**4. Ocular complications with topical or systemic treatments**

Allergic reactions to medication could generate ocular manifestations ranging from mild to severe and it would not be considered infrequent. Demonstration of allergy to topical medi‐ cations could not be easily evaluated by allergen test, but give some information. Direct provocation in conjunctiva with suspicious drug has been reported, [53] the authors of this review do not recommend this method as a diagnostic protocol, however this test could be used as a research tool to investigate immune responses during allergy to topical medica‐ tion. To evaluate ocular allergy to drug medications, epicutaneous allergen test and immedi‐ ate-reading intradermal tests are carried out to diagnose immediate hypersensitivity reactions, while atopy patch tests are usually performed to evaluate delayed reactions, re‐ viewed in [38, 54] with this diagnostic methodology, Wijnmaalen et al reported that the most frequent medication-associated allergies were directed against tobramycin, neomycin sulphate and thimerosal. [55]

Mild to severe ocular reactions to drug-medications are also associated with systemic medi‐ cations (Figure 3) and in some extreme cases could be life threatening or lead to blinding disease such Stevens Johnson syndrome. If Systemic reactions to medications are mediated by IgE hypersensitivity, it could be easy evaluated by flow cytometry with the Basophil Ac‐ tivation Test. (Figure 4)

Principle of this test is simple, basophils are activated in vitro by suspicious medication, if basophils are sensitized to the drug, basophils became active and up regulate on its surface a molecule named CD63. [56] CD63 is an intracellular lysosomal protein whose surface ex‐ pression is up regulated also on activated platelets, degranulated neutrophils, monocytes, macrophages, and endothelium. To be sure that CD63 expressing cells are basophils, ana‐ lysed cells are also labelled against CD123 and HLA-DR. CD123 is the IL-3Rα, the granulo‐ cytic line, including basophils, express constitutively this cluster of differentiation; [57] while HLA-DR is expressed on B lymphocytes, monocytes, macrophages, activated T lym‐ phocytes, activated natural killer (NK) lymphocytes, but is absent in Basophils. Altogether means that by flow cytometry basophils would be CD123+HLA-DR- and only if they were activated by IgE-allergen or drug-medication basophils would be CD63+ [58] (Figure 4).

eosinophils or the release of IL-6, IL-8, CCL5/RANTES, and TNF-α from a human mast cell line with equal potency as dexamethasone, whereas it was clearly less potent than this glu‐ cocorticoid in inducing annexin I and CXCR4 expression on the human eosinophil surface; in other hand, animal model of allergic conjunctivitis showed that mapracorat was similar to dexamethasone eye drops in analogous reduction in clinical symptoms of allergic conjuncti‐ vitis and conjunctival eosinophil accumulation. [47] The authors suggest this novel gluco‐

Omalizumab is a biological engineered molecule, targeting the Cε3 domain of the IgE mole‐ cule. It binds with free IgE and prevents free IgE from attaching to high-affinity IgE receptor (FcεRI) on effector cells such as mast cells, basophils and also on dendritic cells. An IgE-anti-IgE complex is formed, and as a result, free IgE is decreased. [48] Omalizumab has been well studied and used in treatment of asthma [49, 50, 51] and other allergic diseases such as uriti‐ caria and and stational rhinitis [52] Like other immunomodulators mentioned above, clinical trials with allergic conjunctivitis patients are needed to asses the real impact in ocular aller‐

Allergic reactions to medication could generate ocular manifestations ranging from mild to severe and it would not be considered infrequent. Demonstration of allergy to topical medi‐ cations could not be easily evaluated by allergen test, but give some information. Direct provocation in conjunctiva with suspicious drug has been reported, [53] the authors of this review do not recommend this method as a diagnostic protocol, however this test could be used as a research tool to investigate immune responses during allergy to topical medica‐ tion. To evaluate ocular allergy to drug medications, epicutaneous allergen test and immedi‐ ate-reading intradermal tests are carried out to diagnose immediate hypersensitivity reactions, while atopy patch tests are usually performed to evaluate delayed reactions, re‐ viewed in [38, 54] with this diagnostic methodology, Wijnmaalen et al reported that the most frequent medication-associated allergies were directed against tobramycin, neomycin

Mild to severe ocular reactions to drug-medications are also associated with systemic medi‐ cations (Figure 3) and in some extreme cases could be life threatening or lead to blinding disease such Stevens Johnson syndrome. If Systemic reactions to medications are mediated by IgE hypersensitivity, it could be easy evaluated by flow cytometry with the Basophil Ac‐

Principle of this test is simple, basophils are activated in vitro by suspicious medication, if basophils are sensitized to the drug, basophils became active and up regulate on its surface a molecule named CD63. [56] CD63 is an intracellular lysosomal protein whose surface ex‐ pression is up regulated also on activated platelets, degranulated neutrophils, monocytes,

corticoid receptor agonist as a candidate to be used in clinical trials of ocular allergy.

**4. Ocular complications with topical or systemic treatments**

**3.3. Omalizumab and allergic diseases**

gic diseases.

52 Common Eye Infections

sulphate and thimerosal. [55]

tivation Test. (Figure 4)

**Figure 3.** Clinical photograph of a patient with ocular reaction against systemic steroids. Excisional biopsy revealed an extensive eosinophilic infiltrate remaining angiocentric eosinophilic fibrosis. Demonstration of drug allergy was per‐ formed by flow cytometry.

**Figure 4.** Representative cytometer data of Basophil activation test. Analysis gates are shown at upper dot plots. Up‐ per left, a gate was drawn on CD123 positive cells according to SSC characteristics; these cells correspond mainly to basophils. Upper right, A second gate is performed on HLA-DR negative cells; Dot plots of gated CD123+HLA-DR- cells (basophils) are displayed. Low left, negative test; Low right, Positive test, markedly up regulated expression of CD63 is observed.

#### **5. Conclusions**

As the prevalence of allergic disease increases around the world, resistance to antibiotics/ antivirals/or antimicotic drugs grows, and virulence of microorganisms improves its capaci‐ ty of infection, it is clear that more effective therapies and disease-modifying agents are needed. Only treatment evolution will be obtained understanding immune pathophysiologi‐ cal mechanism underlying infectious and allergic diseases. The authors of this review are convinced that immunomodulation is part of our future as health professionals and are working today to make it posible as soon as posible.
