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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 13
| Issue : 1 | Page : 3-12 |
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Management of vernal keratoconjunctivitis in children in Saudi Arabia
Dora Hamad AlHarkan
Department of Ophthalmology, Medical College, Qassim University, Qassim, Saudi Arabia
| Date of Submission | 29-Dec-2018 |
| Date of Decision | 07-May-2019 |
| Date of Acceptance | 25-Nov-2020 |
| Date of Web Publication | 17-Feb-2020 |
Correspondence Address:
Dr. Dora Hamad AlHarkan
Department of Ophthalmology, Qassim University, POB 4490 – Qassim 51491
Saudi Arabia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ojo.OJO_263_2018
 Abstract | | |
Vernal keratoconjunctivitis is a chronic inflammatory disease of the ocular surface and one of the worst types of allergic conjunctival diseases. Because of its chronic nature, it can damage the cornea, resulting in sight-threatening complications if left untreated. The disease affects mainly young children starting around the age of 7 years. We used keywords to search for published English articles in PUBMED, Google Scholar, EMBASE, and Cochrane Database of Systematic Reviews. Most of the published literature is focusing on general management of the disease and few publications focusing on treatment in the pediatric age group. We highlight the importance of how is the topical management differs between age groups. We focused on the importance of doing cycloplegic refraction for each child as the risk of keratoconus and oblique astigmatism is high in these cases. Furthermore, we highlight the importance of using eye lubricants as a therapeutic and preventive tool for the attacks of the disease. We highlight that most of the recent effective medications (especially the off-label ones) are not available in Saudi Arabia, such as tacrolimus, and some are only available to be prepared in tertiary center pharmacies as Cyclosporine A with higher concentrations.
Keywords: Allergy, conjunctivitis, pediatric, vernal keratoconjunctivitis
How to cite this article:
AlHarkan DH. Management of vernal keratoconjunctivitis in children in Saudi Arabia. Oman J Ophthalmol 2020;13:3-12 |
| Introduction | |  |
Vernal keratoconjunctivitis (VKC) is a chronic inflammatory disease of the ocular surface[1] and one of the worst types of allergic conjunctival diseases. Because of its chronic nature, it can damage the cornea, resulting in sight-threatening complications if left untreated.[2] It is a bilateral disease affecting mainly young children, and because of its chronicity and its complications, VKC significantly affects the quality of life of patients and their families and even reduces their productivity.[3] One report showed that nonattendance of school due to ocular reasons during a 3-month period was five times more likely in children with VKC than among those without.[4] A large number of medical consultations for the pediatric age group are due to VKC and have been for many years, affecting the health-care services.
The exact global prevalence of VKC is not known. It is relatively uncommon; with variable prevalence according to the weather, it increases in dry, warm, subtropical climates. It is a disease of young children (generally before 10 years of age), affecting males more than females. The prevalence is reported to be 5.8% among Ethiopian children younger than 18 years.[5] In Jezan, Saudi Arabia, Darraj et al. noted that 1.3% of ophthalmic consultations for eye patients younger than18 years old were for VKC, and among them, the male-to-female ratio was 4:1.[6] Among school children in Minofia, Egypt, the prevalence of VKC was 3.3%.[7] Based on the population of children younger than 15 years of age, it is estimated that as many as 265,000 Saudi children could be suffering from VKC.[8] Around 26,000 of them could be residents of Qassim Province. With such a large number of children in need of treatment, all care providers should know about standard operating procedures to manage VKC.
Endocrine, genetic, neurogenic, environmental, and socioeconomic factors influence VKC and its severity.[9] Hot and dry weather is a risk factor for dry eye, which affects the severity of VKC.[10] The temperature in Saudi Arabia has increased significantly since 1993 and is compounded by low humidity, especially in noncoastal areas.[11] Thus, VKC prevalence is likely to increase in coming years, and medications required to manage these cases will also be needed in larger quantity. The prevalence of dry eye syndrome, a known risk factor for VKC,[12] is very high in Saudi Arabia.[13] Therefore, treatment of VKC in Saudi Arabia could require managing both of these ailments together and is of paramount importance.
