Conjunctivitis is a general term for inflammation of the conjunctiva. It is characterized by hyperemia and edema due to dilation of conjunctival vessels, and is usually accompanied by discharge. The prevalence varies depending on cause, age, and season.
Conjunctivitis is broadly classified into infectious and non-infectious types.
Among infectious conjunctivitis, epidemic keratoconjunctivitis (EKC), pharyngoconjunctival fever (PCF), and acute hemorrhagic conjunctivitis (AHC) are monitored by the Ministry of Health, Labour and Welfare’s infectious disease surveillance system.
In recent years, conjunctivitis has gained attention as an ocular manifestation of COVID-19. The overall incidence of conjunctivitis among hospitalized patients is approximately 5.9%, rising to 12.7% in severe cases4).
Infectious conjunctivitis (viral and bacterial) is transmitted to others through contact. In particular, adenovirus has a high transmission risk of 10–50%. In contrast, allergic conjunctivitis is non-infectious and does not spread. See Causes and Risk Factors for details.
The main subjective symptoms common to conjunctivitis are as follows.
The characteristics of ocular discharge serve as important clues for identifying the cause.
| Etiology | Discharge characteristics |
|---|---|
| Neisseria gonorrhoeae | Profuse, yellow, purulent |
| Streptococcus pneumoniae, Haemophilus influenzae | Profuse, yellowish-white, seropurulent |
| Staphylococcus | Profuse, grayish-white |
| Adenovirus | Profuse, serofibrinous |
| Allergy | Moderate, fibrinous |
The clinical findings of conjunctivitis vary widely depending on the cause and pathology.
Catarrhal
Conjunctival injection: Hyperemia of both the bulbar and palpebral conjunctiva. Most intense in the conjunctival fornix.
Mucopurulent discharge: Typical of bacterial conjunctivitis.
No follicles or papillae: Characteristic of staphylococcal conjunctivitis.
Follicular
Conjunctival follicles: Lymphoid follicles composed primarily of B cells. Commonly occur in the inferior palpebral fornix.
Serous discharge: Characteristic of viral conjunctivitis.
Preauricular lymphadenopathy: Observed in adenovirus and chlamydial infections.
Suppurative
Profuse purulent discharge: Yellow, cream-like discharge overflowing from the palpebral fissure.
Eyelid swelling and chemosis: Reflects severe inflammation.
Risk of corneal perforation: Unique to gonococcal conjunctivitis.
Other important findings:
COVID-19-associated conjunctivitis presents with follicular reaction, conjunctival edema, and serous discharge3). Pseudomembranous inflammation and subconjunctival hemorrhage have also been reported3).
The characteristics of discharge aid in identifying the suspected cause. Large amounts of yellow creamy purulent discharge suggest gonococcus; yellowish-white seropurulent discharge suggests pneumococcus or Haemophilus influenzae; serofibrinous discharge suggests adenovirus. However, microbiological testing is necessary for definitive diagnosis.
The causative bacteria of bacterial conjunctivitis vary by age group.
| Age Group | Main Causative Bacteria |
|---|---|
| Neonates | Neisseria gonorrhoeae, Chlamydia trachomatis, herpes simplex virus |
| Infants and Toddlers | Haemophilus influenzae, Streptococcus pneumoniae, Moraxella species |
| Adults | Staphylococcus species |
| Elderly | Staphylococcus species, Streptococcus pneumoniae, Corynebacterium species |
In recent years, drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and drug-resistant Haemophilus influenzae (BLNAR) have been increasing, and some cases of conjunctivitis have become refractory to treatment.
Neisseria gonorrhoeae is the only bacterium capable of infecting intact corneal epithelium, and inflammation extending to the cornea can lead to perforation. In adults, it presents as a sexually transmitted infection. The proportion of fluoroquinolone-resistant N. gonorrhoeae has been reported to exceed 80% in Japan2).
The representative viruses that cause conjunctivitis fall into the following three groups.
