Phlyctenular keratoconjunctivitis (PKC) is a localized, noninfectious inflammatory disorder of the ocular surface characterized by subepithelial nodules of the conjunctiva and/or cornea. These “phlyctenules,” derived from “phlyctena,” the Greek word for “blister,” were first described in classical Greek and Arabic literature (1). The blister characterization, described later by Saint-Yves (2) and Wardrop (3), was likely chosen due to the tendency for the nodules to ulcerate once necrosis occurs. PKC has been reported throughout the world, most commonly as a disease of children with a higher incidence in females. The disease was initially identified in patients with positive tuberculin skin tests (4), classically in children who lived in crowded, unsanitary conditions (5). In the United States, several studies have documented PKC in Native American and Inuit patients with positive tuberculin skin tests and clinical tuberculosis (6, 7, 8). Sorsby (9) was the first to clinically implicate a hypersensitivity reaction to tuberculin protein as an etiology for PKC, finding that 85% of patients with the disorder had a positive tuberculin skin test. In recent years, as endemic tuberculosis has come under control in developed countries, other antigens have been suggested as etiologies for PKC. In 1974, Ostler and Lanier (10) published a series of five cases of PKC related to staphylococcal infection. Currently in the United States, it appears that most cases of PKC are associated with chronic staphylococcal blepharitis (11, 12, 13).

The pathogenesis of PKC is thought to be a hypersensitivity reaction to an antigen of bacterial origin (14). Although PKC has been clinically associated with M. tuberculosis and other organisms (Table 22-1), the microbe that has been implicated most rigorously from an immunological standpoint in the laboratory is Staphylococcus aureus. Clinically, S. aureus is the most common organism associated with PKC in the United States, via its association with chronic blepharitis. Chlamydial infection has been identified in association with PKC. Culbertson et al. (15) reported 17 cases of PKC in patients under age 18. Five of the 10 patients tested for chlamydial infection were positive. In countries where it is still highly present, however, M. tuberculosis remains a major cause of PKC. A study in India prospectively examined 112 patients with phlyctenular eye disease and found 77% associated with tuberculosis whereas only 6% were associated with staphylococcal blepharitis (16).

Phlyctenules are subepithelial inflammatory nodules containing histiocytes, lymphocytes, plasma cells, and neutrophils (Fig. 22-1). Mononuclear phagocytes, dendritic Langerhans cells, and neutrophils make up the majority of the inflammatory cells in the epithelium overlying the phlyctenule with a moderate number of T lymphocytes also present. The underlying stromal inflammatory infiltrate is typically organized in perivascular cuffs with a scattered subepithelial infiltrate consisting mainly of monocyte derived cells and neutrophils. T lymphocytes are also present, whereas B lymphocytes and plasma cells are infrequent (17).

In a conjunctival lesion, mononuclear phagocytes and neutrophils infiltrate the deep tissue causing edema, which eventually resolves. In a corneal lesion, lymphocytes infiltrate under Bowman’s membrane and stroma. The associated edema may lift and break down the epithelium, forming an ulcer. Bowman’s membrane and anterior stroma may be destroyed and replaced with a vascularized pannus.

Animal models suggest that phlyctenular disease is a hypersensitivity reaction to an antigen, such as ribitol teichoic acid found in the cell wall of S. aureus (18). Mondino et al. (19, 20, 21, 22) established the role of hypersensitivity to staphylococcal antigen in the pathogenesis of peripheral corneal infiltrates and phlyctenular disease in a rabbit model. The rabbits, previously immunized intravenously by ribitol
teichoic acid (the major antigenic determinant of the S. aureus cell wall) developed phlyctenules after topical challenge with viable S. aureus. Subsequent studies have suggested that corneal antibodies to ribitol teichoic acid may be influenced not only by exposure to staphylococcal antigens in the ocular adnexa but to antigens in remote sites as well (e.g., skin) (23). These findings are consistent with the association between rosacea, a dermatologic disorder potentially related to hypersensitivity to staphylococcal antigens, and ocular external disease such as meibomian dysfunction blepharoconjunctivitis, marginal keratitis, recurrent chalazion, and phlyctenular disease (24).