FOLLICLES

A follicle is a nonspecific conjunctival response to chronic irritation: mechanical, chemical, or microbial. After the first few weeks of life, lymphoid tissue becomes evident in the human conjunctiva, with a diffuse and indiscriminate distribution. Under the influence of chronic irritation or stimulation, the lymphocytes increase and aggregate into follicles resembling in structure and function lymph nodes or the solitary lymphatic patches of the intestine.^1,2

Clinically, follicles are yellowish to grayish white, discrete, round elevations of the conjunctiva. The central part of the follicle is avascular, but dilated blood vessels may surround the base and sweep up from the base over the convexity (Figs. 1 and 2). Follicles are 0.2 to 2 mm in size, although larger follicles may be seen, particularly in chlamydial disease.³

Follicles on the superior tarsal conjunctiva are well defined as a result of the close adherence of the tarsus to the epithelial mucosal tissues. They are also seen in the conjunctival fornices, where they are less regularly spaced and tend to be larger. Conjunctival follicles do not appear in the neonatal period because the lymphoid system is immature, and they are less apparent in children under the age of 2. Follicles histologically consist of lymphoid germinal centers with fibroblasts in the center. T cells occupy the periphery and B cells the center of the infiltrates.⁴

PAPILLAE

Follicles are often clinically confused with conjunctival papillae (Fig. 3). Papillae are vascular changes most prominent on the palpebral conjunctiva, where fibrous septa anchor the conjunctiva to the underlying tarsus. In contrast to follicles, they have a dilated vascular core surrounded by edema and a mixed inflammatory infiltrate producing raised elevations of the conjunctival epithelium. They are nonspecific signs of conjunctival inflammation, most commonly associated with allergic or bacterial conjunctivitis.

FOLLICULAR CONJUNCTIVITIS

Follicular conjunctivitis is not a specific disease entity but a connotation for a large number of conditions of varying etiologies that have follicles as a predominant pathologic and clinical manifestation.

PATHOPHYSIOLOGY AND TAXONOMY

Adenoviruses are double-stranded DNA viruses surrounded by a nonenveloped polypeptide icosahedral capsid with glycoprotein projections. They were first detected in 1953 as a latent virus in surgically removed adenoidal tissue from asymptomatic children.⁵ There are at least 51 serotypes of adenovirus,⁶ and they have been classified into six species, A to F, on the basis of their hemagglutination properties and biophysical and biochemical criteria.⁷ Adenoviruses are a common cause of a variety of human illnesses, accounting for approximately 10% of all febrile illnesses in infants and 5% of all such illnesses in children.⁸ Most of the keratoconjunctivitis and all of the epidemic keratoconjunctivitis types are caused by species D. The nine most recently described serotypes all belong to species D and were first isolated from human immunodeficiency virus (HIV)-infected patients.

OCULAR ADENOVIRAL INFECTION

Ocular adenoviral infections have a variety of clinical presentations; the two most common forms are epidemic keratoconjunctivitis (EKC) and pharyngoconjunctival fever (PCF). Both are characterized by a marked follicular response.

Two less common manifestations are recurrent conjunctivitis and chronic papillary conjunctivitis. The different syndromes tend to be caused by distinct serotypes, although the features do overlap. Ad 3 and Ad 4 are the most common pathogens that cause sporadic keratoconjunctivitis and PCF. Ad 8, 19, and 37 have been implicated in sporadic cases as well as outbreaks of severe EKC.^9–11 Although an epidemic due to both types 8 and 19 has been reported, most disease is due to a single serotype.

EPIDEMIC KERATOCONJUNCTIVITIS

The clinical features of adenoviral keratoconjunctivitis were first described by Fuchs¹² in 1889, but it was not until 1955 that adenovirus was identified as the cause of the disease.¹³ EKC has a wide spectrum of duration and intensity of symptoms. After an incubation period of 2 to 14 days, symptoms begin in one eye; symptoms develop in the second eye 2 to 4 days later. Signs include conjunctival hyperemia and chemosis, intense tearing, and swelling of the conjunctival plica. Ipsilateral preauricular lymphadenopathy is found in many patients. The corneal involvement helps distinguish it from other causes of viral conjunctivitis (Figs. 6 and 7).

Corneal subepithelial opacities develop approximately 2 to 4 days after the onset of symptoms. These may stain with fluoroscein and may persist for 2 to 3 weeks. About a week after the onset of symptoms, larger nummular lesions develop. These have irregular, raised borders and a central ulceration that stains with fluorescein. At 2 weeks, the subepithelial infiltrates (SEIs) begin to appear. Focal biopsies have shown these infiltrates to consist of lymphocytes, histiocytes, and fibroblasts accompanied by a disruption of the collagen fiber of Bowman's layer.^14,15 The nummular opacities are thought to represent persisting viral replication in subepithelial keratocytes, triggering a host reaction. The immune basis is supported by the clinical observation that the opacities usually resolve with topical steroids but recur when the steroids are discontinued.¹⁶ Rarely, these nummular opacities or infiltrates may impair visual function and may persist for months or years. Usually, the conjunctival inflammation and epithelial disease resolve in 10 to 16 days but may last a month. The follicles and lymphadenopathy resolve more gradually in 2 to 4 weeks; however, the SEIs may persist for many months. EKC is also the commonest cause of viral membranous or pseudomembranous conjunctivitis (Fig. 8).

