Allergic rhinitis and conjunctivitis are among the most common conditions treated in general practice, yet growing numbers of patients are weary of traditional pharmacological therapies. Enter ectoine, a naturally produced treatment just as effective as pharmaceuticals.
Allergic conjunctivitis (AC) is among the most common conditions seen in family medicine practice (Mehta 2018). In fact, allergies such as AC are the fifth leading group of chronic diseases, affecting as much as 40% of the first-world population (Abelson et al 2015). It has an increasing prevalence worldwide and comorbidity of AC and rhinitis is well recognised (Ackerman et al 2016). AC often co-occurs with rhinitis (in 66% of adults and up to 97% of children), asthma (in 16% of adults and 56% of children), and atopic dermatitis (in 25%-42% of adults and 33% of children) (Sanchez-Hernandez 2015).
AC is a collection of heterogeneous ocular inflammatory conditions mediated by mast cell activation, affecting the conjunctiva, eyelids, and cornea (Komi et al 2017). Conjunctivitis refers to inflammation of the conjunctiva, which is the thin tissue that covers the sclera (white part of the eye) (Castillo et al 2015). The conjunctiva is one of the most common sites of allergic inflammation because its mucosal surfaces are highly accessible to airborne allergens (Komi et al 2017).
AC is caused by an IgE-mediated mechanism or immediate hypersensitivity due to allergen direct contact on the conjunctival surface of sensitised patients, which elicits mastocyte activation and inflammatory mediators’ release (Miranda-Machado 2018). AC’s pathophysiology also has a genetic component, and is driven by the immune system’s sensitised response to antigens and environmental factors (Abelson et al 2015).
Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are the most common forms of ocular allergy subsets and they are estimated to affect 15–25% of the US population (Ackerman et al 2016). PAC differs from SAC in that the persistent IgE-mediated degranulation of mast cells prompts the recruitment of eosinophils (Miraldi and Kaufman 2014).
Despite being the most benign form of conjunctivitis, AC has a considerable effect on patient quality of life, reduces work productivity, and increases healthcare costs (Sanchez-Hernandez 2015). AC patients typically present bilaterally with itching, lacrimation, burning, vasodilation and chemosis; however, it can be asymmetrical (Ackerman et al 2016). AC generally affects both eyes, and patients report symptoms such as conjunctival pruritus (main symptom), tearing and a burning sensation. Blurred vision and photophobia can occur in the most severe cases (Sanchez-Hernandez 2015). Patients consider ocular itching the most disruptive symptom of AC, and may also complain of a concomitant foreign body sensation, blurring, and photophobia if there is corneal involvement (Ackerman et al 2016).
The acute or subacute symptoms of SAC fluctuate with temporal exposure to the offending airborne environmental antigens (Ackerman et al 2016). Seasonal/perennial allergic conjunctivitis is usually paired with acute manifestations when a person is exposed to allergens, with typical signs and symptoms including itching, redness, and tearing (Castillo et al 2015). The persistent symptoms of PAC arise from singular and/or multiple indoor allergens, such as animal dander, moulds and dust mites (Ackerman et al 2016). Reactions are exacerbated by prolonged or concentrated allergenic exposure, and often, comorbidity with dry-eye syndrome (Ackerman et al 2016).
The clinical signs of AC can be assessed by slit lamp examination, but if this is not possible, a light source combined with fluorescein staining can be used when abnormalities of the epithelial cells of the ocular surface are suspected (Sanchez-Hernandez 2015). Diagnosis is confirmed by positive results in skin tests with suspect allergens or serum specific IgE to whole allergens or their purified molecular components, although these are not always conclusive, since up to 24% of patients may be sensitised to multiple allergens (Sanchez-Hernandez 2015).
The eye is a potential target of allergic inflammatory disorders because of its marked vascularity, sensitivity of conjunctival vessels, and direct contact with the environment owing to its anatomical position; thus, to interact with offending antigens, it benefits from a complete array of immune cells and related molecular mechanisms (Komi et al 2017).
The late‐phase reaction is characterised by the release of chemokines including CCL11, CCL24, CCL5, monocyte chemoattractant protein‐3 (MCP‐3,CCL7), CCL13, and macrophage inflammatory protein 1α (MIP‐1α,CCL3) and the infiltration of eosinophils, basophils, T cells, neutrophils, and macrophages that generate a spectrum of other mediators adding to conjunctival inflammation (Komi et al 2017).
As with any allergic disease, general environmental measures are recommended and include specific actions to reduce exposure to house dust mites, moulds, animal dander, and pollen (Sanchez-Hernandez 2015). Other non-pharmacologic interventions are applied cold treatments (e.g., compresses soaked in water, preservative-free artificial tears, and saline solution), which act by washing allergens from the conjunctiva and constricting the conjunctival vessels, thus relieving oedema and hyperemia (Sanchez-Hernandez 2015).
