Abstract
Vernal keratoconjunctivitis (VKC) is a chronic, bilateral corneal and conjunctival problem which typically presents in young individuals. VKC is characterized by itching, photophobia, white mucous discharge, lacrimation, foreign body sensation, and pain due to corneal involvement of shield ulcers. Vernal keratoconjunctivitis is categorized within ocular diseases. The diagnosis is clinical, as no sure biomarkers pathognomonic of the disease have yet been identified. The VKC therapy relies on different types of drugs, from antihistamines and topical steroids to cyclosporine or tacrolimus eye drops. In extremely rare cases, there is also the need for surgical treatment for the debridement of ulcers, as well as for advanced glaucoma and cataracts, caused by excessive prolonged use of steroid eye drops. We performed a systematic review of the literature, according to PRISMA guideline recommendations. We searched the PubMed database from January 2016 to June 2023. Search terms were Vernal, Vernal keratoconjunctivitis, and VKC. We initially identified 211 articles. After the screening process, 168 studies were eligible according to our criteria and were included in the review. In this study, we performed a systematic literature review to provide a comprehensive overview of currently available diagnostic methods, management of VKC, and its treatments.
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Introduction
Vernal keratoconjunctivitis (VKC) is a chronic bilateral keratoconjunctivitis typical of children. It usually manifests in the first decade of life [1], although some cases are described also in adults [2].
Its prevalence shows extreme geographic variability (Table 1). The highest incidence is reported in African countries, with incidence decreasing in direct proportion to the distance from the equator.
VKC is characterized by itching, photophobia, white mucous discharge, lacrimation, foreign body sensation, and pain due to corneal involvement of shield ulcers. The pathognomonic signs of VKC are Trantas dots (aggregations of epithelial cells and eosinophils), cobblestone giant papillae at the upper tarsal lids, and shield ulcers [7]. Other signs described are conjunctival hyperemia, gelatinous infiltrate at the limbus, neovascularization of the cornea, and pseudogerontoxon [8]. There are three forms of VKC: tarsal, limbal, and mixed. The tarsal form is characterized by papillae in the upper tarsal lid, while the limbal form by gelatinous infiltrates in the limbus (characterized by an infiltration of lymphocytes, plasma cells, macrophages, basophils, many eosinophils, and conjunctival goblet cells [9]), Trantas dots (white nodules composed of eosinophils and epithelial debris located at the limbus [9]), and, eventually, punctate keratitis and shield ulcers [1]. In the mixed form, both the cornea and the tarsal conjunctiva are involved.
Although VKC usually resolves after puberty, it can lead to severe visual impairments if the therapy is not adequate. The patient could develop progressively visual loss (reported in 5–30% of cases), shield ulcers, cataracts, and glaucoma, caused by excessive prolonged use of steroid eye drops [1].
VKC therapy relies on different types of drugs. The mild form is usually treated with antihistamine eye drops, mast cell stabilizers, eosinophil inhibition drops (e.g., ketotifen), and short cycles of topical steroids. Moderate and severe forms usually require instead a prolonged course of steroids to control signs and symptoms of the disease, and/or an immunomodulatory therapy with cyclosporine or tacrolimus eye drops [7]. In extremely rare cases, there is also the need for surgical treatment for the debridement of ulcers, as well as for advanced glaucoma and cataracts [1].
VKC is classified among ocular allergies, representing one of the 6 subtypes of ocular allergy (along with seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), atopic keratoconjunctivitis (AKC), contact blepharoconjunctivitis (CBC), and giant papillary conjunctivitis (GPC)). However, the underlying causes of VKC remain unclear. The pathogenesis likely involves a variable combination of genetic and endocrinological pathways, as well as immune-mediated and environmental factors [1].
In this study, we performed a systematic review of the literature to provide a comprehensive overview of the currently available diagnostic methods for VKC, its management, and its treatments.
Materials and Methods
We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline recommendations [10]. We searched the PubMed database from January 2016 to June 2023. We did not restrict the research to language. Search terms were Vernal, Vernal keratoconjunctivitis, and VKC.
In this review, we included systematic and narrative reviews, clinical trials, retrospective and prospective observational studies, case series, and case reports. All the studies were subsequently divided into two categories: those discussing VKC diagnosis and those discussing VKC therapy.
We also included in this review studies describing VKC manifestations and treatment in adult patients.
Study Eligibility and Quality Assessment
We included in this review all articles that provide diagnostic or therapeutic data on VKC. At first, we screened titles and abstracts to discover eligible studies, and then, we analyzed all full texts for the final evaluation.
The inclusion criteria we used to determine if an article was appropriate were (1) VKC populations (both children and adults), (2) diagnosis of VKC made with specified diagnostic criteria, and (3) report of epidemiological, clinical, diagnostic, and/or therapeutic data.
Exclusion criteria were as follows: (1) not the relevant topic (not appropriate population or not appropriate outcome), (2) non-original studies (e.g., duplicate articles or comments), and (3) in vitro studies.
The quality of the eligible studies was evaluated using different methods according to the study design: the Amstar 2 Checklist for Systematic Reviews [11], the SANRA scale for Narrative Reviews [12], the Jadad score for Randomized Clinical Trials (RCT) [13], the Strobe Checklist for the Observational Studies [14], the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports [15], and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series [15].
From each study, we considered information regarding study design, date of publication, country of origin, setting, characteristics of the population sample, objective of the study, and outcome measure.
Results
The selection process is shown in Fig. 1.
We initially identified 211 articles. Twenty studies were excluded from the title, 11 studies were excluded after reading the abstracts, and 15 studies were excluded after the full-text analyses. Nineteen studies were excluded for an inappropriate population (only AKC, SAC, or PAC patients), 16 studies for an inappropriate outcome, 6 studies for having been conducted only in vitro, 3 studies for providing non-useful data (studies still in progress or future study protocols not yet implemented), and 2 studies for providing overlapping data using the same study population as a previously included study.
After the screening process, 168 studies were eligible according to our criteria and were included in the review.
Among the 168 studies finally considered, 65 concerned VKC diagnosis, 88 studies described VKC therapies, and 15 studies discussed both diagnosis and therapy. The flow chart of the final studies considered for diagnosis and treatment is represented in Figs. 2 and 3. Two of the studies included in the treatment were considered both as a narrative review and as a case series [16, 17]. Three articles were included after hand research [18,19,20].
Characteristics of the included studies are reported in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.
Quality Assessment
All the studies considered in the following review were analyzed to evaluate their clinical significance according to appropriate scales. The quality of the eligible studies was evaluated using different methods according to the study design: the Amstar 2 Checklist for Systematic Reviews [11], the SANRA scale for Narrative Reviews [12], the Jadad score for Randomized Clinical Trials (RCT) [13], the Strobe Checklist for the Observational Studies [14], the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports [15], and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series [15]. From each study, we considered information regarding study design, date of publication, country of origin, setting, characteristics of the population sample, objective of the study, and outcome measure.
None of the systematic reviews fulfils all the characteristics required. Meta-analysis was performed only in Rasmussen et al. [22, 100] and Roumeau et al.’s study [99]. Regarding Leonardi et al.’s therapeutic review [21], this study performed excellent systematic research in the literature using multiple databases and selected all the articles with two separate reviewers. However, the included studies were not described in detail, and a complete list of the excluded studies was not presented. The authors did not use a satisfactory technique for assessing the risk of bias. As regards Leonardi et al.’s [20] therapeutic review, also this study performed excellent systematic research in the literature, although there was not a study selection and extraction in duplicate. There was also a lack of assessing the risk of bias and in providing a list of the excluded studies. The systematic review of Singhal et al. [98] performed good systematic research in the literature, but the research was not carried out by separate reviewers. Like Leonardi et al. [20], this review did not provide a complete list of the excluded studies and did not use a technique for assessing the risk of bias. However, all the included studies were described indicating populations, interventions, comparators, outcomes, and research designs.
Roumeau et al. [99] and Rasmussen et al. [22, 100] conducted a detailed meta-analysis of the literature. One author conducted all literature searches and collated the abstracts. Two authors separately reviewed the abstracts and, based on the selection criteria, decided on the suitability of the articles for inclusion. The risk of bias is described in detail. The two systematic reviews of Rasmussen et al. [22, 100] performed an excellent meta-analysis of the literature and described in detail the risk of bias. However, both Roumeau et al. [99] and Rasmussen et al. [22, 100] do not provide a list of the excluded studies.
Narrative reviews were evaluated through The SANRA scale [12]. None of the studies fulfils all the criteria. Only about half of the studies reported information on how the literature search was conducted. The aim of the study was not clearly expressed in six of the narrative reviews. Four studies were found to lack data description. The best performance was attained by Dahlmann-Noor et al. [109] and Doan et al. [110] (11/12), followed by Mehta et al. [36] and Ghauri et al. [111] (10/12). Except for Singh et al. [33], they all performed excellent literature research, detailing search terms and inclusion criteria. In all these works, key statements are supported by adequate references. Stock et al. [17] performed the best data presentation. On the other hand, the worst performance was of Takamura et al. [24] and Kraus [18] (1/12 and 2/12, respectively). Both articles lack a justification of the article’s importance, no concrete aims or questions were expressed, the search strategy was not presented, and data were presented inadequately. In Kraus’s work [18], appropriate evidence was introduced selectively, while in Takamura et al. [24] the article’s point was not based on appropriate arguments.
Randomized clinical trials were evaluated using the Jadad scale [13]. All of them obtained a minimum of 3/5 points.
Leonardi et al. [177], Bremond-Gignac et al. [178], and Gayger Müller et al. [177] fulfil all the checklist criteria. In the trial conducted by Zanjani et al. [176], the randomization model was not described in detail. The study of Chen et al. [180] did not mention how the blinding was performed.
Observational studies were analyzed using the Strobe Checklist [14]. The only study that reached the maximum score was that of Zhang et al. [62]. All the retrospective and observational diagnosis studies included in their works an appropriate abstract, an introduction with the literature underground, the rationale, and the design of their studies. However, in five cases, the context of the study was not described in detail and in three cases were not reported all the relevant dates (recruitment, exposition, follow-up), while in two cases were not cited the setting and hospital in which the study was conducted. All the studies described the inclusion criteria and how the patients were included, but only six of them described how they arrived at the final sample size. Only one study described how the authors managed the confounding factors and the risk of bias (Horinaka et al. [52]). Only seven studies described how they managed the quantitative variables in the analysis. One study (Gupta et al. [79]) did not include in its methods an accurate statistical analysis description. In the discussion section, all the studies described their results, an interpretation of them based on the available literature and a generalization of the results they achieved. However, eighteen studies did not report the limits of their works. Also, all the retrospective and observational therapy studies included in our research had an appropriate abstract (except for González-Medina et al. [136]), an introduction with also the rationale of their works, and a description of how the study was managed. Six articles did not report all the relevant dates, and in one case, the setting was not described. One study (González-Medina et al. [136]) did not report the inclusion criteria for patients’ recruitment. Most of the studies did not explain how they arrived at the final sample size. Only three authors considered the risk of bias in their analysis (Liendo et al. [119], Müller et al. [140], and Feizi et al. [146]). In ten cases, the statistical methods used in their works were not described in detail. In five studies, there was a lack in the demographic description of the patients enrolled. One study (González-Medina et al. [136]) did not discuss the results achieved. Fifteen studies did not report the limits of their works. In one study (Samyukta et al. [123]), the funding sources were not reported.
Case reports and case series were analyzed through the Joanna Briggs Institute (JBI) Critical Appraisal Checklist [15].
None of the case reports completely fulfilled the checklist criteria. In fact, in all the articles, we found missing information about the patient (in particular, ethnicity and anamnestic history). In six articles, it was not reported if the patient developed any adverse effects from the drugs used. In four works, information about how VKC signs were evaluated was missing.
Similarly, none of the analyzed case series completely fulfilled the checklist criteria, scoring 9 out of 10 on the JBI Critical Appraisal Checklist for Case Series [15]. Two studies (Maharana et al. [149], Patil et al. [162]) described inclusion criteria in detail. Only one study (Maharana et al. [149]) performed a consecutive inclusion of the participant, although not all the consecutive patients were included in the study, and performed a statistical analysis of the results that emerged.
In all the cases series, except Stock et al. [17], we found missing information about the patients (particularly race). In two cases, VKC signs and symptoms were not measured in a standard, reliable way (Heffler et al. [158], Callet et al. [160]). In one case (Heffler et al. [158]), it was not described how VKC diagnosis was performed and there was missing information about the patients enrolled.
Clinical Manifestations of VKC
The children affected by VKC come to the ophthalmologist and pediatrician’s attention complaining of intense itching and conjunctival hyperemia. They usually show intense photophobia, white mucous discharge (particularly in the morning), and foreign body sensation. In most severe cases, there is also a burning sensation or ocular pain, suggestive of corneal involvement [1].
None of the symptoms complained by the patients (itching, photophobia, foreign body sensation) is pathognomonic of VKC, but in other ocular allergies, like seasonal allergic conjunctivitis or perennial allergic conjunctivitis, these symptoms are usually milder than in VKC.
