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com/contents/vernal-keratoconjunctivitis
Vernal keratoconjunctivitis
Authors:
Pedram Hamrah, MD
Reza Dana, MD, MPH, MSc
Section Editors:
Robert A Wood, MD
Jonathan Trobe, MD
Deputy Editor:
Elizabeth TePas, MD, MS
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jul 2018. | This topic last updated: Nov 29, 2017.
INTRODUCTION — There are five main types of ocular allergy: seasonal allergic
conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC),
atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC). VKC and AKC are
chronic, bilateral, and severe forms of allergic inflammation affecting the ocular surface. These
two relatively uncommon types of allergic eye disease can cause severe damage to the ocular
surface, leading to corneal scarring and vision loss if not treated properly (this occurs more
commonly with AKC than VKC). Type I hypersensitivity reactions are important in these
diseases, although they are not the only pathophysiologic mechanism. VKC is reviewed in this
topic. AKC is discussed separately. (See "Atopic keratoconjunctivitis".)
GPC is an inflammatory disorder that represents a reaction to lid movement over a foreign
substance, such as hard contact lenses. Toxic conjunctivitis is not allergic in nature, but it is
frequently confused with allergic ocular disease. It develops with protracted use of topical
medications, mostly due to preservatives. GPC and toxic conjunctivitis are discussed in detail
separately. (See "Giant papillary conjunctivitis" and "Toxic conjunctivitis".)
Seasonal and perennial allergic conjunctivitis, the most common forms of ocular allergy, are
also discussed separately. (See "Allergic conjunctivitis: Clinical manifestations and
diagnosis".)
EPIDEMIOLOGY — VKC most commonly occurs in boys living in warm, dry, subtropical
climates, such as the Mediterranean, the Middle East, Central and West Africa, South
America, and Asian countries, such as Japan, Thailand, and India [1]. The limbal form of VKC
is seen most often in dark-skinned individuals from Africa and India. VKC is generally rare in
cooler climates, such as Northern Europe and the temperate areas of North America. In the
past, prevalence in these regions has been approximately 0.03 percent of the population. As
an example, prevalence for Western Europe was 3.2 in 10,000, whereas a higher prevalence
ranging from 2.4 to 27.8 in 10,000 was seen in Italy, a country with a Mediterranean climate
[2]. However, the prevalence in cooler regions has increased, probably due to immigration of
individuals from susceptible populations [3].
Males are more commonly affected than females. In one series, the male-to-female ratio was
3.2:1 in patients <20 years of age but was nearly equal in older patients [4]. Age at onset is
generally before 10 years, with the earliest reported onset at five months of age [5], although
VKC can infrequently occur in adults. Patients usually "outgrow" the disease with the onset of
puberty.
PATHOGENESIS — The exact pathogenic mechanisms of VKC are not fully elucidated.
Classic immunoglobulin E (IgE)-mediated hypersensitivity and T helper cell type 2 (Th2)-
mediated responses are thought to play a major role [6,9-11], but other mechanisms may be
involved, including immunoglobulin G (IgG)-mediated responses, basophil hypersensitivity,
and cellular delayed-typed hypersensitivity.
●Seasonal incidence
●Increased levels of mediators derived from mast cells and eosinophils, including
histamine and tryptase, in tears
Conjunctival accumulation of Th2 CD4+ cells may give rise to hyperreactivity against
substances that commonly contact the conjunctiva. Offending allergens include pollens, dust
mites, molds, and animal epithelium [8,12,13]. Nonspecific stimuli, such as wind, sunlight, and
heat, also probably play a role [14,15].
Mast cells play a key role in the development of IgE-mediated reactions. In addition, they
release inflammatory mediators (eg, histamine, interleukins) [16-18] that stimulate fibroblast
activity and production of collagens I and III, resulting in the typical formation of giant papillae
in VKC [19]. Furthermore, there is increased expression of histamine receptors (H1, H2, and
H4 receptors) in conjunctival tissue [20]. The necessary vascular supply of the forming giant
papillae is provided by capillary proliferation. Chronic conjunctival inflammation in VKC is
associated with increased staining via immunohistochemistry for mediators that may stimulate
vascular proliferation [21].