Management

Currently, there is no specific antiviral therapy available to treat adenoviral keratoconjunctivitis. Cidofovir, or HPMPC, is a broad-spectrum antiviral agent¹⁷ that was shown to have significant antiviral activity, reducing viral shedding in rabbits with adenoviral conjunctivitis.¹⁸ In humans, cidofovir 1% was shown to lower the frequency of severe corneal opacities, but its clinical use four to 10 times daily is limited by local toxicity.¹⁹ The mainstay of treatment is symptomatic in mild cases. In more severe cases, topical corticosteroids are useful where there are SEIs in the visual axis. Topical steroids should otherwise be used with caution in follicular conjunctivitis because herpetic conjunctivitis can occur without corneal involvement. If low-dose steroids are used, they may need to be gradually tapered over months to prevent recurrence.

Adenovirus is highly contagious, and measures to limit the spread of infection should be taken. Spread is by person-to-person contact, contaminated ophthalmic instruments, or swimming water. Transmission in ophthalmology clinics has been well reported, most frequently as a result of applanation tonometry; however, slit lamp examination and application of eye drops may also result in spread,^20–22 emphasizing the need for adherence to strict hand-washing protocols. Adenoviruses are highly stable and resistant to solvents; however, they are deactivated by hypochlorite solution. The live virus has been found to survive as long as 35 days on plastic surfaces.²³ Patients should avoid touching their eyelids and wash their hands frequently. It has been reported that nearly 50% of patients with adenoviral conjunctivitis carry it on their hands.²² Although most patients are culture negative 7 to 10 days after the onset of symptoms,²⁴ positive cultures have been reported for up to 12 months after infection.²⁵ Infected children should be advised to stay at home for 1 week. In the setting of hospital outbreaks, it is essential to implement strict procedures to reduce transmission, and infected personnel should remain off work for 2 weeks.

Conjunctival adenovirus infection is highly contagious and occurs worldwide sporadically and epidemically. Although not permanently blinding, adenoviral ocular infection remains the most common ocular viral infection worldwide. The social and economic cost of community epidemics is high.²⁶

PARAMYXOVIRUSES

Measles—Rubeola

The measles (rubeola) virus causes photophobia, an acute catarrhal papillary conjunctivitis, superficial punctate keratitis, superficial pannus, and occasionally Koplick's spots on the conjunctiva and caruncle.²⁸ Rarely, an immune interstitial keratitis may occur. In a healthy individual, the disease usually resolves with no ocular sequelae. However, in debilitated individuals, particularly those who are vitamin A deficient, it can progress to severe keratitis and keratomalacia.^29,30 Herpes simplex virus (HSV) infection also may affect children with measles and may be responsible for one-fifth of their corneal ulcers.³⁰

Mumps

Conjunctivitis is a common manifestation of mumps characterized by dilatation of the conjunctival and episcleral vessels without marked secretion, and sometimes by chemosis of the bulbar conjunctiva.³¹ It is self-limiting and resolves spontaneously. A follicular conjunctivitis is not typical but was reported once in the literature.³² The other common ocular features are dacryoadenitis and punctate keratitis followed by interstitial keratitis.

Newcastle Disease

Newcastle disease virus causes respiratory infections in poultry; in humans, the virus and the vaccine cause a limited infection. It is unique in causing a unilateral follicular conjunctivitis with mild tearing and preauricular adenopathy. Rarely, there is a transient, fine, superficial keratitis in the first week.³³ Newcastle disease normally occurs by direct inoculation during processing of infected birds by poultry workers and veterinarians. The disease is self-limiting and does not require therapy.

ACUTE HEMORRHAGIC CONJUNCTIVITIS

Acute hemorrhagic conjunctivitis (AHC) has affected millions of people since it first appeared in Ghana in 1969. Large epidemics have occurred in Africa and Asia, and it was first reported in the Western Hemisphere in 1981 in Brazil.³⁵

The major causative agents are enterovirus 70 (EV-70) and coxsackievirus type 24 (CA-24). Adenovirus types 8, 19, and 37 have also recently been recognized as causes of hemorrhagic conjunctivitis, and this may herald a new stage in the evolution of these viruses.³⁶ The clinical features of AHC caused by EV-70 have, in more recent epidemics, been reported to be milder, with a maintained high transmission rate that may be due to biological transformation of EV-70.³⁷Apart from conjunctival secretions, respiratory and oral transmission of coxsackievirus CA-24 variant would explain the rapid and extensive spread of AHC during an outbreak.³⁸