| Methods | | |
On approval of the Institutional Review Board of Qassim University, the proposed review was carried out in 2018. Since no human beings were involved, written consent was waived. The research papers from 2000 to December 2018 were included. We used keywords to search for published English articles in PUBMED, Google Scholar, EMBASE, and Cochrane Database of Systematic Reviews. There were 16,600 articles on vernal conjunctivitis in different databases. Of them, 11,300 were on human beings. Seven thousand eight hundred and twenty articles were on the management of vernal keratoconjunctivitis. On applying filter for articles since 2005 related to review, meta-analysis, randomized clinical trials, multicenter studies, and cohort studies, we got 132 articles of sound evidence. Of them, full articles were collected with the help of library and reviewed for the present study. If an important research paper was found among references of selected manuscripts but was published before a stipulated time period, we included these articles also for review.
| Clinical Presentation | | |
Clinical presentation of VKC in patients is mostly by common allergic conjunctivitis symptoms such as itching, tearing, hyperemia, redness, irritation, and photophobia. The clue to the diagnosis is the seasonal timing of the disease. From its name, vernal, the attack usually starts in the beginning of spring time, especially in the first few years, and then it becomes chronic. VKC affects both the conjunctiva and the cornea and based on the clinical presentation, is classified as limbal VKC, palpebral VKC, or mixed type.[14] The first site causes morbidity, whereas the further sites, if not treated, could result in corneal complications and pose a threat to the vision. Presenting signs of VKC include conjunctival hyperemia, superficial keratopathy, nonpurulent mucus discharge, shield ulcer (with or without plaque formation), Horner–Trantas dots (pathognomonic of limbal form), and a cobblestone appearance of the tarsal conjunctiva. Timely and effective management is crucial to prevent rapid progression to corneal involvement and morbid symptoms. VKC should be differentiated from other types of conjunctival allergic diseases. The pediatricians and primary health-care providers should refer any case of allergic conjunctivitis not responding to a standard treatment with topical antihistamine and lubricants to prevent delay in diagnosis and management of VKC. [Figure 1] shows the classifications of conjunctival allergic diseases.[15] [Figure 2] shows how to differentiate VKC from other forms of allergic conjunctival diseases.[15] | Figure 2: How to differentiate VKC from other allergic conjunctival diseases
Click here to view |
| Pathophysiology | | |
Understanding the pathophysiology of an ocular condition is useful when searching for newer medications to combat the disease effectively. Immunoglobulin E (IgE)-mast cell activation in VKC is evident by finding IgE in serum, tear cytology, increased number of mast cells in conjunctival tissue, clinical observations of allergen exposure, symptom exacerbation, and association with other atopic states.[16] In VKC, T cells and eosinophils predominate with a Th2 cytokine-driven inflammation. CD4+ T cells are found abundantly in conjunctival scrapings and biopsy specimens.[17] It is particularly characterized by T cell-mediated responses and increased concentrations of conjunctival T cells. Cytotoxic proteins released from eosinophils infiltrating locally into the conjunctiva are thought to cause VKC.[18] The level of Alpha-1 antitrypsin, a kind of serine proteinase inhibitor, was noted to be high in VKC.[19] This may help in both the diagnosis and evaluation of the impact of medical treatment on VKC. CCL20 messenger RNA expression in the conjunctival epithelium of patients with VKC was high when compared to healthy persons, which points to its crucial role in exacerbation of VKC.[20] A high infiltration of mast cells in the giant papilla is found in the tarsal conjunctiva of a VKC patient.[21] Thus, mast cells were proposed to be responsible for abnormal connective tissue metabolism in VKC. Thick, ropy discharge in VKC is due to abnormal function of goblet cells. Exposure of mucin-secreting goblet cells to allergic and inflammatory mediators released by local innate and adaptive immune cells modulates proliferation, secretory function, and cell survival.[22] In VKC specimens, the epithelium shows intense cytoplasmic eotaxin staining in all cells and cytoplasmic RANTES (CCL5) staining mainly in the superficial layers. These were also visible on the vascular endothelium, suggesting that these chemokines are linked to the pathogenesis of VKC.[23]
| Management | | |
Diagnosis and management of allergic conjunctivitis is usually by pediatric health-care professionals. Unfortunately, VKC is often misdiagnosed, confused with simple allergic conjunctivitis, and undertreated. The referral to an ophthalmologist is also mostly in late stages and with complications.[24] Therefore, algorithms and guidelines were prepared and presented to care givers.[15],[16],[24] Pediatric doctors and primary health-care providers prescribe antiallergic medication (including topical administration of antihistamine, mast cell inhibitors, or combinations of both) safely to patients presenting with itching and redness. They should refer such cases to ophthalmologists if the children do not improve in 1 week after starting the medication. Treatment of VKC needs a good understanding of the disease and its chronic course. The parents should be educated about the importance of good compliance with medications and the chronic nature of the disease.