VKC patients typically present conjunctival hyperemia (Table 15, Fig. 4), papillae at the upper tarsal lid (Fig. 5), limbal inflammation, and Trantas dots (Figs. 4 and 6) [1]. Other findings are corneal neovascularization and the formation of the so-called “pseudogerontoxon” [8]. If not adequately treated, the disease could evolve into corneal damage, like superficial punctate keratitis and shield ulcers, a pathognomonic sign of VKC [7].
A possible feared complication of VKC, especially in developing countries, is steroid-induced glaucoma. Long-term therapy with steroid eye drops or systemic steroidal drugs may lead, particularly in “steroid-responder” patients, to a progressive increase in intraocular pressure (IOP) and glaucoma [1]. An Indian study by Senthil et al. [82] described a prevalence of steroid-induced glaucoma in VKC patients of 2.24%. In these subjects, IOP was medically controlled in 66% of cases, while 34% required surgical treatment. Gupta et al. [79] observed that among the 1259 patients followed in their clinic for active glaucoma, 4% had been prescribed topical steroids for VKC. In these subjects, IOP was medically controlled in 55% of cases, and 45% required filtering surgery.
Another dramatic complication is the development of keratoconus. Ahmed et al. [50] reported keratoconus in 34% of cases of VKC. According to Kavitha et al. [53], all children affected by VKC should be screened for keratoconus, since they have significantly higher posterior corneal elevation than controls. Furthermore, Yılmaz et al. [61] found an increased incidence of posterior corneal astigmatism in VKC cases compared to age- and gender-matched controls.
VKC Diagnosis
Ophthalmological Evaluation
At the slit lamp exam, the typical findings of VKC are conjunctival hyperemia, papillae at the upper tarsal lids, and gelatinous infiltration of the limbus and Trantas dots. Papillae are extremely variable in dimensions: in fact, they could range from a few millimeters to giant papillae (> 7–8 mm), giving the tarsal conjunctiva a “cobblestone” aspect [1]. In more severe cases, if the cornea is involved in the inflammatory process, the examination with fluorescein stain could also highlight superficial punctate keratitis and shield ulcers [7].
To assess corneal damage, various scales have been proposed in the last year, such as the Oxford grading system [181] and the modified Oxford scale [181], currently used in patients with dry eye. The last scale was proposed by Leonardi et al. in 2020 and was called “penalties-adjusted corneal staining score” [21]. In this scale, Leonardi et al. proposed to use the change in corneal staining with fluorescein (CFS) from baseline in the modified Oxford scale, with the possibility of penalties in case of rescue therapy or corneal ulcer. In patients whose corneal damage was, according to the Oxford scale, at its maximum level (grade 5), any worsening of corneal damage could not be reported. To capture that further aggravation during follow-up, Leonardi et al. proposed to add a penalty to the score, as follows: + 1 point penalty for rescue medication and + 1 point penalty for corneal ulceration. The “penalty-adjusted corneal staining score” appeared to be a reliable method for assessing corneal changes over time and for evaluating the efficacy of new drugs.
Other findings of VKC are also corneal neovascularization and the so-called “pseudogerontoxon,” characteristic lipid deposition in the limbus [8].
Based on the clinical finding at the ophthalmological exam, VKC can be classified into three forms [7]:
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Tarsal VKC: characterized by the presence of papillae at the upper tarsal lid
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Limbal VKC: characterized by the presence of gelatinous infiltrate at the limbus and Trantas dots
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Mixed VKC: characterized both by the presence of papillae and limbal involvement
Recently, Soleimani et al. [91] observed in VKC older patients a particular clinical finding: the “Splendore-Hoeppli phenomenon.” This phenomenon consists of granulomatous inflammation of the cornea with deposition of eosinophilic material in the conjunctiva. It manifests as multiple yellow lobulated subconjunctival masses with tortuous vessels, usually located at the upper portion of the bulbar conjunctiva, beside the upper eyelid. According to the author, the Splendore-Hoeppli phenomenon seems to be a later manifestation of VKC, occurring in patients affected by vernal keratoconjunctivitis for some decades.
Thong [25] observed in their Asian VKC populations also the presence of pseudomembrane at the upper eyelids and lower eyelid creasing, the so-called Dennie’s lines. The Dennie-Morgan line is a fold in the skin below the lower eyelid. In some cases, it can simply be a genetic trait, but various studies linked them with allergy sensitization.
Gokhale [23] in his review observed how VKC severity could be defined as mild, moderate-intermittent, moderate-chronic, severe, and blinding based on symptoms and clinical findings. Patients with mild disease complain of itching and conjunctival hyperemia. On examination, they present fine velvety papillae on the upper tarsal lid, but no corneal involvement. The clinical observation of patients with moderate VKC reveals the presence of superficial punctate keratitis, gelatinous infiltrate of the limbus (< 50% of the limbus), and Trantas dots.
In severe disease, there is also evidence of active giant papillae, keratitis, macroerosions of the cornea and severe limbal infiltrate (> 50% of the limbus). Patients with blinding VKC show extremely active large cobblestones, active shield ulcers, severe annular limbal inflammation, limbal stem cell deficiency, and scarring.
Biomarkers
In the last decade, many studies tried to determine if some biomarkers could help VKC diagnosis, especially when the clinical findings were unclear (Tables 16 and 17).
IgE and eosinophil tear levels were elevated in VKC patients if compared to healthy controls, but high levels were found also in atopic keratoconjunctivitis (AKC) and seasonal (SAC) and perennial conjunctivitis (PAC) [29].
A marker that appeared to be more specific for VKC diagnosis was histamine tear levels. VKC patients revealed twice the histamine levels in tear compared to those in healthy controls. However, histamine tear levels might increase also in other ocular conditions, like Haemophilus influenzae’s conjunctivitis [29].
In other studies, eotaxin-1 and eotaxin-2 tear levels were found to increase in VKC patients, but also in AKC subjects. Furthermore, the levels seemed to correlate with disease severity and corneal involvement [29].
In 2020, Shoji [29] demonstrated that tear levels of CCL17/TARC, CCL24/eotaxin-2, and IL-16 in VKC and AKC patients were significantly higher than in patients with other allergic conjunctivitis, like SAC and PAC (p < 0.01). Thus, the simultaneous evaluation of these markers could help in making the differential diagnosis between AKC/VKC and SAC/PAC. Eotaxin-1 and eotaxin-2 determination had a high sensibility in VKC diagnosis, but low specificity.
Eosinophils cationic protein (ECP), a marker of eosinophil activation, was increased in tears of VKC and AKC patients and correlated with disease severity. Shoji [29] in his recent review described how in patients with VKC tear ECP and eotaxin-2 levels correlated with disease severity (p < 0.01).
Another study observed how alpha-1-antitrypsin levels in tears were lower in VKC rather than in the healthy control group [182]. Other potential biomarkers of VKC could be osteopontin and periostin concentrations in tears. In 2016, Fujishima et al. [39] collected tears from patients with ocular allergic disease to determine the level of periostin in the different forms of allergic conjunctivitis. Their work found significantly high periostin levels in a subject affected by ocular allergies than in allergic patients without conjunctivitis (p < 0.05), with maximal levels in AKC and VKC (p < 0.001).
However, there is a need for further studies to assess if alpha-1-antitrypsin, osteopontin, and periostin dosage may be useful in VKC diagnosis.
Nebbioso et al. [45] evaluated the concentration of the vascular endothelial growth factor (VEGF) in tear and blood samples from patients with VKC. In their study, they found that VKC patients had higher VEGF levels in tears than healthy controls (p < 0.05); however, that difference was not confirmed in the blood (p = 0.29).
Another study by Nebbioso et al. [46] evaluated the characteristic of lacrimal film in VKC patients through the tear ferning test (TFT) method. They observed in those subjects a pathological alteration of the lacrimal mucous layer (p < 0.001) that returned to baseline after a period of treatment with cyclosporine eye drops. This work underlined the possible usefulness of the tear ferning test in the objective evaluation of tear film and as a marker of disease activity and therapeutic efficacy in patients with VKC. Indeed, some factors may change TFT, which are not fully understood.
Inada et al. [41] used impression cytology to determine the levels of H1 and H4 receptors (H1R and H4R) on the ocular surface of VKC and AKC patients. Levels of H1R and H4R were higher in patients in an active stage of disease rather than in the stable group (p < 0.05), without significant differences between the AKC and VKC groups. The determination of H1R and H4R correlated with disease severity. However, it did not allow for making a differential diagnosis between AKC and VKC.
Using impression cytology, Leonardi et al. [48] observed that in VKC conjunctiva, there was an overexpression of several chemokines (CCL24, CCL18, CCL22, CXCL1), proinflammatory cytokines (IL-1β, IL-6, IL-8, TGFβ-1), and genes related to Th2- and Th17-signaling families. Toll-like receptors TLR4 and TLR8, Dectin-1/CLEC7A, mincle/CLEC4E, MCR1, NOD2, and NLRP3 and several of their pathway-related genes were significantly overexpressed in VKC. According to the author, the increased expression of several chemotactic factors and co-stimulatory signals required for T cell activation confirms that VKC is mostly cell-mediated with local eosinophilia. Furthermore, the multiple expression of pattern recognition receptors (PRRs) suggests a role of host–pathogen interaction in VKC development.
Costa Andrade et al. [44] used conjunctival impression cytology to evaluate the expression of galectin-3 (Gal-3) in VKC patients and healthy controls. Gal-3 is a β-galactoside binding protein involved in the pathogenesis of ocular allergy, regulating the eosinophil migration, mast cell activation, and production of local cytokines/chemokines. The study showed a significant increase in Gal-3 expression in the epithelium of VKC patients (p < 0.001). Furthermore, Gal-3 expression was significantly reduced in VKC patients treated with steroidal eye drops or tacrolimus eye drops (p < 0.001). According to the authors, Gal-3 could serve both as a biomarker of VKC and as a relevant therapeutic target to control the disease.
Ocular Cytology
In the previous paragraph, some results obtained with impression cytology for the study of markers in VKC have been described. Another way of performing ocular cytology is through the quantification of cells and markers in tears via conjunctival brushing or conjunctival biopsy. Ocular cytology, described for the first time in 1977 by Egbert et al. [183], is applied in the study of a discrete number of ocular diseases, such as dry eye, allergic conjunctivitis, and inflammatory systemic diseases with uveitis (Table 18).
For example, the finding of at least one eosinophil or mast cell (always absent in the conjunctiva of healthy subjects) is an optimal marker of allergic conjunctival disease [184].
A recent study by Bruschi et al. [47] performed with conjunctival brushing showed that untreated conjunctiva of VKC patients was characterized by an elevated number of eosinophils, neutrophils, mast cells, and epithelial cells. These cell counts progressively reduced when the subjects were treated with steroidal or immunosuppressive eye drops.
Nebbioso et al. [103] using impression cytology demonstrated that VKC patients had an increased number of goblet cells in the conjunctiva compared to healthy controls, although that difference was not statistically significant. After a cycle of therapy with cyclosporine eye drops, the density of goblet cells progressively reduced (p = 0.044).
Conjunctival Biopsy
In conjunctival biopsies of VKC patients, elevated numbers of mast cells, lymphocytes B and T, eosinophils, and fibroblasts are described [29] (Table 19).
Leonardi et al. [48] used conjunctival biopsy specimens to assess Heat Shock Proteins (Hsp) chaperone levels in the conjunctiva of VKC patients. These proteins are involved in intercellular communication both in physiological and pathological conditions. This study demonstrated that some Hsp subtypes (specifically Hsp27, Hsp40, Hsp70, and Hsp90) were higher in patient’s conjunctiva than in healthy controls. According to the authors, the understanding of the chaperones’ roles in VKC conjunctiva could open new therapeutic scenarios leading, for example, to the use of specific topical inducers or inhibitors of Hsps for preventing severe eye complications.
However, given the invasiveness of the sampling, conjunctival biopsies are exceptionally used in VKC diagnosis.
Vitamin D Levels in VKC Patients
In the last years, there was an increased interest in the evaluation of vitamin D levels in VKC patients.
Vitamin D is a prohormone substance regulating a wide range of functions in the human body, including the mineral level of bones and the immune system response. The main source of vitamin D is sunlight exposure. Its deficiency can lead to rickets, increased risk of airway infections, and autoimmune diseases. Serum levels of 25-hydroxyvitamin D (25OHD) below 20 ng/mL, reported in up to 50% of children, indicate a deficiency, while serum levels < 30 mg/dL, reported in 80% of pediatric patients, indicate an insufficient concentration of vitamin D in the blood [185]. Children affected by VKC, because of their remarkable photophobia and the worsening of their symptoms in summer with the solar exposition, tend to avoid sunlight and outdoor activities during spring and summer, thereby possibly increasing the risk of vitamin D deficiency.
Ghiglioni et al. [81] observed that in spring, 81% of VKC children had insufficient 25OHD serum levels (< 30 ng/mL) and 33% had an overt deficiency (25OHD < 20 ng/mL). When the subject was treated with cyclosporine or tacrolimus eye drops during the summer, with an improvement in VKC signs and symptoms and consequent increase in sunlight exposure, there was an increase in vitamin D serum levels. In fact, at the end of summer, 39% of children had still insufficient vitamin D levels, but only 4% had 25OHD < 20 ng/mL.
