Abstract
Purpose:
The main objective of this study is to explore the efficacy of olopatadine 0.1% treatment in the resolution of symptoms of vernal keratoconjunctivitis (VKC) among the Indian population.
Methods:
This single-center, prospective cohort study involved 234 patients with VKC. Patients were treated with olopatadine 0.1%, twice daily for a period of 12 weeks and then followed up in 1st week, 4th week, 3rd month, and 6th month. The extent of relief in the symptoms of VKC was measured using total ocular symptom score (TOSS) and ocular surface disease index (OSDI).
Results:
In the present study, the dropout rate was 5.6%. Total of 136 males and 85 females with a mean age of 37.68 ± 11.35 years completed the study. TOSS score reduced from 58.85 to 5.06 and the OSDI score reduced from 75.41 to 11.2 with statistical significance (P < 0.01) from 1st week to 6th week after olopatadine 0.1% treatment. The data showed relief in subjective symptoms of itching, tearing, and redness, and relief in discomfort in functions related to ocular grittiness, visuals like reading, and environmental like tolerability in dry conditions. Further, olopatadine 0.1% was effective in both males and females, and patients across ages 18–70 years.
Conclusion:
Based on TOSS and OSDI scores, the findings of this study validate safety and tolerability as revealed by low adverse effects and moderate efficacy of olopatadine 0.1% in reducing VKC symptoms in a broader age group (18–70 years) of both genders.
Keywords: Itching, ocular surface disease index (OSDI), olopatadine, redness, total ocular symptom score (TOSS), vernal keratoconjunctivitis
On a global scale, vernal keratoconjunctivitis (VKC), a non-infectious and type of allergic conjunctivitis, constitutes about 0.1–0.5% of allergic eye disorders.[1] VKC is largely regarded as a seasonal (mostly occurring in the spring season), bilateral, chronic, and recurring form of ocular allergy.[2] Mostly prevalent in warm and humid, tropical or subtropical climate regions of the world,[3] this rare and chronic form of allergy mainly affects young boys of ages 5–15 years.[4] However, in some cases, this persists in the later decades of life.[5] Largely caused by airborne allergens including chemicals, dust, pollen, or smoke, this ocular surface disorder involves inflammation of the conjunctiva which is characterized by hypertrophy of limbus and the presence of upper tarsal giant conjunctival papillae.[6] Based on the inflamed part of the conjunctiva, VKC is clinically identified as limbal, palpebral, and mixed type.[7] In addition, based on subjective ocular symptoms like itching, classical ocular signs such as the presence of giant papillae, and involvement of ocular areas like cornea or limbal area, the VKC is graded from quiescent stage to intermittent followed by severe stage.[8] The immunologic mechanism of VKC involves two phases,[9] wherein exposure to allergens initiates the acute phase involving mast cell activation and IgE-mediated release of histamines and inducible mediators followed by activation of late phase which happens 6–72 h after the exposure to the allergen and involves the release of chemokines and infiltration of eosinophils, neutrophils, basophils, T cells, and macrophages which further aggravates the inflammation.[10]
Common signs and symptoms involve severe itching, mild-to-moderate chemosis, swelling of eyelids, redness, ropey and serous discharge, burning, tearing, and photophobia[2,11] which interferes with daily routine activities like watching TV or driving a car thereby affecting the quality of life. Other complications include corneal scarring, eosinophilic granulomas, and corneal ulcers.[12] In fact, the progression of inflammation from the tarsal conjunctiva to the cornea worsens VKC, leading to permanent vision loss.[13] Current guidelines for the management of VKC include a step-wise pharmacologic treatment. Depending on the chronicity of VKC use of mast cell stabilizers as the first-line therapy, corticosteroids, and steroid-sparing agents like cyclosporine and tacrolimus has been reported;[3] however, uniform consensus on the treatment modality for VKC is open for debate.
