CHLAMYDIAL and GONOCOCCAL CONJUNCTIVITIS

Signs and Symptoms

Chlamydial infection is recognized as the world’s most common sexually transmitted disease.1-8 The spectrum of ocular sequelae includes trachoma, adult inclusion conjunctivitis and neonatal conjunctivitis.1-10

Chlamydia trachomatis (CT) is the most prevalent sexually transmitted bacterial infection in the world, with more than 100 million cases reported annually.1-6 The disease is transmitted by the C. traucomatis organism serotypes A-C via close human contact and is endemic to countries with water purity issues (Middle East, parts of Africa, India and Southeast Asia).2-8 Trachoma is often transmitted either via sexually active young adults or through contaminated water secondary to poor hygiene or faulty purification.2,4,7 It remains among the leading causes of worldwide blindness, progressing from a painful suppurative follicular conjunctivitis with ocular injection and limbal follicles to florid follicular palpebral conjunctival scarring (Herbert’s pits) and fibroproliferative scarring on the superior palpebral conjunctiva, which produces horizontal linear cicatrization (Arlt’s lines) capable of inducing corneal panus, ulceration and ultimately sight-threatening keratopathy.1-10 Permanent eyelid deformities, trichiasis, entropion and ectropion result and contribute to catastrophic corneal compromise.1-8

Adult inclusion conjunctivitis is caused by the C. trachomatis organism serotypes D-K.1,2 It also presents in sexually active teens and young adults.1-4 The classic ocular sign of adult chlamydial conjunctivitis includes a suppurative eye infection that persists despite treatment with topical antibiotics.1-12 The symptoms include global conjunctival injection, variable mucopurulent discharge, matting of the eyelashes, variable ocular irritation, punctate epithelial keratitis, corneal pannus, peripheral corneal subepithelial infiltrates and, in severe cases, iritis.2,12-18 A palpable preauricular node is almost always present.14,15 Affected female carriers may show genitourinary symptoms such as chronic vaginitis or cervicitis, while affected males may remain relatively asymptomatic.2,7,8

Neonatal chlamydial conjunctivitis (ophthalmia neonatorum) has been reported to have an overall incidence of 0.65 of 1,000 live births with numbers remaining consistent over the years.5 Along with gonococcal infection, it is a frequent infectious cause of neonatal conjunctivitis in the United States.2,4,5 Risk factors for ocular infection in the newborn include a history of active vaginitis, pelvic inflammatory disease or urethritis in the mother at the time of delivery.1-3,10 Neonatal chlamydial or gonococal conjunctivitis typically presents within four weeks of birth.2 Hemorrhagic eye discharge is a highly specific sign of neonatal chlamydial conjunctivitis.11 Unlike the other forms, follicles or similar responses are not expected here since they are not developed that early.

An estimated 498 million new cases of curable sexually transmitted infections occur worldwide annually.19 Of these, 106 million are gonococcal infections, caused by Neisseria gonorrhoeae, rendering gonorrhea the second most prevalent sexually transmitted infection after chlamydia.19 Gonococcal conjunctivitis (or keratoconjunctivitis, should the cornea also be involved), is sometimes referred to as hyperacute conjunctivitis.20-23 While most cases are the result of sexually transmitted vectors, infected individuals have been detected without evidence of genital signs or symptoms.21

Although sensitive to heat and drying, N. gonorrhoeae may remain viable in discharge on a cloth for several days.22 As such, communal baths, towels or fabrics, rectal thermometers and poorly sanitized caregiver hands are alternate means of transmission.20,22 The infection is prevalent worldwide with more than 60 million new cases documented.23 Immunity from prior infection does not protect against reinfection even with the same strain, and a viable vaccine remains elusive.20,22 Gonococcal ophthalmia neonatorum is the most common manifestation in infants born to mothers with gonococcal genital tract infections.5,13,23

Systemically, gonococcal infections are associated with organism colonization of the urethra, cervix and rectum.18,24,25 The unusually contagious ocular disease typically presents as an acute, red eye with severe mucopurulent discharge of less than four weeks duration.17 The conjunctivitis has an incubation period of two to seven days.20,24 Matting of the eyelashes, conjunctival papillae, superficial punctate keratitis and marked chemosis are almost always present.20-25 Subconjunctival hemorrhage, hemorrhagic conjunctivitis, pseudo- or true membrane formation and preauricular adenopathy are usually present. In chronic, recalcitrant or severe cases, peripheral subepithelial corneal infiltration may occur, leading to corneal ulceration with iritis.25 Sight-threatening consequences are possible.26

