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REVIEW

Use of Topical Steroids in Conjunctivitis: A Review of the


Evidence
Edward J. Holland, MD,* Murray Fingeret, OD,† and Francis S. Mah, MD‡

long-term steroid uses that are dissimilar to applications for


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Purpose: Conjunctivitis, or inflammation of the conjunctiva, is infectious conjunctivitis. Clinical data show that ophthalmic
a common condition that can be caused by infectious (eg, bacterial or formulations that combine corticosteroids with broad-spectrum
viral infections) and noninfectious (eg, allergy) etiologies. Treatment anti-infectives could be effective and well tolerated when used for
involves diagnosis of the underlying cause and use of appropriate short-term treatment (#2 weeks).
therapies. A broad-spectrum therapy that can address multiple
etiologies, and also the accompanying inflammation, would be very Conclusions: Corticosteroids, in combination with anti-infectives,
useful. In this review, we discuss the usefulness of topical could be a promising treatment option for acute conjunctivitis
ophthalmic corticosteroids and ophthalmic formulations that com- subject to development of further evidence on their effectiveness
bine corticosteroids with anti-infectives/antibiotics for treating acute and safety in conjunctivitis treatment.
infectious conjunctivitis.
Key Words: conjunctivitis, dexamethasone, inflammation,
Methods: A review of the published literature and relevant povidone–iodine, topical corticosteroids
treatment guidelines.
(Cornea 2019;38:1062–1067)
Results: Topical corticosteroids are useful in treating ocular
inflammation, but most treatment guidelines recommend steroid
use generally in severe cases of conjunctivitis. This is partly due to
risks associated with steroid use. These risks include potential for
prolonging adenoviral infections and potentiating/worsening herpes
C onjunctivitis, or conjunctival inflammation, is a common
eye condition that accounts for ;1% of all primary care
visits in the United States.1,2 It carries a significant burden of
simplex virus infections, increased intraocular pressure, glaucoma, symptoms and imposes a considerable economic burden.3,4
and cataracts. Most of these perceived risks are not, however, Conjunctivitis can be infectious or noninfectious5:
supported by high-quality clinical data. They are also associated with
1. Infectious: viral or bacterial;
2. Noninfectious: allergic, mechanical, toxic, immune
Received for publication October 23, 2018; revision received March 13,
2019; accepted March 15, 2019. Published online ahead of print May 3, mediated, and neoplastic.
2019.
From the *Cincinnati Eye Institute, Edgewood, KY; †Department of Veterans
Adenoviral conjunctivitis is a major cause of acute
Affairs, New York Harbor Health Care System, Brooklyn, NY; and infectious conjunctivitis cases among adults.5 Infections are
‡Departments of Cornea and External Diseases, Scripps Clinic Torrey generally self-limited and do not require antibiotic treatment.
Pines, La Jolla, CA. There is no approved treatment, but topical corticosteroids may
E. J. Holland has been a consultant for Alcon, Allergan, Bausch + Lomb,
Kala, Mati, Omeros, PRN, RPS, Senju, Shire (a Takeda company),
be helpful in alleviating symptoms of adenoviral conjunctivitis
TearLab, and TearScience and has received research support from Alcon, and may prevent scarring in severe cases. It should be noted,
Allergan, Mati, Omeros, PRN, and Senju. M. Fingeret has been however, that treatment guidelines suggest caution in the use of
a consultant for Aerie, Allergan, Bausch + Lomb, Novartis, and Shire corticosteroids because they can potentially prolong infection.5
(a Takeda company). F. S. Mah has been a consultant for Abbott Medical
Optics, Inc., Alcon, Aerie, Allergan, Avedro, Avellino, Bausch + Lomb,
Bacterial conjunctivitis is responsible for the majority of cases
CoDa, EyePoint, inVirsa, iView, Kala, Mallinckrodt, NovaBay, Novartis, among children.6 Mild bacterial conjunctivitis typically re-
Ocular Science, Ocular Therapeutix, Okogen, Omeros, PolyActiva, solves spontaneously, but topical antibacterial therapy is
RxSight, Shire (a Takeda company), Slack Publishing, Sun, Sydnexis, generally preferred as it is associated with a shorter infectious
and TearLab; has received research support from Abbott Medical Optics,
Inc., Ocular Therapeutix, and Senju; is an investor in Ocular Science,
period and earlier resolution of clinical signs and symptoms.5
Okogen, and Sydnexis; holds a patent/royalty in Slack Publishing; and Allergic conjunctivitis is typically treated with antihistamines
has received lecture fees from Abbott Medical Optics, Inc., Alcon, and mast cell stabilizers, but if the symptoms persist, therapy
Bausch + Lomb, Novartis, Shire (a Takeda company), and Sun. may be supplemented with topical corticosteroids.5
Correspondence: Edward J. Holland, MD, Cincinnati Eye Institute, 580 S
Loop Rd Ste 200, Edgewood, KY 41017 (e-mail: eholland@holprovision.
Corticosteroids are extensively used to treat ocular
com). inflammatory conditions and are among the most prescribed
Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. class of drugs in ophthalmology. In this article, we will review
This is an open-access article distributed under the terms of the Creative evidence for and against the use of corticosteroids in patients
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the
with conjunctivitis and discuss the potential for ophthalmic
work provided it is properly cited. The work cannot be changed in any formulations of corticosteroid and anti-infective combinations
way or used commercially without permission from the journal. to treat acute infectious conjunctivitis in adults and children.