Zicari et al. [43] and Sorkhabi et al. [59] observed that children affected by VKC had lower levels of vitamin D compared to healthy controls. According to Zicari et al. [43], after 6 months of cyclosporine therapy, these levels increased (p = 0.004) but were lower than in healthy controls (p < 0.05).
Vitamin D levels appear to be a marker of disease control in VKC patients. A treated subject could receive levels of sun exposure similar to other children, allowing for an improvement in vitamin D serum levels. Instead, when the disease is severe and not adequately treated, vitamin D levels remain low.
Therapy
At the basis of VKC therapy, there are behavioral rules. Among them, the most useful are [20, 31]
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avoiding contact with aeroallergens, like flowers and plants
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avoiding prolonged sunlight exposure
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wearing solar glasses
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applying cold wraps on the eyes
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using artificial tears that could remove or almost dilute allergens present on the ocular surface
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washing face, hands, and hair frequently, especially before going to sleep
However, behavioral rules and artificial tears alone are not able to control VKC symptoms, except in milder forms.
Drugs that proved their efficacy in the treatment of VKC are topical antihistamines, anti-inflammatory eye drops, steroidal eye drops, cyclosporine and tacrolimus eye drops, and, recently, omalizumab [20].
Antihistamines and Topical Non-Steroidal Anti-Inflammatory Drugs
Among antihistamines and anti-inflammatory eye drops, the most used molecules are shown in Table 20.
All these drugs proved their efficacy in the mildest form of VKC. However, only in a few cases, they are able alone to control the disease. Antihistaminic and anti-inflammatory therapy could help in the treatment of VKC, but it frequently requires concomitant therapy with steroidal eye drops or immunomodulatory molecules [20].
Ketorolac and diclofenac eye drops, interfering with prostaglandin E2 and I2 synthesis, reduce itching and conjunctival hyperemia but have no effect on papillae dimensions or corneal lesion repair [186].
Steroid Therapy
Steroidal drugs are effective in controlling inflammation through various mechanisms:
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reducing leucocyte numbers and activity
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blocking IL-2 production and the consequent clonal expansion of lymphocyte T helper
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blocking fibroblast proliferation
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interfering with cyclooxygenase 2 (COX2) activity and blocking prostanoid synthesis
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interfering with the synthesis of histamine, IgG, and other phlogistic factors
Steroidal eye drops are the gold standard therapy for VKC, but, because of their severe adverse effects (increase in IOP, corneal infections, cataract, and glaucoma), the goal is to control the disease using the lowest dose possible of steroid [20].
In the treatment of VKC, the steroid can be administered in three different ways: eye drops (the commonest way of administration), topical injection in the conjunctiva, and oral medications (major efficacy, but higher adverse effects).
Steroid Eye Drops
Steroidal eye drop administration is one of the most useful therapies for VKC. They are always effective. If a patient does not show a clinical response within a few days, he might be affected by an ocular bacterial or viral infection complicating VKC, and he should be promptly referred to an ophthalmologist.
The newest steroidal drug loteprednol [187] appears to be safer than previous generation drugs.
Jongvanitpak et al. observed in his retrospective observational study on Thai children that 68.8% of VKC patients use topical steroids to control the disease [83].
In everyday practice, local steroids are used with significantly different therapeutic schemes varying from a gradual tapering scheme over 2–3 weeks, to short and repeatable 3–5-day cycles, to low-dose prolonged daily administrations after a 1–3-week tapering cycle [20, 31]. The most appropriate choice seems to be the 3–5-day scheme [20, 31].
Tarsal Injection of Steroid
In a severe form of VKC, the clinician could consider supratarsal injection of corticosteroid to control VKC signs and symptoms. Dexamethasone sodium succinate, triamcinolone acetonide, and hydrocortisone sodium succinate could be used [20].
In 2017, Costa et al. [118] performed a supratarsal injection of triamcinolone acetonide in 17 children with severe VKC, observing a rapid improvement in VKC signs and symptoms without any adverse reaction.
Similarly, McSwiney et al. [142] performed supratarsal injections of triamcinolone acetonide in VKC patients, with an improvement in visual acuity (p < 0.0001) and in VKC symptoms in 100% of cases.
Steroidal Systemic Therapy
Oral administration of steroids, although very effective in controlling the disease, is rarely implemented as VKC treatment, because of the high frequency and severity of adverse effects reported.
Because of the long duration of VKC symptoms during the year (5–6 months at least), the use of steroid therapy alone is not feasible as chronic therapy. A 6-month steroidal treatment can cause bacterial superinfection, herpetic keratitis, ocular hypertension, glaucoma, and cataract, as described in 3.5% of treated children [1]. In light of these adverse effects, there has been the development over the past few decades of ophthalmic preparations based on cyclosporine and, more recently, tacrolimus eye drops.
Immunomodulatory Eye Drops
Cyclosporine has numerous effects on the organism [188]:
-
blocks lymphocyte T activation
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stops the production of IL-2 and its receptors
-
blocks histamine’s release from basophils and mast cells
-
reduces the expression of Human Leukocyte Antigen-II (HLA-II) on the cells
Furthermore, cyclosporine [188]
-
interferes with hypersensitivity reactions and mast cell degranulation
-
reduces ECP and eosinophil levels in tears
-
rapidly controls local phlogosis and acts as a steroid-sparing agent
Differently from a corticosteroid, cyclosporine therapy does not cause cataracts or glaucoma. Its potential side effects, when administered orally, are mainly on the liver and kidney.
However, various studies demonstrated that cyclosporine administered as eye drops is not absorbed into the circulation and consequently does not cause systemic side effects [30, 31]. The only adverse reaction described in the literature is burning at the drops’ instillation [189]. This is due to the pharmaceutical formulation of the compound, in which ethylic acid is also present. However, the burning is always transient, lasting only a few minutes [189].
Being an immunosuppressive agent, it could cause bacterial or viral superinfections, rarely reported in the literature [30].
In the last three decades, cyclosporine has been tested in various formulations (diluted in castor oil or artificial tears) and in various concentrations (2%, 1%, 0.5%, 0.25%) (Table 21). Up to now, it is still not known the minimal effective dose for VKC ocular therapy.
In 2017, Thong [25] reviewed cyclosporine 0.05%, 0.1%, and 1% eye drop administration in a large cohort of VKC children, observing the efficacy of these preparations in reducing VKC signs and symptoms. Cyclosporine 0.05% was tested also in 2016 by Yücel and colleagues [115] on 20 children and adolescents with VKC, obtaining the same results. No adverse effects were reported.
Nebbioso et al. [103] focused their attention on cyclosporine 0.1% ophthalmic solution (Papilock mini® and Verkazia®). They found in the literature a cohort of 3198 patients in which the treatment with cyclosporine 0.1% eye drops administered 2–4 times a day for 4–6 months was effective in controlling VKC severe manifestations.
In 2019, Leonardi and colleagues [177] conducted a randomized clinical trial (the “Vektis Study”) that aimed to assess the efficacy and safety of cyclosporine 0.1% cationic emulsion treatment compared to a placebo in severe VKC. Patients were randomized into three groups: one group received cyclosporine eye drops 4 times a day (high-dose group), another group cyclosporine eye drops 2 times a day (low-dose group), and the third group a placebo. Patients treated with cyclosporine 4 times/day or 2 times/day showed a higher improvement in VKC signs and symptoms compared to the placebo group (p = 0.007 and 0.010) and had lower usage of rescue steroid eye drops (p = 0.010 and 0.055, respectively). Most treatment-emergent adverse events were mild or moderate in severity and consisted especially of local burning during the instillation. This finding was described also by Bremond-Gignac et al. [178], who confirmed Leonardi et al.’s conclusions also in the 8-month follow-up. The commonest adverse effects were instillation pain and pruritus.
Westland et al. in 2018 [161] described an intense regimen of 0.05% cyclosporine for vernal shield ulcers. In their case series, all three children treated with cyclosporine eight times a day showed quick resolution of the shield ulcers and complete re-epithelialization.
In 2020, Modugno et al. [126] observed that a course of cyclosporine therapy, acting at the level of epithelium, sub-basal nerve plexus, and stroma, performed progressive corneal microstructural changes, helping to restore the normal corneal microstructure (p < 0.001).
Borrego-Sanz et al. [167] described the case of a 10-year-old boy to whom cyclosporine was administered orally for months. In that report, daily oral cyclosporine therapy allowed the re-epithelialization of vernal shield ulcer and permitted the tapering of steroid eye drops.
Although very effective in controlling VKC signs and symptoms, 8–15% of children do not show the expected improvement with therapy. In these patients, tacrolimus eye drops may be a useful alternative [1].
Tacrolimus is an alternative therapy to cyclosporine in controlling signs and symptoms of the disease (Table 22).
It acts on ocular inflammation [190]:
-
blocking IL-2 production
-
stopping the secretions of IL-3 and IL-4
-
reducing mast cell degranulation
In 2017, Thong [25] reviewed the use of tacrolimus ophthalmic solution in literature in a large cohort of patients, observing its efficacy in reducing VKC signs and symptoms at various concentrations (0.005%, 0.03%, 0.1%).
Erdinest and colleagues [102] found in the literature 1121 patients treated with tacrolimus ophthalmic solutions (with a concentration variable from 0.003 to 0.1%): the larger number of patients showed clinical improvement after the treatment.
In 2016, Al-Amri et al. [112] tried a 6-week tacrolimus 0.1% therapy on 20 adult patients with VKC, concluding that the treatment allowed a significant improvement in VKC symptoms (p < 0.001) and signs (p < 0.001).
The same year, Barot and colleagues [113] also experimented with the administration of tacrolimus 0.1% ointment in VKC. That study observed an important improvement in disease control (p < 0.0001). About 36% of patients complained of a transient burning sensation during the treatment.
In 2018, Wan et al. [120] observed a significant improvement in signs and symptoms (p < 0.001) after 1 week of tacrolimus 0.1% therapy.
Tacrolimus 0.1% concentration was analyzed also in 2019 by Liu and colleagues [141]. They administered tacrolimus to ten children, observing an important reduction in conjunctival and corneal reaction (p = 0.0003 and 0.0002) and its consequent potential as a steroid-sparing agent. In fact, in 6 out of 10 patients, tacrolimus treatment enabled the discontinuation of steroid therapy (p < 0.05).
In 2017, Al-Amri and his team [117] administered a less concentrated tacrolimus 0.003% therapy for 6 weeks to 20 adolescents affected by a severe and resistant form of VKC. In all patients, the prescribed therapy permitted a significant improvement in VKC symptoms (p < 0.001) and signs (p < 0.001), with no important side effects.
In 2019, Samyukta et al. [123] tried an 8-month treatment with a more concentrated tacrolimus ophthalmic solution (0.3%) in 30 children with VKC, observing an important decrease in VKC’s signs and symptoms (p < 0.001) and an improvement in visual acuity (p = 0.04).
In 2019, Shoji et al. [124] wanted to evaluate if the efficacy of tacrolimus ophthalmic solution was different in patients with concomitant atopic dermatitis or not. To do so, they enrolled a cohort of 1821 adolescents and young adults affected by the chronic allergic conjunctival disease (AKC or VKC) with and without atopic dermatitis. Tacrolimus therapy showed its efficacy in reducing ocular signs and symptoms in both groups (p < 0.0001). The concomitant use of topical steroids significantly increased the likelihood of remission (p < 0.0001).
A 0.03% tacrolimus ophthalmic solution was tested in 2016 by Chatterjee and Agrawal [114] with the administration of that drug in 23 adolescents with VKC. In his study, symptoms and signs were significantly reduced at 4 and 12 weeks (p < 0.0001). Furthermore, visual acuity showed an improvement after 12 weeks of treatment (p = 0.05).
The same results were observed also in 2019 when Fiorentini and Khurram [122] administered tacrolimus 0.03% ointment in 10 Arabian children with VKC. After a 4-week course of therapy, all subjects showed an improvement in their symptomatology without any adverse effects. Müller and colleagues [140] achieved similar results in the same year. In fact, in their VKC patients, topical tacrolimus 0.03% ointment achieved disease control. Furthermore, in 47.6% of patients, steroid treatment could be interrupted.
González-Medina et al. [136] tested 17 adolescents with VKC 0.03% tacrolimus eye ointment. The therapy permitted the cessation of antihistamine therapy in 8 patients (p < 0.05). The number of flare-ups per year was not reduced, but the duration and the severity of each exacerbation were reduced.
In the literature, several studies with a minimal concentration of tacrolimus are reported, such as the 0.01% tested by Shoughy et al. in Saudi Arabia [135]. In his study, 62 children with VKC have been treated with tacrolimus 0.01% ophthalmic solution, with an important improvement in VKC signs and symptoms (p < 0.001).
In 2017, Zanjani et al. [176] conducted an RCT that aimed to compare the efficacy of tacrolimus 0.005% versus interferon alpha-2b (IFN alpha-2b) eye drops in the treatment of VKC. Both patients treated with tacrolimus and patients treated with IFN alpha2b showed an improvement in VKC signs and symptoms after 3 years (p < 0.0001 for both groups), without significant statistical difference between the two groups (p > 0.05). No major ocular complications or systemic side effects related to tacrolimus and IFN alpha-2b were noted.
