Sistematik Review Konjungtivitis PDF

Review Article
Conjunctivitis: A Systematic Review

Amir A. Azari, MD1,2 , Amir Arabi, MD, MPH1,2
1
Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
2
Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
ORCID:
Amir A. Azari: https://orcid.org/0000-0003-2013-3284
Abstract
Conjunctivitis is a commonly encountered condition in ophthalmology clinics throughout
the world. In the management of suspected cases of conjunctivitis, alarming signs for
more serious intraocular conditions, such as severe pain, decreased vision, and painful
pupillary reaction, must be considered. Additionally, a thorough medical and ophthalmic
history should be obtained and a thorough physical examination should be done in
patients with atypical findings and chronic course. Concurrent physical exam findings
with relevant history may reveal the presence of a systemic condition with involvement
of the conjunctiva. Viral conjunctivitis remains to be the most common overall cause of
conjunctivitis. Bacterial conjunctivitis is encountered less frequently and it is the second
most common cause of infectious conjunctivitis. Allergic conjunctivitis is encountered
in nearly half of the population and the findings include itching, mucoid discharge,
chemosis, and eyelid edema. Long-term usage of eye drops with preservatives in a
patient with conjunctival irritation and discharge points to the toxic conjunctivitis as the
underlying etiology. Effective management of conjunctivitis includes timely diagnosis,
appropriate differentiation of the various etiologies, and appropriate treatment.
Keywords: Allergic; Bacterial; Conjunctivitis; COVID-19; Coronavirus; Viral; Toxic
J Ophthalmic Vis Res 2020; 15 (3): 372–395
INTRODUCTION by engorgement of the blood vessels, ocular

discharge, and pain. Many subjects are affected
Conjunctivitis is characterized by inflammation and
with conjunctivitis worldwide, and it is one of
swelling of the conjunctival tissue, accompanied
the most frequent reasons for office visits to
general medical and ophthalmology clinics. More
Correspondence to: than 80% of all acute cases of conjunctivitis are
Amir A. Azari, MD. Ophthalmic Research Center, reported to be diagnosed by non-ophthalmologists
Research Institute for Ophthalmology and Vision
Science, Shahid Beheshti University of Medical including internists, family medicine physicians,
Sciences, No. 23, Paidarfdard St., Boostan 9 St.,
Pasadaran Ave., Tehran 16666, Iran.
Email: [email protected] This is an open access journal, and articles are distributed under the terms of
the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which
Received: 18-02-2020 Accepted: 25-04-2020 allows others to remix, tweak, and build upon the work non-commercially, as
long as appropriate credit is given and the new creations are licensed under the
identical terms.
Access this article online

Website: https://knepublishing.com/index.php/JOVR
How to cite this article: Azari AA, Arabi A. Conjunctivitis: A Systematic
DOI: 10.18502/jovr.v15i3.7456 Review. J Ophthalmic Vis Res 2020;15:372–395.
372 © 2020 JOURNAL OF OPHTHALMIC AND VISION RESEARCH | PUBLISHED BY PUBLISHED BY KNOWLEDGE E
Conjunctivitis; Azari and Arabi
pediatricians, and nurse practitioners.[1] It is extremely important to differentiate

This imposes a great economic burden conjunctivitis from other causes of “red eye”
to the healthcare system and occupies a associated with severe sight- or life-threatening
great proportion of the office visits in many consequences such as acute angle closure
medical specialties. It is estimated that the glaucoma, uveitis, endophthalmitis, carotid-
cost of treating bacterial conjunctivitis is cavernous fistula, cellulitis, and anterior segment
$857 million annually in the United States tumors.
alone.[2]
It has been reported that nearly 60% of METHODS
all patients with acute conjunctivitis receive
antibiotic eye drops; and the vast majority receive The scientific literature published as of
their prescription from a non-ophthalmologist February 2020 was thoroughly reviewed by
physician. For example, 68% of patients searching PubMed, the ISI web of knowledge
who visited a physician at an emergency database, and the Cochrane library using
room received antibiotic eye drops while this relevant keywords. The following keywords
figure dropped to 36% for those who saw an were used: ”bacterial conjunctivitis”, ”viral
ophthalmologist.[1] Interestingly, patients from conjunctivitis,” ”allergic conjunctivitis”, ”treatment
a higher socioeconomic status were more of bacterial conjunctivitis”, and ”treatment of
likely to receive and fill a prescription for their viral conjunctivitis”. No language restriction was
conjunctivitis.[1] applied.
There are several ways to categorize Articles published between March 2013 and
conjunctivitis; it may be classified based on February 2020 were screened and those that
etiology, chronicity, severity, and extend of provided the best evidence-based information
involvement of the surrounding tissue. The were included in this review. A total of 167 articles
etiology of conjunctivitis may be infectious or were finally included. The first study was published
non-infectious. Viral conjunctivitis followed by in 1964 and the last study was published in 2020.
bacterial conjunctivitis is the most common
cause of infectious conjunctivitis, while allergic History and clinical examination
and toxin-induced conjunctivitis are among
the most common non-infectious etiologies. How to diagnose conjunctivitis
In terms of chronicity, conjunctivitis may
be divided into acute with rapid onset and Conjunctival injection or “red eye” is a shared
duration of four weeks or less, subacute, and presentation for many ophthalmic diseases,
chronic with duration longer than four weeks.[3] and it accounts for up to 1% of all primary
Furthermore, conjunctivitis may be labeled care office visits.[6] The clinicians, whether
as severe when the affected individuals are ophthalmologist or not, must be aware that “red
extremely symptomatic and there is an abundance eye” may be the presenting sign for serious
of mucopurulent discharge. Conjunctivitis may eye conditions such as uveitis, keratitis, or
be associated with the involvement of the scleritis, or it may be secondary to more benign
surrounding tissue such as the eyelid margins conditions that are limited just to the conjunctival
and cornea in blepharoconjunctivitis and viral tissue (e.g., conjunctivitis or subconjunctival
keratoconjunctivitis, respectively. hemorrhage). Traditionally, it was believed that
Additionally, conjunctivitis may be associated more harmful ophthalmic disorders are associated
with systemic conditions, including immune- with disturbances in vision, disabling pain, and
related diseases [e.g., Reiter’s, Stevens-Johnson photophobia.[6] However, in a recent large meta-
syndrome (SJS), and keratoconjunctivitis analysis,[6] anisocoria and mild photophobia
sicca in rheumatoid arthritis], nutritional were significantly associated with “serious
deprivation (vitamin A deficiency), and eye conditions”; the presence of these two
congenital metabolic syndromes (Richner- signs could discover 59% of cases of “serious
Hanhart syndrome and porphyria)[4, 5] (Table eye conditions”, including anterior uveitis and
1). keratitis. Table 2 provides a summary of the
JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 15, ISSUE 3, JULY-SEPTEMBER 2020 373
Table 1. Guideline to help differentiate the major etiologies in conjunctivitis
Clinical history and exam findings Most probable etiologies

