conjunctivitis may be accompanied by a painful blistering vesicular rash over the forehead and scalp with or without inflammation of the cornea, sclera, uvea, retina, or optic nerve (42).

Infection with molluscum contagiosum virus (MCV), a double-stranded DNA virus of the poxvirus family, tends to occur in warm, humid regions. Molluscum contagiosum most commonly affects children ages 2 to 5 years old, though it may also affect sexually active adults and immunocompromised persons (43,44). MCV is a disease of the skin and mucous membranes. While ocular involvement is rare, it can cause a chronic, follicular conjunctivitis, secondary to periocular skin lesions (45). A key exam finding includes a pale, waxy umbilicated nodule found on the lid margin (11). The presence of such findings in an adult patient with unknown immunocompromised status should prompt the clinician to consider human immunodeficiency virus (HIV) testing.

Measles, or Rubeola, infection also commonly affects children younger than 5 years old. Affected patients in this population will frequently experience follicular conjunctivitis with diarrhea (21). Early symptoms include a high fever followed by cough, coryza, and conjunctivitis. Two to 3 days thereafter, tiny white spots, called koplik spots, may appear inside the mouth. Three to 5 days following initial symptoms, a diffuse maculopapular starting on the face or neck and spreading down the body is characteristic of the disease (46). A clinical history of known exposure, lack of vaccination, or known loss of immunity may point to an underlying measles infection.

Coxsackie virus A24, a single-stranded RNA enterovirus, is a cause of acute hemorrhagic conjunctivitis that is more common in tropical climates. This virus has a short incubation period, followed by an acute onset of unilateral follicular conjunctivitis and subconjunctival hemorrhage, which progresses bilaterally within 48 hours (47).

Bacterial conjunctivitis

Bacterial conjunctivitis can affect people of all ages but is more common in children. It classically presents with mucopurulent discharge, papillary morphology, and matted eyelashes, without lymphadenopathy.

Haemophilus influenzae (H. influenzae) is the most common pathogen affecting children, followed by Streptococcus pneumoniae (S. pneumoniae), Moraxella catarrhalis (M. catarrhalis), and staphylococcal species (48-50). In adults, Staphylococci, followed by H. influenzae and S. pneumoniae, are the most common etiologies (51). Exam findings alone will not typically distinguish these infections from one another, but bacterial cultures can be collected if desired. Clinical history may include poor contact lens hygiene or use of contaminated cosmetic products. Crowded conditions with close contact, including preschools, elementary schools, college dormitories, or military barracks, can also pose a risk of bacterial infection. Clinicians should consider whether patients have known concurrent ocular conditions such as blepharitis, abnormal eyelid morphology, or a history of recent ocular surgery with the possibility of suture material that could serve as a nidus for bacterial infection. Clinical response to the use of topical antibiotics for acute infectious conjunctivitis should not be utilized as a definitive diagnostic tool.

Studies on antibiotic efficacy for bacterial conjunctivitis have yielded mixed results. One recent meta-analysis suggested antibiotic use improved clinical resolution and microbial clearance (49), while another multicenter case-control study found no significant difference in the rate of resolution in pediatric patients with most children achieving resolution within 5 days with or without antibiotics (49). Potential ocular or systemic complications following antibiotics range from none (50) to eye pain, stinging, burning, and photosensitivity (49). One study found that patients who were not prescribed topical antibiotics at initial presentation did not require more follow-up care or subsequent antibiotic therapy compared with those who received them, suggesting that most cases may resolve without such intervention. These results, in addition to the potential for adverse drug effects and increased antibiotic resistance, lend support to reducing overtreatment with topical antibiotics (52). According to the American Academy of Ophthalmology, immediate topical antibiotic use for acute bacterial conjunctivitis is generally unadvised (2). Despite this recommendation, studies show that antibiotics are frequently prescribed (53).