Among different pharmacologic treatments, the efficacy of olopatadine 0.1% in the relief of different clinical entities of allergic conjunctivitis including VKC and associated symptoms like itching, discomfort, and photophobia has been reported.[14,15] Olopatadine, a dual-action agent, with antihistamine property selectively blocks histamine H1 receptors and prevents vasoconstriction in the initial phase of VKC while the mast cell stabilizing effects prevent the degranulation of mast cells in the later stages, thereby controlling the allergic reaction. The rapid onset of action, shorter treatment period, long-lasting effectiveness, effective in reducing both early and late phases of allergic inflammation, easy availability, and low cost of drug[16,17] have widely increased the administration of olopatadine in the treatment of allergic conjunctivitis including VKC.[9]
Among the Indian population, nearly 5.8% of VKC cases contribute to ocular morbidity.[12] Based on clinical grading, mild[18]-to-severe[12] form of VKC and all three types of VKC—mixed,[12] palpebral,[19] and limbal[20] form are reported among the Indian population. Yet, a limited number of studies have addressed the effectiveness of olopatadine in the treatment of VKC. Further, there have been increased incidences of seasonal allergies and VKC among children from Bengaluru,[21] yet only a few studies of VKC and their management among the Bangalore population is performed.[21,22] Besides, in one of the studies from the Bengaluru pediatric population it was found that the treatment for VKC was adopted by less than 22% of patients.[21] Thus, there is a lack of awareness, poor diagnosis of the disease, and inadequate management measures for the treatment of VKC. Considering this, the present study aims to study the efficacy of olopatadine (0.1%) in the resolution of symptoms of VKC in a long term in a wide range of the population.
Methods
The present study was a single-center, prospective cohort study conducted during the period October 2019–October 2020. The approval and clearance for the study were obtained from the institutional ethics committee. The study population included 234 patients of both genders between 18 and 70 years, inclusively presented with signs and symptoms of itching sensation, foreign body sensation, ropy discharge, and papillae, and diagnosed with VKC [Fig. 1a and 1b]. Patients using contact lens and with a history of acute ocular infection, extra- and intraocular surgery within the last 6 months, any gross lid abnormalities and without informed consent were excluded from the present study.
Figure 1.
(a) Congestion of tarsal conjunctiva with papillae. (b) Congestion of tarsal conjunctiva with concretion
Treatment
Patients were administered olopatadine 0.1%, twice daily for a period of 12 weeks and the follow-up was performed in 1st week, 4th week, 3rd month, and 6th month.
Questionnaire
The total ocular symptom score (TOSS) questionnaire was used to measure the severity of allergic conjunctivitis in four domains, specifically, itchy, redness, tearing (eyes watering), and swelling (puffy eyes).[23] The ocular surface disease index (OSDI) questionnaire containing 12 questions measured ocular symptoms, vision-related function, and environmental triggers.[24] For both the questionnaires, the patient’s response was rated on a 5-point scale ranging from “all of the time” (score 4) to “none of the time” (score 0). The TOSS score was calculated using the TOSS formula: (sum of scores/n) × 100, where “n” corresponded to 4, 8, 12, or 16 depending on the number of questions answered. The OSDI score was determined using the formula: (sum of severity for all questions answered) × 100/(total # of questions answered*) × 4. The TOSS and OSDI scores were scored as percentages from 0–100, where 0 indicated no symptoms or no disability while 100 referred to no relief in symptoms or complete disability.
Statistical analysis
The Statistical Package for Social Sciences (SPSS) software version 24.0 was used for all statistical analyses. Collected data were presented in the form of frequency, percentage, mean, and standard deviation. Association analysis was studied using the Pearson Chi-square test. Further, the Kruskal–Wallis test was performed to identify the underlying difference in the follow-up period. All tests with a P value less than 0.05 were accepted as statistically significant.