Alarming signs and symptoms
Decreased vision, severe pain, painful pupillary reaction, Uveitis, scleritis, keratitis, glaucoma, orbital, or parasellar
anisocoria, orbital signs pathology
Chronicity
Sudden onset, lasting less than four weeks Infectious conjunctivitis, allergic conjunctivitis, acute systemic
reactions (SJS/TEN)
Insidious onset, chronic course Conjunctivitis associated with systemic diseases, toxic
conjunctivitis, allergic conjunctivitis
Recurrent course Allergic conjunctivitis, conjunctivitis associated with systemic
diseases
Associated symptoms
Skin lesions, arthropathy, genito-perineal involvement, Conjunctivitis associated with systemic diseases, infectious
oropharyngeal lesions diseases
Drug history
Long-term eye drop usage Toxic conjunctivitis, allergic conjunctivitis
Recent initiation of a systemic medication Acute systemic reactions (SJS/TEN)
SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis
main etiologies of “red eye” and their clinical the palpebral conjunctiva for the presence of
characteristics. pseudomembranes, symblepharon, papilla or
follicles, and the corneal tissue for the presence of
opacities and infiltrates is absolutely essential.
How to distinguish infectious conjunctivitis
from non-infectious conjunctivitis Some of the clinical signs and symptoms that
are used to help diagnose infectious conjunctivitis
Obtaining history from patients who present include the following: eye discharge, conjunctival
with conjunctivitis is crucial in order to arrive injection, presence of red eye(s), eyelashes being
at the correct diagnosis. A focused ocular stuck together in the morning, grittiness of the
history should include the following: onset and eye(s), eyelid or conjunctival edema, and history of
duration of symptoms; laterality; impairment of contact with individuals with conjunctivitis.[7]
vision; presence of itching; contact lens wear Allergic conjunctivitis may be underdiagnosed
history; presence of fellow travelers such as and undertreated.[8] It is presented with itching,
recent upper respiratory infection, sinusitis, chemosis, and redness in the absence of any
and lymphadenopathy; previous episodes of significant corneal involvement.[9] The degree of
conjunctivitis; systemic allergies and medication; conjunctival swelling is often out of proportion
and history of exposure to chemical agents. to conjunctival hyperemia. The main findings in
The presence of constitutional signs such vernal keratoconjunctivitis (VKC) are the presence
as fever, malaise, fatigue, and contact with of giant papillae in the superior tarsal conjunctiva
individuals with conjunctivitis helps to further accompanied by severe itching,[10] while the
narrow down the differential diagnosis. Physical presence of conjunctival scar and anterior
examination, including checking for palpable subcapsular cataract supports the diagnosis
lymph nodes, especially in the periauricular and of atopic keratoconjunctivitis (AKC).[11]
submandibular areas, is of great importance. Another similar condition, chronic toxic
Ophthalmic examination should be performed conjunctivitis, may present with watery discharge,
to determine the type of discharge. Closer an initial papillary conjunctival reaction followed by
examination using a slit-lamp biomicroscope a follicular reaction, punctate epithelial erosion of
to evaluate the ocular surface structures including the cornea, and eyelid dermatitis.[12–14]
374 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 15, ISSUE 3, JULY-SEPTEMBER 2020
Table 2. Selected non-conjunctivitis etiologies of red eye
Differential diagnosis Symptoms Exam findings
Dry eyes Burning and FB sensation. Symptoms are Bilateral redness, superficial punctate
usually transient, worse with reading or keratopathy, meibomian glands
watching TV due to decreased blinking. dysfunction, decreased tear break-up
Symptoms are worse in dry, cold, and time, small tear meniscus
windy environments due to increased
evaporation
Blepharitis Similar to dry eyes Redness greater at the margins of eyelids,
inflammation, telangiectasia, and crust
around eyelashes
Pterygium Recurrent ocular redness Visible conjunctival extension over the
cornea
Hordeolum, chalazion Eyelid pain and swelling Palpable eyelid mass, may be tender or
not
Anterior segment tumors Variable Variable
Corneal abrasion, keratitis, corneal foreign FB sensation, relevant history including Corneal epithelial defects, corneal
body contact lens usage and occupational infiltration, corneal FB
exposure
Contact lens overwear Relevant history Corneal epithelial defect
Subconjunctival hemorrhage Ocular redness Blood under conjunctiva
Scleritis Decreased vision, moderate to severe Redness, bluish scleral hue
pain
Iritis Photophobia, pain, blurred vision. Decreased vision, poorly reacting pupils,
Symptoms are usually bilateral constant eye pain radiating to temple and
brow. Redness, severe photophobia,
presence of inflammatory cells in the
anterior chamber
Angle closure glaucoma Headaches, nausea, vomiting, ocular Firm eye upon palpation, ocular redness
pain, decreased vision, light sensitivity, with limbal injection. Appearance of a
and seeing haloes around lights. hazy/steamy cornea, moderately dilated
Symptoms are usually unilateral. pupils that are unreactive to light.
Carotid cavernous fistula Chronic red eye, may have a history of Dilated tortuous vessels (corkscrew
head trauma vessels), bruits upon auscultation with a
stethoscope
Endophthalmitis Severe pain, photophobia, may have a Redness, puss in the anterior chamber
history of eye surgery or ocular trauma and photophobia
Cellulitis Pain, double vision, and fullness Redness and swelling of lids, may have
restriction of the eye movements, may
have a history of preceding sinusitis
(usually ethmoiditis)
FB, foreign body; TV, television
How to distinguish bacterial conjunctivitis one study, centers with expertise in ocular surface
from viral conjunctivitis disease had an accuracy rate of only 48% in making
the correct diagnosis of adenoviral conjunctivitis.[15]
Predicting the underlying etiology of conjunctivitis Several other studies demonstrated that bacterial
based on the presenting signs and symptoms pathogens are only isolated in 50% of cases of
may often result in an inaccurate diagnosis. In suspected bacterial conjunctivitis.[16] In addition,
one study reported that up to 52% of presumed A more recent meta-analysis, which analyzed
cases of viral conjunctivitis were culture-positive for the clinical data of 622 patients from three clinical
bacteria.[15] trials,[19] found that patients with purulent discharge
Traditionally, the following associations between or mild to moderate red eye were less likely
the clinical history and the etiology of conjunctivitis to benefit from topical antibiotics; this finding
were believed to be true; these principles were reiterates lack of meaningful correlation between
presented in many textbooks and were used signs and symptoms and the underlying etiology
to select patients in many clinical trials.[17] For in most cases of conjunctivitis. Another recent
example, according to the major text books study in 2013 found a strong likelihood of positive
in ophthalmology (e.g., Krachmer, Duane, and bacterial culture results in patients with the “gluing
Kanski), involvement of one eye followed by the of the eyelids” upon waking up in the morning, and
involvement of the second eye within 24–48 the age above 50 at presentation.[20]
hours is indicative of bacterial infection, while if
the second eye becomes infected after 48 hours How do laboratory findings help us?
with an accompanying enlarged periauricular
lymph node, a viral etiology should be considered. Clinicians may collect discharge samples from