Chlamydia trachomatis (C. trachomatis), particularly serovars D through K, is another major cause of adult bacterial conjunctivitis. Its clinical features can resemble those of viral infections, including subacute onset of unilateral or bilateral follicular conjunctivitis and preauricular lymphadenopathy (11). Corneal involvement may be observed throughout the course of infection with early superficial punctate keratitis and perilimbal subepithelial corneal infiltrates presenting weeks after onset. If left untreated, the disease can become chronic. During this time, papillae and superior corneal pannus may develop (11). Conjunctivitis is but one potential manifestation of this oculogenital infection, which can be accompanied by urethritis, dysuria, and discharge. Pelvic inflammatory disease and epididymitis may be documented in female and male patients, respectively. That said, C. trachomatis infection is often asymptomatic (54), underscoring the importance of testing sexual partners when infection is diagnosed or suspected (3). Unlike the former examples, patients with chlamydia conjunctivitis must be treated with systemic antibiotics.

Giant fornix syndrome (GFS) is a form of conjunctivitis that mainly affects elderly patients, commonly presenting in the seventh decade of life (55). GFS primarily involves the upper fornices, which naturally deepen with age and form a suitable environment for bacterial colonization, especially Staphylococci. It is characterized by a chronic, relapsing tarsal papillary conjunctivitis, presenting with purulent discharge and possible pseudomembranes (11). Findings are often unilateral, though bilateral involvement is possible. Inferior fornixes are typically not involved. Eyelid findings may include blepharitis with telangiectasias, and patients may develop ptosis in long-standing disease. Though rare, chronic secondary punctate keratopathy can lead to corneal neovascularization, scarring, or ulceration.

Parinaud oculoglandular syndrome (POS) is a rare disease marked by a unilateral granulomatous conjunctivitis. It is typically caused by Bartonella henselae or Francisella tularensis, though viral, fungal, parasitic, and other bacterial etiologies have also been identified. Even when etiology is bacterial, POS can present with a chronic low-grade fever and ipsilateral preauricular lymphadenopathy, mimicking a typical viral conjunctivitis. History may reveal recent exposure to animals, such as cats, rabbits, or rodents, or gardening activity (11).

Neonatal conjunctivitis

Infectious conjunctivitis in neonates is considered a distinct category of disease, referred to as ophthalmia neonatorum (ON) with numerous potential etiologies. Infection is the leading cause of ON, as pathogens can be transmitted from mother to infant during delivery. A thorough medical and birth history of the neonate as well as the birthing parent should always be taken. Factors such as premature rupture of membranes, prolonged delivery, premature birth, lack of prenatal care, and HIV-infection in the mother all increase the risk of ON. The timing of onset is a crucial factor in considering the most likely etiology (Table 2). Appropriate lab tests should be acquired including conjunctival cultures, gram stain, Giemsa stain, scrapings for PCR or immunofluorescent antibody testing, and viral swabs, to help identify etiology in suspected cases of infectious ON. It is critical to ensure these patients are also undergoing appropriate systemic monitoring and workup.

In the US, chlamydial ON has been reported to make up 40% of ON cases, whereas gonococcal ON, which has decreased dramatically since the implementation of ocular prophylaxis, comprises less than 1% of cases (56). ON secondary to C. trachomatis infection is associated with mucopurulent discharge and possible pseudomembranes presenting 5 to 12 days after birth (6). Systemic complications are more common in chlamydial infection, namely pneumonia occurring at 1 to 3 months of age (57). Gonococcal ON is characterized by hyperpurulent discharge and severe eyelid edema presenting within the first week of life (11). Gonococcal infection can quickly progress to corneal perforation and permanent vision loss within hours or days (58,59). Any patient suspected of having ON during this time frame should be monitored very closely with repeat eye exams daily or twice daily.

Gram-positive Staphylococci infection is another common bacterial cause of ON, usually attributed to a prolonged stay in the NICU. Staphylococcal infections are commonly associated with mildly matted lids due to mucopurulent discharge (11). A recent meta-analysis identified Staphylococci and Serratia marcescens to be the most frequently isolated bacteria associated with ON (60).