Histologic analysis of ocular tissue reveals proliferative changes in the epithelium, hyperplasia
of connective tissue, and cellular infiltration of the substantia propria [4,19]. The inflammatory
infiltrate includes eosinophils, neutrophils, basophils, lymphocytes, plasma cells, mast cells,
and fibroblasts. Conjunctival scrapings of VKC patients show a predominance of eosinophils,
while basophils, neutrophils, and lymphocytes are rare. Increased numbers of mast cells,
eosinophils, and lymphocytes are seen in conjunctival biopsies. Cytologic examination of
mucus secretions reveals a predominance of eosinophils [22-24].
CLINICAL MANIFESTATIONS
Symptoms — Almost all patients with VKC note ocular pruritus [1,4].
Other symptoms of VKC include (in approximate order of frequency from high to low, although
the frequency of each is highly variable):
●Photophobia
●Tearing
●Burning
●Pain
●Blurred vision
VKC is named as such because severe symptoms most commonly occur in the spring (hence
"vernal"), at least in the first few years of the disease. In one series of 195 patients in Italy,
over three-quarters of patients had seasonal symptoms that began in March/April and
resolved in September [4]. However, over one-fifth had chronic symptoms since disease
onset, and an additional 16 percent of patients went on to have chronic symptoms after a
seasonal presentation.
Signs — Bilateral eye involvement and presence of giant cobblestone-like papillae on the
upper tarsal conjunctiva (conjunctiva lining the upper eyelid) are nearly universal findings in
patients with VKC (picture 1) [1,4].
Other signs of VKC include (in approximate order of frequency from high to low, although the
frequency of each is highly variable):
●Superficial keratopathy
●Horner-Trantas dots
●Corneal shield ulcers
●Ptosis
●Blepharospasm
Examination of VKC patients may reveal a predominance of upper tarsal signs (palpebral
VKC), limbal signs (limbal VKC), or a combination thereof:
●The tarsal or palpebral form involves the part of the conjunctiva that covers the inside
of the eyelid (tarsus). Upper tarsal papillae are discrete, enlarged (>1 mm), and give rise
to a classic "cobblestone" appearance with flattened tops (picture 2). Subepithelial
fibrosis resulting from papillae hypertrophy can cause increased eyelid thickening and
ptosis. Thick, ropy mucus secretions are usually present and associated with tarsal
papillae. The skin or lid margins are rarely involved, and the cornea is also typically not
involved.
●The limbal form involves the limbus of the eye, the thin border between the cornea and
the sclera. Gelatinous, confluent, yellow-gray infiltrates (Horner-Trantas dots) are
pathognomonic of the limbal form of the disease (picture 3). Punctate collections of
epithelial cells, eosinophils, and calcified corneal concretions may also be observed.
Other corneal signs, which may also be sight threatening, include superficial peripheral
neovascularization, punctate corneal epitheliopathy, shield ulcers, subepithelial scarring,
and plaque formation secondary to accumulation of inflammatory debris. Shield ulcers
are usually found in the upper half of the visual axis (picture 4). After resolution, the
ulcerated area leaves a ring-like scar.
DIAGNOSIS — There are no established diagnostic criteria for VKC. The diagnosis of VKC is
based upon the typical epidemiology and clinical features of VKC (eg, young boys living in
warm climates who present with ocular pruritus and giant papillae on the conjunctival lining of
the upper eyelid). A clinical grading system was proposed to aid in the diagnosis and
management of VKC (table 1) [25,26]. (See 'Epidemiology' above and 'Clinical
manifestations' above and 'Signs' above.)
TREATMENT — Therapy for VKC is long term and requires frequent follow-up. The
management approach includes both pharmacologic and nonpharmacologic therapies
(algorithm 1) [27].
Topical antihistamines and mast cell stabilizers are first-line pharmacologic therapies.
