Giant papillary conjunctivitis (GPC), also called contact lens–induced papillary conjunctivitis (CLPC), is a common complication of contact lens wear. First described by Spring,[1, 2, 3, 4] GPC is characterized by hypersensitivity-related inflammation of the ocular tarsal palpebral conjunctivae.[5] It is associated with the use of all types of contact lenses (eg, rigid, hydrogel, silicone hydrogel, piggyback,[6] scleral, prosthetic), although similar reactions have been noted with ocular prostheses, extruding scleral buckles, exposed ocular sutures, and even elevated corneal scars.
GPC was once considered an allergic disease similar to other immunoglobulin E (IgE)–mediated ocular allergy such as allergic conjunctivitis and vernal keratoconjunctivitis because of the similar clinical symptoms seen in allergic diseases (eg, itchiness, tearing, mucous hyperproduction, increase in symptoms during allergy season). The mechanical irritation of contact lenses and sutures that causes GPC supports the classification of GPC into a group of nonallergic hypersensitivity disorders.[7]
Initially, small papillae coalesce with expanding internal collections of inflammatory cells. When the lesions reach diameters of more than 0.3 mm, often approaching or exceeding 1 mm, the condition is referred to as GPC. Images of eyelid papillae appear below.
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Very large papillae in the everted upper lid of a patient who wears hydrogel (soft) contact lenses.
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Giant papillary conjunctivitis (GPC) response (slightly out of focus) seen in the upper lid of a young patient recovering from cataract extraction wit....
Because of the high prevalence of GPC among contact lens wearers, GPC should be considered in every patient with characteristic symptoms who wears contact lenses.
The antigen(s) responsible for GPC have yet to be identified. From circumstantial evidence, the initiating event is believed to be mechanical irritation and/or antigenic stimulus of the tarsal conjunctiva of the upper lids by a contact lens surface or edge (rigid or flexible) or deposit. Histologic changes in the tissue occur with mast cell degranulation and a secondary inflammatory cascade. This leads to conjunctivitis and further tissue changes with increasing inflammatory markers in the tears.
GPC can be caused by all forms of ocular prostheses, including rigid and hydrogel (soft) contact lenses, prosthetic eyes, extruding scleral buckles, exposed portions of sutures, filters, knots, and even corneal scars.[8] Heat sterilization, poor cleaning, thick or rough contact lens edges, and extended wearing times also predispose to the development of GPC.
Lipid and protein deposits from the tears, as well as debris coating the surface of contact lenses, may also lead to a spiral of inflammation. This, in turn, causes even more lens deposits to form, leading to additional inflammation.[1, 2, 3] The level of coating on the lenses varies among individuals and the polymer of the contact lenses.
High-water hydrogel (HEMA) contact lenses tend to coat more than lower-water HEMA contact lenses. Silicone contact lenses tend to accumulate more lipid deposits than HEMA lenses. First-generation silicone hydrogel contact lenses may be more prone to GPC development, perhaps because of their mechanical stiffness or their higher propensity for lipid deposition. Silicone hydrogel lenses tend to induce more local GPC (similar to the changes seen with rigid lenses), whereas hydrogel lenses tend to induce more generalized GPC reactions in the palpebral conjunctiva.[9]
In the United States, the prevalence of GPC is highest among wearers of hydrogel contact lenses—approximately 20%. Rigid gas-permeable contact lens wearers constitute approximately 5% of all cases. One study found that 85% of 221 patients with GPC had been wearing hydrogel lenses, whereas only 15% used rigid lenses.[10] With an increased frequency of contact lens replacement from more than four weeks to less than four weeks, the incidence of GPC has dropped from 36% to 4.5%.[11] This rate should drop even lower with the greater availability and popularity of one-day disposable contact lenses.
The international prevalence of GPC is similar to that in the United States.
Both sexes develop GPC.
GPC can be more aggressive in children who wear contact lenses.
The prognosis of GPC is good. Approximately 80% of patients can return to comfortable contact lens wear with appropriate treatment.[11]
GPC has been a common cause of temporary and permanent contact lens intolerance. It can also cause ptosis of the upper lids.
The lids of some patients return to normal appearance following the resolution of GPC, whereas other lids retain small, white, capped scars of the giant papillary lesions for long periods, sometimes indefinitely.