The disease is characterized by a short incubation period and sudden onset of lacrimation, lid swelling, itching, foreign body sensation, and periorbital pain, which rapidly become bilateral. The common signs are papillary conjunctivitis with a minor follicular response; subconjunctival hemorrhages, which are more pronounced temporally; a fine punctate epithelial keratitis; and preauricular adenopathy. The hemorrhages are petechial at first but rapidly become confluent. Subepithelial opacities and erosions are rare, and the conjunctivitis resolves within 4 to 6 days, although the hemorrhages may take longer. Respiratory and gastrointestinal involvement may occur.³⁹ More rarely, neurologic complications, including Guillain-Barré syndrome and Bell's palsy, may develop.⁴⁰ Corneal superinfection may occur after AHC, and use of topical steroids may predispose an already compromised cornea to develop microbial keratitis. Folk remedies, such as the use of human urine on the eye, have also resulted in gonococcal ophthalmia.⁴¹

PARAPOXVIRUS

Orf virus is a member of the paravaccinia group of DNA viruses that cause a contagious pustular dermatitis, predominantly in sheep and goats.⁴² It occasionally affects humans, commonly causing lesions of the hand. Ocular infection is unusual; however, it was reported in a farmwife who developed a raised ulcerated lesion at the inner canthus, follicular conjunctivitis, and lymphadenopathy after handling sheep.⁴³ This may have been as a result of direct finger inoculation occurring while she carried an infected lamb. Treatment in this case was with idoxuridine 0.5% for the eye, with resolution in 3 weeks. Blindness has been reported in human orf infection, possibly because of secondary bacterial infection.⁴⁴

It has been reported that the incidence of HSV ocular infection presenting as acute follicular conjunctivitis in the absence of corneal or lid signs in cases of clinically diagnosed epidemic keratoconjunctivitis is 1.4% to 7%.⁴⁶ There is no significant difference in clinical features between primary and recurrent HSV conjunctivitis.⁴⁷ The clinical features of HSV conjunctivitis are those of a moderate follicular conjunctivitis, sometimes with preauricular node swelling and upper respiratory tract signs. There are rarely corneal changes, and it is bilateral in 13% of cases.⁴⁷ It has a mean duration of 8 days. The low rate of bilateral disease and the short duration may help discriminate HSV from adenoviral conjunctivitis as clinically differentiating the two disease entities is extremely difficult, particularly in the early stages.

Most herpetic infections of the eye are caused by human herpesvirus type 1 (oral); however, type 2 (genital) may occur in the newborn and adults after oral–genital inoculation. Neonates who develop herpes simplex primary conjunctivitis should receive intravenous treatment with acyclovir in addition to topical treatment.

The Herpetic Eye Disease Study (HEDS) assessed whether long-term prophylactic treatment with acyclovir would prevent recurrence of ocular herpetic disease.⁴⁸ This was a prospective randomized, multicenter trial, and although it did not primarily address herpetic conjunctivitis, its findings did suggest that the use of 800 mg (or 400 mg b.i.d) oral acyclovir daily over a year reduced the recurrence of ocular herpetic disease.

Serotypes D to K of C. trachomatis cause an acute follicular conjunctivitis with a mucopurulent discharge. Historically, the diagnosis was made after visualization of chlamydial inclusion bodies on the conjunctival smears, thus giving the disease its name. These trachomata are transmitted sexually, may be asymptomatic, and may involve multiple sites simultaneously. Transmission is through direct contact of the eye with infected genital or urinary secretions.^50,51 Indirect transmission can occur in poorly chlorinated swimming pools.⁵² Eye-to-eye transmission is probably more common than previously thought.⁵³

Adult inclusion conjunctivitis (AIC) is more common in developed countries in the young and sexually active; it occurs within 2 to 3 months after the patient has a new sexual partner. The serious nonocular complications of chlamydial infection, such as epididymitis and salpingitis, make it an important diagnosis to establish and treat. Chlamydia has been reported to be the cause of a follicular conjunctivitis in adults in 5% to 18% of conjunctivitis.⁵⁴ Approximately 40% to 50% of men with nongonococcal urethritis and 70% of their partners are infected with C. trachomatis,⁴⁹ although 25% of the females are asymptomatic.⁵⁵

Serotypes D to K produce a syndrome clinically distinct from trachoma and do not cause permanent visual loss. It is not clear why AIC is more benign, but reasons may include a lack of re-exposure to the agent, the patient's age at initial infection, and a lower innate pathogenicity of the organism.