Results
Out of 234 patients, 221 patients completed the study. During the course of study, two patients dropped out due to adverse effects and 11 patients switched to a stronger treatment protocol involving steroids [Fig. 2a and 2b]. A larger number of patients were male (61.5%) and represented young-to-middle-aged adults (84%). The adverse effects of olopatadine 0.1% treatment included headache (1.4%), intraocular pressure (1.4%), and burning (0.9%); however, the frequency was very low suggestive of safety and tolerability of the treatment [Table 1].
Figure 2.
(a) Severe VKC with Horner-Trantas spots. (b) Severe VKC with corneal vascularization
Table 1.
Patient’s profile
| Number of patients | Frequency | Percent |
|---|---|---|
| No. of patients who completed the study | 221 | 94.4 |
| Dropout | ||
| Adverse effect | 2 | 0.8 |
| Switch to steroid treatment | 11 | 4.7 |
| Total | 234 | 100 |
| Gender | ||
| Male | 136 | 61.5 |
| Female | 85 | 38.5 |
| Age (years) | ||
| 18-20 | 8 | 3.6 |
| 21-30 | 53 | 24 |
| 31-40 | 85 | 38.5 |
| 41-50 | 50 | 22.6 |
| 51-60 | 12 | 5.4 |
| 61-70 | 13 | 5.9 |
| Adverse effects | ||
| Headache | ||
| No | 218 | 98.6 |
| Yes | 3 | 1.4 |
| Intraocular pressure | ||
| No | 218 | 98.6 |
| Yes | 3 | 1.4 |
| Burning | ||
| No | 219 | 99.1 |
| Yes | 2 | 0.9 |
| Total | 221 | 100 |
Table 2 shows a gradual decrease in the TOSS score from 58.85 in 1st week to 5.06 in 6th month and a reduction in the OSDI score from 75.41 at 1st week to 11.72 in 6th month after olopatadine 0.1% treatment. A gradual decrease in the TOSS and OSDI score indicates an overall effectiveness of olopatadine 0.1% treatment in reducing the symptoms of itching, redness, and tearing and the discomfort associated with VKC [Table 2].
Table 2.
TOSS and OSDI scored during follow-up
| Symptoms | Weeks | n | Mean | Std. Deviation | Std. Error |
|---|---|---|---|---|---|
| Total ocular symptom scoring (TOSS) | 1st week | 221 | 58.852 | 9.093 | 0.612 |
| 4th week | 221 | 21.295 | 18.69 | 1.257 | |
| 3rd month | 221 | 16.148 | 17.146 | 1.153 | |
| 6th month | 221 | 5.062 | 9.719 | 0.654 | |
| Ocular surface disease index (OSDI) | 1st week | 221 | 75.419 | 11.876 | 0.799 |
| 4th week | 221 | 31.572 | 15.771 | 1.061 | |
| 3rd month | 221 | 14.4 | 14.924 | 1.004 | |
| 6th month | 221 | 11.278 | 14.6 | 0.982 |
Kruskal–Wallis test revealed a statistically significant difference in the mean rank value of the TOSS score (Chi-square = 539.56, P < 0.001) and OSDI score (Chi-square = 576.36, P < 0.001) during the follow-up period [Table 3].
Table 3.