Patients should be educated about appropriate contact lens cleaning and follow-up care. Regular professional evaluations (perhaps once or twice a year in the absence of other complications) and additional appointments are recommended if they experience any increasing ocular itching, mucous discharge, or dirty contact lenses.
Patients should also be educated about the chronic nature of GPC and its symptoms (eg, ocular itch, mucous discharge, contact lens intolerance). Patients should be counseled to present within a week of any relapsing symptoms.
For patient education information, see the Eye and Vision Center, as well as Pinkeye and Contact Lenses.
Patients with giant papillary conjunctivitis (GPC) often report an increase in contact lens soilage, ocular itching, and mucous discharge in tears, as well as blurred vision and conjunctival injection. This can be accompanied by decreased contact lens tolerance and mechanical stability. Patients often report that the contact lenses move noticeably with each blink.
GPC can follow a seasonality pattern similar to that of environmental allergies. Environmental allergens may exasperate contact lens–induced GPC in patients with atopy.[12] GPC development does not correlate with ocular bacterial bioburden.[12]
Clinicians commonly note increased deposition on contact lenses. In addition, contact lenses appear to ride higher under the upper lids than expected. Rigid lenses, in particular, show deposits around the lens edge.
With eversion of the lids, inflammation of the vasculature (hyperemia) and papillary hypertrophy are noted.
Mucous strands can be seen in the tears and between the papillae.
Papillae can range from small uniform lesions (uniform cobblestone appearance [UCA]) to irregular changes (nonuniform cobblestone appearance [NUCA]) to clusters of giant lesions with whitish centers that can ulcerate and stain with sodium fluorescein dye.[13] Originally, the papillae of the upper tarsal conjunctiva were thought to have to be at least 1 mm to diagnose GPC. Today, the clinical sign is generally accepted as follows: the papillae are at least 0.3 mm in diameter on the upper palpebral conjunctiva in association with classic symptoms.
GPC that is associated with hydrogel contact lenses is more commonly at the fold of the everted lid, spreading over the entire tarsal conjunctival surface.
GPC that is associated with rigid contact lens wear shows an opposite pattern, corresponding to the position of the contact lens edge meeting the lid tissues. This provides evidence for the mechanical etiology hypothesis.
Silicone hydrogel lenses tend to induce more local than general GPC responses, similar to that seen with rigid lens wear.
Attending eye doctors should routinely invert and visually inspect lids, especially in patients who wear contact lenses for any ocular complaints.
Subjective ocular itching, mucus, contact lenses with significant protein deposits, and contact lenses that become less comfortable, more mobile, or ride higher underneath the upper lids should all raise suspicion for GPC.
No laboratory studies are necessary for the diagnosis of giant papillary conjunctivitis (GPC). However, some clinicians advocate screening patients who wear contact lenses for increased levels of immunoglobulin E (IgE) in their tears.
Quantitative histologic findings of GPC suggest multiple abnormalities.
In patients with GPC, the conjunctival epithelium and substantia propria have increased presence of degranulating mast cells, plasma cells, neutrophils, lymphocytes, basophils, and eosinophils. Although the density of inflammatory cells may not change much between healthy patients and patients with GPC, the increase in tissue mass due to the disease means that the number of inflammatory cells doubles.[15] Levels of decay-accelerating factor, which inhibits C3 amplification in the complement cascade, is decreased in patients with GPC,[16] whereas lactoferrin levels (also present in VKC) are increased,[17, 18] as are neutrophilic chemotactic factor,[19] leukotriene,[20] and eotaxin.[21] The tear film of patients with GPC also have elevated levels of histamine,[22] immunoglobulin G (IgG), IgE, and immunoglobulin M (IgM),[23] as well as complement factors, such as C3, factor B, and C3 anaphylatoxin.[24] Increased levels of exotoxin, which attracts eosinophils, and increased tear immunoglobulins IgG and IgE correlate with the severity of the papillary reaction.
Zhong et al found that the membranous epithelial cells that participate in the binding, uptake, and translocation of antigens in mucosa-associated lymphoid tissue over-proliferate during the course of this disease. In addition, increased lymphocytes give rise to the conjunctival changes in GPC.[25]
These multiple changes, regardless of whether the initiating insult is mechanical or immunologic, document the substantial inflammatory activities that result in the clinical picture of contact lens–associated GPC.