Pathophysiology

Chlamydia trachomatis is an intracellular parasite that contains its own DNA and RNA.7,8,27 The subgroup A causes chlamydial infections, while the serotypes A, B, Ba and C cause trachoma. Serotypes D through K produce adult inclusion conjunctivitis.4,7,8,27 The mode of ocular transmission may be by hand contact from a genital site of infection to the eye, laboratory accidents, mother infecting the newborn, shared cosmetics and occasionally an improperly chlorinated hot tub.1-5,22 In 1911, Lindner and colleagues identified the microscopic finding of intracytoplasmic inclusions in the cells of infants with conjunctivitis. They called the disease “inclusion conjunctivitis of the newborn.”1 In their report, they were able to demonstrate that mothers of affected infants had these “inclusions” within their cervical epithelial cells, along with the fact that the fathers also had “inclusions” in their urethral cells.1 This confirmed their suspicion that the disease was caused by sexually transmitted chlamydial infection.1

C. trachomatis is protected from the humoral immune response by residing within remodeled intracellular vacuoles.8 The vacuole-bound pathogen manipulates host-cellular functions, invading host cells and establishing a replicative niche.8 The first immune response to the infection is a local one, whereby immune cells such as leukocytes are recruited to the site of infection and subsequently secrete proinflammatory cytokines and chemokines, which initiate and potentiate chronic inflammation through the production of reactive oxygen species and the release of molecules with degradative properties, including defensins, elastase, collagenase, cathepsins and lysozyme.4 Long-term inflammation leads to cell proliferation (a possible precursor to cancer), tissue remodeling and scarring.4

While the neonatal and adult variations of the disease are considered acute, trachoma is a chronic process with distinct stages.2,28 The Maccallan classification system, first described in 1908, stages the progress based on conjunctival findings: (I) Lymphoid hyperplasia; (IIa) Mature follicles on the superior tarsus; (IIb) Mature follicles with florid inflammation; (III) Early cicatrization; and (IV) Follicles replaced by papillae as scarring.2,28 Today, The World Health Organization uses a simplified derivative of that system to include all phases of the disease: (I) Follicular conjunctivitis; (II) Diffuse inflammation; (III) Tarsal scarring; (IV) Trichiasis; and (V) Corneal opacification.2,29

The causative organism in gonococcal infection is Neisseria gonorrhoeae.20-23 N. gonorrhoeae is a gram-negative, intracellular diplococcus that possesses the capability of invading an intact mucosal membrane.20 Additionally, via its natural mechanisms or via chemokines released at the limbus secondary to resultant scleral inflammation, this organism can penetrate an intact corneal epithelium.23 Transmission to the eye is generally by direct or indirect sexual contact or contact with an infected individual.20-23

Management

Clinicians diagnose sexually transmitted conjunctivitis empirically by the history, indicative signs and symptoms, along with a suggestive history.29-31 The Centers for Disease Control and Prevention (CDC) mandates that a doctor suspecting a sexually transmitted disease complete confirmation with appropriate laboratory studies and proper reporting.31 While the standard method of clinical testing has been a combination of local, urethral, rectal and pharyngeal culturing, the use of nucleic acid amplification tests (NAAT) associated with serology testing has gained momentum for diagnosis.9,31,32 C. trachomatis and N. gonorrhoeae infections can be diagnosed by cell culture, direct immunofluorescence, enzyme immunoassay, direct DNA hybridization and more recently by NAAT.32,33 The development of NAAT has been a major advance in the diagnosis of chlamydia and gonorrhea.32,33 The introduction of assays based on amplification of genetic material has subsequently increased the sensitivity of detecting both organisms and offers the opportunity to use non-invasive sampling techniques.32,33