1062 | www.corneajrnl.com Cornea  Volume 38, Number 8, August 2019


Cornea  Volume 38, Number 8, August 2019 Topical Steroids in Conjunctivitis: Review

CHALLENGES OF CONJUNCTIVITIS DIAGNOSIS A review of literature on adverse outcomes associated


AND MANAGEMENT with the short- and long-term use of topical corticosteroids
Early detection and use of appropriate therapies is the shows that the majority of adverse outcomes are related to an
key to expeditious resolution of the disease and helps increase in IOP. However, in most cases, the observed
minimize potential harmful effects or transmission of increase in IOP was not related to the short-term use of
untreated conjunctivitis. Accurate diagnosis of conjunctivitis corticosteroids for conjunctivitis. Increases in IOP tend to be
and identification of the etiology (eg, bacterial, viral, or associated with a longer duration of treatment—typically
allergic) require focused ocular examination and, in some more than 2 weeks.11–13 A #2-weeks treatment course of
cases, laboratory investigation. According to the American corticosteroids is unlikely to affect IOP. Other common
Academy of Ophthalmology guidelines, ocular examination adverse outcomes of corticosteroid therapy include risk of
should include comprehensive slit-lamp biomicroscopy eval- cataract formation and glaucoma,14,15 which are also associ-
uation.5 However, most patients with conjunctivitis are seen ated with long-term steroid use.14,15
at primary care and urgent care clinics, where ocular When used alone, topical steroid use is associated with
examination does not include a slit lamp.7 Distinguishing prolonged periods of viral shedding and infection.16–18 The
between the different forms of conjunctivitis (bacterial, viral, anti-inflammatory and immunosuppressive effect of cortico-
or allergic) can therefore be challenging. Primary or urgent steroids is thought to inhibit normal viral clearance by the
care physicians may prescribe antibiotics without making an immune system. However, when used in combination with
informed differential diagnosis. Misdiagnosis of viral etiolo- anti-infectives, corticosteroids such as dexamethasone have
gies as bacterial conjunctivitis and the resulting inappropriate been shown to be well tolerated19–22 and efficacious in
use of antibiotics can occur in as much as 50% of cases.8 treating inflammatory conditions associated with viral and
It is important to note that irrespective of the underlying bacterial infections.18,21,22
etiology, conjunctivitis is characterized by inflammation of Topical ophthalmic steroids are contraindicated in
the conjunctiva.5 Inflammation is caused by an ocular epithelial herpes simplex keratitis.14,23 However, the use of
immune response against the underlying etiology (eg, bacte- topical steroids is also associated with the perceived risk of
rial, viral, allergic, etc). Treatment of conjunctivitis should reactivating latent HSV in the absence of active epithelial
therefore recognize this inflammation and, in severe cases of disease. HSV is a less frequent cause of acute conjunctivitis
conjunctivitis, aim to manage this inflammation. Cortico- of infectious etiology and may be indistinguishable from
steroids are well known to be effective and fast-acting anti- adenoviral conjunctivitis without further diagnostic test-