CLINICAL FEATURES

The disease affects initially one eye, 1 to 2 weeks after exposure to the organism. The symptoms may be acute or subacute, with redness, irritation, and a mucopurulent discharge. A palpable, nontender preauricular node may develop, but there are no systemic symptoms. Most of the conjunctival findings are located inferiorly, with a predominantly follicular reaction also associated with some degree of papillary reaction (Fig. 9). Limbal swelling is also often present.

Pseudomembranes do not occur, and conjunctival scarring, if it does occur, is minimal. In the second week, the cornea may have a mild or moderate superficial punctate keratitis that may be fine or coarse. Later in the infection, peripheral epithelial or subepithelial infiltrates may occur, which have an intact epithelium. Occasionally, iritis will occur in the later stages and, rarely, Reiter's syndrome. A superficial micropannus may develop in those who had subepithelial infiltrates, but there is no frank corneal scarring.

DIAGNOSIS

After a detailed history and clinical examination a fluorescent monoclonal antibody test is the most sensitive method of rapid diagnosis.⁵⁶ Giemsa-stained conjunctival smears looking for perinuclear inclusion bodies have a high false-negative rate⁵⁷ (Fig. 10). In recent years, polymerase chain reaction (PCR) assay has become more widely used as an effective diagnostic tool to accurately detect the presence of chlamydial material in ocular specimens (see section on laboratory diagnosis).

TREATMENT

Patients and their partners should be screened for nonocular chlamydial infection and for other venereal diseases. Systemic treatment is mandatory. The recommended treatment for chlamydial infection is azithromycin 1 g as a single daily dose for 7 days, or doxycycline 100 mg twice daily for 7 days. Alternative regimes are erythromycin 500 mg four times a day for 7 days, or ofloxacin 300 mg twice a day for 7 days.⁵⁸

Acute conjunctivitis with purulent discharge develops 5 to 12 days after birth. This may manifest earlier if there is premature rupture of membranes. The infection may initially be unilateral, with a papillary reaction, as the immune system is too immature to cause a follicular reaction, and there is no preauricular lymphadenopathy. Pseudomembranes occur in more severe cases as does corneal scarring and neovascularization. Diagnosis is based on laboratory tests. Giemsa-stained inclusion bodies may often be seen, unlike in AIC. Monoclonal fluorescent antibody staining should also be done to assist in the rapid diagnosis. Although McCoy cell culture may be used as a diagnostic tool, the advent of PCR techniques has enabled rapid and accurate diagnosis.⁶¹

About half of neonates with chlamydial pneumonitis have had NIC.⁶² Treatment is oral erythromycin syrup 50 mg/kg per day in two to four divided doses for 14 days. The mother also requires systemic treatment. Tetracycline is contraindicated for the baby or for the mother if she is breast-feeding. Neonatal ocular prophylaxis with silver nitrate or antibiotic ointments does not prevent perinatal transmission of C. trachomatisfrom mother to infant; however, these agents do prevent gonococcal ophthalmia.

Table 1. Diagnostic Features of Chronic Follicular Conjunctivitis

Trachoma has disappeared from Western Europe and North America as a result of improved living conditions. However, trachoma continues to affect 150 million people in 48 countries, of which 6 million are blind.⁶³ In areas where trachoma is constantly present at high prevalence, active disease is found in more than 50% of preschool children. As many as 75% of women and 50% of men over the age of 45 may show signs of scarring disease.⁶⁴ Infected children are the major reservoir for trachomatous infection in a community.^65,66 The prevalence of active trachoma decreases with increasing age, with less than 5% of adults showing signs of active disease. Although similar rates of active disease are observed in male and female children, the later sequelae of trichiasis, entropion and corneal opacification are more common in women than men.⁶⁷ This is probably related to the close contact of women with children who are suffering from the active disease.

In endemic areas, trachoma is directly transmitted from person to person through ocular secretions.⁶⁸ Flies also act as vectors by feeding on these ocular secretions.^65,66 Children with trachoma in endemic areas have C. trachomatisin the upper respiratory tract and gastrointestinal tract, so it may also be transmitted by droplet or fecal contamination.

PATHOGENESIS

C. trachomatisis an obligate intracellular organism that more closely resembles bacteria than viruses. They contain DNA and RNA, possess a cell wall, and are treatable with tetracycline, erythromycin, and sulfonamides. Acute infection with C. trachomatisimmunotypes A, B, Ba, or C is usually self-limiting with few long-term sequelae. Repeated exposure leads to conjunctival cicatrization and corneal scarring.⁶⁹ Both humoral and cell-mediated immune responses to infection occur.⁷⁰ The early formation of follicles that regress is followed by prolonged papillary hypertrophy of the conjunctival epithelium and deposition of subepithelial connective tissue, which contains a diffuse infiltration of lymphocytes and plasma cells. Antichlamydial antibodies can neutralize Chlamydiae, block attachment and internalization of the organism, and produce partial immunity. It may be that the T lymphocytes and cell-mediated immunity are responsible for the conjunctival scarring.

