Conjunctivitis, 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 symptoms and imposes a considerable economic burden.3,4 Conjunctivitis can be infectious or noninfectious5:
- Infectious: viral or bacterial;
- Noninfectious: allergic, mechanical, toxic, immune mediated, and neoplastic.
Adenoviral conjunctivitis is a major cause of acute infectious conjunctivitis cases among adults.5 Infections are generally self-limited and do not require antibiotic treatment. There is no approved treatment, but topical corticosteroids may be helpful in alleviating symptoms of adenoviral conjunctivitis and may prevent scarring in severe cases. It should be noted, however, that treatment guidelines suggest caution in the use of corticosteroids because they can potentially prolong infection.5 Bacterial conjunctivitis is responsible for the majority of cases among children.6 Mild bacterial conjunctivitis typically resolves spontaneously, but topical antibacterial therapy is generally preferred as it is associated with a shorter infectious period and earlier resolution of clinical signs and symptoms.5 Allergic conjunctivitis is typically treated with antihistamines and mast cell stabilizers, but if the symptoms persist, therapy may be supplemented with topical corticosteroids.5
Corticosteroids are extensively used to treat ocular inflammatory conditions and are among the most prescribed class of drugs in ophthalmology. In this article, we will review evidence for and against the use of corticosteroids in patients with conjunctivitis and discuss the potential for ophthalmic formulations of corticosteroid and anti-infective combinations to treat acute infectious conjunctivitis in adults and children.
CHALLENGES OF CONJUNCTIVITIS DIAGNOSIS AND MANAGEMENT
Early detection and use of appropriate therapies is the key to expeditious resolution of the disease and helps minimize potential harmful effects or transmission of untreated conjunctivitis. Accurate diagnosis of conjunctivitis and identification of the etiology (eg, bacterial, viral, or allergic) require focused ocular examination and, in some cases, laboratory investigation. According to the American Academy of Ophthalmology guidelines, ocular examination should include comprehensive slit-lamp biomicroscopy evaluation.5 However, most patients with conjunctivitis are seen at primary care and urgent care clinics, where ocular examination does not include a slit lamp.7 Distinguishing between the different forms of conjunctivitis (bacterial, viral, or allergic) can therefore be challenging. Primary or urgent care physicians may prescribe antibiotics without making an informed differential diagnosis. Misdiagnosis of viral etiologies as bacterial conjunctivitis and the resulting inappropriate use of antibiotics can occur in as much as 50% of cases.8
It is important to note that irrespective of the underlying etiology, conjunctivitis is characterized by inflammation of the conjunctiva.5 Inflammation is caused by an ocular immune response against the underlying etiology (eg, bacterial, viral, allergic, etc). Treatment of conjunctivitis should therefore recognize this inflammation and, in severe cases of conjunctivitis, aim to manage this inflammation. Corticosteroids are well known to be effective and fast-acting anti-inflammatory agents that ameliorate symptoms of pain and swelling.9 However, the use of a corticosteroid alone can reactivate and potentiate herpes simplex virus (HSV) infection,5 which makes some primary urgent care physicians reluctant to prescribe it. A combination of a corticosteroid (eg, dexamethasone) and an antiseptic (eg, povidone–iodine [PVP-I]) that has the potential to treat both inflammatory and infectious components of conjunctivitis might be very useful. Several combinations of dexamethasone and PVP-I are currently under development.
TREATMENT GUIDELINES AND PUBLISHED LITERATURE ON TOPICAL CORTICOSTEROID USE
The American Academy of Ophthalmology guidelines on treatment of conjunctivitis list corticosteroids as a treatment option, but suggest caution in their use5:
- Indiscriminate use should be avoided due to the potential for prolonging adenoviral infections and worsening HSV infections;
- Patients who are prescribed corticosteroids for a long term should be periodically monitored for increases in intraocular pressure (IOP) and evaluated for glaucoma and cataract formation;
- Steroids should be avoided if HSV conjunctivitis is suspected due to their ability to potentiate the infection.