According to the same textbooks, a papillary eyes with conjunctivitis and send them for
conjunctival reaction or pseudomembranous microbiological evaluation. Conjunctival cultures
conjunctivitis strongly suggests a bacterial origin are generally reserved for cases of suspected
for conjunctivitis while follicular conjunctival infectious neonatal conjunctivitis, recurrent
reaction is more likely to indicate a viral etiology. conjunctivitis, conjunctivitis recalcitrant to therapy,
There are many other associations between the conjunctivitis presenting with severe purulent
etiology of conjunctivitis and symptoms that are discharge, and cases suspicious for gonococcal or
thought to be true, but lack strong clinical evidence. chlamydial infection.[21] Swabs from the discharge
For example, association between lack of itching are better to be taken before the initiation of
and bacterial conjunctivitis have come under antimicrobial therapy. The swabs are then plated
scrutiny in the recent years. Other associations in various growth mediums in the laboratory for
that once thought to be true but lack evidence obtaining cultures. Sabouraud agar plates are
include: recent upper respiratory tract infection and used to identify fungus, and it should be utilized
lymphadenopathy in favor of viral conjunctivitis; in patients with chronic blepharitis and those
sinusitis, fever, malaise, and fatigue in association who are immunocompromised. Anaerobic culture
with bacterial conjunctivitis; and previous history plates may also be helpful, especially in patients
of conjunctivitis with bilateral involvement of the with a history of previous surgery or trauma.[22] If
eyes in favor of viral and allergic but not bacterial antimicrobial therapy has already been started,
conjunctivitis. they should be stopped 48 hours prior to obtaining
cultures. In a five-year review of 138 pediatric ocular
A meta-analysis in 2003 failed to find any
surface infections, the most common organisms
clinical studies correlating the signs and symptoms
were coagulase-negative staphylococci, followed
of conjunctivitis with its underlying etiology.[17]
by Pseudomonas aeruginosa and Staphylococcus
Following the above meta-analysis, a prospective
aureus.[23]
study was conducted and found that combination
of three signs, bilateral mattering of the eyelids, Nucleic acid amplification techniques, requiring
lack of itching, and no previous history of special swabs, may be used in diagnosing viral
conjunctivitis were strong predictors of bacterial infections, where a multitude of polymerase chain
conjunctivitis.[18] Having both eyes matter and reaction (PCR) tests for detection of viruses are
their eyelashes adhere together in the morning available.
was a stronger predictor for positive bacterial Although primary studies from in-office rapid
culture, and either itching or a previous episode of antigen testing for adenoviruses report 89%
conjunctivitis made a positive bacterial culture less sensitivity and up to 94% specificity,[21] the results of
likely. In addition, types of the discharge (purulent, more recent studies point toward a high specificity
mucus, or watery) or other symptoms were not but only moderate sensitivity ranging from 39.5%
specific to any particular class of conjunctivitis. to 50%.[24] Accordingly, it may be suggested
that negative Adeno-Plus test results should be changes and visual disturbances. Ocular
confirmed by real-time PCR owing to its suboptimal manifestations of EKC include conjunctival
sensitivity. discharge, follicular conjunctivitis, corneal
For those suspected of having allergic subepithelial infiltrates (SEI), corneal scarring,
conjunctivitis, skin scratch test or intradermal development of conjunctival membranes and
injection of common allergens, and assays for pseudomembranes, and symblepharon formation
detecting elevated in vitro levels of specific serum (Figures 1 and 2).
IgE may be used; however, the diagnosis of allergic Classically, serotypes 8, 19, 37, and less
conjunctivitis remains a clinical one. frequently serotype 4 were believed to be
associated with EKC, but more recently, HAdV-D53
Viral conjunctivitis and HAdV-D54 have been identified in several
outbreaks and are thought to be responsible for
Viral conjunctivitis is the most common overall the majority of EKC cases.[30]
cause of infectious conjunctivitis, and it is usually Pseudomembranes, which are sheets of fibrin-
secondary to inoculation of the ocular surface rich exudates without blood or lymphatic vessels,
with the adenoviruses.[25, 26] Less frequently, other may be encountered in the tarsal conjunctiva of
viruses may be the underlying etiology in viral the EKC patients.[35] Depending on the intensity
conjunctivitis; amongst them, herpes simplex virus of inflammation, true conjunctival membranes may
(HSV), varicella zoster virus (VZV), and enterovirus also form in EKC. True membranes, once form, can
have been the subject of investigation.[27] lead to the development of subepithelial fibrosis
and symblepharon; additionally, they tend to bleed
Adenoviral conjunctivitis severely upon removal.[36]
Cornea is another tissue that may become
As the leading cause of infectious conjunctivitis adversely affected in EKC. Replication of the virus
worldwide, up to 90% of viral conjunctivitis cases in the corneal epithelium may cause superficial
are caused by adenoviruses.[28] Recent advances punctate keratopathy, followed by focal areas of
in genome sequencing of human adenoviruses epithelial opacities.[37] Focal SEI in the anterior
(HAdV) have identified over 72 unique HAdV stroma of the cornea appears approximately 7–
genotypes classified into seven different species 10 days following the initial involvement of the
(HAdV-A through HAdV-G), with HAdV-D species eyes with EKC[38] (Figure 3). These opacities may
having the most members and the strongest persist for years, and they may be associated
association with viral conjunctivitis.[29, 30] with visual disturbance, photophobia, and
Perhaps the most common form of astigmatism. The incidence of SEI formation
infection by the adenoviruses in children is in EKC has been reported to vary from 49.1 to
pharyngoconjunctival fever (PCF) caused by 80%.[39] An immunologic reaction to the replicating
HAdV types 3, 4, and 7.[31–33] This condition is adenoviruses in anterior stromal keratocytes is
usually characterized by the presence of fever, hypothesized to be the underlying mechanism
pharyngitis, periauricular lymphadenopathy, and for the formation of SEIs. The observation that
acute follicular conjunctivitis. Additional ocular these opacities recur following discontinuation of
surface findings include edema, hyperemia, and steroids supports the hypothesis.[40]
petechial hemorrhages of the conjunctiva as a Adenovirus conjunctivitis is very contagious
result of interaction between pro-inflammatory and it may be transmitted up to 50% of the
cytokines and conjunctival vasculature.[32] time according to some reports.[41, 42] The virus
This condition is self-limited, often resolving may spread through contaminated fingers, medical
spontaneously in two–three weeks without any devices, contaminated water at the swimming
treatment. pools, or by sharing of personal items; as many
The most severe ocular manifestation as 46% of individuals with viral conjunctivitis
of adenoviral infection is the epidemic had positive viral culture grown from their hands
keratoconjunctivitis (EKC); this condition affects according to one study.[43] The adenovirus is
both the conjunctiva and cornea, leaving behind a very hardy organism, and it is reported to
long-lasting and permanent ocular surface be resistant to 70% isopropyl alcohol and 3%
Figure 1. Adenoviral conjunctivitis presenting as bilateral watery eyes.