ON can be viral, most commonly secondary to HSV, and usually presents between the first and second weeks of life. Neonatal HSV infection can present with watery discharge, eyelid and periocular vesicles, and possible dendritic or geographic corneal epithelial lesions (11). Multinucleated giant cells may be present on gram stain. Importantly, HSV infection can cause life-threatening encephalitis, therefore early diagnosis is essential in preventing serious ocular and systemic complications.

Chemical conjunctivitis typically manifests as a watery discharge within the first 24–72 hours of life (11). Non-infectious chemical toxicity from prophylactic treatment of gonococcal infection used to be the most common cause of ON; however, this has become increasingly rare following the substitution of ophthalmic silver nitrate for erythromycin ointment. With these prophylactic measures as the standard of care in the US, incidence of gonococcal ON is estimated to be 0.4 cases per 100,000 births per year. This is in contrast to gonococcal transmission rates without prophylactic treatment in other parts of the world which range from 30% to 50% (61).

Non-infectious conjunctivitis

Non-infectious conjunctivitis can be categorized as allergic or non-allergic. Allergy is the third most common cause of conjunctivitis and can be divided into four major subtypes: seasonal, perennial, vernal, and atopic (Table 3). Non-infectious conjunctivitis, not triggered by allergen exposure, is often associated with autoimmune disorders, genetic conditions, and other mechanical, environmental, or toxic factors.

Allergic conjunctivitis

Both seasonal and perennial allergic conjunctivitis (PAC) are type 1 hypersensitivity reactions caused by IgE-mediated activation of mast cells and histamine release. While seasonal allergic conjunctivitis (SAC) peaks in the spring and summer due to increased pollen exposure, PAC presents year-round and is often triggered by dust, dander, or fungal allergens (11). Patients commonly experience bilateral itching, chemosis, and watery discharge with conjunctival papillae and mild eyelid edema. Rhinitis and rhinorrhea are common secondary features (62).

Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) involve both type 1 and type 4 hypersensitivity responses, causing more severe ocular allergic reactions. Patients may experience intense itching, burning, watering, or foreign body sensation. Photophobia and blurred vision are also possible. VKC and AKC can notably present with thick mucoid discharge (62). Keratoconus due to excess eye-rubbing and early-onset subcapsular cataracts are possible sequalae of both conditions (11).

VKC is a chronic, recurrent disease, which generally follows three clinical forms. Palpebral VKC involves the upper tarsal conjunctiva, presenting with diffuse papillary hypertrophy, potentially progressing to form giant cobblestone papillae (<1 mm). Corneal disease is a major feature of the palpebral form and may manifest as superior punctate epithelial erosions, epithelial macroerosions, shield ulcers or subepithelial scars which may lead to significant vision loss if located centrally (11). Limbal VKC is characterized by gelatinous-appearing giant papillae near the limbus, with small white spots representing accumulated eosinophils called Horner-Trantas dots. Mixed VKC involves features of both palpebral and limbal forms. In all presentations, hyperemia, papillae, and ropy mucus discharge with itching, tearing, and photophobia are classic findings (63). VKC has a distinct predilection for males, with peak incidence at 5 years of age, and has a higher prevalence in regions with warm, dry, and windy climates (11,62,64). Although mild symptoms may persist year-round, exacerbations occur more frequently in the spring and summer seasons.

While most cases of VKC tend to improve by puberty, AKC is typically unremitting. AKC is also a chronic, yet progressive disease that predominantly affects adults 30–50 years old with a history of atopic dermatitis. It presents with characteristic eyelid findings, such as boggy eyelid edema, blepharitis, and watery mucoid discharge. Conjunctival erythema, edema, and papillae appear early, and symblepharon, thickening of the lower tarsal border, ectropion, and madarosis can be observed in severe disease. Mild to severe keratopathy, from inferior punctate epithelial erosions to stromal scarring and peripheral neovascularization may also be found on exam (62,64,65). Compared to VKC, shield ulcers and plaques are less common in AKC, but AKC often presents with severe corneal disease, preferential involvement of the inferior conjunctiva, and greater dryness and tightening of the eyelids and periorbital skin. Individuals with AKC may also be predisposed to secondary bacterial and fungal infections; chronic S. aureus blepharitis is commonly associated with AKC (65).