inflammatory agents that ameliorate symptoms of pain and ing.24,25 In settings where such testing is not feasible,
swelling.9 However, the use of a corticosteroid alone can physicians could be reluctant to prescribe steroids. However,
reactivate and potentiate herpes simplex virus (HSV) infec- the risk of HSV reactivation by topical steroids in the absence
tion,5 which makes some primary urgent care physicians of active epithelial disease is not entirely supported by the
reluctant to prescribe it. A combination of a corticosteroid published literature. Experimental studies and limited clinical
(eg, dexamethasone) and an antiseptic (eg, povidone–iodine evidence have shown no increased production of HSV after
[PVP-I]) that has the potential to treat both inflammatory and steroid administration.24,26–28 In addition, a randomized
infectious components of conjunctivitis might be very useful. placebo-controlled study of dexamethasone 0.1% for the
Several combinations of dexamethasone and PVP-I are treatment of acute follicular (presumed viral) conjunctivitis
currently under development. showed significantly improved response with no harm or
serious complications and no signs of HSV.29 It should be
noted that although data from small clinical trials indicate that
steroids may be well tolerated, larger randomized clinical
TREATMENT GUIDELINES AND PUBLISHED LIT- trials are needed to further confirm safety.
ERATURE ON TOPICAL CORTICOSTEROID USE Several topical corticosteroids are commonly pre-
The American Academy of Ophthalmology guidelines scribed for ophthalmic conditions. Table 1 lists ophthalmic
on treatment of conjunctivitis list corticosteroids as a treatment steroids used to treat ocular inflammation. Several different
option, but suggest caution in their use5: ophthalmic formulations that combine antimicrobials/anti-
infectives and corticosteroids are also available for treatment
1. Indiscriminate use should be avoided due to the
of eye infections and ocular inflammation (Table 2). These
potential for prolonging adenoviral infections and
include loteprednol etabonate and prednisolone formula-
worsening HSV infections;
tions, as well as various dexamethasone formulations that
2. Patients who are prescribed corticosteroids for a long
are discussed in the next section. Loteprednol etabonate
term should be periodically monitored for increases in
0.5%/tobramycin 0.3% (Zylet; Bausch + Lomb, Bridge-
intraocular pressure (IOP) and evaluated for glaucoma
water, NJ)30 has been in clinical use since 2004 and is
and cataract formation;
approved for use in steroid-responsive inflammatory ocular
3. Steroids should be avoided if HSV conjunctivitis is
conditions, for which a corticosteroid is indicated and where
suspected due to their ability to potentiate
superficial bacterial ocular infection or a risk of bacterial
the infection.
ocular infection exists. Prednisolone 0.2%/sulfacetamide
The United Kingdom College of Optometrists lists cortico- 10% (Blephamide; Allergan, Irvine, CA)31 is a combination
steroids as a predisposing factor for bacterial conjunctivitis.10 of a corticosteroid and an anti-infective that has been in

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. www.corneajrnl.com | 1063
Holland et al Cornea  Volume 38, Number 8, August 2019

