DISCUSSION
VKC is characterized by a severe inflammatory pattern, generally resistant to standard anti-inflammatory therapies and sensitive to topical steroids or immunosuppressants.1,3
Several cytokines and chemokines play a pivotal role in keeping the inflammatory cascade active, as it results from previous studies. 3,6,8
The role of oxidative stress has been studied with increasing interest in several allergic or immune-mediated inflammatory diseases20, except for VKC.
Ocular oxidative stress has been investigated both in humans and in animal models in many eye diseases such as uveitis21, corneal inflammation22, and allergic keratoconjunctivitis23. To our knowledge in only one study, Tais H. Wakamatsu et al. 24 evaluated tears and brush cytology samples in 14 adolescent-young adults with atopic dermatitis and allergic conjunctivitis, to assess if there were oxidative-stress related changes in these patients in comparison to healthy children. The authors24 found higher percentages of cells positively stained for the early phase lipid peroxidation marker and the late phase lipid peroxidation marker, in palpebral conjunctiva and tears, suggesting an increased lipid peroxidation status in atopic keratoconjunctivitis, leading to endothelial damage.
Dadaci Z et al., evaluated oxidative stress parameters in 35 patients with seasonal allergic conjunctivitis (SAC) during the pollen season vs. 38 healthy subjects, demonstrating higher levels of oxidative stress parameters in SAC compared to controls, outlining a possible role of oxidative stress in the pathogenesis of this disease.2
This study reports new and intriguing results, never investigated in VKC, providing the first evidence that oxidative stress characterizes VKC disease. We found significantly higher levels of hydrogen peroxide in the serum and in the tears of children in the active phase of disease compared to VKC treated children and CT. No significant differences were observed between CT and VKC undergoing CsA. Moreover, a linear regression analysis reported a significant correlation between serum and tear H2O2 levels.
The reduction of H2O2 values in tears and the serum of VKC treated children, could be considered a parameter for the efficacy of CsA treatment, confirming that this therapy effectively controls both systemic and local inflammation.
CsA reduces H2O2-induced intracellular generation of reactive oxygen species, protecting against H2O2-induced cell injury.25
To confirm the importance of the timely use of CsA, Leonardi A et al. have conducted a trial where 169 children were randomized to receive CsA 0.1% (1 mg/ml) eye drops with higher dosages compared to lower ones, reporting a better efficacy of high-dose CsA to improve keratitis, symptoms and also the quality of life of VKC children.26
Moreover, CsA can interrupt both the helper T-lymphocyte proliferation and the IL-2 production, which inhibit the release of histamine from basophils and mast cells, reducing IL-5 levels.27
This finding leads us to speculate that local immunosuppressive therapy with CsA may control the ocular immunological response and the systemic one.5,7
Although eyes are defined as immunological sanctuaries, the finding of high local H2O2 values lets us speculate that H2O2 could play a key role in ocular dysfunction and inflammation, which is responsible for the serious complications typical of VKC. This reinforces the importance of a prompt start of target therapy with CsA in VKC patients.
Our results must be interpreted, considering some limitations.
First of all, we have studied a small, single-center sample that needs to be implemented into a larger cohort. The presence of allergic diseases in 54% of VKC children may interfere with a realistic estimate of the systemic oxidative stress caused by VKC disease alone, rather than by other allergic coexisting conditions. However, the randomized distribution of these patients exceeds a possible risk of bias. Summing up, this is a pilot study with a cross-sectional design that may reports only associations between H2O2 mediated oxidative stress and inflammation in VKC children.
So further studies are warranted to confirm these results in a long-lasting follow-up.
Several questions remain unsolved, such as the correlation between oxidative stress and the degree of severity of VKC disease.