hydrogen peroxide.[44] The American Academy of medications do not appear to be useful.[47, 48]
Ophthalmology recommends using a 1:10 dilute In addition, antibiotic eye drops do not play
bleach solution (sodium hypochlorite) to disinfect a role in treating viral conjunctivitis and may
the office equipment and instruments against even obscure the clinical picture by inducing
common infectious agents encountered in eye care ocular surface toxicity.[15, 16] Other concerns
clinics including the adenoviruses.[45] with using antibiotic drops include increased
Due to the highly contagious nature of bacterial resistance and the possibility of
viral conjunctivitis, frequent hand washing, spreading the disease to the contralateral eye
meticulous disinfection of medical instruments, by cross-contamination through the infected
and isolation of conjunctivitis patients from the bottles.[42]
rest in the healthcare provider’s office has been Membranes or pseudomembranes may be
recommended.[46] The incubation period for the peeled at the slit-lamp by using a pair of jeweler
adenovirus is approximately 5–12 days, while the forceps or cotton swab after anesthetizing the
infected individuals can transmit the disease for up ocular surface. This is done to alleviate patient
to 14 days from the time they are infected.[41] discomfort and prevent future scar formation.
There is no single effective treatment modality Monotherapy against viral conjunctivitis with
for viral conjunctivitis; however, use of frequent Povidone-iodine 2% have been investigated in a
artificial tears, antihistamines containing eye pilot study. The authors discovered that topical
drops, or cold-compresses seem to alleviate administration of Povidone-iodine 2% four times a
many of the clinical symptoms that are associated day for one week led to complete resolution of the
with this condition.[47, 48] Topical and oral antiviral disease in three-quarters of the eyes.[49]
Figure 2. Pseudomembrane formation in a patient with adenoviral conjunctivitis.
The American Academy of Ophthalmology reduce patient symptoms and eradicate the virus
suggests that topical corticosteroids play an effectively.[50, 53–55]
important role in the treatment of conjunctivitis, but Ongoing phase 3, randomized, double-
they should be used judiciously and with caution masked, controlled studies will further clarify
in selected cases.[47] Indications for steroid usage the efficacy and safety of combined PVP-
in viral conjunctivitis are membrane formation and I/dexamethasone in adenoviral conjunctivitis
sub-epithelial infiltration associated with severe (ClinicalTrials.gov identifiers: NCT0299855441
photophobia and decreased vision. Prolonging the and NCT0299854142) and bacterial conjunctivitis
duration of adenoviral conjunctivitis, exacerbation (ClinicalTrials.gov identifiers: NCT03004924).
of HSV keratitis, and an increase in intraocular
Use of 1 and 2% cyclosporine-A (CsA) eye drops
pressure are the main adverse effects of
have been advocated for the treatment of SEIs,
indiscriminate use of topical corticosteroids.
and it has been demonstrated to be effective
Prolongation of viral shedding following in improving patient symptoms and reducing the
monotherapy with corticosteroids has been amounts of infiltrates.[30, 56] However, Jeng et al
reported;[50] however, combination therapies suggested that it might be difficult to wean patients
with corticosteroids and anti-infective agents (i.e., completely off CsA once they have started it; in
antibiotics) have proven to be effective in treating their study, when CsA was stopped, SEIs returned,
viral and bacterial conjunctivitis.[51, 52] necessitating reinstitution of the CsA eye drops.[57]
Ophthalmic formulations of PVP- This finding is in contrast with the Reinhard’s pilot
I/dexamethasone are widely investigated. study, where no recurrence was observed after
PVP-I 0.4%/dexamethasone 0.1% suspension, discontinuation of the CsA drops.[58] In a small
PVP-I 1.0%/dexamethasone 0.1%, and PVP-I study consisting of 39 patients, administration of
0.6%/dexamethasone 0.1% have been used, and 1% cyclosporine-A (four times a day) during the
the results suggest that the combination therapies acute phase of viral conjunctivitis and continuing
Figure 3. Subepithelial infiltrations in a patient with adenoviral conjunctivitis.
it thereafter for 21 days lowered the incidence of by a thin watery discharge and associated vesicular
corneal opacities significantly.[59] A case-controlled lesions on the skin of the eyelids. Treatment
double-blinded randomized clinical trial is needed consists of topical antiviral agents, including
to investigate the effectiveness of cyclosporine-A ganciclovir, idoxuridine, vidarabine, and trifluridine.
and to formulate an ideal tapering regiment for this The purpose of the treatment is to reduce virus
medication. shedding and the chance of the development of
The use of topical tacrolimus eye drops has keratitis.
also been investigated for the treatment of SEIs Ocular involvement with herpes zoster virus,
secondary to adenoviral keratoconjunctivitis. When especially when the first and second branches
tacrolimus eye drops or ointments were used for of the trigeminal nerve are involved, can lead to
an average of six months, a significant reduction conjunctivitis in 41.1% of cases, eyelid lesions in
in the size and numbers of SEIs was observed in 45.8%, uveitis in 38.2%, and corneal lesions such
60% of the cases, while in 31.76% of the eyes, as SEIs, pseudodendrites, and nummular keratitis
SEIs were eliminated after one year.[60] There was in another 19.1%.[64, 65]
also a statistically significant improvement in the
visual acuity of the patients with the use of topical Acute hemorrhagic conjunctivitis
tacrolimus.
Acute hemorrhagic conjunctivitis (AHC) is an
Herpetic conjunctivitis extremely contagious form of viral conjunctivitis.
It manifests by foreign body sensation, profuse
It is estimated that 1.3–4.8% of all cases tearing, eyelid edema, dilatation of conjunctival
of acute conjunctivitis are caused by HSV vessels, chemosis, and subconjunctival
infection.[61–63] HSV often causes a unilateral hemorrhage. In a small proportion of patients,
follicular conjunctivitis, which may be accompanied fever, fatigue, and leg pain may ensue. Two
picornaviruses, namely enterovirus 70 (EV70) and of the infected individuals.[76] All healthcare
coxsackievirus A24 variant (CA24v), as well as professionals including the ophthalmologists
certain subtypes of adenoviruses are believed should be vigilant in approaching patients with
to be the responsible pathogens.[66–68] Like conjunctivitis and respiratory symptoms, especially
the other forms of conjunctivitis, AHC is also if they report a recent history of travel to high risk
believed to be transmitted primarily by hand-to- regions.[76]
eye-to-hand contact and infected fomites.[69] The
condition is self-limited and the symptoms diminish
Bacterial conjunctivitis
gradually during the first week of infection and
completely resolves after 10–14 days.[69] Medical While in adults, bacterial conjunctivitis is less
intervention aims primarily at controlling the large common than viral conjunctivitis, in children,
outbreaks as well as instituting preventative it is encountered more frequently.[77] Bacterial
measures to protect the vulnerable groups, conjunctivitis can result from either a direct
such as children, elderly, pregnant women, and contact with infected individuals or from abnormal
immunocompromised individuals, by encouraging proliferation of the native conjunctival flora.[78]
frequent handwashing and reducing contact with Contaminated fingers,[41] oculogenital spread,[47]
the affected individuals.[68] and contaminated fomites[79] are common routes