TABLE 1. Corticosteroids Typically Used for Ocular Inflammation


Corticosteroid Trade Name Indication
Dexamethasone Maxidex (Alcon Laboratories, Inc., Fort Worth, TX) Steroid-responsive ocular inflammation of the anterior
eye
Prednisolone Pred Forte (Allergan USA, Inc., Madison, NJ), Pred Steroid-responsive ocular inflammation of the anterior
Mild (Allergan USA, Inc., Madison, NJ), and others eye
Fluorometholone Efflumidex (Allergan Pharmaceuticals Ireland, Mayo, Steroid-responsive ocular inflammation of the anterior
Ireland), Flucon (Novartis Pharmaceuticals Australia, eye
Macquarie Park, New South Wales, Australia), FML
(Allergan USA, Inc., Madison, NJ), Flarex (Eyevance
Pharmaceuticals, Fort Worth, TX), FML Forte
(Allergan USA, Inc., Madison, NJ), and others
Loteprednol etabonate Alrex (Bausch + Lomb, Bridgewater, NJ) Allergic conjunctivitis
Lotemax (Bausch + Lomb, Bridgewater, NJ) Postoperative inflammation and pain after ocular surgery
Rimexolone Vexol (Alcon Laboratories, Inc., Fort Worth, TX) Postoperative inflammation after ocular surgery and
anterior uveitis
Difluprednate Durezol (Alcon Laboratories, Inc., Fort Worth, TX) Inflammation and pain associated with ocular surgery

clinical use since the 1980s. It is typically used to treat eye used for a short course. Most warnings and contraindica-
infections and ocular inflammation. tions, particularly in product monographs, typically relate to
long-term use. For example, the package insert of an
ophthalmic dexamethasone product warns that the pro-
DEXAMETHASONE FORMULATIONS longed use of topical dexamethasone can lead to ocular
FOR CONJUNCTIVITIS hypertension and/or glaucoma, posterior subcapsular cata-
Topical ophthalmic dexamethasone is routinely used ract formation, and suppression of the immune response,
to treat ocular inflammation. It is the most widely used with the consequent risk of secondary ocular infections.14
corticosteroid in ophthalmology and has been studied Published data have demonstrated that when used in
extensively.22 Published adverse event data21,22,32–34 pro- combination with antibiotics or antiseptics, for #7 days,
vide evidence on the topical use of dexamethasone when dexamethasone was well tolerated,21,22 with no significant
increase in IOP33 and with no observed trend toward
increase in viral shedding or viral titers.32,34 Moreover,
TABLE 2. Ophthalmic Anti-infective/Corticosteroid
when preservative-free dexamethasone 0.01% was used and
Combination Products in Clinical Use or Under Investigation follow-up conducted 4 to 60 months later, none of the
patients had IOP elevation of .5 mm Hg above baseline,
Corticosteroid Combination
Product Indication/Status suggesting that the short-term use of low-dose dexametha-
sone may be well tolerated.35
Tobramycin 0.3%, dexamethasone Prescribed for steroid-responsive
0.1% (TobraDex; Alcon inflammatory ocular conditions for
Various formulations of dexamethasone in combination
Laboratories, Inc., Fort Worth, which a corticosteroid is indicated with antibiotics or anti-infectives are in clinical use and/or
TX)36 and where superficial bacterial under clinical investigation (Table 2). Examples include
ocular infection or a risk of combinations of tobramycin and dexamethasone, and differ-
bacterial ocular infection exists ent combinations of PVP-I and dexamethasone.
Tobramycin 0.3%, loteprednol Tobramycin 0.3% (antibiotic) and dexamethasone 0.1%
etabonate 0.5% (Zylet)30
ophthalmic suspension (TobraDex) is indicated for steroid-
Netilmicin 0.3%/dexamethasone
0.1% (Netildex; Knight responsive inflammatory ocular conditions for which a corti-
Therapeutics, Inc., Montreal, costeroid is indicated and where superficial bacterial ocular
Quebec, Canada)22 infection or a risk of bacterial ocular infection exists.36
Neomycin, polymyxin B sulfates, PVP-I is a disinfectant and antiseptic agent with broad-
dexamethasone (Maxitrol; Alcon spectrum antimicrobial activity against various viruses,
Laboratories, Inc., Fort Worth,
TX)23
bacteria, and fungi. It is routinely used in ophthalmic
Sulfacetamide, prednisolone
surgery.37 Advantages of PVP-I include low documented
(Blephamide)31 antibiotic resistance and effect on multiple pathogens
PVP-I 0.4%, dexamethasone 0.1% Tested for acute viral conjunctivitis33 in vitro.38 The combination of PVP-I and dexamethasone
(FST-100) has the potential to treat both viral and bacterial conjunctivitis
PVP-I 0.6%, dexamethasone 0.1% Ongoing phase 3 trials for treatment and also to address the inflammatory component of infectious
(SHP640) of bacterial and adenoviral conjunctivitis. Various combinations of PVP-I/dexamethasone
conjunctivitis41–43 have been studied or are currently under investigation for the
PVP-I 1.0%, dexamethasone 0.1% Tested for treatment of adenoviral treatment of inflammatory conditions associated with ocular
keratoconjunctivitis18
infections.