Combination mast cell stabilizers/antihistamines and modification of contact lens type/hygiene are the primary treatments for giant papillary conjunctivitis (GPC). Topical steroids can be used in the treatment of severe GPC but are not always necessary, especially in mild cases.
For any degree of GPC, the contact lens modality, type, and cleaning needs to be addressed. Refitting patients into one-day disposable contact lenses is most ideal for patients who choose to continue contact lens wear. If daily disposable contact lenses are not available in the patients’ prescription parameters, wearers of hydrogel contact lenses should use peroxide disinfecting solutions with their frequently disposable contact lenses.
In patients who cannot be refit into one-day disposable contact lenses and cannot use hydrogen peroxide–based cleaning solutions, reemphasize contact lens–cleaning techniques, especially rubbing with "no-rub"–labeled multipurpose contact lens solutions.
For mild to moderate GPC, patients can often continue contact lens wear but with a change in contact lens design and materials, care regimens, and education.
Wearers of rigid contact lenses should use some form of enzyme cleaning, at least twice per week or as frequently as every night.[26] This measure, of course, is unnecessary for patients who use daily disposable hydrogel contact lenses.
If severe GPC develops in patients who wear contact lenses purely for cosmesis, they should discontinue contact lens wear for 2-4 weeks (the interval during which symptoms may begin to reverse and signs improve). Steroids can be used in these cases.[27, 28]
Short-term low-potency topical corticosteroid used concurrently with a combination mast cell stabilizer/antihistamine ophthalmic solution is a more effective treatment for papillary conjunctivitis than mast cell stabilizer/antihistamine monotherapy and topical steroid monotherapy alone.[29] However, combination mast cell stabilizers and antihistamine ophthalmic medications generally suffice without exposing the patient to the known risks of topical steroids. Most patients do not require more aggressive treatment.
Long-term use of topical steroid drops, especially for more than a few weeks, is associated with glaucoma, cataracts, and decreased ocular resistance to infection. Topical steroid use is a particular concern in patients with a history of herpetic eye disease. Although topical corticosteroid use is not associated with induction or facilitation of viral recurrence, a fulminant infection could occur if herpes virus infection recurs during topical corticosteroid treatment. Increased concerns exist regarding de novo fungal and other viral infections and potentiating bacterial infections. Contact lenses should not be worn while the patient is being treated with steroids.
Although contact lens cessation is the most effective initial treatment for GPC, some patients may still need to wear contact lenses during treatment (eg, patients with keratoconus). Topical antihistamine/mast cell stabilizer combination solutions are the primary choice of treatment because of the drug efficacy and low frequency of dosing to improve patient compliance.
Topical mast cell stabilizers (eg, sodium cromolyn 0.4%) and antihistamines may also be used.
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) have limited immediate hypersensitivity responses but can be effective in patients with GPC. NSAIDs have rarely been associated with corneal melting.
More recently, immunomodulatory drugs such as tacrolimus 0.05% have been found comparable to fluorometholone 0.1% in efficacy without the adverse effects of steroids in the treatment of GPC. More studies need to be conducted for this recent development.[30]
Given the efficacy and safety of most modern keratorefractive procedures (eg, LASIK), refractive surgery may be a good alternative for patients who refuse conservative management by enabling them to avoid contact lenses.
Increased frequency of contact lens replacement (especially one-day disposables), rigorous cleaning, hydrogen peroxide disinfection, decreased wear times, and appropriate/timely professional supervision appear to reduce the prevalence of GPC among users of hydrogel contact lenses.
Increased enzyme cleaning also appears to be prophylactic for wearers of rigid lenses.[1, 2, 3]
Approximately 80% of patients who develop GPC with contact lens use can return to comfortable contact lens wear with appropriate treatment.[11] Frequent encouragement by the clinician can be essential, because the symptoms may take some time to subside.
The patient should be frequently monitored while GPC is active, perhaps every few weeks to few months.
Once GPC is successfully managed, patients should receive follow-up care as indicated by other aspects of their ophthalmic and medical situation.
Symptoms may be more important than signs.
Therapeutic effect is evidenced by the subjective return of contact lens tolerance, suppression of ocular itching, decreased objective hyperemia of the tarsal conjunctivae, decreased inflammation of the giant papillae, and decreased mucus in the tears.