Alterations in the extracellular matrix components and collagen metabolism occur in the conjunctival tissue, with new collagen type V formation in active trachoma and scarred trachoma. The conjunctival tissue from patients with active trachoma contains an increased amount of collagen types I, II, and IV. Scarred trachoma is characterized by a marked increase in basement membrane collagen IV and a marked decrease in types I and III.

CLINICAL FEATURES

The onset and severity of symptoms vary, and in young children, the condition may be entirely subclinical. Acute infectious trachoma causes bilateral, follicular, nonpurulent conjunctivitis 5 days after inoculation⁵² that may be associated with a tender preauricular lymph node. After 2 to 3 weeks, follicles appear on the superior tarsal conjunctiva and superior limbus. It is not known how long individuals are infectious. There are usually no associated systemic symptoms, although it may sometimes be accompanied by rhinitis, upper respiratory tract infection, or preauricular adenopathy.⁷¹ Repeated infection results in conjunctival scarring, cicatricial entropion, and trichiasis, with risk of blinding corneal ulceration. The dry eyes, scarred tear ducts, keratinization of the conjunctiva, and distortion of the lid margin also contribute to the cornea being susceptible to damage. Trichiasis carries an eightfold risk for corneal opacity.⁷² In countries where the prevalence of active trachomatous infection is higher, such as Tanzania, the progression rate from conjunctival scarring to trichiasis and then corneal opacity is more rapid than in countries, such as the Gambia, where active trachoma is declining.^73–75

WORLD HEALTH ORGANIZATION CLASSIFICATION FOR ACUTE TRACHOMA

In the World Health Organization (WHO) grading system for acute trachoma, grade TF (trachoma follicles) represents mild trachoma with the presence of five or more follicles in the upper tarsal conjunctiva of at least 0.5 mm diameter (Fig. 11). Grade TI (trachoma inflammation) describes a more severe trachoma with pronounced inflammatory thickening of the upper tarsal conjunctiva that obscures more than half of the normal deep vessels (Fig. 12). Repeated infections cause scarring trachoma (grade TS) in which the upper eyelid is shortened and distorted causing entropion and trichiasis (grade TT), which abrades the eye. Blindness results from progressive corneal opacification (grade CO), which is related to the degree of entropion or trichiasis (Fig. 13).

According to the WHO, the diagnosis of trachoma requires at least two of the following signs: superior tarsal follicles, limbal follicles or Herbert's pits, typical conjunctival scarring, or vascular pannus. Herbert's pits are necrosed limbal follicles; they are the only sign unique to trachoma, but they do not occur in every case (Fig. 14). Early pannus formation is a good predictor for severe conjunctival scarring later in the disease.⁷⁶

Corneal vascularization occurs in response to the marginal corneal infiltration and is more extensive at the superior limbus. It should be remembered that other corneal diseases, such as Salzmann nodular degeneration or bacterial corneal ulcers may occur in patients with trachoma. The risk of these conditions and subsequent complications, such as perforation or scarring, is increased due to the presence of trichiasis, entropion, and the chronic dry eye state. Patients with vernal catarrh who contract trachoma may develop severe corneal complications.

The diagnosis of trachoma can be confirmed by conjunctival cytology⁷⁷; however, Giemsa staining has been superseded by fluorescent monoclonal antibody staining. PCR analysis is accurate but expensive for diagnosis.

A previous history of trachoma does not confer immunity to recurrent disease and whole-organism vaccines are ineffective, so other strategies for trachoma control are required.⁷⁸ The WHO is promoting the Global Elimination of Trachoma (GET) by the year 2020 and has adopted the SAFE strategy—Surgery for entropion and trichiasis, Antibiotic treatment for active infection, and the promotion of both Facial cleanliness and Environmental improvement to reduce transmission—to achieve this goal.

RISK FACTORS

Poverty, excessive distance to water, small amounts of water used by the household, the presence of flies, and poor hygiene are risk factors for trachoma.^79,80 Active trachoma is associated with young age and close contact between people. Discharge from the eyes and nose may be a source of reinfection.⁸¹ It is likely that host factors also play a role in a person's susceptibility to C. trachomatis disease.⁸²

HEALTH EDUCATION

Interventions to prevent scarring trachoma by reducing active infection include promotion of facial washing. It has been shown that it is possible to increase facial cleanliness through education even where there is a water shortage.⁸³ Trachoma transmission by flies could be reduced by encouraging the use of latrines and also by insecticides.

MEDICAL TREATMENT

Historically, sulfonamides were found to be effective in controlling trachoma; however, they caused unacceptable side effects in a few cases and thus had to be discontinued.⁸⁴ Topical tetracycline ointment was shown to be effective in individual cases when applied once daily for 6 weeks or for 5 days a month for 6 months. However, poor compliance and rapid reinfection when only individual cases were treated meant that this was not successful at the community level.^85,86 Treatment with azithromycin as a single oral dose (20 mg/kg) is safe and has been shown to be at least as effective as 6 weeks of supervised tetracycline ointment.⁸⁷ This has been a major advance, and in 1998, a new international initiative was launched by the Edna McConnell Clark Foundation and Pfizer Inc, in collaboration with the WHO, in which the drug is provided free to national trachoma control programs in selected countries.