Kruskal–Wallis test for difference in TOSS and OSDI scores based on follow-up weeks
| Follow-up weeks | Mean rank | Chi-square | Asymp. Sig. | |
|---|---|---|---|---|
| Total ocular symptom scoring (TOSS) | 1st week | 746.72 | 539.565 | 0.00 |
| 4th week | 447.68 | |||
| 3rd month | 374.6 | |||
| 6th month | 201 | |||
| Ocular surface disease index (OSDI) | 1st week | 764.45 | 576.364 | 0.00 |
| 4th week | 474.8 | |||
| 3rd month | 277.65 | |||
| 6th month | 253.11 |
Association analysis showed a significant improvement in the TOSS score, related to itching (Χ2 = 694.727, P < 0.001), redness (Χ2 = 669.354, P < 0.001), and tearing (Χ2 = 736.147, P < 0.001) during the follow-up period. Overall, at the end of the 6th month, approximately 89.6%, 88.7%, and 91.4% of patients reported improvement in itching, redness, and tearing respectively. The swelling of the eyes was uncommon and frequented in 10% of patients, and at the end of follow-up period, 8.1% still continued with swelling of the eyes (data not shown). In a similar fashion, based on OSDI scores, association analysis showed a significant improvement in sensitivity to light (Χ2 = 902.415, P < 0.001), grittiness (Χ2 = 613.336, P < 0.001), painful or sore eyes (Χ2 = 874.113, P < 0.001), blurred vision (Χ2 = 602.645, P < 0.001), poor vision (Χ2 = 854.257, P < 0.001), visual functioning related to reading (Χ2 = 602.895, P < 0.001), driving (Χ2 = 863.812, P < 0.001), working with a computer/bank machine (Χ2 = 597.094, P < 0.001), watching TV (Χ2 = 857.623, P < 0.001), and very dry or air-conditioned (Χ2 = 669.265, P < 0.001). Sensitivity to light was completely resolved in 58.8%, grittiness in 59.3%, painful or soreness of the eye in 77.4%, blurred vision in 72.4%, and poor vision in 72.4%. Likewise, 74.2% reported resolution of visual function related to reading, 73.3% could drive at night, 71.9% could work with a computer or bank machine, and 76.5% could watch TV. In addition, it was found that they were comfortable in a dry or air-conditioned environment (data not shown). Thus, based on TOSS and OSDI scores, olopatadine 0.1% treatment was effective in the overall improvement of itchiness, redness, and watering of eyes, the common symptoms of VKC. In addition, the treatment was efficient to improve ocular symptoms, vision-related function, and environmental triggers related to VKC.
Efficacy of olopatadine 0.1% according to age and gender of patients
Kruskal–Wallis test was performed to analyze the statistical significance difference in TOSS and OSDI scores during the follow-up period based on gender [Table 4] and age groups [Table 5]. The mean rank value of TOSS and OSDI decreased for both males (Χ2 = 346.9, P < 0.01 and Χ2 = 353.5, P < 0.01) and females (Χ2 = 194.8, P < 0.01 and Χ2 = 221.9, P < 0.01) with a statistical significance suggestive of efficacy of olopatadine 0.1% treatment in reducing the symptoms and discomforts in both males and females.
Table 4.
Kruskal–Wallis test for the difference in TOSS and OSDI scores in follow-up weeks based on gender
| Sex | TOSS | OSDI | ||||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Mean rank | Chi-square | Asymp. Sig. | Mean Rank | Chi-square | Asymp. Sig. | |
| Male | ||||||
| 1st week | 462.65 | 346.932 | 0 | 472.46 | 353.516 | 0.00 |
| 4th week | 279.92 | 287.31 | ||||
| 3rd month | 226.6 | 173.49 | ||||
| 6th month | 120.82 | 156.74 | ||||
| Female | ||||||
| 1st week | 284.56 | 194.858 | 0 | 292.32 | 221.935 | 0.00 |
| 4th week | 169.08 | 187.78 | ||||
| 3rd month | 148.74 | 104.95 | ||||
| 6th month | 79.62 | 96.95 | ||||
Table 5.
