Phlyctenular keratoconjunctivitis (PKC), Phlyctenular conjunctivitis, Phlyctenulosis or phlyctenular eye disease (PED) is an endogenous type IV delayed hypersensitivity (T cell-mediated) allergic reaction to an antigen. It is an inflammatory condition which causes marked photophobia and mucopurulent discharge. PKC is characterised by sub-epithelial, single or multiple, gray-white, raised conjunctival or corneal nodules, generally at or near the limbus, surrounded by a zone of engorged hyperaemic vessels.
The description of phlyctenulosis dates back to early Greek and Arabic writings. (Thygeson P. The etiology and treatment of phlyctenular keratoconjunctivitis. Am J Ophthalmol. 1951; 34:1217-36). The term phlyctenule comes from the Greek word ‘phlyctena’ which means blister. Sorsby and Thygeson have implicated a higher incidence of PKC amongst children and young adult (Sorsby A. The etiology of phlyctenular ophthalmia. Br J Ophthalmol. 1942; 26: 159-79).
The most common cause of PKC is a hypersensitivity reaction to tuberculoprotein, particularly in the developing world, where Mycobacterium tuberculosis (M. tuberculosis) remains endemic. However, Staphylococcus aureus (S. aureus), Propionibacterium acnes (P. acnes), Chlamydia, parasitic infection, fungal infection, and more recently, HLA subtypes A26, B35, and DR8 have also been demonstrated as causative agents. Other risk factors include those common to communicable disease such as malnutrition, overcrowding, poor hygiene, and sanitation. There is slight overall predilection towards female gender, although this varies depending on the primary aetiology of PKC. PKC is not a blinding disease but it is a source of lowered visual acuity.
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Basak Samar K, Atlas of Clinical Ophthalmology, 2nd ed. Jaypee Brothers Medical Publishers (P) Ltd, 2013, New Delhi, P. 53.
Thygeson P. The etiology and treatment of phlyctenular keratoconjunctivitis. Am J Ophthalmol. 1951; 34:1217-36.
Culbertson WW, Huang AS, Mandelbaum SH, et al. Effective treatment of phlyctenular keratoconjunctivitis with oral tetracycline. Ophthalmology 1993; 100: 1358-66.
Sorsby A. The etiology of phlyctenular ophthalmia. Br J Ophthalmol. 1942; 26: 159-79.
Suzuki T, Sano Y, Sasaki O, et al. Ocular surface inflammation induced by Propionibacterium acnes. Cornea. 2002; 21: 812-7.
Suzuki T, Mitsushi Y, Yoichiro S, et al. Phlectenular keratitis associated with meibomitis in young patients. Am J Ophthalmol. 2005; 140: 77-82.
PKC produces symptoms like:
Phlyctenular keratoconjunctivitis is an endogenous non-infectious inflammatory type IV delayed hypersensitivity (T cell-mediated) allergic reaction to an antigen. The disease is common in malnourished and debilitated children between five and twelve years of age. These children may suffer from enlarged tonsils, adenoids and cervical lymphadenopathy.
Various aetiological factors which contribute to development of PKC are:
Human leukocyte antigen (HLA) subtypes:
Phlectenular keratitis may be associated with meibomitis ( Suzuki T, Mitsushi Y, Yoichiro S, et al. Phlectenular keratitis associated with meibomitis in young patients. Am J Ophthalmol. 2005; 140: 77-82).
M. tuberculosis is the most common cause of PKC worldwide, more so in the developing world, where tuberculosis remains endemic. PKC can occur in:
Tuberculosis related phlyctenulosis is more symptomatic and recurrent than phlyctenulosis caused by other pathogens. It frequently occurs as multiple lesions, and presents bilaterally in just over half of the cases, but may occur unilaterally as well. M. Tuberculosis is not being isolated from culture of ocular tissue. However, the diagnosis is made through systemic screening.
S. aureus is a more common cause of PKC in developed countries. Patients presenting with meibomian gland dysfunction (MGD) or chronic staphylococcal blepharoconjunctivitis are particularly susceptible. Diagnosis is usually based on clinical presentation which may be substantiated with bacterial culture. It is less common and mild as compared to tuberculosis related PKC.
P.acnes is also linked to ocular surface inflammation (Suzuki T, Sano Y, Sasaki O, et al. Ocular surface inflammation induced by Propionibacterium acnes. Cornea.2002; 21: 812-7). Diagnosis depends upon the clinical presentation and bacterial culture.
Helminth is more common than other parasitic infections. Helminths primarily affect limbus and cornea and spare conjunctiva. Delayed hypersensitivity reaction is produced due to eosinophilic response. With antihelminthic therapy, resolution of disease is faster than other infectious causes.
Suzuki et al envisaged a genetic association of PKC. These include Human leukocyte antigen subtype (HLA) A26, B35, DR8. It is proposed that Human leukocyte antigen subtype (HLA) A26, B35 and DR8 play a specific role in the corneal helper T lymphocyte type I reaction that may produce phlyctenule lesions.
Suzuki et al. showed a preponderance of phlyctenulosis related to meibomitis in female patients (Suzuki T, Mitsushi Y, Yoichiro S, et al. Phlectenular keratitis associated with meibomitis in young patients. Am J Ophthalmol. 2005; 140: 77-82).They suggested a link between the expressions of sex steroid hormone receptors on the ocular surface, which predisposes females to PKC secondary to meibomitis.