Azithromycin is a key component of SAFE and is more successful in curing chlamydia and improving clinical outcome, with the added advantage of ease of treatment. It has been recommended that in areas where trachoma is moderately prevalent (more than 35% of children affected), treatment should be undertaken annually; but in hyperendemic areas (more than 50% of children affected), it should be given biannually.⁸⁸ However, azithromycin-resistant pneumococci have been isolated from the nasopharynx of children after two mass treatments, suggesting the need to monitor resistance.⁸⁹

SURGICAL TREATMENT

Preventing blindness from trachoma, even when transmission is stopped, still requires surgery for the irreversible scarring and trichiasis affecting large numbers of the already exposed population. The operation of choice for trachomatous trichiasis is bilamellar tarsal rotation.⁹⁰ It is important that this surgery is done before corneal scarring has started to develop, and earlier uptake of surgery requires health education.⁹¹

To prevent blinding trachoma, it will not be necessary to eradicate ocular chlamydial infection, but only to reduce the frequency of reinfection in endemic populations to such an extent that severe conjunctival scarring, leading to trichiasis and corneal scarring with subsequent visual loss, is prevented.⁹²

Since then, it has been shown that ocular infections with C. psittaci and C. pneumoniae may be more common than previously recognized. PCR species-specific tests are used to further identify chlamydial antigens in patients with chronic conjunctivitis in whom direct fluorescent antibody tests were positive.⁹⁴ In patients with nontrachomatous chlamydial infection, a short course of oral antibiotics is inadequate.

Bartonellainfection of the eye was first described by Henri Parinaud in 1889, when he reported three patients with chronic fever, regional lymphadenopathy and follicular conjunctivitis (Fig. 15).⁹⁶ Subsequent reports noted the history of cat exposure in some patients, and the syndrome became known as Parinaud's oculoglandular syndrome.

Parinaud's oculoglandular syndrome is the most common ocular complication of cat-scratch disease, affecting approximately 5% of symptomatic patients.⁹⁷ It is characterized by unilateral granulomatous follicular conjunctivitis with tender regional lymphadenopathy affecting the preauricular, submandibular, or cervical regions. Conjunctival lesions may ulcerate and usually resolve within several weeks, but the lymphadenopathy may take several months to clear. Other ocular manifestations of cat-scratch disease include neuroretinitis with macular star formation, multifocal retinochoroiditis with panuveitis, branch retinal artery occlusion, serous macular detachment, and papillitis with peripapillary retinal detachment.⁹⁸

DIAGNOSIS

The classic clinical diagnosis of cat-scratch disease requires that at least three of four criteria be met: a history of traumatic cat exposure, a positive skin test in response to cat-scratch disease antigen, characteristic lymph node lesions, and negative laboratory investigations for unexplained lymphadenopathy. The immunosuppressed are more vulnerable to cat-scratch disease from their pets, and systemic dissemination is more likely.⁹⁹

INVESTIGATION

Investigation now depends predominantly on serology testing, but these results can be inconclusive because of several different serotypes leading to antigenic variability.¹⁰⁰ Conjunctival biopsies and PCR molecular techniques can be valuable diagnostic tools for lymph node aspirate.

TREATMENT

Mild disease is self-limiting and does not require antibiotic treatment. Severe disease is treated with rifampicin, ciprofloxacin, trimethoprim, sulfamethoxazole, and gentamicin.¹⁰¹

Inflammatory syndromes, such as vitritis and uveitis, may occur. Neuro-ophthalmic manifestations include neuroretinitis, multiple cranial nerve palsies, optic atrophy, and disc edema. In endemic areas, Lyme disease may be responsible for 25% of new-onset seventh nerve palsy.

Several agents are capable of producing signs and symptoms of ocular medicamentosa. The agents may be prescribed (iatrogenic) or self-instilled (inflicted). The effect may be caused by the drug, its solvent or vehicle, or the preservative used. Toxic follicular reactions with or without inflammation have been described with atropine, miotics, epinephrine, some antiglaucoma medications, and antivirals. Such a reaction is probably the result of the mitogenic effect of the agents.¹⁰⁵ Chronic disease, such as glaucoma and dry eye states are associated with high risk for toxicity. Brimonidine was reported to have an incidence of follicular conjunctivitis of 9.6% in treated patients.¹⁰⁶

Other conjunctival manifestations of toxicity include cicatrization and papillary reaction. Associated corneal involvement may be significant. Features include punctate keratopathy; coarse, focal keratopathy; pseudodentrites; filamentary keratitis; persistent epithelial defects; and band keratopathy.