| Nonpharmacological Management | | |
VKC is a type of allergic conjunctival disease that results from exposure to an allergen, so the first line of management is removal and avoidance of the allergen that exacerbates the disease. Because the role of allergens as a precipitating factor for VKC is not clear, preventing the signs and symptoms is a major challenge.[25] Avoidance of specific/nonspecific triggers could prevent severe manifestations of VKC.[26] The parents should be instructed about the importance of avoiding eye rubbing that can exacerbate the itching and cause eye complications such as keratoconus and lid ptosis. Cool compresses are useful to reduce the symptoms of itching.[27]
| Artificial Tears | | |
Topical lubrication with artificial tears is important as a long-term management of VKC patients, during both active and inactive phases. First, it can reduce the symptoms of itching by a cooling effect. Second, during an acute attack and active VKC, it can wash out the inflammatory mediators present in the tear and by this, reduce inflammation. Third, dry eye is a common complication of VKC secondary to limbal stem cell deficiency (LSCD) and tear film instability as a result of cytological changes in both corneal and conjunctival epithelium. In these cases, lubrication with the use of eye drops in the daytime and eye ointment at bedtime is important.[28]
| Pharmacological Management | | |
The conventional management of VKC using antihistamines, mast cell suppressors, and steroids has changed in the past few years.[24] This has enabled care givers to address exacerbations, reduce symptoms, and avoid drug-related complications in children with VKC. Better understanding of the pathophysiology of VKC and research has added drugs and alternative routes of drug administration to combat VKC.[29]
The main focus of the medical management of VKC is to relieve the debilitating symptoms, reduce the signs, and prevent complications. The impact of management is usually assessed based on the improvement in the composite sign score.[30] The topical eye drops to treat VKC that are approved by the US Food and Drug Administration (FDA) and Saudi FDA, and given at King Khaled Eye Specialist Hospital, are shown in [Table 1].[31] Classes of topical medication used for the treatment of VKC are given in [Table 2].[32] | Table 1: Topical medication for the treatment of vernal keratoconjunctivitis
Click here to view |
 | Table 2: Classes of topical medication used for treatment of vernal keratoconjunctivitis (VKC)
Click here to view |
Antihistamine
Second-generation H (1)-antihistamines are among the most commonly prescribed medicines to treat allergic conjunctivitis, including VKC in children.[30] A number of antihistamine eye drops, such as emedastine and levocabastine (LEVO), have been reviewed and found to be safe and well tolerated. However, their long-term outcomes and use of standard and uniform parameters to compare the impact are needed.[33]
Mast cell stabilizers
- Sodium cromoglycate: In a systematic review comparing sodium cromoglycate and placebo for the treatment of seasonal allergic conjunctivitis, five studies showed an improvement in relieving the symptoms, whereas three studies showed no difference between treatment with placebo or the medicine.[34] The problem with it is the late starting of its action and lack of immediate relief of the symptoms
- Lodoxamide is a mast cell stabilizer and in a low dosage was found to prevent increased cutaneous vascular permeability and antigen-stimulated histamine release and could even prevent calcium influx into mast cells.[35] In a meta-analysis of different randomized clinical trials, using different antiallergic medications for VKC patients (LEVO, lodoxamide, nedocromil sodium, mipragoside, N-acetylaspartylglutamic acid, and sodium cromoglycate), lodoxamide was the most effective.[36] Topically applied 0.1% lodoxamide drops twice a day for at least 6 weeks provides a safe and effective therapeutic option for VKC. It can be used four times daily for a 3-month period safely for children aged 2 years or older.
Antihistamine/mast cell stabilizers
The combination of antihistamine and mast cell stabilizers such as azelastine and olopatadine is safe for children aged 3 years and older.