The authors concluded that both 0.005% tacrolimus and IFN alpha-2b might be promising and effective treatments for resistant VKC.
The same year, Gayger Müller and colleagues [175] evaluated the efficacy of tacrolimus versus sodium cromoglycate monotherapy in VKC. With their RCT, they treated eight patients with tacrolimus 0.03% eye drops and eight patients with sodium cromoglycate. Tacrolimus was more effective than sodium cromoglycate in controlling VKC signs and symptoms (p = 0.001 and 0.015).
In 2021, Maharana et al. [149] performed a combined local therapy with cyclosporine 0.1% and tacrolimus 0.03% in 11 VKC patients, observing that the combination was very helpful in improving VKC signs and symptoms (p < 0.001).
In 2022, Heikal et al. [127] demonstrated that tacrolimus 0.03% permitted a reduction in individual symptoms and signs better than cyclosporine 2% eye drops.
In 2021, the independent study of Caputo et al. [144], Hirota et al. [148], and Yazu et al. [150] demonstrated retrospectively how long-term use of topical tacrolimus is a safe option for refractory VKC.
In fact, like cyclosporine, tacrolimus is generally well tolerated. The only side effect reported is burning at the drops’ instillation. Being an immunosuppressive agent, it could also increase the risk of ocular infections.
If administered orally, it is toxic to the kidney and the neural system. It could also provoke hypertension, diabetes, infections, tumors, and gastrointestinal disorders [190]. If administered topically in the eye, the systemic absorption of tacrolimus is nearly zero; thus, systemic adverse effects have never been reported in the literature [31].
Monoclonal Antibodies
Omalizumab is an anti-IgE monoclonal antibody. It was created to treat allergic asthma, but, in recent years, its use has been extended also to the treatment of other allergic conditions, like atopic dermatitis, chronic urticaria, allergic rhinitis, allergic bronchopulmonary aspergillosis, and food allergy [191]. In the last years, omalizumab has been tested also in the treatment of recalcitrant VKC, with good results (Table 23).
The only adverse effects reported in the literature are pain at the injection site, headache, pharyngitis, upper respiratory tract symptoms, and sinusitis [191].
Doan et al. [16] performed a literature review evaluating the efficacy of omalizumab therapy in severe refractory VKC. Omalizumab, allowing the reduction of signs and symptoms, appeared to be a potent treatment for refractory forms of VKC. The strongest evidence was provided by Doan and colleagues, who administered omalizumab to four children aged 7–13 years. Three out of 4 patients responded to the treatment, but the response was incomplete.
Other studies describing the use of omalizumab in VKC patients were conducted by Heffler et al. [158] (2 patients, both showed an improvement in VKC symptoms, physical examination, and conjunctival cytologic findings), Occasi et al. [159] (4 children aged 6–11 years, all of whom responded to omalizumab therapy without any side effects), Callet et al. [160] (2 children aged 7–9 years, all of them had an improvement in VKC and asthma control), Santamaría and Sánchez [165] (1, 15-year-old patient who had improvement of VKC symptoms once omalizumab was administered; however, upon discontinuation of the drug, the symptoms relapsed), and Simpson and Lee [166] (1 adult with VKC, in which a single dose of omalizumab appeared to resolve all the signs and symptoms of VKC).
In literature, omalizumab has not been the only monoclonal antibody used in VKC, albeit the most widely studied.
In 2022, Tsui et al. [192] administered dupilumab, a human monoclonal antibody against interleukin (IL)-4 receptor alpha, to three children affected by refractory VKC (aged 7–14 years), obtaining total control of VKC signs and symptoms within 1 month of treatment. Dupilumab treatment also resulted in resolution of shield ulcer, corneal re-epithelialization, and complete resolution of giant papillae on the upper tarsal conjunctiva in all patients. However, it should be remembered that in literature treatment with dupilumab is associated with the development of dry eye and conjunctivitis as an adverse reaction [193]. The appearance of side effects in patients treated with dupilumab for atopic dermatitis, already extensively described in the literature [194, 195], has made it possible to demonstrate the efficacy of upadacitinib, a JAK2 inhibitor, in a case of atopic dermatitis severe and AKC [196]. To our knowledge, upadacitinib has not yet been tested in patients with VKC.
In 2022, Anesi et al. [197] tried the administration of lirentelimab, a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8, in a 25-year-old man with VKC, asthma, and allergic rhinitis, founding that lirentelimab was well tolerated, improved VKC symptoms and concomitant allergic symptoms, and reduced inflammatory mediators in patient tears.
Other monoclonal antibodies, such as mepolizumab, reslizumab, and benralizumab, are under investigation for their efficacy in eosinophilic asthma [106, 193] and may also be useful in other allergic diseases and VKC.
Clinical trials are needed to investigate their potential therapeutic benefits in other types of eosinophil-mediated conditions, such as VKC.
Other Drugs
The last year, a large cohort study by Xu and Cai [125] aimed to evaluate the therapeutic effects and safety of houttuynia eye drops combined with olopatadine hydrochloride in VKC patients. They observed that children treated with the association of houttuynia and olopatadine eye drops showed a rapid reduction in VKC symptoms (p < 0.05), without adverse effects.
Surgical Treatment
Surgical treatment used in the VKC is summarized in Table 24.
Stock et al. [17] reviewed surgical debridement of VKC shield ulcers in the literature. They found only four studies on VKC patients, and in all of them, the surgical debridement proved extremely effective in the treatment of shield ulcers. The procedure was followed by a rapid corneal re-epithelialization, and no adverse effects were described. They described also their experience with two children treated with surgical debridement of the ulcer, in which the surgical treatment was curative and definitive in the 7-month follow-up period.
In 2017, Abozaid [116] tried to assess the safety and efficacy of femtosecond laser-assisted Keraring implantation followed by transepithelial accelerated corneal collagen cross-linking (CXL) for the treatment of keratoconus in children with VKC. In their observational study, all the eyes treated showed an improvement in visual acuity, keratometry values, and refraction (p < 0.001). No intraoperative complications were reported.
Also, Alrobaian and colleagues [139] performed a retrospective study to determine the safety and efficacy of corneal collagen cross-linking (CXL) in patients with keratoconus and VKC. However, in the 19 patients treated, they did not observe a significant difference between the baseline and last follow-up of visual acuity (p = 0.99) and keratometry values (p = 0.093). Furthermore, 5 of 27 eyes with VKC exhibited progression of keratoconus (18.5%).
In 2019, Abozaid et al. [138] conducted a retrospective observational study of 28 adolescents with VKC to evaluate femtosecond laser-assisted intrastromal corneal ring segment (ICRS) implantation followed or accompanied by transepithelial accelerated corneal collagen cross-linking (TE-ACXL) as a treatment of keratoconus in VKC. In that study, they observed better visual acuity (p = 0.001) and corneal measure (p < 0.001) in patients treated with Keraring + CXL with respect to patients treated with CXL only.
In 2020, Iqbal et al. [179] performed a controlled trial to compare standard epithelium-off cross-linking (SCXL) versus accelerated epithelium-off cross-linking (ACXL) and transepithelial epithelium-on cross-linking (TCXL) in the treatment of keratoconus in children. One hundred thirty-six patients with keratoconus (of whom 38 had also VKC) were assigned to SCXL, ACXL, or TCXL surgical treatment. The author observed significant differences in visual acuity and refractive measure between the three groups throughout the study (p < 0.0001) in favor of SCXL followed by ACXL. SCXL protocol was superior to ACXL and TCXL, with an overall success rate of SCXL of 100% during 2 years of follow-up.
In 2018, Iyer et al. [137] published a retrospective observational study aimed to evaluate the outcomes of mucous membrane grafting (MMG) for refractory giant papillae in VKC. Six children were treated with MMG. After the surgery, reactivation of the allergic activity was noted in all the eyes, but with no recurrence of shield ulcers or diffuse punctate keratitis.
In 2019, Hopen et al. [168] reported a case of intraocular pressure (IOP) reduction after a gonioscopy-assisted transluminal trabeculectomy (GATT) in a VKC child, in which the only adverse effect was a small hyphema.
In 2016, Das et al. [163] described the case of a 22-year-old man affected by VKC who underwent amniotic membrane transplantation, followed by cataract surgery and optical prosthetics for the treatment of VKC complications, with overall good results.
In 2022, Senthil et al. [153] compared in a retrospective observational study the surgical success rate for trabeculectomy, trabeculectomy with mitomycin C, and combined trabeculectomy with cataract extraction for glaucoma’s treatment, founding it similar at 5-year follow-up. All the three surgical techniques proved to be effective, but the surgical result is inversely proportional to the age of the child, the duration of VKC, the duration of steroid therapy, and mixed type of steroid use.
In the literature, it is a common idea that VKC should be treated “step-by-step.” Most of the authors (Fauquert et al. [27], Takamura et al. [24], Gokhale et al. [23], Berger et al. [19], Sacchetti et al. [26], Esposito et al. [101], AlHarkan et al. [104], Maitra et al. [121], Kraus [18]) agreed to reserve cyclosporine and tacrolimus eye drops and surgical measures at the severest form of VKC, while mild and moderate forms should be treated with antihistamines and cycles of steroid eye drops. Also, the systematic review of Singhal et al. [98] remarked that surgical therapy (like corneal ulcer debridement or resection of giant papillae) should be performed only in severe giant papillary hypertrophy or refractory shield ulcer, while the majority of VKC patients could be managed with medication alone.
Conclusions
VKC is a disease of the anterior chamber of the eye with an unclear etiology. The diagnosis is clinical, as no safe markers of the disease and its severity have yet been identified. Similarly, no markers have been established that can be used for follow-up.
It would be desirable to draw up a score based on standardized and shared parameters of objective signs, subjective symptoms, and possible presence of complications. The score should be corrected based on the geographical reality and the season in which it is detected, to make the data collected comparable and evaluate the effectiveness of the therapy at different latitudes.
In the literature, the graduality of the therapy is described, but without clear objective parameters on which to base its modification. In some cases, the risk is beginning immunomodulatory therapy when the lesions are already too advanced.
The use of biotechnological drugs should also be studied, in the absence of an accurate study of the inflammatory cytokines present in the eye and in the absence of methods for the determination of these cytokines at the tear level that can be used in clinical routine.
Data Availability
Data available on reasonable request.