The diagnosis is based on clinical features, a high index of suspicion, multiple drug usage, and frequent instillation. Increased symptoms of stinging on instillation of the drug may indicate toxicity, as may an initial improvement of symptoms of the underlying condition followed by worsening of symptoms on continued usage. Rose bengal staining helps in identifying early signs of corneal and conjunctival toxicity. A favorable response to withdrawal of drug(s) or substitution with preservative-free preparations is also a strong indicator of toxicity.

Treatment includes cessation of drug use where possible or substitution with an alternative or preservative-free preparation. The period to resolution of symptoms and clinical signs after cessation or substitution of the offending drug may vary from a few days to a few months.¹⁰⁷

Axenfeld's conjunctivitis has an insidious onset and is accompanied by a scanty discharge in which mononuclear cells (lymphocytes) predominate. The follicles involve the entire conjunctiva, including the upper tarsal plate, but are firm and do not break up when pressure is applied. The cornea is not involved, and probably for this reason, the disease is asymptomatic.

Because Axenfeld's chronic follicular conjunctivitis is not associated with florid corneal involvement and does not produce conjunctival scarring, it has been classified as a disease entity separate from trachoma. Most of the observations on Axenfeld's follicular conjunctivitis were made before the slit lamp was widely used, and it is likely that small degrees of keratitis and pannus may have been overlooked. Moreover, in mild trachoma, a chlamydial agent is rarely demonstrated and the disease produces little, if any, scarring. Therefore, it is possible that Axenfeld's conjunctivitis is a mild form of trachoma that runs a self-limiting course under the relatively hygienic conditions of a children's institution. In such cases, a regular course of trachoma therapy with oral tetracycline or erythromycin should be administered.

The entity is characterized by the following findings:

1. follicular hypertrophy most marked in the fornices but occasionally involving the tarsal plate
   
2. punctate epithelial keratitis superiorly
   
3. moderate exudates in the conjunctiva
   
4. foreign-body sensation and photophobia
   
5. subacute or insidious onset
   
6. duration of 4 to 5 months
   
7. no secondary bacterial infection
   
8. occasional micropannus formation
   
9. spontaneous remission without conjunctival or corneal scars
   

This epidemic occurred in a suburban high school in which some trachoma cases were found in the Mexican American students; moreover, most of the cases involved girls who had been trading eye cosmetics. There is the possibility that this may also represent a particularly mild form of trachoma.

CYTOLOGY

Conjunctival cytology remains a rapid, versatile, and cost-effective means to assist in the diagnosis of follicular conjunctivitis and other inflammatory ocular diseases.^111–113 Specimens for cytology are best obtained from the conjunctiva, particularly the upper tarsus, with a sterile spatula following topical anesthesia. Care must be taken to ensure no cross-infection of eyes during the procedure. An adequate specimen should contain visible material when smeared on a glass slide.

Specimens for Giemsa and immunofluorescent staining are air dried before fixation. Giemsa staining reveals cellular morphology and microbial agents, whereas Gram's stain is useful for confirming the presence and identifying the general characteristics of microbial pathogens. Inflammatory cells in smears are suggestive of the underlying disease process: Bacterial infections are characterized by an abundance of polymorphonuclear cells, viral infections by a predominance of lymphocytes, and chlamydial infections by a mixture of both these types, often accompanied by Leber cells (macrophages), plasma cells, or immature lymphocytes (“follicle cells”). Intraepithelial cytoplasmic inclusion bodies are easily visualized and are diagnostic of chlamydial infection. In membranous conjunctivitis, large numbers of polymorphonuclear leukocytes are found, regardless of the etiology. Cytology is also useful to identify dysplasia and keratinization of the ocular surface.

SEROLOGY

Serologic evaluation may be helpful in the identification of infection. For acute infections, a comparison of acute and convalescent specimens showing a fourfold increase in antibody titer is suggestive of recent infection with a particular agent. In many circumstances, however, high endemicity of the suspected pathogen precludes useful interpretation of results; for example, because positive herpes simplex and chlamydial titers are extremely common in the general population, they usually cannot be used to identify ocular infections in individual patients.

CULTURE

Conjunctival culture remains the mainstay of laboratory investigation of follicular conjunctivitis. Samples are easily obtained by minimally invasive techniques, the costs are low, and availability is high. Swabs should be taken with a vigorous stroke through both inferior fornices, swabbing the least affected eye first. Topical anesthetics do not adversely affect viral or chlamydial cultures; however, preservatives present in certain eye drops may interfere with the recovery of bacteria and so should be avoided.

Bacterial Cultures

The common bacterial pathogens responsible for conjunctivitis include Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus sp and Neisseria sp. Immediate inoculation of the ocular swab directly onto solid media (e.g., blood agar plate) provides the best chance of isolating most aerobic bacteria found on the lids and conjunctiva. Chocolate agar is required to grow Neisseria or Haemophilus sp.