of transmission. In addition, certain conditions such
Miscellaneous viral conjunctivitis as compromised tear production, disruption of the
natural epithelial barrier, abnormality of adnexal
Infection with Molluscum contagiosum (MC) is structures, trauma, and immunosuppressed status
characterized by multiple umblicated and papular increase the likelihood of contracting bacterial
skin lesions caused by Pox-2 virus. Skin-to-skin conjunctivitis.[47]
contact and sexual intercourse are the main routes Acute bacterial conjunctivitis is most often
of transmission. Shedding of the viral proteins caused by Staphylococcus species, Haemophilus
from the eyelid lesions into the tear film leads influenza, Streptococcus species, Moraxella
to chronic follicular conjunctival reaction, punctate catarrhalis, and gram-negative intestinal
keratopathy, and subepithelial pannus. Rarely, bacteria.[80] In younger children, minor epidemics
primary MC lesions are found in the conjunctiva.[70] may occur secondary to H. influenza or S.
Ebola hemorrhagic fever is a fatal disease pneumonia. Acute bacterial conjunctivitis
caused by the species of ebolavirus. Conjunctival manifests by foreign body sensation and
injection, subconjunctival hemorrhage, and tearing increased ocular secretion in addition to moderate
have been reported in the affected individuals.[71] conjunctival hyperemia (Figure 4).
Conjunctival injection, which is often bilateral and Several studies on bacterial conjunctivitis[81, 82]
present in up to 58% of cases, has been identified demonstrate that sticky eyelids and itching may
in both the acute and late stages of this disease and be present in approximately 90% of the affected
may play an important role in the early diagnosis of individuals; these findings are followed by the
this potentially deadly condition.[72] While human- less frequently encountered signs and symptoms
to-human transmission through bodily fluids can such as purulent secretion and ocular burning.
spread the infection, the natural reservoir is thought H. influenza conjunctivitis may be associated with
to be the fruit bat.[73] acute otitis media and upper respiratory tract
Coronaviruses include a broad family of viruses infection.[80]
that normally affect animals, although some strains In more than 60% of cases, spontaneous cure
can spread from animals to humans.[74] The most occurs within one–two weeks,[83] and serious
recently isolated strain of coronavirus, “2019- complications are extremely rare.[84] However,
nCoV” , has made the headlines since it was first presence of a large population of bacteria on the
recognized in December 2019 in China. COVID-19 conjunctiva exposes the patient to a higher risk of
has been reported to cause fever, cough, shortness keratitis, particularly in conditions associated with
of breath, and even death.[75, 76] Some reports have corneal epithelial defects, such as dry eye.[80]
suggested that this virus can cause conjunctivitis Although topical antibiotics reduce the duration
and be transmitted via the conjunctival secretions of the disease, no difference in the outcome is seen
between the treatment and placebo groups. In a Serotype D-K are causative agents for neonatal
meta-analysis,[81] , consisting of 3,673 patients from conjunctivitis and adult inclusion conjunctivitis,
11 randomized clinical trials, antibiotic treatment while trachoma is caused by serotypes A, B, Ba,
increased the rate of clinical improvement by 10% and C.[92]
compared to placebo. Both “2 to 5” and “6 to Inclusion conjunctivitis is reported to cause 1.8–
10” day regiments were included in this analysis. 5.6% of all cases of acute conjunctivitis,[61, 62, 93]
Although, highly virulent bacteria can potentially where the majority of cases are unilateral and
inflict serious damage to the ocular surface and the have concurrent genital infection.[94] Patients
eye,[78] , no sight-threatening complications were often present with mild mucopurulent discharge
reported in any of the placebo groups in the and follicular conjunctivitis persisting for weeks
aforementioned meta-analysis.[85] to months.[77] Up to 54% of men and 74% of
All broad-spectrum antibiotic eye drops seem to women are reported to have simultaneous
be effective in treating bacterial conjunctivitis and genital infection.[95] The disease is frequently
it is unlikely that there is a significant difference acquired via oculogenital spread.[47] Treatment
among various antibiotics in achieving clinical cure. with systemic antibiotics such as oral azithromycin
Factors that influence antibiotic choice are local and doxycycline is efficacious, while addition of
availability, patient allergies, resistance patterns, topical antibiotics is not beneficial. Treatment of
and cost. sexual partners and looking for the evidence of
From a large systematic review, it was concluded coinfection with gonorrhea must be instituted.
that topical antibiotics were more effective in As the leading cause of infectious blindness in
achieving clinical and microbial cure when patients the world, trachoma affects 40 million individuals
had positive bacterial cultures.[21] However, worldwide; this infection is prevalent in areas with
no significant difference has been reported in poor hygiene. Although mucopurulent discharge
clinical cure rate when different frequencies is the initial presenting sign, in the later stages,
of the antibiotics were administered.[86, 87] Due scarring of the eyelids, conjunctiva, and cornea
to lengthening the course of the illness and may lead to loss of vision. A single dose of
potentiating the infection, topical steroids should oral azithromycin (20 mg/kg) in addition to oral
be avoided[47] (Table 3). tetracycline or erythromycin for three weeks is
very effective. Patients may also be treated with
Methicillin-resistant S. aureus conjunctivitis topical antibiotic ointments, such as tetracycline
and erythromycin, for six weeks.[96, 97]
The term methicillin-resistant S. aureus (MRSA) In newborns, chlamydia can cause conjunctivitis
refers to Staphylococcus aureus species that following passage through an infected birth canal.
are resistant to methicillin antibiotic; however, The acute phase, which typically begins between
nowadays the term is used to describe resistance days 5 and 14 following vaginal delivery, is
to all β-lactam antimicrobials.[88] Growing in characterized by purulent discharge, erythema and
prevalence, 3–64% of all ocular Staphylococcus edema of the eyelids and conjunctiva.[98] More
conjunctival infections are MRSA conjunctivitis.[89] prevalent than gonococcal conjunctivitis (GC),
Suspected cases need to be treated with fortified neonatal conjunctivitis secondary to C. trachomatis
vancomycin eye drops or ointments.[90] Culture- is considered the most frequent infectious cause of
directed administration of antimicrobials, effective neonatal conjunctivitis worldwide.[98–100]
dosing, considering the local resistance patterns, Although the chlamydial conjunctivitis has a mild
and appropriate antiseptic strategies should course, scarring of the cornea and/or conjunctiva
be applied to restrict the spread of MRSA have been reported in untreated cases.[101] It is
conjunctivitis.[91] important to note that up to 20% of the neonates
who are exposed to chlamydia may develop
Chlamydial conjunctivitis pneumonia; in these, 50% demonstrate a previous
history of conjunctivitis.[102]
Chlamydia trachomatis may cause a variety A recent meta-analysis supports the superiority
of ocular surface infections including trachoma, of traditional treatment with systemic erythromycin
neonatal conjunctivitis, and inclusion conjunctivitis. at 50 mg/kg per day (given in four divided doses
Table 3. Ophthalmic drug therapies for acute bacterial conjunctivitis.
Antibiotic agents Treatment