References
Kumar S (2009) Vernal keratoconjunctivitis: a major review. Acta Ophthalmol 87:133–147. https://doi.org/10.1111/j.1755-3768.2008.01347.x
Di Zazzo A, Bonini S, Fernandes M (2020) Adult vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol 20(5):501–506. https://doi.org/10.1097/ACI.0000000000000672
Alemayehu AM, Yibekal BT, Fekadu SA (2019) Prevalence of vernal keratoconjunctivitis and its associated factors among children in Gambella town, southwest Ethiopia, June 2018. PLoS One 18;14(4):e0215528. https://doi.org/10.1371/journal.pone.0215528
Marey HM, Mandour SS, El Morsy OA, Farahat HG, Shokry SM (2017) Impact of vernal keratoconjunctivitis on school children in Egypt. Semin Ophthalmol 32(5):543–549. https://doi.org/10.3109/08820538.2015.1123737
Smedt SD, Nkurikiye J, Fonteyne Y, Hogewoning A, Esbroeck MV, Bacquer DD et al (2011) Vernal keratoconjunctivitis in school children in Rwanda and its association with socio-economic status: a population-based survey. Am J Trop Med Hyg 85(4):711–717. https://doi.org/10.4269/ajtmh.2011.11-0291
Bremond-Gignac D, Donadieu J, Leonardi A, Pouliquen P, Doan S, Chiambarretta F et al (2008) Prevalence of vernal keratoconjunctivitis: a rare disease. Br J Ophthalmol 92(8):1097–1102. https://doi.org/10.1136/bjo.2007.117812
Bonini S, Sacchetti M, Mantelli F, Lambiase A (2007) Clinical grading of vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol 7(5):436–441. https://doi.org/10.1097/ACI.0b013e3282efb726
Jeng BH, Whitcher JP, Margolis TP (2004) Pseudogerontoxon Clin Exp Ophthalmol 32(4):433–434. https://doi.org/10.1111/j.1442-9071.2004.00849.x
Yanoff M, Duker JS (2019) Ophthalmology. Elsevier, Philadelphia
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 21;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J et al (2017) AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 358:j4008. https://doi.org/10.1136/bmj.j4008.358
Baethge C, Goldbeck-Wood S, Mertens S (2019) SANRA-a scale for the quality assessment of narrative review articles. Res Integr Peer Rev 4:5. https://doi.org/10.1186/s41073-019-0064-8
Jadad AR, Moore R, Carroll D, Jenkinson C, Reynolds DM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12. https://doi.org/10.1016/0197-2456(95)00134-4.0197-2456(95)00134-4
Cuschieri S (2019) The STROBE guidelines. Saudi J Anaesth 13(Suppl 1):S31–S34. https://doi.org/10.4103/sja.SJA_543_18
Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R et al (2015) Conducting systematic reviews of association (etiology): the Joanna Briggs Institute’s approach. Int J Evid Based Healthc 13(3):163–169. https://doi.org/10.1097/XEB.0000000000000064
Doan S, Amat F, Gabison E, Saf S, Cochereau I, Just J (2017) Omalizumab in severe refractory vernal keratoconjunctivitis in children: case series and review of the literature. Ophthalmol Ther 6(1):195–206. https://doi.org/10.1007/s40123-016-0074-2
Stock RA, Lazzari SLT, Martins IP, Bonamigo EL (2020) Surgical debridement of corneal shield ulcers in pediatric patients: two case reports and a review of the literature. J Med Case Rep 14(1):70. https://doi.org/10.1186/s13256-020-02407-8
Kraus C (2016) Vernal keratoconjunctivitis. American Academy of Ophthalmology 2016. https://www.aao.org/disease-review/vernal-keratoconjunctivitis-5. Accessed 28 Apr 2022
Berger WE, Granet DB, Kabat AG (2017) Diagnosis and management of allergic conjunctivitis. Allergy Asthma Proc 38(1):16–27. https://doi.org/10.2500/aap.2017.38.4003
Leonardi A, Silva D, Perez Formigo D, Bozkurt B, Sharma V, Allegri P (2019) Management of ocular allergy. Allergy 74(9):1611–1630. https://doi.org/10.1111/all.13786
Leonardi A, Dupuis-Deniaud M, Bremond-Gignac D (2020) Clinical efficacy assessment in severe vernal keratoconjunctivitis: preliminary validation of a new penalties-adjusted corneal fluorescein staining score. J Mark Access Health Policy 4;8(1):1748492. https://doi.org/10.1080/20016689.2020.1748492
Rasmussen MLR, D’Souza M, Topal DG, Gradman J, Larsen DA, Lehrmann BB et al (2023) Prevalence of allergic sensitization with vernal keratoconjunctivitis: a systematic review with meta-analyses. Acta Ophthalmol 101:9–21. https://doi.org/10.1111/aos.15212
Gokhale NS (2016) Systematic approach to managing vernal keratoconjunctivitis in clinical practice: severity grading system and a treatment algorithm. Indian J Ophthalmol 64(2):145–148. https://doi.org/10.4103/0301-4738.179727
Takamura E, Uchio E, Ebihara N, Ohno S, Ohashi Y, Okamoto S et al (2017) Japanese guidelines for allergic conjunctival diseases 2017. Allergol Int 66(2):220–229. https://doi.org/10.1016/j.alit.2016.12.004
Thong BY (2017) Allergic conjunctivitis in Asia. Asia Pac Allergy 7(2):57–64. https://doi.org/10.5415/apallergy.2017.7.2.57
Sacchetti M, Abicca I, Bruscolini A, Cavaliere C, Nebbioso M, Lambiase A (2018) Allergic conjunctivitis: current concepts on pathogenesis and management. J Biol Regul Homeost Agents 32(1 Suppl. 1):49–60
Fauquert JL (2019) Diagnosing and managing allergic conjunctivitis in childhood: the allergist’s perspective. Pediatr Allergy Immunol 30(4):405–414. https://doi.org/10.1111/pai.13035
Bielory L, Delgado L, Katelaris CH, Leonardi A, Rosario N, Vichyanoud P (2020) Diagnosis and management of allergic conjunctivitis. Ann Allergy Asthma Immunol 124:118–134. https://doi.org/10.1016/j.anai.2019.11.014
Shoji J (2020) Ocular allergy test and biomarkers on the ocular surface: clinical test for evaluating the ocular surface condition in allergic conjunctival diseases. Allergol Int 69(4):496–504. https://doi.org/10.1016/j.alit.2020.05.003
Brindisi G, Cinicola B, Anania C, De Castro G, Nebbioso M, Miraglia Del Giudice M et al (2021) Vernal keratoconjunctivitis: state of art and update on treatment. Acta Biomed 92(S7):e2021517. https://doi.org/10.23750/abm.v92iS7.12419
Ghiglioni DG, Zicari AM, Parisi GF, Marchese G, Indolfi C, Diaferio L et al (2021) Vernal keratoconjunctivitis: an update. Eur J Ophthalmol 31(6):2828–2842. https://doi.org/10.1177/11206721211022153
Sacchetti M, Plateroti R, Bruscolini A, Giustolisi R, Marenco M (2021) Understanding vernal keratoconjunctivitis: beyond allergic mechanisms. Life 11(10):1012. https://doi.org/10.3390/life11101012
Singh N, Diebold Y, Sahu SK, Leonardi A (2022) Epithelial barrier dysfunction in ocular allergy. Allergy 77(5):1360–1372. https://doi.org/10.1111/all.15174
Wajnsztajn D, Solomon A (2021) Vernal keratoconjunctivitis and keratoconus. Curr Opin Allergy Clin Immunol 21(5):507–514. https://doi.org/10.1097/ACI.0000000000000765
Kaur K, Gurnani B (2022) Vernal keratoconjunctivitis. In: StatPearls. Treasure Island (FL): StatPearls Publishing
Mehta JS, Chen WL, Cheng ACK, Cung LX, Dualan IJ, Kekunnaya R et al (2022) Diagnosis, management, and treatment of vernal keratoconjunctivitis in Asia: recommendations from the management of vernal keratoconjunctivitis in Asia Expert Working Group. Front Med (Lausanne) 1;9:882240. https://doi.org/10.3389/fmed.2022.882240
Leonardi A, Righetti G, Giovannini G, De Marchi V, Occhiuto M (2023) Diagnostic criteria of chronic conjunctivitis: atopic keratoconjunctivitis and vernal keratoconjunctivitis. Curr Opin Allergy Clin Immunol. 23. Epub ahead of print. https://doi.org/10.1097/ACI.0000000000000915
Nche EN, Okwen MM, Solomon A (2023) Prevalence and clinical characteristics of vernal keratoconjunctivitis in sub-Saharan Africa. Curr Opin Allergy Clin Immunol 23. Epub ahead of print. https://doi.org/10.1097/ACI.0000000000000928
Fujishima H, Okada N, Matsumoto K, Fukagawa K, Igarashi A, Matsuda A et al (2016) The usefulness of measuring tear periostin for the diagnosis and management of ocular allergic diseases. J Allergy Clin Immunol 138(2):459-467.e2. https://doi.org/10.1016/j.jaci.2015.11.039
Leonardi A, Tarricone E, Corrao S, Alaibac M, Corso AJ, Zavan B et al (2016) Chaperone patterns in vernal keratoconjunctivitis are distinctive of cell and Hsp type and are modified by inflammatory stimuli. Allergy 71(3):403–411. https://doi.org/10.1111/all.12814
Inada N, Shoji J, Shiraki Y, Aso H, Yamagami S (2017) Histamine H1 and H4 receptor expression on the ocular surface of patients with chronic allergic conjunctival diseases. Allergol Int 66(4):586–593. https://doi.org/10.1016/j.alit.2017.03.004
Shoji J, Aso H, Inada N (2017) Clinical usefulness of simultaneous measurement of the tear levels of CCL17, CCL24, and IL-16 for the biomarkers of allergic conjunctival disorders. Curr Eye Res 42(5):677–684. https://doi.org/10.1080/02713683.2016
Zicari AM, Cafarotti A, Occasi F, Lollobrigida V, Nebbioso M, Pecorella I (2017) Vitamin D levels in children affected by vernal keratoconjunctivitis. Curr Med Res Opin 33(2):269–274. https://doi.org/10.1080/03007995.2016
Costa Andrade FE, Corrêa MP, Gimenes AD, Dos Santos MS, Campos M, Chammas R (2018) Galectin-3: role in ocular allergy and potential as a predictive biomarker. Br J Ophthalmol 102(7):1003–1010. https://doi.org/10.1136/bjophthalmol-2017-311473
Nebbioso M, Iannaccone A, Duse M, Aventaggiato M, Bruscolini A, Zicari AM (2018) Vascular endothelial growth factor (VEGF) serological and lacrimal signaling in patients affected by vernal keratoconjunctivitis (VKC). J Ophthalmol 16(2018):3850172. https://doi.org/10.1155/2018/3850172
Nebbioso M, Sacchetti M, Bianchi G, Zicari AM, Duse M, Del Regno P et al (2018) Tear ferning test and pathological effects on ocular surface before and after topical cyclosporine in vernal keratoconjunctivitis patients. J Ophthalmol 14(2018):1061276. https://doi.org/10.1155/2018/1061276
Bruschi G, Ghiglioni DG, Osnaghi S, Rosazza C, Pires Marafon D, Landi M et al (2020) Role of ocular cytology in vernal keratoconjunctivitis. Immun Inflamm Dis 8(1):3–7. https://doi.org/10.1002/iid3.278
Leonardi A, Daull P, Garrigue JS, Cavarzeran F, Docquier M, Di Stefano A et al (2020) Conjunctival transcriptome analysis reveals the overexpression of multiple pattern recognition receptors in vernal keratoconjunctivitis. Ocul Surf 19:241–248. https://doi.org/10.1016/j.jtos.2020.09.009
Zicari AM, Brindisi G, De Castro G, Lollobrigida V, Nebbioso M, Duse M (2020) Is oxidative stress involved in vernal keratoconjunctivitis? Results from a pilot study in children. Pediatr Allergy Immunol 31(Suppl 26):52–56. https://doi.org/10.1111/pai.13382
Ahmed AS, El-Agha MH, Khaled MO, Shousha SM (2021) The prevalence of keratoconus in children with allergic eye disease in an Egyptian population. Eur J Ophthalmol 31(4):1571–1576. https://doi.org/10.1177/1120672120942691
Çağlayan M, Öncül H, Alakus MF, Dag U (2021) Corneal and lens densitometry with Pentacam HR in children with vernal keratoconjunctivitis. Clin Exp Optom 104(2):156–161. https://doi.org/10.1111/cxo.13144
Horinaka M, Shoji J, Tomioka A, Tonozuka Y, Inada N, Yamagami S (2021) Alterations in mucin-associated gene expression on the ocular surface in active and stable stages of atopic and vernal keratoconjunctivitis. J Ophthalmol 31(2021):9914786. https://doi.org/10.1155/2021/9914786
Kavitha V, Heralgi MM, Aafreen S (2021) Comparison of posterior corneal elevation in children with and without vernal keratoconjunctivitis using a new tomographer. Indian J Ophthalmol 69(8):2060–2063. https://doi.org/10.4103/ijo.IJO_35_21
Mashimo K, Usui-Ouchi A, Ito Y, Wakasa-Arai R, Yokoi N, Kawasaki S et al (2021) Role of oncostatin M in the pathogenesis of vernal keratoconjunctivitis: focus on tissue remodeling. Jpn J Ophthalmol 65(1):144–153. https://doi.org/10.1007/s10384-020-00791-8