The United Kingdom College of Optometrists lists corticosteroids as a predisposing factor for bacterial conjunctivitis.10
A review of literature on adverse outcomes associated with the short- and long-term use of topical corticosteroids shows that the majority of adverse outcomes are related to an increase in IOP. However, in most cases, the observed increase in IOP was not related to the short-term use of corticosteroids for conjunctivitis. Increases in IOP tend to be associated with a longer duration of treatment—typically more than 2 weeks.11–13 A ≤2-weeks treatment course of corticosteroids is unlikely to affect IOP. Other common adverse outcomes of corticosteroid therapy include risk of cataract formation and glaucoma,14,15 which are also associated with long-term steroid use.14,15
When used alone, topical steroid use is associated with prolonged periods of viral shedding and infection.16–18 The anti-inflammatory and immunosuppressive effect of corticosteroids is thought to inhibit normal viral clearance by the immune system. However, when used in combination with anti-infectives, corticosteroids such as dexamethasone have been shown to be well tolerated19–22 and efficacious in treating inflammatory conditions associated with viral and bacterial infections.18,21,22
Topical ophthalmic steroids are contraindicated in epithelial herpes simplex keratitis.14,23 However, the use of topical steroids is also associated with the perceived risk of reactivating latent HSV in the absence of active epithelial disease. HSV is a less frequent cause of acute conjunctivitis of infectious etiology and may be indistinguishable from adenoviral conjunctivitis without further diagnostic testing.24,25 In settings where such testing is not feasible, physicians could be reluctant to prescribe steroids. However, the risk of HSV reactivation by topical steroids in the absence of active epithelial disease is not entirely supported by the published literature. Experimental studies and limited clinical evidence have shown no increased production of HSV after steroid administration.24,26–28 In addition, a randomized placebo-controlled study of dexamethasone 0.1% for the treatment of acute follicular (presumed viral) conjunctivitis 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 trials are needed to further confirm safety.
Several topical corticosteroids are commonly prescribed for ophthalmic conditions. Table 1 lists ophthalmic steroids used to treat ocular inflammation. Several different ophthalmic formulations that combine antimicrobials/anti-infectives and corticosteroids are also available for treatment of eye infections and ocular inflammation (Table 2). These include loteprednol etabonate and prednisolone formulations, as well as various dexamethasone formulations that are discussed in the next section. Loteprednol etabonate 0.5%/tobramycin 0.3% (Zylet; Bausch + Lomb, Bridgewater, NJ)30 has been in clinical use since 2004 and is approved for use in steroid-responsive inflammatory ocular conditions, for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. Prednisolone 0.2%/sulfacetamide 10% (Blephamide; Allergan, Irvine, CA)31 is a combination of a corticosteroid and an anti-infective that has been in clinical use since the 1980s. It is typically used to treat eye infections and ocular inflammation.
DEXAMETHASONE FORMULATIONS FOR CONJUNCTIVITIS
Topical ophthalmic dexamethasone is routinely used to treat ocular inflammation. It is the most widely used corticosteroid in ophthalmology and has been studied extensively.22 Published adverse event data21,22,32–34 provide evidence on the topical use of dexamethasone when used for a short course. Most warnings and contraindications, particularly in product monographs, typically relate to long-term use. For example, the package insert of an ophthalmic dexamethasone product warns that the prolonged use of topical dexamethasone can lead to ocular hypertension and/or glaucoma, posterior subcapsular cataract formation, and suppression of the immune response, with the consequent risk of secondary ocular infections.14 Published data have demonstrated that when used in combination with antibiotics or antiseptics, for ≤7 days, 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, when preservative-free dexamethasone 0.01% was used and follow-up conducted 4 to 60 months later, none of the patients had IOP elevation of >5 mm Hg above baseline, suggesting that the short-term use of low-dose dexamethasone may be well tolerated.35
Various formulations of dexamethasone in combination with antibiotics or anti-infectives are in clinical use and/or under clinical investigation (Table 2). Examples include combinations of tobramycin and dexamethasone, and different combinations of PVP-I and dexamethasone.
Tobramycin 0.3% (antibiotic) and dexamethasone 0.1% ophthalmic suspension (TobraDex) is indicated for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.36
PVP-I is a disinfectant and antiseptic agent with broad-spectrum antimicrobial activity against various viruses, bacteria, and fungi. It is routinely used in ophthalmic surgery.37 Advantages of PVP-I include low documented antibiotic resistance and effect on multiple pathogens in vitro.38 The combination of PVP-I and dexamethasone has the potential to treat both viral and bacterial conjunctivitis and also to address the inflammatory component of infectious conjunctivitis. Various combinations of PVP-I/dexamethasone have been studied or are currently under investigation for the treatment of inflammatory conditions associated with ocular infections.
- PVP-I 0.4%/dexamethasone 0.1% suspension: Preclinical data in rabbit eyes showed that it reduced symptoms of adenovirus infection and was effective in reducing viral titers and the duration of viral shedding.39 In vitro studies showed that it was effective in killing all bacterial, Candida, and Fusarium isolates within 60 seconds of exposure.40 In an open-label, single-arm, descriptive phase 2 study in presumed viral conjunctivitis, 8 of 9 eyes achieved clinical resolution by days 3/4, and no adverse events or increased duration of viral shedding were observed.32 In a randomized, masked, controlled study in acute viral conjunctivitis, the formulation shortened the disease duration, and no prolonged viral shedding or differences in IOP versus artificial tears were observed.33
- PVP-I 1.0%/dexamethasone 0.1%: In a randomized controlled trial, it reduced symptoms and expedited recovery among patients with adenoviral keratoconjunctivitis.18
- PVP-I 0.6%/dexamethasone 0.1% (SHP640): In a randomized, placebo-controlled, phase 2 trial, SHP640 improved clinical resolution and adenoviral eradication in patients with acute adenoviral conjunctivitis.34 Ongoing phase 3, randomized, double-masked, controlled studies will further evaluate its efficacy and safety in adenoviral conjunctivitis (ClinicalTrials.gov identifiers: NCT0299855441 and NCT0299854142) and bacterial conjunctivitis (NCT03004924).43
Ophthalmic formulations of PVP-I/dexamethasone are promising treatment options for acute conjunctivitis and are currently under investigation. By addressing both infectious and inflammatory components of infectious conjunctivitis, they would simplify diagnosis and treatment. Moreover, they have the potential to treat adenoviral conjunctivitis that does not currently have any approved treatment options.