Conjunctivitis caused by Chlamydia trachomatis is broadly classified into trachoma and inclusion conjunctivitis. What is currently seen in Japan is inclusion conjunctivitis, which is one of the sexually transmitted conjunctival infections. Chlamydial infection should be suspected in prolonged follicular conjunctivitis that does not respond to antibiotics (the follicles become giant). Chlamydia can only replicate intracellularly, and treatment requires a long duration.
This is a type I allergic reaction to transient allergens (e.g., pollen) or persistent allergens (e.g., house dust mites). A history of current or past atopic diseases (eczema, asthma, urticaria, rhinitis) is a risk factor. It is more common from spring to summer.
Neonatal conjunctivitis is primarily caused by birth canal infection (vertical transmission). The causative microorganism and the time to onset show characteristic patterns. N. gonorrhoeae presents at 1–3 days after birth, Chlamydia at 3–10 days, and Moraxella at 7–10 days or later. Gonococcal conjunctivitis carries a high risk of corneal perforation.
In Japan, neonatal ocular prophylaxis with fluoroquinolone eye drops is performed, but breakthrough infections due to fluoroquinolone-resistant gonococcus have been reported2).
Conjunctival hyperemia can occur as a partial symptom of systemic infections. It is seen in measles, rubella, Kawasaki disease, dengue fever, etc., and does not require eye drop treatment. In Kawasaki disease, bilateral non-suppurative conjunctivitis (sparing the limbus) is one of the diagnostic criteria7).
Conjunctivitis is the most common ocular symptom of COVID-196). ACE-2 receptors for SARS-CoV-2 are expressed in the cornea and conjunctiva, making the ocular surface a potential infection target3). Cases have also been reported where conjunctivitis appears as the only symptom of COVID-193).
Contact lens wear can cause giant papillary conjunctivitis (CL-GPC). Constant contact and friction between the lens and the upper tarsal conjunctiva leads to inflammation and giant papillae. In addition, contamination of lenses or storage solution poses a risk of infectious conjunctivitis, making proper lens care important.
The diagnosis of conjunctivitis is based on clinical findings and microbiological examination.
Microbiological examination to detect causative microorganisms is key to diagnosis8).
Chlamydia is diagnosed by fluorescent antibody testing or PCR of conjunctival scrapings. If a diagnosis of chlamydial infection has already been made in another department, there is no need for repeat testing in ophthalmology. Fluorescent antibody testing and PCR are useful for herpes simplex virus, but because asymptomatic shedding in tear fluid can occur, a positive result may not reflect pathogenicity.
The following clinical findings are useful for differentiating infectious conjunctivitis.
| Cause | Conjunctival Findings | Incubation Period | Preauricular Lymph Node |
|---|---|---|---|
| Adenovirus (EKC) | Acute follicular (severe) | ~7 days | Yes |
| Adenovirus (PCF) | Acute follicular (mild) | ~7 days | Yes |
| Enterovirus (AHC) | Acute hemorrhagic | Half to 1 day | Yes |
| Bacterial | Catarrhal | Variable | No |
| Chlamydia | Subacute follicular | Variable | Yes |
Treatment for conjunctivitis is selected according to the underlying cause. Determining the treatment approach based on an accurate diagnosis is fundamental.
Empiric therapy is initiated as the initial treatment, and the medication is changed based on culture results.
The effect of antibacterial eye drops usually appears within a few days, and healing occurs in approximately one week. If symptoms persist, consider the possibility of resistant bacteria, chlamydial infection, allergic conjunctivitis, or canaliculitis.
Mild to Moderate
Antihistamine eye drops: Olopatadine (Patanol®), Epinastine (Alesion®), Levocabastine (Livostin®), etc.
Mast cell stabilizers: Sodium cromoglicate (Intal®), etc. Prophylactic administration before the pollen season is effective.
Severe
Steroid eye drops: Used at low doses for short periods. Be aware of the risk of increased intraocular pressure and glaucoma.
Cyclosporine eye drops: Used for severe cases such as vernal keratoconjunctivitis.