Menta V, Agarwal S, Das US, Moksha L, Srividya G, Anandan AM et al (2021) Ocular surface sphingolipids associate with the refractory nature of vernal keratoconjunctivitis: newer insights in VKC pathogenesis. Br J Ophthalmol 20:bjophthalmol-2021-319324. https://doi.org/10.1136/bjophthalmol-2021-319324
Messina A, Palmigiano A, Tosto C, Romeo DA, Sturiale L, Garozzo D et al (2021) Tear N-glycomics in vernal and atopic keratoconjunctivitis. Allergy 76(8):2500–2509. https://doi.org/10.1111/all.14775
Muamba Nkashama L, Kayembe Lubeji D, Mwanza Kasongo JC, Kadima Mutombo T, Nyembue Tshipukane D (2021) Sensitization and clinical characteristics of Congolese children with vernal keratoconjunctivitis in Kinshasa. Ocul Immunol Inflamm 28:1–6. https://doi.org/10.1080/09273948.2021.1976217
Sacchetti M, Nebbioso M, Segatto M, Abicca I, Bruscolini A, Zicari AM et al (2021) Vernal keratoconjunctivitis activity induces decrease of ocular surface CD14, TLR-4 and TLR-9 expression. Eur J Ophthalmol 5:11206721211048814. https://doi.org/10.1177/11206721211048814
Sorkhabi R, Ahoor MH, Ghorbanihaghjo A, Jafari S (2021) Serum vitamin D levels in patients with vernal keratoconjunctivitis and its relationship with disease severity. Eur J Ophthalmol 31(6):3259–3264. https://doi.org/10.1177/1120672120978886
Vishwakarma P, Mitra S, Beuria T, Barik MR, Sahu SK (2021) Comparative profile of ocular surface microbiome in vernal keratoconjunctivitis patients and healthy subjects. Graefes Arch Clin Exp Ophthalmol 259(7):1925–1933. https://doi.org/10.1007/s00417-021-05109-z
Yılmaz YC, Ipek SC, Ozer MD (2021) Corneal and lens densitometry in patients with vernal keratoconjunctivitis. Int Ophthalmol 41(8):2667–2676. https://doi.org/10.1007/s10792-021-01822-0
Zhang SY, Li J, Liu R, Lao HY, Fan Z, Jin L et al (2021) Association of allergic conjunctivitis with health-related quality of life in children and their parents. JAMA Ophthalmol 1;139(8):830–837. https://doi.org/10.1001/jamaophthalmol.2021.1708
Kausar A, Akhtar N, Akbar N (2022) Epidemiological aspects of allergic conjunctivitis. J Ayub Med Coll Abbottabad. 34(1):135–140. https://doi.org/10.55519/JAMC-01-9432
Micera A, Di Zazzo A, De Piano M, Sharma S, Mori T, De Gregorio C et al (2022) Tissue remodeling in adult vernal keratoconjunctivitis. Exp Eye Res 225:109301. https://doi.org/10.1016/j.exer.2022.109301
Ninomiya I, Yamatoya K, Mashimo K, Matsuda A, Usui-Ouchi A, Araki Y et al (2022) Role of oncostatin M in the pathogenesis of vernal keratoconjunctivitis: focus on the barrier function of the epithelium and interleukin-33 production by fibroblasts. Invest Ophthalmol Vis Sci 63(13):26. https://doi.org/10.1167/iovs.63.13.26
Sabu S, Gupta N, Raj N, Panigrahi A, Lomi N, Vanathi M et al (2022) Ocular surface characteristics in pediatric vernal keratoconjunctivitis: a clinico-cytological study. J AAPOS 26(5):240.e1-240.e6. https://doi.org/10.1016/j.jaapos.2022.05.015
Sacchetti M, Nebbioso M, Segatto M, Abicca I, Bruscolini A, Zicari AM et al (2022) Vernal keratoconjunctivitis activity induces decrease of ocular surface CD14, TLR-4 and TLR-9 expression. Eur J Ophthalmol 32(4):2274–2281. https://doi.org/10.1177/11206721211048814
Singh A, Rana J, Kataria S, Bhan C, Priya P (2022) Demographic and clinical characteristics of childhood and adult onset vernal keratoconjunctivitis in a tertiary care center during Covid pandemic: a prospective study. Rom J Ophthalmol 66(4):344–351. https://doi.org/10.22336/rjo.2022.61
Syed NH, Shahidan WNS, Shatriah I, Zunaina E (2022) MicroRNA profiling of the tears of children with vernal keratoconjunctivitis. Front Genet 13:847168. https://doi.org/10.3389/fgene.2022.847168
Albadawi MA, Nassar GA, El Gendy HA, Ghalwash DA (2023) Evaluation of corneal epithelial thickness mapping using anterior segment OCT in children with vernal keratoconjunctivitis. Int Ophthalmol 43(6):1967–1976. https://doi.org/10.1007/s10792-022-02596-9
Csorba A, Maneschg OA, Resch MD, Nagy ZZ (2023) Examination of corneal microstructure in the quiescent phase of vernal keratoconjunctivitis using in vivo confocal microscopy. Eur J Ophthalmol 33(1):196–202. https://doi.org/10.1177/11206721221099778
Dubbaka S, Agrawal M, Sati A, Vats S, Mahajan S (2023) An observational study on the presence of perilimbal conjunctival pigmentation in vernal keratoconjunctivitis. Indian J Ophthalmol 71(5):1816–1821. https://doi.org/10.4103/ijo.IJO_2128_22
Gupta S, Rahman M, Tibrewal S, Gaur A, Ganesh S, Sangwan VS (2023) Evaluation of dry eyes in children with vernal kerato-conjunctivitis using clinical tests and ocular surface analysis. Indian J Ophthalmol 71(4):1488–1494. https://doi.org/10.4103/IJO.IJO_2836_22
Ito Y, Usui-Ouchi A, Ebihara N (2023) Galectin-3, a damage-associated molecular pattern, in tears of patients with vernal keratoconjunctivitis. Jpn J Ophthalmol 67(4):431–439. https://doi.org/10.1007/s10384-023-00994-9
Mazumdar S, Satsangi SK, Garg M, Rajan PG (2023) Prevalence of dry eye disease in the patients of allergic conjunctivitis: hospital-based cross-sectional study. Indian J Ophthalmol 71(4):1495–1498. https://doi.org/10.4103/IJO.IJO_2816_22
Thiagarajan D, Zainal S, Alias R, Bastion MC (2023) Clinical study on corneal topographical changes in vernal keratoconjunctivitis by using OCULUS Pentacam®. Cureus 15(1):e33798. https://doi.org/10.7759/cureus.33798
Yilmaz YC, Ipek SC, Gobeka HH (2023) Corneal topometric indices and proclivity toward corneal ectasia in vernal keratoconjunctivitis. J Fr Ophtalmol S0181–5512(23):00194–00198. https://doi.org/10.1016/j.jfo.2023.01.010
Zhang X, Huang F, Qiu J, Yang Y, Zhang C (2023) Corneal biomechanical properties in vernal keratoconjunctivitis and its subtypes: a preliminary study. Int Ophthalmol 43(6):2083–2090. https://doi.org/10.1007/s10792-022-02608-8
Gupta S, Shah P, Grewal S, Chaurasia AK, Gupta V (2015) Steroid-induced glaucoma and childhood blindness. Br J Ophthalmol 99(11):1454–1456. https://doi.org/10.1136/bjophthalmol-2014-306557
Gómez-Henao CM, Herrera-Morales CI, Ramírez-Giraldo R, Cardona-Villa R (2018) Quality of life and clinical characterization of patients with vernal keratoconjunctivitis in a pediatric population in Colombia. Allergol Immunopathol (Madr) 46(4):370–377. https://doi.org/10.1016/j.aller.2017.12.002
Ghiglioni DG, Bruschi G, Gandini S, Osnaghi S, Peroni D, Marchisio P (2019) Vitamin D serum levels in children with vernal keratoconjunctivitis and disease control. Int J Immunopathol Pharmacol 33:2058738419833468. https://doi.org/10.1177/2058738419833468
Senthil S, Thakur M, Rao HL, Mohamed A, Jonnadula GB, Sangwan V et al (2020) Steroid-induced glaucoma and blindness in vernal keratoconjunctivitis. Br J Ophthalmol 104(2):265–269. https://doi.org/10.1136/bjophthalmol-2019-313988
Jongvanitpak R, Vichyanond P, Jirapongsananuruk O, Visitsunthorn N, Pacharn P (2020) Clinical characteristics and outcomes of ocular allergy in Thai children. Asian Pac J Allergy Immunol. https://doi.org/10.12932/AP-160519-0564
Artesani MC, Esposito M, Sacchetti M, Sansone A, Romanzo A, Buzzonetti L et al (2021) Health-related quality of life in children at the diagnosis of vernal keratoconjunctivitis. Pediatr Allergy Immunol 32(6):1271–1277. https://doi.org/10.1111/pai.13520
Donthineni PR, Varma S, Kethiri A, Shanbhag S, Mishra DK, Singh V et al (2021) Histopathological characteristics of limbal stem cell deficiency secondary to chronic vernal keratoconjunctivitis. Cornea. https://doi.org/10.1097/ICO.0000000000002775
Ghauri AJ, Fisher K, Kenworthy A (2021) Understanding the journey of patients with vernal keratoconjunctivitis: a qualitative study of the impact on children and families. J Pediatr Ophthalmol Strabismus 58(5):298–303. https://doi.org/10.3928/01913913-20210319-01
Wadhwani M, Kursange S, Chopra K, Singh R, Kumari S (2021) Knowledge, attitude, and practice among caregivers of children with vernal keratoconjunctivitis in a tertiary care pediatric hospital. J Pediatr Ophthalmol Strabismus 58(6):390–395. https://doi.org/10.3928/01913913-20210426-02
Artesani MC, Esposito M, Sacchetti M, Mennini M, Romanzo A, Buzzonetti L et al (2022) The effect of COVID-19 imposed lockdown on Italian children with vernal keratoconjunctivitis. World Allergy Organ J 15(10):100701. https://doi.org/10.1016/j.waojou.2022.100701
Masini M, Brindisi G, Giovannini M, Pignataro E, Di Grande L, De Libero C et al (2022) Impact of screen exposure on pediatric vernal keratoconjunctivitis: a survey during the COVID-19 pandemic in Italy. Ital J Pediatr 48(1):74. https://doi.org/10.1186/s13052-022-01253-2
Yang S, Zhang W, Qiong Da CR, Wu Y (2023) Characteristics of vernal keratoconjunctivitis in Lhasa: a single-center, observational study. Ocul Immunol Inflamm 1–4. https://doi.org/10.1080/09273948.2023.2190804
Soleimani M, Tabatabaei SA, Mirshahi R, Nozarian Z, Jabbarvand Behrbouz M (2016) New finding in vernal keratoconjunctivitis: Splendore-Hoeppli phenomenon. Cornea 35(6):892–893. https://doi.org/10.1097/ICO.0000000000000793
Jaffet J, Singh V, Chaurasia S, Jakati S, Hazari A, Sangwan V (2022) Clinical, histological and immunohistochemistry characteristics of cornea in the sequelae stage of chronic vernal keratoconjunctivitis. Indian J Ophthalmol 70(1):59–64. https://doi.org/10.4103/ijo.IJO_1179_21
Alharbi SS, Edward DP (2020) Rosai-Dorfman disease: isolated epibulbar mass in patient with vernal keratoconjunctivitis. Saudi J Ophthalmol 22;34(1):53–55. https://doi.org/10.4103/1319-4534.301290
Bajracharya L, Agrawal N, Dhungel S, Parajuli R, Adhikari S (2020) A teenager with vernal keratoconjunctivitis and pellucid marginal degeneration, presenting with exotropia. Int Med Case Rep J 7(13):399–408. https://doi.org/10.2147/IMCRJ.S262999
Farias RJM, Gama MEA, Mendes R, Lobão NTM, Sousa LB (2021) Vernal keratoconjunctivitis as the only clinical manifestation of HIV infection. Ocul Immunol Inflamm 7:1–3. https://doi.org/10.1080/09273948.2021.1891442
Fukushima A, Tabuchi H (2022) A case of vernal keratoconjunctivitis with growth hormone deficiency. Cureus 14(10):e30615. https://doi.org/10.7759/cureus.30615
Artesani MC, Esposito M, Valentini D, Villani A, Fiocchi AG, Buzzonetti L (2023) Vernal keratoconjunctivitis in down syndrome: a case report. BMC Ophthalmol 23(1):106. https://doi.org/10.1186/s12886-023-02855-y
Singhal D, Sahay P, Maharana PK, Raj N, Sharma N, Titiyal JS (2019) Vernal Keratoconjunctivitis. Surv Ophthalmol 64(3):289–311. https://doi.org/10.1016/j.survophthal.2018.12.001
Roumeau I, Coutu A, Navel V, Pereira B, Baker JS, Chiambaretta F et al (2021) Efficacy of medical treatments for vernal keratoconjunctivitis: a systematic review and meta-analysis. J Allergy Clin Immunol 148(3):822–834. https://doi.org/10.1016/j.jaci.2021.03.026
Rasmussen MLR, Schou MG, Bach-Holm D, Heegaard S, Jørgensen CAB, Kessel L et al (2022) Comparative efficacy of medical treatments for vernal keratoconjunctivitis in children and young adults: a systematic review with network meta-analyses. Acta Ophthalmol 100(1):35–44. https://doi.org/10.1111/aos.14858
Esposito S, Fior G, Mori A, Osnaghi S, Ghiglioni D (2016) An update on the therapeutic approach to vernal keratoconjunctivitis. Paediatr Drugs 18(5):347–355. https://doi.org/10.1007/s40272-016-0185-1
Erdinest N, Ben-Eli H, Solomon A (2019) Topical tacrolimus for allergic eye diseases. Curr Opin Allergy Clin Immunol 19(5):535–543. https://doi.org/10.1097/ACI.0000000000000560
Nebbioso M, Alisi L, Giovannetti F, Armentano M, Lambiase A (2019) Eye drop emulsion containing 0.1% cyclosporine (1 mg/mL) for the treatment of severe vernal keratoconjunctivitis: an evidence-based review and place in therapy. Clin Ophthalmol 13:1147–1155. https://doi.org/10.2147/OPTH.S181811