CORTICOSTEROIDS FOR CONJUNCTIVITIS IN THE PEDIATRIC POPULATION
Published data do not show a clear difference in corticosteroid response between the pediatric and adult populations, but pediatricians have been trained to avoid ocular steroid use because of the risk of potentiation of latent HSV infection and a lack of slit lamps to detect HSV keratitis, which is a contraindication for topical steroid use. Nevertheless, several ophthalmic corticosteroids have been approved for treatment in pediatric populations. For example, FML (fluorometholone 0.1%)44 and TobraDex36 are approved for use in children aged >2 years.
A 1980 Israeli study investigated IOP response in children (aged 4–19 years) treated with dexamethasone for 6 weeks. They found that the steroid-associated increase in IOP among children was similar to that in adults.45 A 1991 Japanese study reported that dexamethasone 0.1% temporarily raised IOP among children aged <10 years after 1 to 2 weeks of treatment, but not among children aged ≥10 years.46 A 1997 study among Chinese children aged <10 years reported that topical dexamethasone increased IOP more frequently, more severely, and more rapidly among children compared with what was previously reported for adults.47 Most children (89%) in this study achieved peak IOP within 8 days after dexamethasone treatment.
Later studies showed that this ocular hypertensive response to dexamethasone may be dose and age dependent in children.48–50 Ng et al48 reported that among children aged 2 to 10 years, peak IOP and net increase in IOP were higher among those receiving topical dexamethasone 4 times daily versus twice daily. Lam et al49 also reported a greater net increase in IOP with topical dexamethasone doses of 4 times daily versus twice daily among children aged 3 to 10 years. Patients in both studies were treated with dexamethasone for 4 weeks. Lee et al50 examined age dependence of IOP response to topical dexamethasone among children aged 3 to 13 years. They reported that peak IOP and net increase in IOP were significantly higher in children aged ≤5 years compared with those aged >5 years.
It should be noted that accurately identifying the type of conjunctivitis and proper follow-up present greater challenges in the pediatric population compared with the adult population. The short-term use of PVP-I/dexamethasone, currently under investigation, may be useful for shortening disease duration and reducing inappropriate antibiotic prescriptions. Isenberg et al51 investigated the efficacy of PVP-I versus neomycin–polymyxin B–gramicidin for treatment of infectious conjunctivitis in children aged 7 months to 21 years (mean age, 6.6 years). Their data showed that PVP-I was as effective as the antibiotic for treating bacterial conjunctivitis and is somewhat more effective against chlamydia. Bacterial conjunctivitis constitutes a majority of conjunctivitis cases among children,6 but survey data show that very few primary care physicians are able to discriminate between viral and bacterial etiologies.6,8 This can lead to inappropriate antibiotic prescriptions and risk of antibiotic resistance. PVP-I has 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 significant virucidal activity against a range of viruses that include HSV.52,53 Although clinical trials would be needed to evaluate the efficacy and safety of PVP-I/dexamethasone in HSV conjunctivitis cases, or cases where an HSV etiology cannot be ruled out, the virucidal activity of PVP-I in conjunction with the anti-inflammatory activity of steroids has the potential to make these combination agents effective treatment options.
Corticosteroids, in combination with anti-infectives/antiseptics, have the potential to address both infectious and inflammatory components of acute infectious conjunctivitis. Some of these combination products could reduce the need for differential diagnosis of bacterial or adenoviral conjunctivitis, and available data show that they may be appropriate for use in both adult and pediatric populations. Perceived risks associated with corticosteroid use (eg, increased IOP, prolonged viral shedding, and HSV reactivation) are not supported by high-quality evidence in the literature, at least in some situations (eg, short-term use). In fact, a review of the literature indicates that topical corticosteroids have been shown to be efficacious and well tolerated when used for short periods, in combination with antibiotics, antiseptics, or anti-infectives. Future randomized clinical trials to investigate the effectiveness and safety of steroids in conjunctivitis treatment are needed.
The authors thank Ira Probodh, PhD, of Excel Medical Affairs, who provided medical writing assistance funded by Shire, a member of the Takeda group of companies.
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