Surgical care is extremely rare, although there have been limited cases when surgery is used when medical therapy was not effective. GPC is surgically removed and a free autologous conjunctival graft is used to cover the tarsal conjunctival defect.[30]
Pharmacologic management is a moderately effective adjunctive treatment when patients with giant papillary conjunctivitis (GPC) cannot or will not discontinue wearing contact lenses. GPC is a Gel-Coombs type 1 disease with degranulated conjunctival mast cells as the chief histologic feature; therefore, drugs that inhibit mast cell degranulation are effective.[31]
The most commonly used topical medications are combination, dual-acting H1 receptor antagonists and inhibitors of histamine release from mast cells (ie, olopatadine hydrochloride, ketotifen fumarate). These are more ideal for patient compliance because of their once-daily to twice-daily dosing.
Topical mast cell stabilizers were the original treatment for GPC. Topical sodium cromolyn 0.4%[3] is effective but does not promote compliance with the four-times-per-day dosing frequency. NSAIDs and antihistamines are also used.
Steroids can be useful for severe cases.[27, 28] Mild steroids such as loteprednol would be more ideal than stronger steroids because of their low risks of inducing glaucoma. More recently, topical immunomodulators have been used with results as efficacious as those of corticosteroids but without the adverse effects of corticosteroids.[29, 32]
Topical ophthalmic medications should be used cautiously with contact lens wear, because these medications are commonly preserved with benzalkonium chloride (BAK). BAK is associated with corneal epithelial toxicity episodes (a greater concern with hydrogel contact lenses).
If medication must be administered concomitantly with hydrogel contact lenses, application should be restricted to a maximum of 3 times a day (ie, one drop just prior to contact lens wear, one drop immediately upon contact lens removal, and one drop before going to bed). Once-daily and twice-daily ophthalmic medications are more ideal (eg, olopatadine ophthalmic, ketotifen, epinastine, alcaftadine ophthalmic) for increased patient compliance and convenience, especially for contact lens wearers. Patients should wait at least 10-15 minutes after medication instillation before contact lens insertion.
Clinical Context:
Alcaftadine is an H1-receptor antagonist. It inhibits histamine release from mast cells, decreases chemotaxis, and inhibits eosinophil activation. Lastacaft is administered once a day to improve patient compliance.
Clinical Context:
Bepreve is a histamine H1 receptor antagonist indicated for the treatment of itching associated with allergic conjunctivitis. It is dosed twice a day in each eye.
Clinical Context:
Epinastine is a direct histamine-1 receptor antagonist. It is indicated for symptoms due to allergic conjunctivitis. Its recommended dosage is twice a day.
Clinical Context:
Olopatadine is a histamine H1 receptor antagonist that inhibits the release of histamine from mast cells and histamine-induced effects on conjunctival epithelial cells. Pazeo's recommended dosing is once a day, which can improve patient compliance.
Clinical Context:
Ketotifen is a relatively selective, non-competitive H1 receptor antagonist and inhibitor of histamine release from mast cells. This is an over-the-counter product. Its recommended dosage is twice a day.
The dual-acting antihistamine and mast cell stabilizer makes them effective for the immediate itching and long-term management of GPC by controlling the degranulation of mast cells. Mast cell–stabilizing medications/antihistamine combination drops are most likely to achieve the therapeutic effect with minimal complications. The low dosing schedule of twice a day makes them practical for most patients. If patients are to wear contact lenses, have them wait 10-15 minutes before lens insertion.
Clinical Context:
Azelastine ophthalmic is a selective H1-receptor competitor with H1-receptor sites on effector cells. It also exhibits H2-blocking properties. It inhibits the release of histamine and other mediators involved in the allergic response. Its recommended dosage is twice a day.
Clinical Context:
Emedastine difumarate is a relatively selective H1 receptor antagonist that appears to be devoid of effects on adrenergic, dopaminergic, and serotonin receptors. It affects both the early and late phases of the ocular allergic reaction. Its recommended dosage is four times a day.
These agents are used for the temporary relief of the signs and symptoms (itching) of allergic conjunctivitis. Compared to first-generation antihistamines, second-generation antihistamines do not sting and had longer durations of efficacy.
Clinical Context:
Cromolyn sodium is a mast cell stabilizer that inhibits histamine and SRS-A from mast cell. It was the first drug of its class. Its recommended dosage is four times a day.