Numerous treatment modalities may be employed to address allergic conjunctivitis. A recent meta-analysis found that among various antihistamines, Olopatadine 0.1%, showed the highest efficacy and safety profiles for both SAC and PAC, while tacrolimus 0.1%, ahead of cyclosporine and steroid therapies, served as the most effective topical therapy for more severe ocular allergies, VKC, and AKC (66).

Giant papillary conjunctivitis (GPC) is characterized by papillary hypertrophy of the superior tarsal conjunctiva. Primary GPC can be seen in VKC or AKC. Secondary GPC, also known as mechanically-induced GPC, is linked to physical irritants causing giant papillae formation, frequently affecting the superior tarsal conjunctiva. The condition can be triggered by contact lenses, ocular prostheses, sutures, and scleral buckles (67). Accumulation of protein deposits and cellular debris on the surface of contact lenses has been attributed to the increased risk (11). Secondary GPC can be unilateral or bilateral depending on the underlying causative factor.

Contact allergic blepharoconjunctivitis is an immune-mediated conjunctivitis caused by direct contact with an inflammatory agent. This condition can present similarly to AKC with boggy eyelid edema, blepharitis, and watery discharge. Contact lens wearers are at increased risk, as Benzalkonium chloride (BAK), a preservative found in 70% of ophthalmic solutions, is a common culprit (68). In addition to having direct, toxic damage against the conjunctival epithelium, BAK acts as a hapten, triggering a type 4 hypersensitivity reaction that leads to contact allergic blepharoconjunctivitis (11,68). Other possible causes include cosmetics, soaps, and perfumes.

Non-allergic conjunctivitis

While infection and allergy serve as primary causes of conjunctivitis, systemic diseases, genetic disorders, and adverse drug reactions can trigger conjunctival inflammation as well.

Blepharoconjunctivitis is a multifactorial disease characterized by inflammation of the eyelid margin and conjunctiva. Careful history taking and thorough examination is crucial for proper diagnosis. Patients frequently experience burning, grittiness, and foreign body sensation. Crusting and swelling at the lid margins with conjunctival hyperemia and a short tear break-up time are key signs. Blepharoconjunctivitis can be seen as an advanced form of chronic non-infectious blepharitis or can be associated with certain pathogens. An acute onset of blepharoconjunctivitis with superficial punctate keratitis or corneal ulcer may indicate an infectious process (69). Primary HSV infection has been reported to cause blepharoconjunctivitis in children younger than age 5 (70). Categorized anatomically, anterior blepharitis is commonly caused by seborrheic dermatitis and bacteria colonization (usually Staphylococci), posterior blepharitis is associated with meibomian gland dysfunction, and angular blepharitis has been linked to Moraxella and Staphylococcus strains (71-73). Demodex mites can cause anterior or posterior types (74). Drugs such as dupilumab and lebrikizumab can cause blepharoconjunctivitis, with reports of mild to severe forms of papillary or follicular conjunctivitis (75-78).

Superior limbic keratoconjunctivitis (SLK), primarily involves the superior conjunctiva, limbus, and cornea. Physical exam reveals fine papillary hypertrophy of the upper tarsal plate and superior limbus, intense hyperemia, redundancy, and laxity of the superior bulbar conjunctiva. These features can be appreciated with rose bengal staining and light pressure to the upper lid (79). The superior cornea may reveal punctate epithelial erosions, filamentary keratitis in about one-third of cases, and mild pannus resembling arcus senilis if left untreated (11). Common symptoms include burning, photophobia, mucoid discharge, and notably frequent blinking. Although the pathogenesis of SLK remains poorly understood, it has been attributed to blink-related trauma caused by tear film insufficiency or an excess of lax conjunctival tissue, as seen in thyroid disease (11). Loose conjunctival tissue rubs against the upper tarsal plate inducing chronic microtrauma and an inflammatory response with each blink. SLK typically affects middle-aged women, about half of whom have thyroid disease. Both SLK and GPC involve the superior conjunctiva, yet pertinent history and exam findings can aid in their differentiation. In addition to a thorough slit lamp exam, thyroid function testing and impression cytology for conjunctival keratinization can serve as useful diagnostic tools (11).