Aminoglycosides
Gentamicin Ointment: 4 ×/d for 1 wk Solution: 1-2 drops 4 ×/d for 1 wk
Tobramycin Ointment: 3 ×/d for 1 wk
Fluoroquinolones
Besifloxacin 1 drop 3 ×/d for 1 wk
Ciprofloxacin Ointment: 3 ×/d for 1 wk Solution: 1-2 drops 4 ×/d for 1 wk
Gatifloxacin 3 ×/d for 1 week
Levofloxacin 1-2 drops 4 ×/d for 1 wk
Moxifloxacin 3 ×/d for 1 wk
Ofloxacin 1-2 drops 4 ×/d for 1 wk
Macrolides
Azithromycin 2 ×/d for 2 d; then 1 drop daily for 5 d
Erythromycin 4 ×/d for 1 wk
Sulfonamides
Sulfacetamide Ointment: 4 ×/d and at bedtime for 1 wk Solution: 1-2 drops
every 2-3 h for 1 wk
Combination drops
Trimethoprim/polymyxin B 1 or 2 drops 4 ×/d for 1 wk
Figure 4. Thick purulent discharge in a patient with acute bacterial conjunctivitis.
Figure 5. Spectrum of allergic conjunctivitis. CS, corticosteroid
Figure 6. Cobblestone appearance of large conjunctival papillae in a patient with VKC (left). Limbal VKC with Horner-Trantas dots
in another patient (right).
for two weeks), in comparison to topical antibiotic reveal conjunctival injection and chemosis
therapy alone.[103] A recent study evaluating the along with copious mucopurulent discharge; a
efficacy of azithromycin in neonatal chlamydial tender globe with periauricular lymphadenopathy
conjunctivitis[104] demonstrated superiority of may also be associated with this type of
erythromycin over azithromycin; however, conjunctivitis.[106]
risk of pyloric stenosis related to the use of The suggested treatment for neonates include
erythromycin may reduce its clinical use in single dose of ceftriaxone (25 to 50 mg/kg), or
neonates in the future.[103] Additionally, less- cefotaxime (100 mg/kg IV or IM), in addition to
frequent dose of azithromycin may improve hourly saline irrigation of the ocular surface.[106–108]
compliance.[105] Non-neonates can be treated with combination
of 1 gm of IM ceftriaxone given in a single
Gonococcal conjunctivitis (GC) dose and 1 gm of oral azithromycin (which
is used to treat the frequently encountered
Typically viewed as a condition affecting the chlamydial coinfection). Irrigation of the ocular
neonates, GC, however, affects other age surface with saline solution is not necessary in
groups as well.[106] Neisseria gonorrhoeae is a adults.[106]
common cause of hyperacute conjunctivitis in
neonates and sexually active adults.[78] Ocular Allergic conjunctivitis
infection with N. gonorrhea is associated with
a high prevalence of corneal perforation.[80] GC Ocular allergy can affect the entire ocular surface
should be considered as the causative agent including conjunctiva, eyelids, and cornea.
in neonates who present with conjunctivitis in According to the immunological mechanism
days 2 to 5 after delivery.[106] In both neonatal responsible for the final clinical picture, Leonardi
and non-neonatal populations, eye exam may et al have classified ocular allergic conditions
Figure 7. Some systemic and dermatological conditions associated with conjunctivitis.
Figure 8. Symblepharon formation in a patient with ocular cicatricial pemphigoid.
into three main categories:[109] IgE-mediated including VKC and AKC; and non-IgE-mediated
reactions, including seasonal allergic conjunctivitis reactions, including giant papillary conjunctivitis
(SAC) and perennial allergic conjunctivitis (PAC); (GPC) and contact dermatoconjunctivitis (CDC)
combined IgE and non-IgE-mediated reactions, (Figure 5).
Seasonal allergic conjunctivitis (SAC) and allows for the differentiation of VKC from other
perennial allergic conjunctivitis (PAC) related entities such as SAC and PAC.[123]
Conjunctival injection, profuse tearing, severe
SAC and PAC are considered as the most prevalent itching, and photophobia are the main clinical
allergic ocular conditions, affecting 15–20% of the signs and symptoms that are associated with VKC.
population.[110] The pathogenesis is predominantly There are three clinical forms of VKC that include
an IgE-mediated hypersensitivity reaction, and limbal, palpebral, and mixed type.[112] Limbal type
allergen-specific IgE antibodies are found in almost is characterized by limbal papillary reaction and
all cases of SAC and PAC.[111] Activation of mast gelatinous thickening of the limbus; when the
cells contributes to increased levels of histamine, disease is active, Horner-Trantas dots are usually
prostaglandins, and leukotrienes in the tear film. present at the superior limbal margins.[112] The
This phase, which is known as the early response hallmark of the palpebral VKC is the presence
phase, clinically lasts 20–30 min.[8] of giant papillae, with consequent cobblestone
SAC, also known as hay fever conjunctivitis, is appearance. The mixed type has the features of
seen in all age groups. The ocular manifestations palpebral and limbal VKC simultaneously (Figure 6).
occur predominantly during the spring and summer The corneal pathology that is seen in VKC is
months when pollens from the trees and plants partly caused by the mechanical trauma from the
are released into the air. PAC on the other hand tarsal conjunctival papillae and the inflammatory
can occur throughout the year with exposure responses secondary to the release of cytokines.
to more common allergens such as animal hair, The inflammatory mediators are believed to be
mites, and feathers.[112] Clinical signs and symptoms released by the eosinophils and mast cells that
are similar in SAC and PAC, and include itching are infiltrated into the conjunctival tissue.[124, 125]
and burning of the eyes, tearing, and rhinorrhea. In up to 6% of patients, corneal ulcers (i.e.,
Corneal involvement is rarely seen.[9] shields ulcer) and plaques may develop, leading
to the exacerbation of the clinical symptoms and
Vernal keratoconjunctivitis (VKC) worsening of the vision.[126, 127] These ulcers are
usually found as oval lesions with elevated margins
VKC is known as the disease of young males who surrounding a chronic epithelial defect covered by
live in warmer climates.[113, 114] Although VKC is eosinophilic and epithelial debris in the upper parts
frequently diagnosed in children, adults can also of the cornea.[128] Keratoconus is another entity that
be affected with this condition.[115] A mixture of IgE is highly associated with VKC affecting nearly 15%
and non-IgE reaction in response to nonspecific of the patients with this condition.[129]
stimuli, such as wind, dust, and sunlight is often
elucidated in this condition. Accordingly, skin Atopic keratoconjunctivitis (AKC)
tests and serum IgE antibody tests to well-known
allergens are generally negative.[116] Both clinical AKC is characterized by chronic allergic disease of
and histological findings support the concomitant the eyelid, cornea, and conjunctiva. It is considered
role of T-helper 2 and IgE in the pathogenesis the ocular component of atopic dermatitis (AD),
of VKC.[8, 117] Recently, IL-17 has been reported and roughly 95% of the patients with AKC have
to be linked to VKC, where its serum levels concomitant AD;[8, 11] however, less than half of
can serve as a marker for the severity of the patients with AD have involvement of their ocular
disease.[118, 119] High percentage of antinuclear tissue.[130] Many cytokines are released from the
antibodies (ANA) positivity and family history epithelial cells of the conjunctiva as well as
of autoimmune disorders in patients with VKC the inflammatory cells that have infiltrated the
suggests a strong link between this condition conjunctival tissues in AKC. This causes constant
and other autoimmune disorders including remodeling of the ocular surface connective tissue
atopy.[120, 121] leading to mucus metaplasia, scar formation, and
Typical seasonal patterns as well as perennial corneal neovascularization.[131]
forms have been reported in patients affected AKC is typically diagnosed in the second and
with VKC.[122] Presence of papillary hyperplasia is third decades of life, although scattered cases are
essential for the diagnosis of VKC, and its presence seen in the early childhood as well as in the fifth
decade of life.[132] Age of the onset, duration of Contact allergy