Clinical signs may vary slightly according to the specific causative organism. It may occur either unilaterally or bilaterally in the conjunctiva, cornea or at limbus. The presence of phlycten on the palpebral conjunctiva is a rarity. Phlyctenulosis may also be an incidental finding in asymptomatic patients with a recent history of bacterial, parasitic, or fungal infection.
Phlyctenulosis begins as phlyctenular keratoconjunctivitis or phlyctenular conjunctivitis. Phlyctenulosis rarely starts as keratitis only. Phlyctenular conjunctivitis is more common on bulbar than over palpebral conjunctiva, in association with hyperaemia and little discharge. Symptoms are often mild and many patients may have asymptomatic phlyctenulosis. Disease limited to the conjunctiva is self-limiting and usually resolves within two weeks.
PKC presents as a small, round, elevated, grey or yellow, localised sub-epithelial infiltrate in the conjunctiva, limbus, or cornea, located adjacent to an area of hyperaemic blood vessels. Limbus is the most commonly affected site in PKC. In about two to three weeks time, these infiltrates ulcerate, leaving behind wedge-shaped fibro-vascular scars at limbus or in cornea. Phlyctenules of the conjunctiva do not form scars.
Diagnosis requires examination under slit-lamp (bio-microscopy) by an eye-specialist.
Clinical signs of PKC:
Phlyctenulosis may show patterns such as:
Phlyctenules are sub-epithelial inflammatory infiltrates that contain cells such as histiocytes, lymphocytes, plasma cells, and neutrophils. The basal epithelium overlying these nodular infiltrates is composed of mononuclear phagocytes, neutrophils and Langerhans cells.
The inflammation in phlyctenular infiltrates is a delayed hypersensitivity response that predominantly has monocyte derived cells. Phlycten shows a characteristic sub-epithelial mononuclear infiltration in a triangular area, the apex being directed towards deeper layers of cornea. There is cuffing around stromal blood vessels with sub-epithelial mononuclear, polymorphonuclear leukocytes and eosinophils. Perivascular infiltrate transforms into macrophages and finally into dendritic cells that react with monoclonal antibodies. Helper and inducer T-lymphocytes become sensitised, leading to the generation of activated T-cells and finally the release of lymphokines. Lymphokines cause an influx of inflammatory cells. Lymphocytes are less abundant than mononuclear cells in phlyctenular infiltrates.
When secondary infection supervenes, additional polymorphonuclear cells appear and the overlying epithelium undergoes necrosis.
Phlyctenular keratoconjunctivitis should be distinguished from conditions such as:
Management should be carried out under medical supervision only.
The treatment of PKC is directed to improve general health of the child and management of local condition. Infected tonsils and adenoids should be properly treated. Attempts should be made to desensitise the patient against tubercular or staphylococcal allergens. Concurrent infections should be treated with systemic antibiotic therapy. Recurrences are frequent if general condition is not treated properly.
Management of phlyctenulosis consists of antimicrobial and anti-inflammatory measures. Even asymptomatic patients should be treated because of high rate of recurrence.
Topical antibiotic agents are indicated for use in conjunction with anti-inflammatory medications such as corticosteroids or cyclosporine regardless of aetiology.
Antibiotics like oral tetracycline or erythromycin are effective in treating cases of S. aureus and P. acnes related disease. It has also been successfully used to treat patients with recurrent disease that has failed other therapeutic measures. Care should be taken when treating paediatric patients younger than eight years of age to avoid potential side-effects. Other antibiotics which may be used are gatifloxacin, bacitracin, and azithromycin.
In tuberculosis associated PKC, patients should be screened for underlying active infection, and are treated with the appropriate anti-tubercular medical therapy. Family members or close contacts should also be screened and treated.
Patients with helminthic infections should be treated with parasite-specific oral medication like mebendazole. PKC in these patients typically resolves quickly with therapy, with a low recurrence rate. Recurrence may be due to re-infection with the parasites.
Anti-fungal medicines: Anti-fungal medicines are used for a fungal infection and these diseases generally follow a successful course after treatment.
Topical corticosteroids are used as anti-inflammatory therapy and is usually started early in the course of management. Corticosteroids should be tapered gradually since rapid tapers are associated with recurrence of the disease. Topical corticosteroids may be associated with ocular complications like raised intraocular pressure, cataract formation, and disturbance of accommodation.
Topical cyclosporine A:
Topical cyclosporine A, an immune-modulator, may be used to control signs of inflammation.
Cycloplegic agent may be required when cornea is involved.
Phlyctenular conjunctivitis often has mild symptoms and many patients may be asymptomatic. Disease limited to the conjunctiva is self-limiting and usually resolves within two weeks without leaving any scar. However, recurrences are common.
Phlyctenular keratoconjunctivitis commonly affects limbus with nodular infiltrates. In about two to three weeks time, these infiltrates ulcerate, leaving behind wedge-shaped fibro-vascular scars at limbus or in cornea.
Potential complications of Phlyctenular conjunctivitis may be:
Measures taken to prevent Phlyctenular keratoconjunctivitis may be: