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.

Table 1 VKC epidemiology
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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.

Fig. 1
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Flow chart of the study selection

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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].

Fig. 2
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Flow chart of VKC diagnosis studies

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Fig. 3
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Flow chart of VKC treatment studies

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Characteristics of the included studies are reported in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14.

Table 2 Diagnosis systematic review
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Table 3 Diagnosis narrative reviews
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Table 4 Diagnosis prospective observational studies
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Table 5 Diagnosis retrospective observational studies
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Table 6 Diagnosis case series
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Table 7 Diagnosis case report
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Table 8 Therapy systematic reviews
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Table 9 Therapy narrative reviews
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Table 10 Therapy prospective observational studies
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Table 11 Therapy retrospective observational studies
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Table 12 Therapy cases series
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Table 13 Therapy case reports
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Table 14 Therapy randomized clinical trials
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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].

Table 15 Main finding in VKC
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Fig. 4
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Conjunctival hyperemia and Trantas dots present in VKC patients

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Fig. 5
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Papillae at the upper tarsal lid present in VKC patients

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Fig. 6
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Trantas dots present in VKC patients

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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]:

  • Tarsal VKC: characterized by the presence of papillae at the upper tarsal lid

  • Limbal VKC: characterized by the presence of gelatinous infiltrate at the limbus and Trantas dots

  • 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).

Table 16 Potential biomarkers in tears
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Table 17 Potential biomarkers using impression cytology
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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).

Table 18 Main finding in ocular cytology
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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).

Table 19 Main finding in conjunctival biopsy
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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]

  • avoiding contact with aeroallergens, like flowers and plants

  • avoiding prolonged sunlight exposure

  • wearing solar glasses

  • applying cold wraps on the eyes

  • using artificial tears that could remove or almost dilute allergens present on the ocular surface

  • 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.

Table 20 First line drugs in VKC
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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:

  • reducing leucocyte numbers and activity

  • blocking IL-2 production and the consequent clonal expansion of lymphocyte T helper

  • blocking fibroblast proliferation

  • interfering with cyclooxygenase 2 (COX2) activity and blocking prostanoid synthesis

  • 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

  • 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.

Table 21 Cyclosporine formulations in VKC from January 2016 to June 2023
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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).

Table 22 Tacrolimus formulations in VKC from January 2016 to June 2023
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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).

Table 23 Omalizumab treatment in VKC from January 2016 to June 2023
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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.

Table 24 Surgical treatment for VKC from January 2016 to June 2023
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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.