- Olopatadine: Through its dual action (H (1)-antihistamine/mast cell stabilization effects), olopatadine is superior to sodium cromoglycate.[37] Olopatadine eye drops are a safe and effective treatment modality, but it is limited in reducing ocular itching[38]
In another study, the efficacy of N-acetylaspartylglutamate (NAAGA) was compared to LEVO eye drops. The former is a mast cell stabilizer, whereas the latter is an H (1)-antihistamine eye drop. Both were preservative-free preparations. NAAGA was found to be safe and effective and reduced symptoms significantly better than LEVO.[39]
Steroids
These are the most potent and effective medications that can be applied as eye drops as well as ointment to treat moderate-to-severe cases of VKC (severe itching with inflamed conjunctiva, presence of limbal infiltrates, corneal involvement, and presence of giant papillae). Usually, it is given for a short period to reduce the inflammation in combination with other medications to reduce its dosage and thus minimize the side effects. Increased intraocular pressure, glaucoma, lens opacities, and secondary infections are the dreaded complications of steroid eye medications. Self-medication among VKC patients is very common because they experience dramatic relief from their symptoms following steroid use. A study by McGhee et al. showed that daily administration of topical steroid for 4–6 weeks can raise the intraocular pressure between 6 mmHg and 15 mmHg in one-third of the normal population.[40] Proper patient and parent counseling is therefore strongly recommended before prescribing steroids to treat VKC. Pulse therapy with topical steroids during disease exacerbations is a common practice. Prednisolone, fluorometholone, and dexamethasone eye drops are prescribed, and with adequate monitoring, this is acceptable. However, loteprednol has the least effect on intraocular pressure (safer than others) and is as effective as prednisolone to treat VKC.[16] The dosage and type of steroid medications available in Saudi Arabia are given in [Table 1].[31]
Immunosuppressive eye drops
- Cyclosporine A (CsA) is a neutral, hydrophobic, cyclic metabolite of the fungi Tolypocladium inflatum and Beauveria nevus. It is a nonsteroidal immune modulator and is most effective in treating VKC with minimal side effects,[30],[41] but tolerance of it is low because of its burning and irritant effect, and it is expensive.[9] It is available in 0.05%, 0.1%, and 1% concentrations.[42] In Saudi Arabia, only the 0.05% concentration is available in the pharmacies and higher concentrations should be prepared by a local pharmacy of the hospitals in tertiary centers. One percent CsA applied four times daily effectively controlled symptoms and local inflammation in moderate and severe forms of VKC and is a good alternative to steroids.[43] Use of 0.05% CsA topical eye drops has been found to prevent exacerbation of VKC.[44] The minimum effective concentration to treat shield ulcer is 1% CsA.[45] The effect of CsA can start as rapidly as 2–14 days. Relapse after stopping the medication is the problem, so long-term use is indicated, with a high dose of 1% during an acute attack. The dose should be reduced to 0.05% in between the attacks as a prophylactic. CsA has been shown to be less effective in cases with giant papillae
- Tacrolimus: Tacrolimus, also known as FK 506, is a macrolide derivative with anti-inflammatory and immunomodulatory activity (a mode of action similar to CsA). Tacrolimus is produced by the Streptomyces tsukubaenis fungus and can suppress T cell activation and interleukin-2 production by binding to an immunophilin and inhibiting the enzymatic activity of calcineurin.[46] Tacrolimus ointment and drop uses in ophthalmic diseases are off-label; it is FDA approved for dermatological use in a concentration of 0.1% and 0.03%. For dermatological use in children, only a 0.03% concentration is allowed for children aged 2 years and older, and it should be used for only a short period. In a randomized, placebo-controlled trial of 0.1% tacrolimus eye drops, twice daily drops for 4 weeks were safe and effective in treating severe allergic conjunctivitis.[47] In a concentration of 0.03%, it was found to be effective, safe, and well tolerated in the treatment of giant papillary conjunctivitis and other chronic allergic conjunctivitis cases, including VKC.[48],[49] It is a steroid-sparing agent and is found to be effective in cases refractory to topical CsA.[50]
Other medications
Topical acetylcysteine 5%–10% has been used to reduce mucus adherence to the cornea during acute exacerbations.[16] Alteration in goblet cell functions due to the effects of allergens such as histamine, leukotrienes, and prostaglandins in VKC results in their proliferation, apoptosis, and excessive mucin secretion.[22] Rebamipide 2% ophthalmic suspension is also found to be effective in reducing symptoms and signs in severe VKC and restores corneal damage in VKC. However, it is used as adjunct treatment and its effect is visible after 5 weeks of its usage.[51] Kimura et al.[52] documented that rebamipide protects corneal epithelial cells from tumor necrosis factor-α-induced disruption of barrier function.