AlHarkan DH (2020) Management of vernal keratoconjunctivitis in children in Saudi Arabia. Oman J Ophthalmol 13(1):3–12. https://doi.org/10.4103/ojo.OJO_263_2018
Biermann J, Bosche F, Eter N, Beisse F (2021) Treating severe pediatric keratoconjunctivitis with topical cyclosporine A. Klin Monbl Augenheilkd. https://doi.org/10.1055/a-1556-1182
Chigbu DI, Labib BA (2021) Immunopharmacology in vernal keratoconjunctivitis: current and future perspectives. Pharmaceuticals (Basel) 14(7):658. https://doi.org/10.3390/ph14070658
Feizi S, Javadi MA, Alemzadeh-Ansari M, Arabi A, Shahraki T, Kheirkhah A (2021) Management of corneal complications in vernal keratoconjunctivitis: a review. Ocul Surf 19:282–289. https://doi.org/10.1016/j.jtos.2020.10.005
Fernandez A, Asbell P, Roy N (2022) Emerging therapies targeting eosinophil-mediated inflammation in chronic allergic conjunctivitis. Ocul Surf 26:191–196. https://doi.org/10.1016/j.jtos.2022.08.004
Dahlmann-Noor A, Bonini S, Bremond-Gignac D, Heegaard S, Leonardi A, Montero J et al (2023) Novel insights in the management of vernal keratoconjunctivitis (VKC): European expert consensus using a modified nominal group technique. Ophthalmol Ther 12(2):1207–1222. https://doi.org/10.1007/s40123-023-00665-5
Doan S, Papadopoulos NG, Lee JK, Leonardi S, Manti S, Lau S et al (2023) Vernal keratoconjunctivitis: current immunological and clinical evidence and the potential role of omalizumab. World Allergy Organ J 16(6):100788. https://doi.org/10.1016/j.waojou.2023.100788
Ghauri AJ, Biswas S, Manzouri B, Barua A, Sharma V, Hoole J et al (2023) Management of vernal keratoconjunctivitis in children in the United Kingdom: a review of the literature and current best practice across six large United Kingdom centers. J Pediatr Ophthalmol Strabismus 60(1):6–17. https://doi.org/10.3928/01913913-20220328-01
Al-Amri AM, Mirza AG, Al-Hakami AM (2016) Tacrolimus ointment for treatment of vernal keratoconjunctivitis. Middle East Afr J Ophthalmol 23(1):135–138. https://doi.org/10.4103/0974-9233.164616
Barot RK, Shitole SC, Bhagat N, Patil D, Sawant P, Patil K (2016) Therapeutic effect of 0.1% tacrolimus eye ointment in allergic ocular diseases. J Clin Diagn Res 10(6):NC05–9. https://doi.org/10.7860/JCDR/2016/17847.7978
Chatterjee S, Agrawal D (2016) Tacrolimus in corticosteroid-refractory vernal keratoconjunctivitis. Cornea 35(11):1444–1448. https://doi.org/10.1097/ICO.0000000000000918
Yücel OE, Ulus ND (2016) Efficacy and safety of topical cyclosporine A 0.05% in vernal keratoconjunctivitis. Singapore Med J 57(9):507–510. https://doi.org/10.11622/smedj.2015161
Abozaid MA (2017) Sequential Keraring implantation and corneal cross-linking for the treatment of keratoconus in children with vernal keratoconjunctivitis. Clin Ophthalmol 24(11):1891–1895. https://doi.org/10.2147/OPTH.S150022
Al-Amri AM, Fiorentini SF, Albarry MA, Bamahfouz AY (2017) Long-term use of 0.003% tacrolimus suspension for treatment of vernal keratoconjunctivitis. Oman J Ophthalmol 10(3):145–149. https://doi.org/10.4103/ojo.OJO_232_2014
Costa AXD, Gomes JÁP, Marculino LGC, Liendo VL, Barreiro TP, Santos MSD (2017) Supratarsal injection of triamcinolone for severe vernal keratoconjunctivitis in children. Arq Bras Oftalmol 80(3):186–188. https://doi.org/10.5935/0004-2749.20170045
Liendo VL, Vola ME, Barreiro TP, Wakamatsu TH, Gomes JÁP, Santos MSD (2017) Topical tacrolimus for the treatment of severe allergic keratoconjunctivitis in children. Arq Bras Oftalmol 80(4):211–214. https://doi.org/10.5935/0004-2749.20170052
Wan Q, Tang J, Han Y, Wang D, Ye H (2018) Therapeutic effect of 0.1% tacrolimus eye drops in the tarsal form of vernal keratoconjunctivitis. Ophthalmic Res 59(3):126–134. https://doi.org/10.1159/000478704
Maitra A, Bhattacharyya S, Biswas A, Samanta SK, Mukherjee S, Era N (2018) Assessment of drug usage pattern in patients treated for vernal keratoconjunctivitis attending a tertiary eye care centre in Eastern India: a cross-sectional study. Nepal J Ophthalmol 10(19):57–65. https://doi.org/10.3126/nepjoph.v10i1.21690
Fiorentini SF, Khurram D (2019) Therapeutic effects of topical 0.03% tacrolimus ointment in children with refractory vernal keratoconjunctivitis in Middle East. Saudi J Ophthalmol 33(2):117–120. https://doi.org/10.1016/j.sjopt.2019.04.001
Samyukta SK, Pawar N, Ravindran M, Allapitchai F, Rengappa R (2019) Monotherapy of topical tacrolimus 0.03% in the treatment of vernal keratoconjunctivitis in the pediatric population. J AAPOS 23(1):36.e1–36.e5. https://doi.org/10.1016/j.jaapos.2018.09.010
Shoji J, Ohashi Y, Fukushima A, Miyazaki D, Uchio E, Takamura E et al (2019) Topical tacrolimus for chronic allergic conjunctival disease with and without atopic dermatitis. Curr Eye Res 44(7):796–805. https://doi.org/10.1080/02713683.2019.1600197
Xu X, Cai Y (2019) Therapeutic effects of Houttuynia eye drops combined with olopatadine hydrochloride eyedrops on vernal keratoconjunctivitis. Exp Ther Med 17(2):1224–1227. https://doi.org/10.3892/etm.2018.7079
Modugno RL, Scalora T, Bonaldo A, Lazzarini D, Leonardi A (2020) Corneal microstructural changes by confocal microscopy in vernal keratoconjunctivitis patients treated with topical cyclosporine. Ocul Immunol Inflamm 29(7–8):1599–1605. https://doi.org/10.1080/09273948.2020
Heikal MA, Soliman TT, Abousaif WS, Shebl AA (2022) A comparative study between ciclosporine A eye drop (2%) and tacrolimus eye ointment (0.03%) in management of children with refractory vernal keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol 260(1):353–361. https://doi.org/10.1007/s00417-021-05356-0
Malhotra C, Singh H, Jain AK, Gupta A, Ram J (2021) Efficacy of 2% rebamipide suspension for vernal keratoconjunctivitis: a clinical comparison with topical immune modulators cyclosporine and tacrolimus. Ocul Immunol Inflamm 1–9. https://doi.org/10.1080/09273948.2020.1867870
Sruthi V, Reddy RN, Sowmini K, Grace NS (2020) To evaluate the efficacy and safety of olopatadine 0.1% ophthalmic solution and bepotastine 1.5% ophthalmic solution in patients with vernal keratoconjunctivitis in a tertiary care hospital. Indian J Pharmacol 52(6):476–481. https://doi.org/10.4103/ijp.IJP_174_20
Bourcier T, Dory A, Dormegny L, Alcazar J, Gaucher D, Sauer A (2022) Efficacy and safety of 0.1% cyclosporine versus 2% cyclosporine in the treatment of severe vernal keratoconjunctivitis in children. Clin Ophthalmol 16:3589–3596. https://doi.org/10.2147/OPTH.S37041
Pradhan A, Pattanayak S, Dora J, Subudhi P (2022) Effectiveness of a modified therapeutic protocol for the management of vernal keratoconjunctivitis based on Bonini’s graded clinical severity. Indian J Ophthalmol 70(7):2408–2414. https://doi.org/10.4103/ijo.IJO_3190_21
Tanaka H, Tatsukawa Y, Yoshitomi K, Tabuchi H, Fukushima A (2022) Effects of antihistamine-releasing contact lenses on severe allergic conjunctivitis. Ocul Immunol Inflamm 1–3. https://doi.org/10.1080/09273948.2022.2103001
Giannaccare G, Rossi C, Borselli M, Bonzano C, Carnovale Scalzo G, Nicolò M et al (2023) Clinical outcomes of topical 0.1% ciclosporin cationic emulsion used on label in children with vernal keratoconjunctivitis. Ophthalmol Ther 12(3):1787–1793. https://doi.org/10.1007/s40123-023-00707-y
Mohan S, Kumar S, Kumar GP, Maheswari A, Bhatia A, Sagar A (2023) Assessment of the efficacy of olopatadine 0.1% in the treatment of vernal keratoconjunctivitis in terms of clinical improvement based on total ocular symptom score and ocular surface disease index. Indian J Ophthalmol 71(5):1822–1827. https://doi.org/10.4103/ijo.IJO_2048_22
Shoughy SS, Jaroudi MO, Tabbara KF (2016) Efficacy and safety of low-dose topical tacrolimus in vernal keratoconjunctivitis. Clin Ophthalmol 10:643–647. https://doi.org/10.2147/OPTH.S99157
González-Medina M, Blasco-Valero C, Martín-Begué N, Vilà-Indurain B, Garriga-Baraut T (2018) Tacrolimus as an effective and safe therapeutic alternative in vernal keratoconjunctivitis resistant to conventional treatment. J Investig Allergol Clin Immunol 28(5):345–346. https://doi.org/10.18176/jiaci.0282
Iyer G, Agarwal S, Srinivasan B (2018) Outcomes and rationale of excision and mucous membrane grafting in palpebral vernal keratoconjunctivitis. Cornea 37(2):172–176. https://doi.org/10.1097/ICO.0000000000001421
Abozaid MA, Hassan AA, Abdalla A (2019) Intrastromal corneal ring segments implantation and corneal cross-linking for keratoconus in children with vernal keratoconjunctivitis – three-year results. Clin Ophthalmol 13:2151–2157. https://doi.org/10.2147/OPTH.S219688
Alrobaian M, Elsayed M, Alotaibi AK, AlHarbi M, May W, Stone DU (2019) Safety and efficacy of corneal cross-linking in pediatric patients with keratoconus and vernal keratoconjunctivitis. Middle East Afr J Ophthalmol 26(2):95–100. https://doi.org/10.4103/meajo.MEAJO_240_18
Müller GG, José NK, de Castro RS, de Holanda EC (2019) Long-term use of topical tacrolimus ointment: a safe and effective option for the treatment of vernal keratoconjunctivitis. Arq Bras Oftalmol 82(2):119–123. https://doi.org/10.5935/0004-2749.20190026
Liu FY, Liu HY, Chu HS, Chen WL, Hu FR, Wang IJ (2019) Dermatologic tacrolimus ointment on the eyelids for steroid-refractory vernal keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol 257(5):967–974. https://doi.org/10.1007/s00417-019-04287-1
McSwiney TJ, Power B, Murphy CC, Brosnahan D, Power W (2019) Safety and efficacy of supratarsal triamcinolone for treatment of vernal keratoconjunctivitis in Ireland. Cornea 38(8):955–958. https://doi.org/10.1097/ICO.0000000000001963
Sen P, Jain S, Mohan A, Shah C, Sen A, Jain E (2019) Pattern of steroid misuse in vernal keratoconjunctivitis resulting in steroid induced glaucoma and visual disability in Indian rural population: an important public health problem in pediatric age group. Indian J Ophthalmol 67(10):1650–1655. https://doi.org/10.4103/ijo.IJO_2143_18
Caputo R, Marziali E, de Libero C, Di Grande L, Danti G, Virgili G et al (2021) Long-term safety and efficacy of tacrolimus 0.1% in severe pediatric vernal keratoconjunctivitis. Cornea 40(11):1395–1401. https://doi.org/10.1097/ICO.0000000000002751
Elubous KA, Al Bdour M, Alshammari T, Jeris I, AlRyalat SA, Roto A et al (2021) Environmental risk factors associated with the need for penetrating keratoplasty in patients with keratoconus. Cureus 13(7):e16506. https://doi.org/10.7759/cureus.16506
Feizi S, Javadi MA, Moshtaghion SM, Abolhosseini M (2021) Comparison of penetrating keratoplasty and deep anterior lamellar keratoplasty in keratoconus eyes with vernal keratoconjunctivitis. Ther Adv Ophthalmol 13:25158414211010550. https://doi.org/10.1177/25158414211010551
Gupta S, Singh P, Singh M, Naik M, Srivastava K (2021) Is interferon alpha-2b 1 millionIU/mL truly better than tacrolimus 0.03% for steroid-resistant VKC? Our 2-year experience at a tertiary health-care centre. Clin Ophthalmol 15:2993–2999. https://doi.org/10.2147/OPTH.S322378
Hirota A, Shoji J, Inada N, Shiraki Y, Yamagami S (2022) Evaluation of clinical efficacy and safety of prolonged treatment of vernal and atopic keratoconjunctivitis using topical tacrolimus. Cornea 41(1):23–30. https://doi.org/10.1097/ICO.0000000000002692
Maharana PK, Singhal D, Raj N, Sharma N, Titiyal JS (2021) Role of combined immunomodulator therapy in severe steroid intolerant vernal keratoconjunctivitis. Eye (Lond) 35(3):979–987. https://doi.org/10.1038/s41433-020-1013-y
