Insect bite hypersensitivity is the most common allergic skin disease in horses, causing a localised pruritus to the feeding sites of the biting midge (Scott and Miller, 2011; Schaffartzik et al, 2012) (Figures 1 and 2). The seasonal nature of this disease has been attributed to the biting insects of the genus Culicoides, which are traditionally associated with dry warm days between the spring and autumn in the UK (Meiswinkel et al, 2000; Van Grevenhof et al, 2007). Midges tend to congregate in breeding sites around densely wooded areas, or near stagnant water, leading to increased numbers of biting insects (Carpenter et al, 2008). However, the prevalence of insect bite hypersensitivity is also subject to considerable variations depending on the equine's breed and, even more so, on family lineage (Littlewood, 1998; Van Grevenhof et al, 2007).
It is important to have an effective understanding of the pathogenesis of insect bite hypersensitivity at a cellular level. Avoiding allergens may seem a sensible suggestion, but the consequences of climate change mean that it is becoming ever more difficult to evade the Culicoides midges. As it stands, a total of 27 salivary gland proteins have been identified as causative allergens in insect bite hypersensitivity (Novotny et al, 2021). Therefore, the management of this condition will likely require a greater understanding of targets within the cellular allergic response. The phenotype of insect bite hypersensitivity is predominated by a Type I hypersensitivity reaction in which allergen-specific T cells with a Th2-like cytokine profile and specific IgE are involved (Schaffartzik et al, 2012). IL-4 and IL-13 also play important roles (Jonsdottir et al, 2019), and in the latter phase of Type 1 hypersensitivities, TH2-derived IL-5 will trigger an eosinophilia (Larché et al, 2006). IL-31 is also derived from Th2 cells and is integral in the manifestation of allergic pruritus via interactions with receptors on the dorsal root ganglia within the skin (Sonkoly et al, 2006).
Delayed hypersensitivities (Type 4) are also characterised by IL-5 producing TH2 cells and eosinophilia, which has led some clinicians to interpret insect bite hypersensitivity as a combination of Type 1 and Type 4 hypersensitivity (Kurotaki et al, 1994). However, this is difficult to discern as separate from chronic and repeated inflammatory changes, which ultimately lead to eosinophils as the predominant cell type associated with insect bite hypersensitivity.
Approaches to managing insect bite hypersensitivity can be divided into four categories: allergen avoidance, skin integrity, anti-inflammatories and immunotherapy.
Allergen avoidance
Although many different approaches for treatment of insect bite hypersensitivity have been described, the most effective method is the avoidance of Culicoides allergens. Avoidance or reduced allergen exposure is commonly achieved by covering the skin with rugs (Olsén et al, 2011). Anecdotally, it would seem the most effective of these rugs is the Boett Sweet Itch Blanket, but this is also by far the most expensive. Beside these rugs, horses can be stabled from mid-afternoon to mid-morning to avoid peak feeding times of midges, which are crepuscular feeders, around dawn and dusk (Ayllón et al, 2014).
Regions with lower insect populations tend to be near the sea-side, or sometimes higher altitudes, providing dense heathered and woody areas are avoided. Mosquito netting can be used to seal stable doors and windows to minimise the entry of Culicoides (Baker et al, 2015; Lincoln et al, 2015).
Some owners readily apply insect repellants, with variable results. Topical cypermethrin is the only scientifically reported pour-on to partially protect against biting flies, as exposure can kill midges if they are exposed for at least 3 minutes (Papadopoulos et al, 2010). Whether this is enough time before an insect-bite results in clinical signs remains to be determined. Some essential oils, such as lemon grass extract, have been proven to be repellent in laboratory studies, and have been considered an alternative to chemical compounds (Baldacchino et al, 2013; González et al, 2014).
Skin integrity
Allergic reactions result in inflammation and pruritus, which will lead to trauma and subsequent compromise to skin integrity. Although skin health is not necessarily an impenetrable barrier to Culicoides midge bites, there is certainly evidence that topical emollients and in-feed supplementation may aid in reducing clinical signs of insect bite hypersensitivity.