1064 | www.corneajrnl.com Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc.
Cornea  Volume 38, Number 8, August 2019 Topical Steroids in Conjunctivitis: Review

1. PVP-I 0.4%/dexamethasone 0.1% suspension: Preclin- children compared with what was previously reported for
ical data in rabbit eyes showed that it reduced adults.47 Most children (89%) in this study achieved peak IOP
symptoms of adenovirus infection and was effective within 8 days after dexamethasone treatment.
in reducing viral titers and the duration of viral Later studies showed that this ocular hypertensive
shedding.39 In vitro studies showed that it was effective response to dexamethasone may be dose and age dependent
in killing all bacterial, Candida, and Fusarium isolates in children.48–50 Ng et al48 reported that among children aged
within 60 seconds of exposure.40 In an open-label, 2 to 10 years, peak IOP and net increase in IOP were higher
single-arm, descriptive phase 2 study in presumed viral among those receiving topical dexamethasone 4 times daily
conjunctivitis, 8 of 9 eyes achieved clinical resolution versus twice daily. Lam et al49 also reported a greater net
by days 3/4, and no adverse events or increased increase in IOP with topical dexamethasone doses of 4 times
duration of viral shedding were observed.32 In a ran- daily versus twice daily among children aged 3 to 10 years.
domized, masked, controlled study in acute viral Patients in both studies were treated with dexamethasone for
conjunctivitis, the formulation shortened the disease 4 weeks. Lee et al50 examined age dependence of IOP
duration, and no prolonged viral shedding or differ- response to topical dexamethasone among children aged 3 to
ences in IOP versus artificial tears were observed.33 13 years. They reported that peak IOP and net increase in IOP
2. PVP-I 1.0%/dexamethasone 0.1%: In a randomized con- were significantly higher in children aged #5 years compared
trolled trial, it reduced symptoms and expedited recovery with those aged .5 years.
among patients with adenoviral keratoconjunctivitis.18 It should be noted that accurately identifying the type of
3. PVP-I 0.6%/dexamethasone 0.1% (SHP640): In a ran- conjunctivitis and proper follow-up present greater challenges
domized, placebo-controlled, phase 2 trial, SHP640 in the pediatric population compared with the adult popula-
improved clinical resolution and adenoviral eradication tion. The short-term use of PVP-I/dexamethasone, currently
in patients with acute adenoviral conjunctivitis.34 under investigation, may be useful for shortening disease
Ongoing phase 3, randomized, double-masked, con- duration and reducing inappropriate antibiotic prescriptions.
trolled studies will further evaluate its efficacy and Isenberg et al51 investigated the efficacy of PVP-I versus
safety in adenoviral conjunctivitis (ClinicalTrials.gov neomycin–polymyxin B–gramicidin for treatment of infec-
identifiers: NCT0299855441 and NCT0299854142) and tious conjunctivitis in children aged 7 months to 21 years
bacterial conjunctivitis (NCT03004924).43 (mean age, 6.6 years). Their data showed that PVP-I was as
effective as the antibiotic for treating bacterial conjunctivitis
Ophthalmic formulations of PVP-I/dexamethasone are
and is somewhat more effective against chlamydia. Bacterial
promising treatment options for acute conjunctivitis and are
conjunctivitis constitutes a majority of conjunctivitis cases
currently under investigation. By addressing both infectious
among children,6 but survey data show that very few primary