Treatment of the underlying disease is fundamental. Steroid eye drops (dexamethasone 4–6 times daily or fluorometholone 3 times daily) are used for conjunctival inflammation. Pseudomembranes are carefully removed with forceps when they cause corneal epithelial damage. Care should be taken to minimize conjunctival invasion and bleeding. In ligneous conjunctivitis, if tranexamic acid is involved, discontinuation leads to improvement5).
No effective antiviral drug exists for adenovirus. Antibacterial eye drops are sometimes used for secondary infection prevention, but routine use is not recommended. Most cases resolve spontaneously within 1–2 weeks. If MSI (multiple subepithelial infiltrates) appear, steroid eye drops are effective.
The conjunctiva is a thin, vascularized mucous membrane composed of non-keratinized stratified squamous epithelium that covers the inner surface of the eyelids and the anterior sclera. Mucin (MUC-5AC) secreted by conjunctival goblet cells contributes to tear film stability. Accessory lacrimal glands (glands of Krause and Wolfring) are scattered in the lamina propria and secrete tear fluid.
Type I allergic reaction is fundamental. When allergens crosslink surface IgE receptors, conjunctival mast cells are activated, releasing histamine, leukotrienes, prostaglandins, and cytokines. These increase vascular permeability, causing edema and infiltration of eosinophils and neutrophils.
A pseudomembrane is a membranous substance composed of fibrin, neutrophils, and exudate, formed on the conjunctival surface due to intense inflammation. Ligneous conjunctivitis is caused by type I plasminogen deficiency due to recessive mutations in the PLG gene5). Plasminogen is the precursor of plasmin, the main enzyme for fibrinolysis; its deficiency impairs fibrin removal from mucosal surfaces, leading to the formation of thick, woody pseudomembranes5).
SARS-CoV-2 uses the ACE-2 receptor to enter host cells. ACE-2 receptors are also expressed on the cornea and conjunctiva3), making the ocular surface a potential target for infection. It has also been suggested that the virus may be shed into the respiratory tract via the nasolacrimal duct3). The high frequency of conjunctivitis in severe COVID-19 may reflect the spillover of a systemic cytokine storm onto the ocular surface4).
In the phase 3 INVIGORATE trial (crossover, quadruple-blind) involving patients with seasonal allergic conjunctivitis, 0.25% reproxalap ophthalmic solution significantly improved itching score (mean difference −0.50, p < 0.001) and conjunctival hyperemia score (mean difference −0.14, p < 0.001) compared to vehicle1). Reproxalap is a drug with a novel mechanism of action that chemically captures reactive aldehyde species (RASP) and indirectly modulates upstream inflammatory cascades including NF-κB and the inflammasome1). Given that 45% of FDA adverse event reports for existing antihistamines cite “treatment failure,” it is expected as a new therapeutic option1).
Neonatal gonococcal conjunctivitis caused by fluoroquinolone-resistant Neisseria gonorrhoeae (levofloxacin MIC 12 μg/mL) has been reported from Japan2). It developed despite prophylactic levofloxacin eye drops and was cured with intravenous cefotaxime and oral azithromycin2). Whole-genome analysis confirmed missense mutations in the gyrA and parC genes2). Some European countries have reported no increase in gonococcal conjunctivitis after discontinuing routine neonatal ocular prophylaxis2), prompting recommendations for enhanced maternal screening and reconstruction of prevention strategies.
A meta-analysis of 11 studies involving 2,308 patients showed that the incidence of conjunctivitis was significantly higher in patients with severe COVID-19 (OR 2.4, 95% CI 1.4–4.0, p = 0.002)4). This association was confirmed in both Asian (OR 2.5) and European/Mediterranean (OR 2.3) populations4). Further prospective studies are needed to determine whether conjunctivitis can serve as a severity marker for COVID-19.
In a patient with late-onset ligneous conjunctivitis complicated by congenital hydrocephalus, temporary symptom resolution has been reported following a combination of tacrolimus 0.01% eye drops, 20% autologous serum, fresh frozen plasma (FFP) eye drops, and surgical excision5). Plasminogen eye drops and intravenous administration are available in some regions and are considered promising future treatment options5).