Kruskal–Wallis test for the difference in TOSS and OSDI scores in follow-up weeks based on age
| Follow-up period | Age (years) | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| 18-20 | 21-30 | 31-40 | 41-50 | 51-60 | 61-70 | |
| TOSS Score | Mean rank | |||||
| 1st week | 20.44 | 169.28 | 296.01 | 175.5 | 42.5 | 46 |
| 4th week | 20.44 | 127.98 | 156.92 | 98.48 | 26.17 | 31.15 |
| 3rd month | 20.44 | 86.08 | 144.17 | 93.22 | 17.46 | 19.96 |
| 6th month | 4.69 | 42.66 | 84.91 | 34.8 | 11.88 | 8.88 |
| Chi-square | 23.71** | 127.8** | 217.12** | 156.29** | 34.22** | 44.93** |
| OSDI Score | Mean rank | |||||
| 1st week | 27.63 | 182.19 | 296.51 | 175.5 | 42.5 | 46 |
| 4th week | 21.38 | 129.92 | 159.95 | 83.62 | 30.42 | 20.69 |
| 3rd month | 8.5 | 57.65 | 133.73 | 96.39 | 8.5 | 7 |
| 6th month | 8.5 | 56.24 | 91.82 | 46.49 | 16.58 | 32.31 |
| Chi-square | 27.67** | 173.38** | 209.42** | 133.91** | 43.51** | 48.7** |
A significant improvement in TOSS and OSDI scores during the follow-up period across all the age groups was observed [Table 5]. The results indicate the effectiveness of olopatadine 0.1% treatment in reducing the symptoms and discomforts of VKC across all age groups during the follow-up period.
Discussion
Clinical trials have indicated efficacy and tolerability of 0.1% and 0.2% olopatadine against allergic conjunctivitis,[25] while certain studies narrowed their research effort to evaluate the efficacy of anti-histamine and mast cell stabilizing action of olopatadine to alleviate the symptoms of VKC. Olopatadine alone has been effective to resolve the signs and symptoms of VKC.[26] In the present study, the extent of relief in the symptoms of VKC following olopatadine 0.1% treatment was assessed by measuring TOSS and OSDI scores in both male and female patients across a broad age group.
In the present study, 221 patients including 136 males and 85 females, in the age range of 18–70 years, completed the study. As indicated in earlier reports, the male preponderance for VKC was noticed in this study. The male-to-female ratio of 1.6:1 was in agreement with other studies, whereas male-to-female ratio of 4:1[27] and 2.1:1[28] was reported. The present study had a dropout rate of 5.6% (n = 13). About 11 patients switched to steroid therapy and the remaining two dropped out of the study due to adverse side effects. In general, the application of olopatadine (0.1%) was found to be safe as indicated by minimal and very few incidences of adverse effects including headache, intraocular pressure, and burning. Ayyappanavar et al.[23] mainly reported dizziness followed by headache burning sensation, redness, and taste impairment as the adverse effect of olopatadine 0.2%, while Sruthi et al.[16] reported headache and sinusitis after using olopatadine 0.1%. In addition, it cannot be ignored that a history of any atopic diseases like sinusitis or allergic rhinitis can increase the severity of VKC, and thus, an additional or strong alternative therapy involving steroids may be used for the faster relief of VKC symptoms.
Subjective symptoms like itching were predominant followed by redness and tearing among the recruited VKC patients. Similar findings wherein itching was the most common complaint followed by tearing, redness, and swelling were reported by other researchers.[23] In the present study, based on the TOSS score, olopatadine 0.1% was effective in reducing the subjective symptoms of itching, redness, and tearing following 4th week of treatment indicating the faster onset of action. Further, there was a gradual and significant decrease in the subjective symptoms at 3rd and 6th months. The present finding was in concordance with previous findings. Çorum et al.[26] found that olopatadine 0.1% treatment for two months reduced both subjective and objective symptoms of VKC, while Malahat et al.[27] found reduced symptoms of itching and tearing within a follow-up to the 12th week (3rd month) after olopatadine 0.1% intervention. Yet in another study, olopatadine 0.1% showed significant improvement in itching, ocular discomfort, watering, and hyperemia within 8 weeks of follow-up.[16] Similar to our study with a follow-up period of 6 months, a long-term therapy involving treatment with olopatadine 0.1% up to the 18th month was found to be effective in reducing the subjective symptoms of itching, foreign body sensation, tearing, and mucus discharge.[28] Further in one such comparative study, olopatadine showed higher efficacy in reducing itching and lacrimation against individual drugs like antihistamine (azelastine) and mast cell stabilizer (cromolyn sodium), thereby showing the superiority of dual action of olopatadine in faster relief of VKC symptoms.