Treatment with topical corticosteroids is best undertaken by an ophthalmologist. Patients who
do not respond to these therapies may benefit from an allergy evaluation and possibly allergen
immunotherapy. Additional medications that may be effective in some patients include
calcineurin inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and oral antihistamines.
A proposed grading system may aid in choice of treatment (table 1) [26].
Basic eye care and avoidance of triggers — All patients should be counseled in basic eye
care and trigger avoidance (algorithm 1). These include:
●Avoidance of nonspecific triggers, such as wind, heat, salt water, and sunlight whenever
possible
●Artificial tears, especially in patients who develop tear film insufficiency due to the
anticholinergic effect of systemic antihistamines
●Cool compresses
Initial topical therapy — Topical dual-acting mast cell stabilizers and antihistamines are
typically chosen as first-line therapy (algorithm 1) and should be used on a daily basis
throughout the affected season (usually just the spring, but symptoms may extend into other
seasons depending upon levels of pollen allergens and may occur nearly year round). If a
dual-acting agent is not an option, alternatives are a combination of a separate topical mast
cell stabilizer and a topical antihistamine or a mast cell stabilizer alone. However, the dual
agents were more effective than mast cell stabilizers alone in studies using a conjunctival
allergen challenge model [28-33]. Topical antihistamines alone are minimally effective for VKC
and are not used as monotherapy.
Dual-acting agents have two main actions. As mast cell stabilizers, they inhibit mast cell
degranulation, which is the first step in the allergic cascade. They also inhibit leukocyte activity
and dampen mediator release from mast cells, basophils, eosinophils, and neutrophils. As
antihistamines, they competitively and reversibly block histamine receptors in the conjunctiva
and eyelids, thereby blocking the actions of the primary mast cell-derived mediator [34]. This
also helps reduce the late phase of the allergic response.
Topical mast cell stabilizers include cromolyn sodium [39], nedocromil sodium [40,41],
and lodoxamide [42,43]. Mast cell stabilizers have repeatedly been shown to be effective in
patients with VKC [39-43]. A systematic review and meta-analysis of these agents showed
that all resulted in significant improvement in signs and symptoms of VKC, with the exception
of photophobia [44]. Comparison of the efficacy of the different drugs was not possible due to
variability in the study designs. Mast cell stabilizers have no effect on mediators once they are
released but are effective in preventing mast cell degranulation. The onset of action of these
drugs is 5 to 14 days after initiation of therapy. Thus, these drugs are not useful for acute
symptoms. In addition, dosing of mast cell stabilizers is three to four times daily compared with
twice daily for most agents with combined actions. These features may limit patient
compliance.
Add-on initial therapy for moderate to severe disease — There is no widely accepted
grading scheme for VKC. In general, the condition is considered severe when it affects vision
or leads to symptoms of itch and irritation most of the time. Patients with mild to moderate
disease have intermittent symptoms (more frequent in the moderate group but not nearly
continuous as with severe disease) and no visual deficits. Oral antihistamines,
including fexofenadine, loratadine, desloratadine, cetirizine, and levocetirizine, have
demonstrated efficacy in the treatment of allergic conjunctivitis but have not been well studied
in patients with VKC [45]. These agents have a slower onset of action compared with topical
agents (one-half to two hours rather than a few minutes). In our experience, oral
antihistamines may be useful as add-on therapy in patients with moderate to severe disease.
Maximizing the dose of nonsedating antihistamine will often improve efficacy. (See "Allergic
conjunctivitis: Management".)
Oral antihistamine use may be associated with drying of mucosal membranes and decreased
tear production in some patients, especially those with concomitant dry eye. This side effect
can usually be countered with the liberal application of artificial tears. Cetirizine causes
sedation in a subset of patients, despite its categorization as nonsedating.
Treatment of refractory disease — We refer patients who do not respond to two or three
weeks of initial therapy (first confirming consistent use) to an ophthalmologist for topical
corticosteroid therapy (algorithm 1). However, a topical calcineurin inhibitor such
as cyclosporine is recommended rather than topical corticosteroids if the corneal epithelium
is compromised, particularly in the presence of shield ulcers. Several classes of medications
may need to be used concurrently. Starting one does not mean others have to be terminated.