the disease, and clinical presentations may help
clinicians to distinguish this condition from VKC.[132] CDC is a classic example of type-IV delayed
Clinical manifestation of AKC includes hypersensitivity reaction that occurs through
epiphora, itching, redness, and decreased interaction of antigens with T cells followed by
vision. Presentation is often bilateral; however, release of cytokines.[139] Low molecular weight
unilateral disease has been reported.[133] allergens combine with host proteins to form
The eyelid skin may be edematous with a the final allergens capable of exerting immune
sandpaper-like texture. Conjunctival injection response. Some of the known allergens for CDC
and chemosis range from mild to severe, and include poison ivy, poison oak, neomycin, nickel,
conjunctival scarring is common.[11] Trantas latex, atropine and its derivatives.[8] Primary
dots and giant papillae may or may not be sensitization phase describes the process through
present. In contrast to VKC, AKC is associated with which memory T cells derive from resident T cells
conjunctival fibrosis and corneal vascularization of the ocular tissue, while the following elicitation
and opacities. An early cataract surgery is not phase includes the interaction between these
uncommon in AKC patients, as this condition is memory cells and allergens.[8] IL-17-producing Th
associated with formation of “atopic cataracts” cells and regulatory T cells also play a role in the
at a relatively young age. Shield-like cataracts, pathogenesis of CDC.[140]
as well as nuclear, cortical and even posterior Similar to AKC, contact allergy involves the
subcapsular cataracts may also occur. Nearly conjunctiva, cornea, and eyelids. The condition
50% of AKC patients test negative for common may be associated with itching, lid swelling,
allergens.[8] follicular reaction, and even cicatrization in later
stages of the disease. The corneal involvement
may be in the form of punctate keratitis,
Giant papillary conjunctivitis (GPC) pseudodendritic keratitis, and grayish stromal
infiltrates.[112, 141]
Similar to vernal conjunctivitis, GPC is
characterized by papillary hypertrophy of the
superior tarsal conjunctiva.[134] Although GPC Treatment
is primarily considered as a complication of
contact lens usage, this condition has also been Avoidance of the allergens is the main stay of
reported in association with corneal foreign treatment for many forms of allergies including
bodies, filtering blebs, ocular prostheses, allergic conjunctivitis. Artificial tears provide a
exposed sutures, limbal dermoids, and tissue barrier function, dilute various allergens, and flush
adhesives.[135–137] The classic signs of GPC consist the ocular surface clean from many inflammatory
of excessive mucous secretion associated with mediators.
decreased contact lens tolerance.[137] Mast cells The treatment options for allergic conjunctivitis
and eosinophils may be found in the conjunctiva; include lubricating eye drops, anti-histamines,
however, there are no increases in the levels of and mast cell stabilizers.[142, 143] Many studies
IgE or histamines in the tears of patients with have demonstrated the superiority of topical
GPC.[8] antihistamines and mast cell stabilizers compared
GPC can occur with both hydrogel and to placebo in alleviating the symptoms of
rigid contact lenses, and it has been reported allergic conjunctivitis; in addition, it has been
with either hydroxyethyl methacrylate (HEMA), demonstrated that antihistamines are more
silicone polymers, or the new gas permeable beneficial than mast cell stabilizers for providing
polymers.[134] However, it is less frequent with short-term relief.[144] Several eye drop preparations
rigid contact lenses. Mechanical injuries due to with dual action (antihistamine and mast cell-
contact lens wear and inflammatory reactions stabilizing effects) including olopatadine, ketotifen,
secondary to surface proteins of the lens azelastine, and epinastine have been introduced
can contribute to the chronic inflammatory to market in the recent years. These agents
damage of the ocular surface[110, 138] seen in can provide simultaneous histamine receptor
this condition. antagonist effects, stabilize mast-cell membranes,
and modify the action of eosinophils.[145] summary of systemic diseases associated with
Mast cell stabilizers require a loading period conjunctivitis is provided in Figure 7.
of several weeks, and therefore, they are
better to be administered before the antigen Reactive arthritis
exposure.
Oral antihistamines are commonly used for Conjunctivitis is one of the most common
alleviating the ocular symptoms in patients ocular manifestations of reactive arthritis;
with allergic conjunctivitis. Second generation other associated ocular entities include uveitis,
antihistamines are preferred due to their fewer episcleritis, scleritis, and keratitis.[149] Conjunctivitis
adverse systemic side effects.[146] Unfortunately, in reactive arthritis entities manifests itself as
oral antihistamines induce ocular drying, which conjunctival hyperemia with purulent discharge.
can significantly worsen the symptoms of allergic Occurring in nearly one third of the patients,
conjunctivitis.[147] conjunctivitis is an essential component of the
Steroids should be used judiciously and only “Reiter’s triad”.[150] Conjunctivitis usually happens
in selected cases. Topical and oral administration, early in the course of reactive arthritis and it may
in addition to supratarsal injections are often even precede it in some instances; given its mild
required if the condition is severe; unfortunately, initial clinical presentation, it is often missed. The
any route of corticosteroid administration is signs and symptoms usually abate within one to
associated with formation of cataracts and four weeks; however, in some cases, progression
elevated intraocular pressure.[112] Non-steroidal to more severe ocular surface problems may
anti-inflammatory drugs such as ketorolac ensue.[151]
and diclofenac can also be added to the
treatment regimen to provide additional benefits. Rosacea
Moreover, other steroid-sparing agents such
as cyclosporine-A and tacrolimus are effective Ocular surface may also be involved in
in treating severe and chronic forms of ocular the inflammatory course of ocular rosacea.
allergies. The clinical findings include a follicular and
Allergen-specific immunotherapy, which has papillary conjunctival reaction in association
gained popularity in the recent years, works with interpalpebral conjunctival hyperemia. In
by inducing clinical tolerance to a specific addition, cicatrization of the conjunctival tissue,
allergen. This appears to be an effective mimicking trachoma, may be seen in these
treatment options for those with allergic patients. Conjunctival scarring secondary to
rhinoconjunctivitis who demonstrate specific entropion and trichiasis has been reported
IgE antibodies.[148] Traditionally, immunotherapy to occur in approximately 10% of the cases.
is performed via subcutaneous injections; Conjunctival granuloma, pinguecula, phlyctenule,
however, sublingual immunotherapy (SLIT) and peripheral corneal infiltration and phlyctenule
has drawn the attention among allergists are amongst some of the other findings associated
as an alternative. SLIT has been shown to with ocular rosacea.[152]
effectively reduce the ocular and nasal signs
and symptoms of allergic conjunctivitis, with
Graft-versus-host disease
a greater benefit toward improving the nasal
symptoms.[112] Conjunctival involvement is rarely seen in acute
graft-versus-host disease (GVHD); however,
Conjunctivitis associated with systemic its presence indicates more severe systemic
diseases involvement and a poor prognosis. Conjunctival
involvement in GVHD ranges from mild
Conjunctivitis may be the initial presentation for conjunctival injection to pseudomembranous
many systemic diseases; therefore, a thorough and cicatrizing conjunctivitis.[153, 154] In acute
history and systemic evaluation in selected cases GVHD, conjunctivitis is often ulcerative and
may help in early diagnosis of many potentially manifests itself with numerous alternating
disabling and even life-threatening conditions. A episodes of conjunctival hemorrhage and
exudative discharge. Sterile purulent discharge, conjunctiva and lid margins.[159] Acute ocular
pseudomembrane formation, and scarring involvement is reported to occur in up to 88% of the
are amongst the other findings in this cases.[159] It remains unclear whether the severity
condition.[153] In the chronic form of GVHD, of ocular involvement is any different between SJS
one-fourth to three-fourth of the patients suffer and TEN.[160] Long-term adverse consequences
from dry eyes, where its severity correlates following the acute stage of ocular surface disease
with the severity of GVHD.[155] Frequently, include severe dry eyes, symblepharon formation,
keratoconjunctivitis sicca persists after remission corneal limbal stem cell deficiency, and corneal
of GVHD.[156] scarring.[160]
Four stages of conjunctival GVHD have been
described in the literature. Stage 1 is marked
by simple conjunctival injection. Stage 2 is Toxic conjunctivitis
characterized by an exudative response, which
may lead to conjunctival chemosis. Stage 3 is It has been recently realized that long-term
characterized by pseudomembrane formation; use of topical eye medications may induce
majority of the patients are diagnosed at this ocular surface changes including dry eyes,
stage of the diseases. Stage 4 is manifested conjunctival inflammation, ocular surface fibrosis,
by scarring and cicatrization of the conjunctival and scarring.[161, 162] Another area where the side
tissue.[153, 156] effects of topical eye drops cause significant
ocular morbidity is their use in glaucoma and
in patients who have undergone glaucoma
Ocular cicatricial pemphigoid surgery. Subclinical infiltration of the conjunctival
epithelium and substantia propria by inflammatory
Ocular cicatricial pemphigoid is a rare
cells has also been reported.[163, 164] The published
condition. Patients are often in their fifth and
literature during the past decade has pointed to
sixth decades of life at presentation, and
the deleterious effects of benzalkonium chloride
females are up to three times more frequently
(BAK), which is used as a preservative in eye drops,
affected than males.[157] Chronic inflammation,
on the ocular surface.[165]
loss of conjunctival goblet cells along with
an abnormal mucosal epithelial turn-over Allergic reactions are the most clinically
leads to desiccation of the ocular surface noticeable side effect of the eye drops; however,
in this condition[158] (Figure 8). Disruption they are far less frequent and harmful than
of conjunctival immune network increases their adverse toxic side effects.[166] The allergic
the risk of ocular surface infection.[158] reaction to eye drops includes simple conjunctival
Recurrent infectious conjunctivitis and trichiasis congestion, papillary conjunctivitis, and GPC.[165]
may lead to keratinization of the surface The signs and symptoms usually manifest a few
epithelium.[158] Definitive diagnosis requires days after starting the offending eye drop and
direct immunofluorescence, where deposits tend to resolve quickly when the medication is
of immunoglobulins and/or complements stopped.[166]
produce areas of linear hyperfluorescence at Observational studies have confirmed the high
the epithelial basement membrane. Systemic prevalence of dry eyes in glaucoma patients related
immunosuppression along with frequent to the number of eye drops being used. This ranges
lubrication is often needed to adequately control from 11% in those who use only one eye drop
this condition. to 43% in those who use two or three different
eye drops.[167] Similarly, a cross-sectional study
Stevens-Johnson syndrome and toxic evaluating the ocular surface in 101 patients being
epidermal necrolysis treated for glaucoma reported that approximately
60% of them were symptomatic in at least one
Ophthalmic manifestations of the acute stages eye.[168] In a survey performed on 300 patients
of Stevens-Johnson syndrome (SJS) and toxic in the US between 2001 and 2004, adverse side
epidermal necrolysis (TEN) range from conjunctival effects were reported to be the second most
hyperemia to near-complete sloughing of palpebral common reason for switching eye drops.[169]
Increase in fibroblast density in the conjunctiva, patients that do not respond to therapy, and
and development of subconjunctival fibrosis those suspected to have chlamydial infection
has been reported in patients who use and hyperacute conjunctivitis.[47] Treatment with
antiglaucoma drops chronically.[165] In a series of topical antibiotics is usually recommended for
145 patients, Thorne et al reported that exposure suspected cases of chlamydial and gonococcal
to antiglaucoma eye drops was the primary reason conjunctivitis and contact lens wearers.[61, 80] The
for development of pseudopemphigoid.[170] majority of cases of allergic conjunctivitis are due
Despite the indisputable data and the findings to seasonal allergies. Antihistamines and mast cell
from multiple observational studies on the stabilizers are widely used for treating allergic
harmful side effects of BAK, it is still used as conjunctivitis. Steroids must be used judiciously
the main preservative ingredient in most eye drop and only when indicated. For patients with chronic
preparations due to lack of a better alternative.[165] conjunctivitis, possibility of systemic diseases and
Limiting the exposure to preservatives may adverse effects of eye drops with preservatives
diminish the toxic side effects of eye drops; this will should be kept in mind.
likely lead to higher patient compliance and result
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Review Article