Omega fatty acids 3 and 6 are approved for the treatment of canine atopic dermatitis (Müller et al, 2016; Olivry et al, 2010), and while they are thought to help stabilise the epidermal lipid barrier (Hansen et al, 1985), there is also good evidence that they aid in the suppression of enzymes integral to the inflammatory cascade (Vaughn et al, 1994). Considering these findings, a study by O'Neill et al (2002) suggested some benefit to using flaxseed oil to mitigate the skin test response to Culicoides extract from hypersensitive horses. Although this is encouraging, Friberg and Logas (1999) found that linseed oil supplementation had no effect on the level of pruritus observed between control and experimental groups. Given that beneficial effects have only been seen at doses of 1g/kg of bodyweight, the cost of the oil volume required can hinder its use in horses and ponies. High fat feeds should be avoided in obese horses because of their high energy contents (Durham et al, 2019), so feeding large amounts of oil could be contraindicated in patients that have clinical indicators of equine metabolic syndrome.
There is only one more recent study that showed topical creams to be useful for resolving lesions incurred by insect bite hypersensitivity, but pruritus persisted in the horses sampled and some had adverse reactions to the emollient (Humann and Muller, 2019). Topical essential oils have also shown some promise in improving skin lesions and pruritus scores in a small group of horses (Cox et al, 2020), but a commercial essential oil product can prove difficult and expensive to source at the correct concentration.
Despite the lacking scientific evidence, the consensus across many veterinarians is that regular shampooing can be one of the most beneficial tools with regards to soothing skin and repairing the skin barrier (Table 1) (Loeffler et al, 2018). However, owner compliance is the determining factor in the success of this therapy.
Table 1. Examples of common shampoos and conditioners used to improve skin integrity for horses and ponies suffering from insect bite hypersensitivity and other allergic skin diseases
| Topical product | Primary base | Mode of action | Frequency of application |
|---|---|---|---|
| Coatex (VetPlus) | Oatmeal shampoo |
|
Bathe once–twice weekly |
| Episooth (Virbac) |
|
Bathe once–twice weekly | |
| DermAllay (Dechra) |
|
Bathe once–twice weekly | |
| Skin So Soft (Avon) | Jojoba oil conditioner |
|
Apply to affected areas once daily |
No commercial essential oil product exists on the market that is equivalent to that used by Cox et al (2020).
Anti-inflammatories
The primary focus of controlling the inflammatory process of insect bite hypersensitivity is often through the use of corticosteroids, but other pharmaceutical preparations are available to help in management of the disease.
Topical steroids in the form of creams or sprays are rarely effective as a sole treatment, but when used in conjuction with insect avoidance measures and management changes, they can help avoid the need for systemic steroids, or reduce the systemic dose if used as an adjuct to oral steroids. No topical steroid products are licensed for use in horses (Table 2), but there are many preparations available for use in small animal allergic skin disease. These topical products can become costly and inefficient when treating large areas of affected skin.
Table 2. Listed formulations of topical corticosteroids that can be applied to localised areas of pruritus
| Topical corticosteroid | Commercial formulation |
|---|---|
| Hydrocortisone | Cortavance cutaneous spray (Virbac) |
| Triamcinolone | Dermanolon cutaneous spray (Dechra) |
| Betamethasone | Isaderm cream (Dechra)Betnovate cream (GSK)Betafuse cream (Norbrook) |
Antihistamines can be of some use as a sole treatment in allergic horses, but have been shown to work best as a preventative because of histamine having a greater effect in the initial phases of insect bite hypersensitivity (Marsella, 2013; Loeffler et al, 2018). Therefore, antihistamines should ideally be given before exposure to Culicoides bites (Marsella, 2013). There are no licenced antihistamine formulations for horses, so there are a wide range of doses used (Table 3). One study has shown that cetirizine has no benefit in the treatment of insect bite hypersensitivity (Olsén et al, 2011). The use of antihistamines in combination with corticosteroids might be effective at reducing the systemic steroid dose, while effectively managing pruritis associated with insect bite hypersensitivity.