Clinical Context:
Nedocromil inhibits the release of various inflammatory cell mediators (mast cell stabilizer). It has greater efficacy than cromolyn sodium. Its recommended dosage is twice a day.
Clinical Context:
Pemirolast is a mast cell stabilizer indicated for the prevention of itching due to allergic conjunctivitis. Its recommended dosage is four times a day.
GPC primarily appears to be a Gel-Coombs type 1 hypersensitivity disease. The primary pathological event is inappropriate degranulation of the conjunctival mast cells, which release many inflammatory mediators, such as histamine (resulting in itch). Pure mast cell stabilizers are indicated for long-term use after the acute phase of symptoms is abated.[31] They are well tolerated. Symptoms may include burning. Their four-times-a-day dosing decreases the rate of compliance and may result in treatment failure.[33]
Clinical Context:
Loteprednol modulates the activity of prostaglandins and leukotrienes. Placebo-controlled studies have demonstrated that loteprednol reduces the signs and symptoms of GPC after 1 week of treatment, continuing for up to 6 weeks while on treatment. It has a reduced risk of increasing intraocular pressure by rapidly converting into inactive metabolites after corneal penetration. Its recommended dosage is four times a day.
These agents inhibit many aspects of the inflammatory response from inciting agents: edema, capillary dilation and proliferation, leukocyte migration, and fibroblast proliferation.
Clinical Context:
Bromfenac ophthalmic solution is an ophthalmic that blocks prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2. It is indicated to treat postoperative inflammation and to reduce ocular pain after cataract extraction.
Clinical Context:
Ketorolac inhibits prostaglandin synthesis by decreasing the activity of the enzyme cyclooxygenase, which results in decreased formation of prostaglandin precursors, which, in turn, results in reduced inflammation. Its recommended dosage is four times a day.
NSAIDs inhibit prostaglandin synthesis, which results in vasoconstriction, decreased vascular permeability, leukocytosis, and decreased intraocular pressure (IOP). However, these agents do not significantly affect IOP. Topical NSAIDs (especially a generic version of Voltarin) have been associated with rare corneal melting as a severe complication.
Clinical Context:
Tacrolimus binds to the FK506-binding proteins within the T lymphocytes and complexes with calcineurin-dependent proteins, inhibiting calcineurin activity. Calcineurin inhibition suppresses dephosphorylation of the nuclear factor of activated T cells and its transfer into the nucleus, which results in the suppressed formation of cytokines by T lymphocytes. Inhibition of T lymphocytes leads to the release of inflammatory cytokines and decreased stimulation of other inflammatory cells. Tacrolimus eyedrops have lower adverse effects of transient foreign body sensation, burning, and blurry vision compared to tacrolimus ointment.[31] Its recommended dosage is twice a day.
Karen K Yeung, OD, FAAO, Senior Optometrist, Arthur Ashe Student Health and Wellness Center, University of California, Los Angeles
Disclosure: Nothing to disclose.
Coauthor(s)
Barry A Weissman, OD, PhD, FAAO, Professor of Optometry, Southern California College of Optometry; Professor Emeritus of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Avedro; Bio-Tissue; Shire<br/>Received income in an amount equal to or greater than $250 from: AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab.
Chief Editor
Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Ballow M, Donshik PC, Mendelson I. Complement proteins and C3 anaphylatoxin in the tears of patients with contact lens associated conjunctivitis. J Allergy Clin Immunol. 1985. 76(3):473-6.
Irani AM, Burtus I, Tabbar KF, et al. Human conjunctival mast cells; distribution of MCT and MCTC in vernal conjunctivitis and giant papillary conjunctivitis. J Allergy Clin Immunol. 1990. 86(1):34-40.
Very large papillae in the everted upper lid of a patient who wears hydrogel (soft) contact lenses.
Giant papillary conjunctivitis (GPC) response (slightly out of focus) seen in the upper lid of a young patient recovering from cataract extraction with an exposed suture barb (in focus).
Very large papillae in the everted upper lid of a patient who wears hydrogel (soft) contact lenses.
Giant papillary conjunctivitis (GPC) response (slightly out of focus) seen in the upper lid of a young patient recovering from cataract extraction with an exposed suture barb (in focus).
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