Viruses

Isolation procedures for viruses require consultation with the local laboratory prior to taking the specimen. For many viruses, Dacron or calcium alginate–tipped swabs should be placed in refrigerated transport media immediately after procurement and transported to the laboratory within 24 hours for viral isolation in cell cultures. Yields decrease rapidly after 24 hours and also with specimen freezing. The physician must indicate to the laboratory which viruses are suspected and document the specimen site, thereby allowing the laboratory to select the best cell lines to inoculate.¹¹⁴

Chlamydia

McCoy cell culture has been used to good effect for many years in the laboratory diagnosis of chlamydial conjunctivitis.¹¹⁵ Recently, however, newer nonculture tests have become widely available and are less expensive, with similar or better diagnostic sensitivities and specificities.

Other methods used to identify chlamydial infection include immunofluorescent staining of smears, enzyme-linked immunoassay, measurement of tear and serum antibodies, and immunofluorescence.^116–122

ENZYME IMMUNOASSAY

Enzyme immunoassay kits that employ monoclonal antibodies to adenovirus group-reactive antigens are now widely available and are being used for the diagnosis of ocular infections.¹²³ They involve the placement of conjunctival swab material into contact with adenovirus-specific monoclonal antibodies (usually in special wells) with subsequent exposure to adenovirus monoclonal conjugate antibody.¹²⁴ These tests are relatively cheap and have been shown to have a sensitivity of 56% when applied within 1 week of onset of symptoms, decreasing to 25% specificity when used thereafter, up to a limit of 11 days. Results are available within 2 hours; however, recent work on immunochromatography may give comparable results within 10 minutes.¹²⁵

Enzyme-linked immunoassays directed toward chlamydial antigens have been shown to be effective in the diagnosis of both chronic (trachomatous) and acute follicular chlamydial disease.¹²⁶

Numerous diagnostic kits have also been made available for the diagnosis of herpes simplex infection, HIV, and Lyme disease.^127,128

POLYMERASE CHAIN REACTION

Polymerase chain reaction assay is a procedure in which segments of DNA or RNA are amplified by the use of flanking oligonucleotides called primers and repeated cycles of amplification with DNA polymerase. The initial step is heating in order to separate the DNA into single strands. Each strand is annealed with complementary target DNA sequences or primers and extended by the action of DNA polymerase. The amount of DNA material is doubled with each cycle, and often 30 cycles are undertaken to obtain enough material for further analysis. This process allows isolation and identification of minute amounts of pathogenic material. In the past, PCR has been prohibitively expensive; however, in recent years, it has become more widely available and costs have decreased. DNA amplification is rapidly becoming the gold standard for diagnosis of infective processes.

PCR kits designed for the detection of C. trachomatis, such as the Amplicor (Roche Diagnostic Systems, Branchburg, NJ), are becoming widely available and are generally superior to culture techniques of diagnosis.^129,130 PCR has been shown to be both sensitive and specific when used for the diagnosis of trachoma or for analysis of conjunctival swabs in acute chlamydial conjunctivitis. The sensitivity, specificity, and positive and negative predictive values of PCR compared with culture for conjunctival specimens have been reported to be as high as 92.3%, 100%, 100%, and 98.4%, respectively.^131,132 Subjects without clinical signs of infection who are PCR positive for chlamydia are more likely to develop acquired signs of disease within the next 6 months.¹³³ It is a technique capable of detecting as few as 100 plasmid copies (10 elementary bodies) of C. trachomatis¹³⁴ and has also been utilized for detection of Chlamydia in the nasopharynx of infected children and the urine of their mothers.¹³¹

Rapid identification of adenovirus by PCR is possible,^135–141 and it has been advocated that it could replace antigen detection and virus isolation as the initial test for adenoviruses in conjunctival swabs, with cell culture being retained only for adenovirus serotyping in PCR-positive specimens and for other viruses, such as herpes simplex.¹³⁵ Sensitivities of 100% and specificity of 97% have been reported, making it a superior diagnostic technique when compared with immunoassay techniques.¹³⁶

PCR testing has a more uncertain role in the diagnosis of herpetic conjunctivitis. Herpesviruses may be identified successfully in conjunctival swabs and from tears.^142,143 For typical presentations of ocular HSV disease, clinical examination has been shown to be as accurate as PCR. However, for atypical presentations of ocular HSV disease, PCR has been more accurate in detecting HSV infection than the clinical examination, and it thus remains a useful tool in such situations.¹⁴⁴

PCR testing has been shown to be of value in the analysis of ocular specimens and has been used to identify a number of infective organisms from patients with follicular conjunctivitis. As it becomes cheaper and more widely available, its role will inevitably increase. At present, it is certainly useful in cases of chronic, atypical, or unresponsive follicular conjunctivitis.

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