| Surgical Treatment | | |
Surgical treatment is recommended in cases of corneal involvement and large tarsal papillae resulting in ptosis. Removal of corneal plaque in cases of shield ulcer enables corneal reepithelialization. Giant papillae excision of tarsal conjunctiva is complemented with intraoperative mitomycin-C.[16],[53]
| Complications and Treatment | | |
Association of keratoconus with spring catarrh was demonstrated as early as 1988.[54] Severe cases of VKC are also at a high risk of keratoconus.[55] Variable incidence of keratoconus among children with VKC has been reported to be 2.1%–15%;[56] therefore, in addition to treating VKC, one must closely monitor the corneal topography of both eyes of a VKC patient for early detection of keratoconus. Shield ulcer and plaque is a common complication in severe cases, with a reported incidence of 3%–11%.[56] It is commonly presented in the upper one-third of the cornea and will result in a permanent reduction of vision. In addition to aggressive medical therapy, corneal epithelial debridement, amniotic membrane transplantation (AMT), or both are recommended to treat shield ulcer and LSCD and to prevent severe visual impairment due to the complications.[57],[58],[59] Microbial keratitis secondary to shield ulcer has been reported, with an incidence of 9%–10%.[56] Cornea scarring with reduced vision can be caused by healed shield ulcer, healed microbial keratitis, or LSCD. LSCD is secondary to the chronic inflammatory process and frequent eyelid rubbing against giant papillae that results in damaging limbal stem cells.[56] The large papillae at the tarsal plate, causing ptosis, was managed in the past using cryotherapy,[60] but now both palpebral and limbal papillae are managed by excision and AMT with good outcomes.[61]
| Cycloplegic Refraction | | |
One of the most common complications of VKC is astigmatism that can lead to decreased vision if not discovered and treated with glasses. Tabbara investigated ocular complications in 58 children in Saudi Arabia with severe active VKC.[62] Fifty-five percent had severe visual loss, and of those, 12.5% had irregular astigmatism. De Smedt et al.[4] reported that children with VKC are >6 times more likely to have corneal astigmatism >2 diopters in their worse eye. Frequent eye rubbing and chronic inflammation will result in ectasia and changes in corneal stroma that result in refractive changes.[56] Usually, VKC cases are managed by general ophthalmologists, and unfortunately, they forget to do cycloplegic refraction. It is recommended that every patient with VKC undergoes cycloplegic refraction at least once at first presentation. It is preferable for cycloplegic refraction to be done after the eye is quieted so the patient will be cooperative enough to open the eye and the reflex of the retinoscope will be clear.
VKC is mainly a disease affecting children and teenagers.[63],[64] Evidence shows that male hormones are linked to the presence as well as severity of VKC, and further research could help reduce gender and prepubertal risk for VKC. Vitamin D deficiency has been associated with allergic diseases.[65] Further studies are recommended to investigate the association of Vitamin D levels and VKC and remedial action to be taken accordingly. Genome-wide analyses for VKC were nearing completion in the past decade. It is hoped that these data will point to unique, disease-associated gene products that might be exploited for new drug design.[66]
In the past two decades, a number of new medications have been marketed to treat VKC; new biologics such as topical calcineurin and IgE inhibitors could be safe alternatives to corticosteroids in the treatment of VKC.[10] Their efficacy has been compared and described in a number of reviews and many industry-sponsored drug trials.[36],[67],[68] They are promising but unfortunately have only short-term impact evaluations. The assessment methodology as well as indicators of success has varied widely; hence, consensus is difficult to achieve.[69] In addition, the high cost of new, patented medication makes these drugs inaccessible to VKC patients in developing countries. Furthermore, these medications have adult dosages and concentrations in eye drops, raising concern for how suitable they are for children. As shown in [Table 1], many medications used in the treatment of VKC are nonformulary, and some are not approved by the US FDA or Saudi Arabia FDA; many are not prescribed at a tertiary eye hospital in central Saudi Arabia. Thus, there will be a large discrepancy in the prescription of medical treatment in government and private-sector eye institutions. A standard operating procedure for VKC is therefore strongly recommended to adopt in KSA.
| Conclusions | | |
Although a number of comprehensive reviews, including a Cochrane review, have been undertaken on the management of VKC, we highlight that most of the recent effective medications (especially the off-label ones used once) are not available in Saudi Arabia, such as tacrolimus, and some are only available to be prepared in tertiary center pharmacies as CsA with higher concentrations. Using eye lubrications for both active and inactive cases of VKC is important and should be included in the management. Oblique astigmatism is one of the treatable causes of reduced vision in some VKC patients, so cycloplegic refraction is crucial for every patient. Ophthalmologists, pediatricians, and family physicians of Persian Gulf countries should be aware of newer medications, their advantages, and their limitations for treating children with VKC.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]
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