Ocular mucous membrane pemphigoid (OMMP) features a chronic, progressive, cicatrizing conjunctivitis underpinned by autoimmune disease and type 2 hypersensitivity reaction (80). The Foster staging system categorizes the condition, beginning with chronic palpebral and bulbar conjunctival inflammation that is refractory to topical treatment (type I), followed by forniceal shortening (type II), symblepharon formation (type III), and ankyloblepharon formation (type IV) (81). Early destruction of goblet cells and accessory lacrimal glands leads to severe dry eye, so patients may be misdiagnosed with dry eye syndrome or keratoconjunctivitis sicca at this point (11). Misdiagnosis has been found to result in irreversible, subconjunctival fibrosis in approximately 40% of patients (82), so it is important to have a high index of suspicion for this rare condition. Corneal opacification and ankyloblepharon mark the end (81). Perilesional biopsy with direct immunofluorescence is the gold standard for diagnosis, but false negatives are possible (81,83). Recent studies have shown that patients with OMMP have lower titers of circulating autoantibodies compared to those without ocular involvement, thereby limiting the efficacy of serology as a definitive diagnostic tool (84,85). Therefore, systemic exam findings, such as oral and laryngeal mucosal lesions along with blistering of the head, neck, groin, and extremities are crucial elements used to identify the correct diagnosis.

Like OMMP, ocular Stevens-Johnson syndrome (OSJS), is characterized by a blistering skin disease and bilateral cicatrizing conjunctivitis, but patient histories differ. While OMMP has an insidious onset and typically affects the elderly, OSJS presents acutely, mostly in young adults. This medical emergency is most often triggered by a type 4 hypersensitivity reaction to a medication. Commonly implicated drug classes include xanthine-oxidase inhibitors, anti-convulsants, anti-epileptics, sulfa drugs, and oxicam non-steroidal anti-inflammatory drugs (86). A minority of cases can be traced back to infection, mainly by M. pneumoniae, and cancers in both children and adults (87-90).

A flu-like prodrome generally precedes a painful rash, which spreads over the trunk and face, as well as blistering of the lips, tongue, oropharynx, nasal mucosa, and genitalia (11,91). Initial symptoms can last up to 14 days before skin or mucosal lesions arise, which can delay diagnosis. This is followed by an acute onset papillary conjunctivitis with pseudomembranes. Additional ocular findings include eyelid matting, hemorrhagic crusting of lid margins, punctate corneal erosions or epithelial defects, and iritis (11). The acute phase typically lasts 8 to 12 days (92). In the late stages of disease, conjunctival scarring, forniceal shortening, and symblepharon occur (11,92). Clinical sequelae of the lids include trichiasis, cicatricial entropion or ectropion, posterior lid margin keratinization, and ankyloblepharon (93). Persistent keratopathy can result in corneal neovascularization, limbal stem cell deficiency, severe dry eye, and permanent blindness (94). A skin biopsy with consistent clinical features can confirm the diagnosis (11).

Ligneous conjunctivitis is a rare condition characterized by fibrin-rich, woody growths on the conjunctiva. It presents with pseudomembranes over the tarsal conjunctiva and large and lobular conjunctival masses covered by thick mucoid discharge (11). If left untreated, it can progress to corneal scarring, neovascularization, and permanent vision loss. While the condition can present at any age, onset at around age 5 years is most common. Exacerbations can be triggered by minor trauma or antifibrinolytic treatment. Systemic symptoms may also be seen in the periodontal tissue, respiratory tract, kidneys, middle ear, and female genitalia (11). Ligneous conjunctivitis is the most prevalent symptom of type 1 plasminogen deficiency, and homozygous PLG gene mutation can lead to a definitive diagnosis (95).