In general, we recommend starting, stopping, and tapering medication based upon the
patient's symptoms. If control is not obtained after two to three weeks of topical corticosteroid
therapy, we refer to an allergy specialist for possible allergen immunotherapy (VKC is unlikely
if testing to aeroallergens is negative, and the patient should be evaluated for other causes of
conjunctivitis). For patients who have trouble controlling symptoms when topical
corticosteroids are reduced, we add topical calcineurin inhibitors as steroid-sparing agents.
Most patients have adequate control with these measures over time, but a small percentage
require systemic immunosuppressive therapy (eg, cyclosporine).
In severe cases of VKC, prednisolone acetate 1% eight times daily for one week leads to
significant symptom relief and thereafter should be tapered rapidly once control is gained [46].
In less severe cases, pulse therapy with topical "soft" steroids on a two to four times per day
basis for approximately two weeks is effective in gaining control of the allergic response so
that mast cell stabilizers, antihistamines, and artificial tears have a greater chance to work
[40,47]. Use of topical "soft" corticosteroids for greater than six weeks is associated with a
significantly increased risk of complications.
Prednisolone acetate 1% and dexamethasone 0.1% have the greatest efficacy/potency but
also the greatest risk of raising intraocular pressure (IOP) among all topical corticosteroids.
By comparison, "soft" steroids are a group of topical corticosteroids that have a greatly
reduced risk of causing increased IOP because they bind with high affinity to the glucocorticoid
receptor and the unbound drug undergoes rapid inactivation upon penetration of the cornea.
Topical "soft" corticosteroids include prednisolone acetate 0.12%, fluorometholone,
medrysone, loteprednoletabonate 0.5 or 0.2%, and rimexolone 1%.
Observational studies and one randomized trial have shown that topical corticosteroids are
effective in treating VKC [4,40,47]. In the small, randomized trial, a two-week course
of fluorometholone0.1% was more effective than nedocromil 2% in decreasing signs and
symptoms of VKC, including papillary hypertrophy, Horner-Trantas dots, mucus discharge,
conjunctival hyperemia, and tearing [40].
Corticosteroids suppress the late-phase reaction in both experimental and clinical settings.
These drugs, in part, limit the inflammatory cascade by inhibiting phospholipase A2.
Consequently, they reduce the formation of lipid-derived mediators from arachidonic acid,
which prevents leukocyte migration, hydrolytic enzyme release, fibroblast growth, and
changes in vascular permeability.
Calcineurin inhibitors — The calcineurin inhibitors that are most commonly used in ocular
allergy include topical cyclosporine and tacrolimus and systemic cyclosporine. An important
advantage of the topical calcineurin inhibitors is that they do not cause the same side effects
typically seen with topical corticosteroids, such as an increase in IOP. Thus, long-term use of
these agents is considered safe when used topically, unlike chronic use of topical
corticosteroids, and only minimal amounts can be traced systemically. However, topical
cyclosporine and tacrolimus are generally not chosen over topical corticosteroids for acute
exacerbations, because of their much slower onset of action (weeks to a couple of months
rather than hours to days). We suggest using topical cyclosporine 2% one drop each eye twice
daily (can be increased to four times daily in severe cases) as a corticosteroid-sparing agent
in patients with moderate to severe disease who require frequent or prolonged courses of
topical corticosteroids. Systemic cyclosporine is reserved for corticosteroid-dependent
patients who do not respond to other therapies. Systemic glucocorticoids are not used for
VKC.
Cyclosporine diminishes the effect of interleukin-2 (IL-2) on T cells and leads to decreased
expansion of T helper cells. It may also inhibit mast cell proliferation and survival. Cyclosporine
reduces collagen production and induces apoptosis of conjunctival fibroblasts from VKC
patients. Tacrolimus has similar mechanisms of action [49,50].