Mast cell stabilisers inhibit degranulation and consequently the release of histamine by interrupting the normal chain of intracellular signals (Castillo et al 2015). Mast cell activation takes place in two phases: an acute phase, occurring within minutes, and a late phase, spanning from 6 to 72hours after exposure. The acute‐phase reaction is due to the release of preformed (eg, histamine) and inducible mediators after the cross‐linking of allergen‐specific IgE on the surface of resident MCs (Komi et al 2017).
Azelastine is a second-generation antihistamine applied topically as nasal spray or eye drops and often used as a treatment of allergic rhinitis, hay fever, and allergic conjunctivitis (Werkhauser et al 2014). Although azelastine is regarded as an effective treatment option for allergic rhinitis, common side effects, such as bitter taste of the drug and local irritation reactions and rare side effects such as fatigue or headache, can occur (Werkhauser et al 2014).
Cromoglycic acid is an anti-allergic drug which inhibits the degranulation of mast cells, thereby blocking the release of inflammatory mediators (Cox 1972). Cromoglycic acid is thought to be a safe medication, and adverse events which might occur are usually mild, such as sneezing and sensation of burning (Werkhauser et al 2014).
Ocular corticosteroids are the most potent anti-inflammatory agents because they interfere with intracellular protein synthesis and cause blockade of phospholipase A2, the enzyme responsible for the formation of arachidonic acid (Sanchez-Hernandez 2015). These drugs also act by inhibiting production of cytokines and migration of inflammatory cells (Sanchez-Hernandez 2015).
Not all of the pharmacological treatments are ideal, however, and many allergic rhinitis patients are still unsatisfied with the control of symptoms, complain about incomplete relief of symptoms, and suffer from unwanted side effects (Werkhauser et al 2014). Therefore, it is not surprising that increasing interest in the use of alternative and complementary medicine (CAM) for treating rhinitis exists (Roehm et al 2012). Thus, it was demonstrated that 40% of the American population uses CAM, 17% of which uses it for treating otorhinolaryngologic diseases (Roehm et al 2012). However, so far no general recommendation for the use of CAM can be given by ARIA guidelines as ambiguous study results are available (Werkhauser et al 2014).
A naturally produced treatment, ectoine (2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxyclic acid) is a compatible solute which is naturally produced by bacteria, conferring resistance to external stress factors such as extreme temperatures, high salt concentrations and ultraviolet radiation which has given rise to its extremolyte status (Eichel et al 2014). It acts via a mechanism called ‘preferential exclusion’ and ‘preferential hydration’, by which ectoine is expelled from proteins or lipid membranes, resulting in the modulation of the solvent characteristic of surrounding water and thus allowing ectoine to form a protective and stabilising hydrate capsule around the protein and therefore helps to protect biomolecules and proteins from irreversible structural modifications by inhibiting dehydration (Eichel et al 2014).
Its membrane stabilising as well as inflammation reducing capacities makes ectoine an interesting candidate for the treatment of allergic rhinoconjunctivitis (Werkhauser et al 2014). In a non-interventional study carried out with ectoine-containing eye drops, assessing its efficacy in comparison with azelastine nasal spray and eye drops, it was found that ectoine eye drops can safely be applied in patients with allergic rhinitis and conjunctivitis (Sonnemann 2014). Patients judged the tolerability of the product as similarly good as the azelastine products and the very low numbers of adverse effects reflected a very good safety profile (Sonnemann 2014).
In the study, it was shown that both the ectoine and the azelastine products resulted in a clear decrease of symptoms of allergic rhinitis over the study period of 7 days with no statistical differences found between the groups (TOSS) (Sonnemann 2014). Mean decreases in TOSS were −45.96% in the ectoine group and −44.98% in the azelastine group (Sonnemann 2014).
In vitro experiments have further shown that ectoine inhibits apoptosis, triggered by nanoparticles, and likewise blocks the activity of ceramides, which are regarded as central molecules in the sphingolipid metabolism as well as in the induction of apoptosis (Eichel et al 2014).
Perhaps the most promising characteristic of ectoine treatment, however, is the lack of adverse effects associated with it. During the two non-interventional study mentioned above, no serious adverse events (SAEs) occurred (Sonnemann 2014).
Taken together, ectoine containing eye drops has been demonstrated to be a promising alternative to pharmacological drugs with both good efficacy and a very good safety profile (Werkhauser et al 2014). As the ectoine eye drops act purely physically on the ocular mucosa, it makes those products particularly interesting for patients with reservations about pharmacological therapy (Werkhauser et al 2014).
The efficacy of ectoine-based products on eye symptoms is clearly clinically significant (Werkhauser et al 2014). In a clinical trial, ectoine reduced ocular symptoms such as ‘conjunctivitis’, ‘eye itching’ and ‘tearing’ significantly compared to azelstine (Werkhauser et al 2014). Study results clearly and consistently demonstrate good safety profiles of the ectoine products comparable to those of azelastine and even better to those of cromoglycate products (Sonnemann 2014).
This implies that ectoine is a feasible, natural alternative to current pharmacological treatments that could be an attractive alternative for the growing numbers of patients who do not want pharmacological medications (Werkhauser et al 2014).