[29] Likewise, in agreement with our data in the relief of symptoms of VKC, the comparative study of olopatadine with another dual-action agent, namely, ketotifen[30] and epinastine[31] showed the superiority of olopatadine in reducing multiple symptoms like itching, watering, photophobia, foreign body sensation, and ropy discharge at 4th week and 6th week, respectively. Thus, overall, the findings of the present study support the efficacy of antihistamine and mast-cell stabilizing action to reduce the symptoms of VKC. Based on the OSDI score, olopatadine 0.1% was found to be moderately effective in reducing sensitivity to light, grittiness, and blurriness in the weeks following treatment. In addition, relief in visual-related functions like reading, driving, watching TV, and working with computers was also found. The efficacy of olopatadine 0.1% in relieving discomforts due to environmental triggers was also noted during the follow-up period from 1st week to 3rd month. As reported earlier, olopatadine 0.1% was effective in reducing foreign body sensation and ocular discomfort.[27] In a study with a follow-up period of the second week, third week, and 5th week, OSDI improved by 26%;[24] however, improvement in visual acuity was not observed which supports our data on improvement in OSDI score after 0.1% olopatadine treatment. Furthermore, based on TOSS and OSDI scores, olopatadine was found to be effective in relieving symptoms and discomfort in both males and females, and patients across different age groups above 18 years and up to 70 years.
Strength and limitations of the study
The efficacy of olopatadine 0.1% was tested using both TOSS and OSDI scores. The TOSS score evaluated the relief of symptoms while the OSDI score evaluated the relief in discomforts due to VKC following olopatadine 0.1% treatment. Yet, the present study has its own limitations. A single-center study from one geographical location, mainly, Bengaluru city was observed. In the present study, anti-inflammatory action of olopatadine against any particular allergen particles was not tested. However, Berdy et al.[32] reported on the efficacy of 0.1% olopatadine against SAC caused by allergens of different origins like ragweed, grass, and tree pollen which further supported the use of olopatadine to alleviate the symptoms of VKC among the population of Bengaluru city where there is a high rise of pollen during the seasons. The study lacked a control group, compared with higher strength of olopatadine concentrations (0.2% and 0.7%) and with any other dual-action agents. The relief of objective symptoms like papillary hypertrophy, hyperemia, change in absolute eosinophil count (AEC), etc., was not performed. Future studies can be performed on a larger sample population from multiple clinical centers and also an attempt can be made to perform experiments using different topical eye drugs to overcome the limitations of the present study and strengthen the findings of the present study.
Conclusion
To conclude, the outcome of this study supports the safety and efficacy of olopatadine, a dual-action allergic drug, in the management of symptoms of VKC in young as well as adult patients. The TOSS score showed effective control of itching, redness, and tearing during a follow-up period. Likewise, the OSDI score revealed reduced ocular discomforts like blurred vision, grittiness or sore eyes, discomfort due to environmental triggers, and discomfort in ocular-related functions like reading and driving following treatment with olopatadine 0.1%. Further, the effect of olopatadine 0.1% treatment across gender and different age groups was significant. The outcome of this study suggests a moderate effect of 0.1% olopatadine in reducing the symptoms of VKC in a 6-month follow-up period.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Acknowledgement
I thank my guide Lt Col (Dr) Santhosh Kumar, Anterior segment surgeon, Associate Professor, Department of Ophthalmology, for his teachings on Ophthalmology, constant guidance, support, and encouragement. I am thankful to Air Cmde (Dr) H S Trehan VR Surgeon Consultant, Professor and Head of the Department, Ophthalmology for his suggestions in the preparation of this dissertation. I express my gratitude to members of the teaching staff members for their knowledge and expertise. I extend my sincere gratitude to my fellow postgraduate colleagues for helping me in the preparation of this dissertation. I thank the respondents of this study and the staff and trainees for their valuable contributions. I thank my family members for providing vital support.
References
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