Yazu H, Fukagawa K, Shimizu E, Sato Y, Fujishima H (2021) Long-term outcomes of 0.1% tacrolimus eye drops in eyes with severe allergic conjunctival diseases. Allergy Asthma Clin Immunol 17(1):11. https://doi.org/10.1186/s13223-021-00513-w
Arnon R, Rozen-Knisbacher I, Yahalomi T, Stanescu N, Niazov Y, Goldberg D et al (2022) When to start tacrolimus ointment for vernal keratoconjunctivitis? A proposed treatment protocol. Int Ophthalmol. https://doi.org/10.1007/s10792-021-02174-5
Salami E, Righetti G, Cavarzeran F, Leonardi A (2022) Efficacy and satisfaction of cyclosporine 0.1% in patients with vernal keratoconjunctivitis. Ocul Immunol Inflamm 1–3. https://doi.org/10.1080/09273948.2022.2103833
Senthil S, Rao HL, Ali MH, Krishnamurthy R, Dikshit S, Choudhari N (2022) Long-term outcomes and risk factors for failure of glaucoma filtering surgery in eyes with vernal keratoconjunctivitis and steroid-induced glaucoma. Indian J Ophthalmol 70(3):820–825. https://doi.org/10.4103/ijo.IJO_1897_21
Arora R, Sanoria A, Jain P, Gupta I, Gupta P (2023) Repeat deep anterior lamellar keratoplasty (DALK) for failed primary DALK. Indian J Ophthalmol 71(6):2462–2465. https://doi.org/10.4103/IJO.IJO_2505_22
Priyadarshini SR, Das S (2023) Practice patterns and opinions in the treatment of allergic eye disease: a survey among Indian ophthalmologists. Indian J Ophthalmol 71(1):80–85. https://doi.org/10.4103/ijo.IJO_1360_22
Rashid ZA, Moodley VR, Mashige KP (2023) Diagnosis and management of keratoconus by eye care practitioners in Kenya. BMC Ophthalmol 23(1):37. https://doi.org/10.1186/s12886-023-02792-w
Saha BC, Kumari R, Ambasta A (2023) Comparision of efficacy and safety of 0.03% and 0.1% tacrolimus ointment in children with vernal keratoconjunctivitis. Ther Adv Ophthalmol 15:25158414231173532. https://doi.org/10.1177/25158414231173532
Heffler E, Picardi G, Liuzzo MT, Pistorio MP, Crimi N (2016) Omalizumab treatment of vernal keratoconjunctivitis. JAMA Ophthalmol 134(4):461–463. https://doi.org/10.1001/jamaophthalmol.2015.5679
Occasi F, Duse M, Nebbioso M, De Castro G, Di Fraia M, Capata G (2017) Vernal keratoconjunctivitis treated with omalizumab: a case series. Pediatr Allergy Immunol 28(5):503–505. https://doi.org/10.1111/pai.12737
Callet M, Stolowy N, Zanin E, Denis D (2018) Interêt de l’omalizumab dans le traitement de la kérato-conjonctivite vernale sévère. Quand une kérato-conjonctivite vernale résiste aux traitements classiques [Omalizumab for severe vernal keratoconjunctivitis]. J Fr Ophtalmol 41(10):e499-e500. https://doi.org/10.1016/j.jfo.2018.06.001
Westland T, Patryn EK, Nieuwendaal CP, van der Meulen IJE, Mourits MP, Lapid-Gortzak R (2018) Vernal shield ulcers treated with frequently installed topical cyclosporine 0.05% eyedrops. Int Ophthalmol 38(1):363–368. https://doi.org/10.1007/s10792-016-0424-z
Patil M, Mehta JS (2021) Long term outcomes of surgical excision of giant papillae with mitomycin C and amniotic membrane transplantation in the treatment of refractory palpebral vernal keratoconjunctivitis. Medicina (Kaunas) 58(1):19. https://doi.org/10.3390/medicina58010019
Das S, Pasari AS, Sangwan VS (2016) Vernal keratoconjunctivitis: culmination of management using immunosuppression, surgical and prosthetic therapy over quarter century. BMJ Case Rep 2016:bcr2016217759. https://doi.org/10.1136/bcr-2016-217759
Agarwal S, Srinivasan B, Iyer G, Sudharshan S, Kalaivani K (2018) Vernal keratoconjunctivitis in human immunodeficiency virus – the possible role of T-helper 1–T-helper 2 shift. Indian J Ophthalmol 66(7):1004–1006. https://doi.org/10.4103/ijo.IJO_76_18
Santamaría L, Sánchez J (2018) [Long-term efficacy of omalizumab in patients with conventional treatment-resistant vernal keratoconjunctivitis]. Rev Alerg Mex 65(2):192–196. https://doi.org/10.29262/ram.v65i2.292
Simpson RS, Lee JK (2019) Omalizumab as single-dose therapy for vernal keratoconjunctivitis. Ann Allergy Asthma Immunol 122(1):119–120. https://doi.org/10.1016/j.anai.2018.09.458
Borrego-Sanz L, López Abad C, Méndez Fernández R, Pato Cour E, Díaz Valle D et al (2019) Oral cyclosporine for severe vernal keratoconjunctivitis in children. J Fr Ophtalmol 42(1):e12–e13. https://doi.org/10.1016/j.jfo.2018.04.009
Hopen ML, Gallardo MJ, Grover D (2019) Gonioscopy-assisted transluminal trabeculotomy in a pediatric patient with steroid-induced glaucoma. J Glaucoma 28(10):e156–e158. https://doi.org/10.1097/IJG.0000000000001326
Kurtul BE, Koca S (2021) Giant papilla prolapse from the upper tarsal conjunctiva in a 3-year-old child: a case presentation and a brief literature review. Beyoglu Eye J 6(1):70–73. https://doi.org/10.14744/bej.2021.65807
Özkaya D, Usta G, Karaca U (2021) A case of shield ulcer due to vernal keratoconjunctivitis. Iran J Allergy Asthma Immunol 20(4):505–508. PMID: 34418905
Singh A, Murthy SI, Gandhi A, Sangwan VS (2021) “Doughnut” amniotic membrane transplantation with penetrating keratoplasty for vernal keratoconjunctivitis with limbal stem cell disease. Cornea 1;40(7):914–916. https://doi.org/10.1097/ICO.0000000000002553
Jain N, Kate A, Chaudhary S, Basu S (2022) Allogeneic simple limbal epithelial transplantation for bilateral limbal stem cell deficiency in chronic vernal keratoconjunctivitis: a case report. Int J Surg Case Rep 94:106968. https://doi.org/10.1016/j.ijscr.2022.106968
Kate A, Jain N, Jakati S, Basu S (2022) Conjunctival autograft for bilateral tarsal keratinization in a case of chronic vernal keratoconjunctivitis. Cureus 14(3):e23089. https://doi.org/10.7759/cureus.23089
Shih EJ, Lin JC, Peng KL, Chen JL (2022) Treating refractory corneal hydrops in a male patient with vernal keratoconjunctivitis and mental retardation: a case report. BMC Ophthalmol 22(1):36. https://doi.org/10.1186/s12886-021-02241-6
Gayger Müller E, Santos MSD, Freitas D, Gomes JÁP, Belfort R Jr (2017) Tacrolimus eye drops as monotherapy for vernal keratoconjunctivitis: a randomized controlled trial. Arq Bras Oftalmol 80(3):154–158. https://doi.org/10.5935/0004-2749.20170038
Zanjani H, Aminifard MN, Ghafourian A, Pourazizi M, Maleki A, Arish M et al (2017) Comparative evaluation of tacrolimus versus interferon alpha-2b eye drops in the treatment of vernal keratoconjunctivitis: a randomized, double-masked study. Cornea 36(6):675–678. https://doi.org/10.1097/ICO.0000000000001200
Leonardi A, Doan S, Amrane M, Ismail D, Montero J, Németh J et al (2019) A randomized, controlled trial of cyclosporine A cationic emulsion in pediatric vernal keratoconjunctivitis. Ophthalmology 126(5):671–681. https://doi.org/10.1016/j.ophtha.2018.12.027
Bremond-Gignac D, Doan S, Amrane M, Ismail D, Montero J, Németh J et al (2020) Twelve-month results of cyclosporine A cationic emulsion in a randomized study in patients with pediatric vernal keratoconjunctivitis. Am J Ophthalmol 212:116–126. https://doi.org/10.1016/j.ajo.2019.11.020
Iqbal M, Elmassry A, Saad H, Am Gad A, Ibrahim O, Hamed N et al (2020) Standard cross-linking protocol versus accelerated and transepithelial cross-linking protocols for treatment of paediatric keratoconus: a 2-year comparative study. Acta Ophthalmol 98(3):e352–e362. https://doi.org/10.1111/aos.14275
Chen M, Wei A, Ke B, Zou J, Gong L, Wang Y et al (2021) Combination of 0.05% azelastine and 0.1% tacrolimus eye drops in children with vernal keratoconjunctivitis: a prospective study. Front Med (Lausanne) 8:650083. https://doi.org/10.3389/fmed.2021.650083
Bron AJ, Evans VE, Smith JA (2003) Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 22(7):640–650. https://doi.org/10.1097/00003226-200310000-00008
Ahsan A, Salman KA, Alam S, Siddiqui AH, Naeem SS, Ahmad A et al (2014) Alpha-1 antitrypsin, a diagnostic and prognostic marker of vernal keratoconjunctivitis. J Clin Diagn Res 8(5):CC08–10. https://doi.org/10.7860/JCDR/2014/6342.4362
Egbert PR, Lauber S, Maurice DM (1977) A simple conjunctival biopsy. Am J Ophthalmol 84(6):798–801. https://doi.org/10.1016/0002-9394(77)90499-8
Tsubota K, Takamura E, Hasegawa T, Kobayashi T (1991) Detection by brush cytology of mast cells and eosinophils in allergic and vernal conjunctivitis. Cornea 10:525–531. https://doi.org/10.1097/00003226-199111000-00011
Elder CJ, Bishop NJ (2014) Rickets Lancet 383(9929):1665–1676. https://doi.org/10.1016/S0140-6736(13)61650-5
Sharma A, Gupta R, Ram J, Gupta A (1997) Topical ketorolac 0.5% solution for the treatment of vernal keratoconjunctivitis. Indian J Ophthalmol 45(3):177–80
Oner V, Türkcü FM, Taş M, Alakuş MF, Işcan Y (2012) Topical loteprednol etabonate 0.5 % for treatment of vernal keratoconjunctivitis: efficacy and safety. Jpn J Ophthalmol 56(4):312–8. https://doi.org/10.1007/s10384-012-0152-5
Fahr A (1993) Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 24:472–495. https://doi.org/10.2165/00003088-199324060-00004
Erdinest N, Solomon A (2014) Topical immunomodulators in the management of allergic eye diseases. Curr Opin Allergy Clin Immunol 14(5):457–463. https://doi.org/10.1097/ACI.0000000000000089
Rondeau E (1992) Mécanisme d’action des nouveaux immunosuppresseurs: ciclosporine A, FK 506 et rapamycine (suite) [Mechanism of action of the new immunosuppressants: cyclosporin A, FK 506 and rapamycin]. Nephrologie 13(3):137
Yu L, Zhang H, Pan J, Ye L (2021) Pediatric usage of omalizumab: a promising one. World Allergy Organ J 14(12):100614. https://doi.org/10.1016/j.waojou.2021.100614
Tsui MC, Chiang BL, Wang IJ (2022) Successful treatment and prevention of the recurrence of refractory vernal keratoconjunctivitis with dupilumab. Clin Exp Ophthalmol 50(9):1100–1103
Fukuda K, Kishimoto T, Sumi T, Yamashiro K, Ebihara N (2023) Biologics for allergy: therapeutic potential for ocular allergic diseases and adverse effects on the eye. Allergol Int 72(2):234–244. https://doi.org/10.1016/j.alit.2022.09.005
Nahum Y, Mimouni M, Livny E, Bahar I, Hodak E, Leshem YA (2020) Dupilumab-induced ocular surface disease (DIOSD) in patients with atopic dermatitis: clinical presentation, risk factors for development and outcomes of treatment with tacrolimus ointment. Br J Ophthalmol 104(6):776–779. https://doi.org/10.1136/bjophthalmol-2019-315010
Cheng J, Jiang L, Morrow NC, Avdic A, Fairley JA, Ling JJ et al (2021) Recognition of atopic keratoconjunctivitis during treatment with dupilumab for atopic dermatitis. J Am Acad Dermatol 85(1):265–267. https://doi.org/10.1016/j.jaad.2020.09.046
Ghiglioni DG, Cozzi L, Pigazzi C, Bruschi G, Osnaghi S, Colonna C et al (2023) Improvement of atopic keratoconjunctivitis during treatment with upadacitinib for atopic dermatitis. Austin J Dermatolog 10(1):1103
Anesi SD, Tauber J, Nguyen QD, Chang P, Berdy GJ, Lin CC et al (2022) Lirentelimab for severe and chronic forms of allergic conjunctivitis. J Allergy Clin Immunol 150(3):631–639. https://doi.org/10.1016/j.jaci.2022.03.021
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Daniele Ghiglioni had the idea for the article. Gaia Bruschi performed the literature search. Daniele Ghiglioni and Gaia Bruschi drafted the work. Laura Cozzi, Daniele Ghiglioni, Silvia Osnaghi, Francesco Viola, and Paola Marchisio critically revised the work. All authors read and approved the final manuscript.
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Bruschi, G., Ghiglioni, D.G., Cozzi, L. et al. Vernal Keratoconjunctivitis: A Systematic Review. Clinic Rev Allerg Immunol 65, 277–329 (2023). https://doi.org/10.1007/s12016-023-08970-4
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DOI: https://doi.org/10.1007/s12016-023-08970-4