and inflammatory components of infectious conjunctivitis,
care physicians are able to discriminate between viral and
they would simplify diagnosis and treatment. Moreover, they
bacterial etiologies.6,8 This can lead to inappropriate antibi-
have the potential to treat adenoviral conjunctivitis that does otic prescriptions and risk of antibiotic resistance. PVP-I has
not currently have any approved treatment options.
the potential to circumvent these risks, and it may also be
a useful option in conditions when antibiotics are unavailable/
costly. Further, in vitro studies show that PVP-I has
CORTICOSTEROIDS FOR CONJUNCTIVITIS IN significant virucidal activity against a range of viruses that
THE PEDIATRIC POPULATION include HSV.52,53 Although clinical trials would be needed to
Published data do not show a clear difference in evaluate the efficacy and safety of PVP-I/dexamethasone in
corticosteroid response between the pediatric and adult HSV conjunctivitis cases, or cases where an HSV etiology
populations, but pediatricians have been trained to avoid cannot be ruled out, the virucidal activity of PVP-I in
ocular steroid use because of the risk of potentiation of latent conjunction with the anti-inflammatory activity of steroids
HSV infection and a lack of slit lamps to detect HSV keratitis, has the potential to make these combination agents effective
which is a contraindication for topical steroid use. Neverthe- treatment options.
less, several ophthalmic corticosteroids have been approved
for treatment in pediatric populations. For example, FML
(fluorometholone 0.1%)44 and TobraDex36 are approved for CONCLUSIONS
use in children aged .2 years. Corticosteroids, in combination with anti-infectives/
A 1980 Israeli study investigated IOP response in antiseptics, have the potential to address both infectious and
children (aged 4–19 years) treated with dexamethasone for inflammatory components of acute infectious conjunctivitis.
6 weeks. They found that the steroid-associated increase in Some of these combination products could reduce the need
IOP among children was similar to that in adults.45 A 1991 for differential diagnosis of bacterial or adenoviral conjunc-
Japanese study reported that dexamethasone 0.1% temporar- tivitis, and available data show that they may be appropriate
ily raised IOP among children aged ,10 years after 1 to 2 for use in both adult and pediatric populations. Perceived
weeks of treatment, but not among children aged $10 risks associated with corticosteroid use (eg, increased IOP,
years.46 A 1997 study among Chinese children aged ,10 prolonged viral shedding, and HSV reactivation) are not
years reported that topical dexamethasone increased IOP supported by high-quality evidence in the literature, at least in
more frequently, more severely, and more rapidly among some situations (eg, short-term use). In fact, a review of the

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. www.corneajrnl.com | 1065
Holland et al Cornea  Volume 38, Number 8, August 2019

literature indicates that topical corticosteroids have been 20. Holland EJ, Bartlett JD, Paterno MR, et al. Effects of loteprednol/
shown to be efficacious and well tolerated when used for tobramycin versus dexamethasone/tobramycin on intraocular pressure in
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22. Faraldi F, Papa V, Rasà D, et al. Netilmicin/dexamethasone fixed
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23. Maxitrol [package insert]. Fort Worth, TX: Alcon Laboratories, Inc.;
ACKNOWLEDGMENTS 2016.
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