Table 3. Listed corticosteroids and antihistamines with associated dose ranges, frequency of administration and commercial products available
| Drug | Dose | Frequency | Trade name | |
|---|---|---|---|---|
| Corticosteroids | Prednisolone | 1mg/kg per os | Once daily | EquiPred (Virbac)Equisolon (Dechra) |
| Dexamethasone (per os) | 0.01–0.1mg/kg | Once daily or every other day | Dexadreson (MSD Animal Health)Colvasone (Norbrook)Rapidexon (Dechra)Duphacort Q (Zoeitis | |
| Dexamethasone (intravenous) | 0.01–0.1mg/kg | Once daily | ||
| Antihistamines | Chlorpheniramine | 0.2–0.5mg/kg per os | Twice or three times daily | Piriton (GSK) |
| Hydroxyzine hydrochloride | 0.25–1.5mg/kg per os | Twice or three times daily | Atarax (GSK) |
For cases where pruritis and self-trauma associated with insect bite hypersensitivity cannot be controlled with topical therapy and antihistamines, systemic medication with corticosteroids can be implemented. Injectable therapy is often initially suitable for acute pruritic episodes, but this is rarely practical in the long term (Mora Pereira et al, 2018). Oral corticosteroid treatment could be safer, although care should still be taken in horses with susceptibility to laminitis, and once clinical remission is achieved, the aim should be to reduce the dose to the lowest effective maintenance dose to limit the risk of undesirable side effects, ideally on an alternate day basis.
Immunotherapy
Despite the popular use of allergen-specific immunotherapy in horses with atopy, this has not translated into treatment of insect bite hypersensitivity. The trials exploring allergen-specific immunotherapy use in horses with insect bite hypersensitivity used whole body extract sourced from midges that were unfamiliar to the horses' environment (Barbet et al, 1990; Anderson et al, 1996; Ginel et al, 2014). At best, the results of these studies are weakly positive, and do not always take into account improved environmental control during the trial. The identification of pure salivary gland proteins from various Culicoides species will be integral to successful allergen-specific immunotherapy in horses with insect bite hypersensitivity.
It is important to remember that the aim of allergen-specific immunotherapy is to stimulate an appropriate Th1/Treg cell type response, as opposed to a Th2 type response. This is the possible basis behind the anecdotal success of the Insol® Dermatophyton (Boehringer Ingleheim) ringworm vaccine. Despite a lack in statistically significant clinical improvement, one study did demonstrate increased inflammatory markers indicative of a Th1/Treg cell type response (Gehlen at al, 2016). Two injections (1ml) are given intramuscularly, approximately 4 weeks apart, before the start of the sweet itch season. This can be followed by booster injections every 6 months to 1 year. It is important to note that this protocol is based on a small placebo control trial that found no statistical improvement in horses that received the vaccine (Gehlen et al, 2016).
On an experimental level, there have been some exciting advances in targeting interleukins that are integral to the inflammatory process involved in insect bite hypersensitivity. The use of lokivetmab (Cytopoint, Zoetis) is now commonplace in the treatment of canine atopic dermatitis following successful doubleblind placebo control trials (Michels et al, 2016; Moyaert et al, 2017). This is a dose-dependent monoclonal antibody designed to target IL-31. Trials using an equine active immunisation equivalent have been reported, providing evidence for a role of IL-31 in insect bite hypersensitivity, and documenting improved improved clinical scores of patients following treatment (Olomski et al, 2020; Fettelschoss et al, 2021).
Attempts have also been made to produce an active immune response against IL-5. The vaccine was found to initially reduce peripheral eosinophil counts, and consequently improved clinical symptoms in the second year of vaccination (Fettelschoss-Gabriel et al, 2019).
Conclusions
Although many management methods remain the same, our understanding of insect bite hypersensitivity is ever improving. With greater knowledge of the immunopathogenesis of this debilitating disease comes an ability to tackle new targets in the inflammatory and allergic process.
KEY POINTS
- The sweet itch ‘season’ is becoming broader as a result of changes in the climate.
- Our understanding of the immunopathogenesis is still developing, but the presence of IgE and eosinophils is consistent across all models.
- It is important to tackle the symptoms of sweet itch with a multimodal approach: allergen avoidance, skin integrity, anti-inflammatories, and immunotherapy.
- Pharmacological therapeutics have not changed for many years. A multimodal approach using corticosteroids and antihistamines can be attempted, but is not always effective.
- Scientific advances are happening in the field of immunotherapy, targeting IL-31 and IL-5. These have proven successful in small animal medicine.