Non-conjunctivitis conditions

Many non-conjunctivitis conditions—ranging from mild, self-limited to emergent, vision-threatening—may present with a red eye and thus belong on the differential diagnosis. Findings such as abnormal or asymmetric pupillary response, ciliary flush, intraocular inflammation, and severe, radiating pain are more likely to indicate a non-conjunctivitis diagnosis of red eye (96).

Dry eye syndrome can exhibit overlapping symptoms with blepharoconjunctivitis including redness, burning, and foreign body sensation, but has an increased likelihood for excess tearing, photophobia, and visual changes (97). Patients of any age or demographic can experience dry eye syndrome; however, older age, post-menopausal hormone changes, autoimmune diseases, thyroid diseases, and certain medications such as antidepressants, antihistamines, or hormone-altering therapy are more specific risk factors (98). Exam findings will depend on the underlying pathomechanism (evaporative, aqueous-deficient, or mixed) of the dry eye condition. Slit lamp exam may reveal superficial punctate keratitis, mucous strands, reduced tear meniscus height, reduced tear break-up time, conjunctival chalasis, telangiectatic lids, inspissated glands, or irregular eyelid margins (99). Fluorescein staining, Schirmer testing, examination of the meibomian gland orifices, and evaluation of eyelid position are essential diagnostic tools. Over 80% of patients with dry eye syndrome experience blepharitis (98). Blepharitis and dry eye syndrome can present similarly to allergic conjunctivitis; however, crusting at lid margins, burning or foreign body sensation, and positive fluorescein staining are more consistent with the former, while intense itching may indicate the latter. Clinicians should take a thorough history, inquiring about onset, duration, timing, and associated symptoms, which may elucidate the correct diagnosis.

Keratitis, inflammation of the cornea, may present with eye redness. Both conjunctivitis and keratitis can cause conjunctival hyperemia, discomfort, and discharge. Photophobia, blurry or hazy vision, and severe eye pain are more commonly experienced symptoms in the latter. Corneal edema, corneal infiltrate, and hypopyon are specific to keratitis. Infectious keratitis can be caused by viral, bacterial, fungal, or protozoal etiologies. Gram-positive pathogens are typically associated with localized cellular infiltration whereas gram-negative bacteria, such as pseudomonas, typically cause a diffuse infiltrate (100). HSV and VZV infections can cause a herpetic keratitis characterized by dendritic or pseudodendritic corneal ulcers (101). Non-infectious causes of keratitis can be secondary to trauma, contact lens wear, irritant exposure, or systemic conditions, such as systemic lupus erythematosus, rheumatoid arthritis, and granulomatosis with polyangiitis.

Scleral inflammatory disorders, such as episcleritis and scleritis, can also present as eye redness in one or both eyes. In episcleritis, edema of the episcleral tissue and injection of the superficial vasculature can cause a segmental or diffuse redness. Patients may experience mild discomfort, without discharge or vision loss. The condition is usually idiopathic and self-limited. Scleritis, however, is a potentially-blinding disease requiring treatment, and ought not to be mistaken with its milder counterpart. Scleritis can be defined as edema of the episcleral and scleral tissue with injection of both the superficial and deep vascular plexus (102). Patients commonly report a deep, boring eye pain, especially upon eye movements, as well as photophobia or decreased vision (97,103). Ophthalmic exam will reveal tenderness to palpation and exacerbation of pain with eye movements. Scleral injection can be focal or diffuse, with possible nodular erythema or local infiltrate, and typically takes on a violet or bluish appearance (104,105). Although etiology can be inflammatory, infectious, or idiopathic, scleritis is commonly secondary to autoimmune disease (105). Female patients comprise about 70% of all patients with scleritis, with rheumatoid arthritis identified as the most common cause (106). Diagnosis should be accompanied by systemic evaluation and workup. Clinicians should carefully examine the pattern of ocular injection to differentiate episcleritis from scleritis. Administration of 2.5% phenylephrine is a helpful diagnostic tool: blanching of the superficial episcleral vessels indicates episcleritis, while persistent vasculature engorgement suggests scleritis (105). Injection of deep scleral vessels is likely to suggest scleritis rather than conjunctivitis.