A number of prophylactic antibiotic or antiseptic agents have been used to prevent newborn chlamydial and gonococcal conjunctivitis.1-5,11,12-14,17-24 Prophylaxis with 1% silver nitrate ophthalmic drops, 0.5% erythromycin ophthalmic ointment or 1% tetracycline ointment has demonstrated comparable efficacy for the prevention of chlamydial infection.3 Topical erythromycin or tetracycline have been used as prophylactic agents with the advantage of reducing secondary chemical conjunctivitis as compared to silver nitrate (the traditional Crede’s prophylaxis).3 Povidone-iodine ophthalmic solution 2.5% also showed success for preventing ophthalmia neonatorum at a reduced cost.3

In cases of sexually transmitted chlamydial conjunctivitis, options include oral tetracycline 250mg to 500mg QID PO for three weeks or its alternatives (doxycycline, minocycline or azithromycin) along with a topical antibiotic (fourth generation fluoroquinolone), QID-Q2H, topical corticosteroids QID-Q2H and cycloplegia as necessary.2,4,26 Since tetracycline requires administration one hour before or after meals to avoid gastrointestinal side effects, is less effective with interference by dairy products and can deform bones and teeth in the young (less than 10 years old), its alternatives may present a better option. Amoxicillin and erythromycin, 250mg to 500mg QID PO for three weeks or doxycycline 100mg BID PO for one week are acceptable alternatives.1-5,12,13,15,16,20,21,26 Ceftriaxone, cefixime, spectinomycin and azithromycin are all acceptable alternatives that have shown effectiveness against resistant strains of gonorrhea and chlamydia.26.32,33 The CDC recommends oral doxycycline (100mg BID x 7 days) or oral azithromycin (1g in a single bolus dose) as first-choice antibiotic options for the treatment of chlamydial infection.

Topical azithromycin has been evaluated in clinical studies for use in the treatment of trachomatous conjunctivitis.34 Azithromycin 1.5% ophthalmic solution has been shown to have excellent in vitro activity against C. trachomatis.34 In children, three-day treatment with azithromycin 1.5% solution was noninferior to a single dose of azithromycin oral suspension. The azithromycin ophthalmic solution was well tolerated in all patients.34 It should be noted that topical azithromycin 1.5% ophthalmic solution is not commercially available in the United States at the present time. AzaSite (1% azithromycin ophthalmic solution, Akorn) is indicated only for the treatment of bacterial conjunctivitis caused by susceptible isolates.

Medical management of gonococcal conjunctivitis begins with an intramuscular 1g loading dose of ceftriaxone.15 Ideally, therapy should continue with hospital admission and intravenous administration of ceftriaxone 1g Q 12 to 24 hours.35-37 Continuing treatment is completed via oral antibiotics that are added following discharge.35,36

Mechanical removal of all discharge and debris is a critical element to both the success of infection resolution and improving patient functioning. The eyelids should be everted to rule out the presence of large follicles and pseudomembranes. Follicles will self-resolve as the treatment takes effect. In the event that a shield ulcer develops, topical anti-inflammatory therapy should be added. If present, pseudomembranes can be removed via topical anesthesia and a cotton-tipped applicator. Over-the-counter oral analgesics can be used to increase patient comfort along with palliative measures such as cold compresses and ocular lubricants.

The high rates of reinfection with sexually transmitted diseases suggest a need for retesting patients with confirmed cases at an interval of three to six months after symptom resolution.38 It is also important to treat sexual partners to avoid reinfection.

Clinical Pearls

Inclusion conjunctivitis should be one of the differential diagnoses any time a patient presents with a chief complaint of chronically red eyes or when any conjunctivitis is recalcitrant to topical antibiotic therapies.

Patients with hyperacute conjunctivitis should be examined frequently until consistent improvement is noted; they should also be educated that they are contagious until they are symptom free for three days.

Patients should be educated that partners need to be informed and systemic genitourinary examination is in order.

If a sexually transmitted disease is confirmed, the CDC should be contacted for instructions and recommendations. Lab testing should be considered to rule out the presence of other sexually transmitted diseases such as syphilis and human immunodeficiency virus.

Unfortunately, genital and pharyngeal gonococcal infections in young children are almost always acquired via a sexual encounter with an infected adult and may be a sign of sexual abuse. In cases where these signs or symptoms accompany an ocular condition, authorities or the patient’s pediatrician should be notified.

While hyperacute conjunctivitis has been widely thought to be gonococcal in origin, remember that other virulent organisms can cause an equally severe conjunctivitis and not all hyperacute presentations are necessarily an STD.

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