In one study, topical cyclosporine 0.1% was less effective than topical dexamethasone 0.15%
for acute flare ups, with less improvement in symptoms and signs and a greater number of
patients requiring rescue therapy with topical dexamethasone [60].
Topical tacrolimus — Efficacy of topical tacrolimus in patients with VKC was demonstrated
in small, observational studies [49,50]. Topical tacrolimus 0.1% was also shown to be effective
in a double-blind crossover trial of 30 patients with severe VKC who failed to respond to
topical cyclosporine [61].
Treatment for subsequent seasons — In patients with known disease, a dual-acting agent
should be started approximately a month before the usual onset of their seasonal symptoms
and continued for the duration of season. Dual-acting agents have a quick onset of action, but
the start of the season can vary from year to year and allergic responses, once activated, can
last up to two months. Thus, it is better to start treatment a bit early to ensure that the mast
cells are stabilized before the onset of the season. While mast cell stabilizers have a slower
onset of action than dual-acting agents, starting one of these drugs a month before the usual
onset of symptoms is usually sufficient. Topical cyclosporine, while effective, is typically not
used as initial therapy for subsequent seasons, because it would need to be started even
further in advance of the season due to its very slow onset of action [59,60]. The approach for
patients who fail to respond to initial therapy in subsequent seasons is similar to that outlined
above. Patients who are asymptomatic on just a dual-acting agent or mast cell stabilizer for a
season can do a trial without therapy the following season to determine if the disease has
resolved. (See 'Add-on initial therapy for moderate to severe disease' above and 'Treatment
of refractory disease' above and 'Prognosis' below.)
Omalizumab, an anti-IgE monoclonal antibody, was shown to resolve ocular signs and
symptoms of VKC in a series of four children despite negative blood and skin testing for
environmental allergies [72]. Dosing was based upon weight and total IgE level using the same
dosing schedule used for patients with asthma. Improvement was noted within the first few
weeks of treatment, and none of the patients relapsed after treatment was discontinued after
six months of therapy. These results are consistent with other case reports [73-76]. The exact
mechanism that leads to clinical improvement in these patients is unclear, and further study is
needed. (See "Anti-IgE therapy", section on 'Dosing and administration'.)
PROGNOSIS — Overall, most patients do well with treatment and only require seasonal
therapy. Patients typically outgrow VKC, but it can take a number of years. Vision loss in VKC
is rare but can occur due to corneal scarring, neovascularization, and amblyopia. A more
severe baseline grade, a younger age of onset, and a higher rate of recurrences of ocular
inflammation were all associated with a worse visual outcome in a series of 110 patients,
suggesting that more aggressive treatment may be appropriate in these higher-risk patients
[26].
●VKC most commonly occurs in boys living in warm, dry, subtropical climates.
(See 'Epidemiology' above.)
●The most common manifestations of VKC are ocular pruritus and giant cobblestone-like
papillae on the upper tarsal conjunctiva (picture 2). (See 'Clinical manifestations' above
and 'Signs'above.)
●The diagnosis of VKC is based upon the typical epidemiology and clinical features of
VKC (eg, young boys living in warm climates who present with ocular pruritus and giant
papillae on the conjunctival lining of the upper eyelid). (See 'Diagnosis' above.)
●The management approach includes both nonpharmacologic measures (ie, basic eye
care and trigger avoidance) and pharmacologic therapies (algorithm 1).
(See 'Treatment' above.)
●We suggest a topical dual-acting mast cell stabilizer and antihistamine as first-line
therapy (Grade 2C). Alternatives are a combination of a separate topical mast cell
stabilizer and a topical antihistamine or a mast cell stabilizer alone. We suggest adding
a second- or third-generation oral antihistamine in patients with moderate to severe
disease (Grade 2C). (See 'Initial topical therapy' above and 'Add-on initial therapy for
moderate to severe disease' above.)
●Vision loss in VKC is uncommon but can occur due to corneal scarring,
neovascularization, and amblyopia. (See 'Prognosis' above.)
REFERENCES