Conjunctivitis: A Systematic Review

J Ophthalmic Vis Res 2020; 15 (3): 372–395

INTRODUCTION by engorgement of the blood vessels, ocular

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pediatricians, and nurse practitioners.[1] It is extremely important to differentiate

Table 1. Guideline to help differentiate the major etiologies in conjunctivitis

Clinical history and exam findings Most probable etiologies

SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis

Table 2. Selected non-conjunctivitis etiologies of red eye

Differential diagnosis Symptoms Exam findings

FB, foreign body; TV, television

Figure 1. Adenoviral conjunctivitis presenting as bilateral watery eyes.

Figure 2. Pseudomembrane formation in a patient with adenoviral conjunctivitis.

Figure 3. Subepithelial infiltrations in a patient with adenoviral conjunctivitis.

Table 3. Ophthalmic drug therapies for acute bacterial conjunctivitis.

Antibiotic agents Treatment

Figure 4. Thick purulent discharge in a patient with acute bacterial conjunctivitis.

Figure 5. Spectrum of allergic conjunctivitis. CS, corticosteroid

Figure 7. Some systemic and dermatological conditions associated with conjunctivitis.

Figure 8. Symblepharon formation in a patient with ocular cicatricial pemphigoid.

decade of life.[132] Age of the onset, duration of Contact allergy

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