Anterior uveitis, or iritis, refers to inflammation of the iris and/or ciliary body, which can be unilateral or bilateral. Conjunctival injection that is predominantly around the limbus, known as ciliary flush, indicates inflammation of deeper ocular structures and should provide a clue that the underlying condition may not be conjunctivitis. Symptomatic patients will commonly describe eye pain, photophobia, and may have decreased vision. Slit lamp examination classically reveals cell and flare. Posterior synechiae indicating prior episodes of inflammation may also cause an irregularly shaped pupil, and keratic precipitates may also be found along the corneal endothelium (107,108). Patients can exhibit inflammation in any part of the eye, so complete anterior and posterior dilated exams are mandatory. Uveitis is most often idiopathic; however, it can be caused by blunt trauma, systemic infection, autoimmune conditions including juvenile idiopathic arthritis (JIA), sarcoidosis, nephritis, ankylosing spondylitis, inflammatory bowel disease, reactive arthritis, and other conditions (107,109,110). It is therefore important that underlying systemic conditions are considered, and systemic workup and treatment may be indicated. JIA-associated iritis is often asymptomatic until vision has been compromised, so it is imperative that children with JIA are followed by rheumatologists and ophthalmologists (107).

Acute angle-closure glaucoma occurs when aqueous humor outflow is obstructed, causing a sudden rise in IOP. This ophthalmic emergency is marked by sudden onset eye redness, which is why it may be misdiagnosed as conjunctivitis. However, these patients are expected to exhibit severe pain, blurred vision, halos, and acute vision loss. Headache, nausea, and vomiting are common associated symptoms. Ophthalmic exam reveals elevated IOP, typically greater than 50 mmHg, a dilated, non-reactive pupil, shallow anterior chamber, corneal edema, and optic nerve edema (1). If gonioscopy is possible through the patient’s cornea, the angle will appear closed. Risk factors include older age, female sex, Asian race, family history, hyperopia, and certain medications including anticholinergics, anti-epileptics, first generation anti-psychotics, and serotonin-norepinephrine reuptake inhibitors (111-115).

Conclusions

Conjunctivitis encompasses a wide range of conditions involving inflammation of the conjunctiva. Infectious conjunctivitis is most commonly due to viral, followed by bacterial pathogens, while most non-infectious cases are associated with allergy. Underlying systemic diseases, genetic conditions, and other environmental triggers can also cause chronic non-infectious, non-allergic conjunctivitis.

This article illustrates how patterns can be used to help differentiate types of conjunctivitis, while reminding clinicians to take care not to miss other serious, vision-threatening conditions that may present similarly (Figure 2). Conjunctivitis is primarily a clinical diagnosis, requiring a thorough history and physical exam. Most cases of infectious conjunctivitis rarely require routine lab tests and are self-limited. In severe, refractory cases, or in the case of suspected neonatal conjunctivitis, cultures are an essential diagnostic tool. In neonatal conjunctivitis, the timing of onset can be a particularly important factor in determining etiology. An important limitation of this topic review is that individual patient presentations and findings may vary or produce exceptions, which providers must consider when delivering patient care.

Conjunctivitis is a common condition that involves a broad differential. This review highlights characteristic presentations, features, and pathophysiology to aid in diagnosis.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Roy S. Chuck, Joann J. Kang and Viral V. Juthani) for the series “Inflammatory Disorders of the Cornea and Ocular Surface” published in Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-46/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-46/coif). The series “Inflammatory Disorders of the Cornea and Ocular Surface” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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