Alexis Ceecee Zhang, Alex Muntz, Michael T M Wang, Jennifer P Craig and Laura E Downie

Published: July 2020

Abstract:

“There is increasing clinical and research interest in the potential contribution of Demodex to ocular surface disease. The aim of this systematic review was to summarise and synthesise current clinical evidence relating to the aetiology, diagnosis and treatment of ocular Demodex…

… A total of 87 studies were eligible for inclusion, including two systematic reviews.

Most studies (60%) were observational, describing the prevalence of ocular Demodex in different clinical populations. There was a high degree of variability in the epidemiological data derived from cross-sectional aetiology studies. There was mostly consistent evidence to support an association between ocular Demodex and chronic blepharitis.”

Findings:

“Several studies have reported Demodex infestation to be more frequent in older individuals and in people with blepharitis.

A prospective study by Bonnar et al., involving 100 consecutive pre-operative cataract patients, found that 53% of patients showed varying degrees of demodectic eyelash cuffing, but emphasised that this did not necessarily indicate pathology as the cuffing was not associated with eyelid redness, swelling or flaking.

Two studies reported that the number of Demodex mites on the eyelashes significantly correlated with increasing age.

Lee et al. also described a strong correlation between the number of mites and the severity of ocular dis- comfort. Erbagci et al. observed a positive correlation between advancing age and ocular Demodex mite number in the control group of a study that investigated the relationship between demodicosis and BCC; the correlation was not observed in individuals with BCC.

There may be an association between ocular Demodex infestation and rural living, spectacle wear and microscopy use, although further research is required to confirm these initial reports. The species D. folliculorum was found to be more prevalent than D. brevis in both community populations and those with blepharitis. D. brevis has been reported to be more common in individuals with cylindrical eyelash dandruff and chalazia…

… Anterior blepharitis affects the external aspect of the eyelid, with inflammation primarily centred on the eyelashes, eyelash follicles and eyelid skin. Posterior blepharitis involves inflammatory changes to the posterior aspect of the lid margin, including the meibomian glands and tarsal plate…

… The relationship between Demodex mites and blepharitis may not be causal, but instead may result from a common association with one or more other factors, such as poor hygiene or excessive sebum production…

D. folliculorum primarily inhabits the base of eyelashes, feeding on sebum and follicular and glandular epithelial cells.

Demodex in ciliary follicles dilate and irritate the pores.

The mites possess sharp mouth parts, resembling an ‘oral needle’; they burrow deep into the eyelash base, causing epithelial abrasion, follicular distension, hyperplasia, and hyperkeratinisation in the eyelash base…

… Demodex mites can also carry bacteria, such as Staphylococci sp. and Streptococci sp., on their surfaces, which have the capacity to disrupt the homeostasis of the ocular microbiome.

In a healthy population, Lee et al., found a similar bacterial distribution on eyelashes of people with and without D. folliculorum. In contrast, Zhu et al. recently reported higher bacterial colony counts and a higher incidence of Propionibacterium acnes on the eyelashes of individuals with blepharitis and D. folliculorum compared to controls with Demodex but no clinical signs of blepharitis. They concluded that D. folliculorum and P. acnes may have a role in the pathogenesis of chronic blepharitis.

Bacillus oleronius bacteria have also been identified to commonly coexist with Demodex.

Li et al. identified a strong correlation between serum B. oleronius reactivity and ocular Demodex, suggesting bacterial overload could trigger host inflammatory cascades that contribute towards the clinical profile of blepharitis. This concept is supported by the findings of Szkaradkiewicz et al., who suggested B. oleronius bacteria may be an important co-pathogen in the development of chronic blepharitis. However, it is unclear whether B. oleronius are associated with all Demodex mites or only in cases characterised by active eyelid inflammation…

… Rosacea: Rosacea is an inflammatory dermatological condition characterised by facial flushing, telangiectasias, and papules and pustules on the skin.

Individuals with rosacea are considered predisposed to ocular Demodex as a result of congested oil-producing glands, which create a favourable environment for the mites to populate.

Demodex mites have also been described to be associated with, and likely play a causative role in, both papulopustular and erythemato-telangiectatic rosacea, by obstructing sebaceous ducts and hair follicles, directly damaging follicular epithelia, and by acting as a vector for transmitting bacteria and microbes, such as B. oleronius.

That the surface of the skin is relatively more acidic in individuals with facial rosacea, may be additionally conducive to Demodex infestation by providing a favourable environment for hosting mite proliferation…

… Immune-mediated conditions: With conflicting reports in the literature, the potential link between Demodex-related pathology and immunocompromise is unclear. It has been hypothesised that immunocompromise may be a predisposing factor for Demodex mite overpopulation. In addition, it is possible that a compromised immune system may have a role in facilitating the transition of Demodex from a relatively innocuous parasite to a pathogen, without necessarily an increase in density.

Consistent with a link between immune response(s) and Demodex, the mites have been reported to produce a humoral factor that induces selective T-cell suppression to inhibit local immune responses.

This association is thought to be most common in patients with severe immunodeficiency, such as in acquired immunodeficiency syndrome (AIDS)….

… Individuals with proliferative diabetic retinopathy due to type-II diabetes have also been reported to have a higher prevalence of ocular Demodex compared with age-matched controls (55% vs 38%).

In a small prospective study undertaken in Turkey, ocular demodicosis was found to be more common among females with gestational diabetes (n=33) relative to a group of pregnant women without gestational diabetes (n=30, controls) (24% vs 3%), as determined by eyelash sampling.

A sub-group analysis of the gestational diabetes group revealed that the density of eyelash Demodex mites was significantly higher in individuals with poorly regulated blood glucose (based upon their postprandial 1st- and 2nd-h glucose values)…

… Allergic rhinitis: Allergic rhinitis, also known as hayfever, is a common chronic condition characterised by nasal congestion, rhinorrhea, sneezing, ocular itching and lacrimation. One study, undertaken in a hospital setting in Turkey, considered the relationship between ocular Demodex and allergic rhinitis.

The frequency of Demodex mites on the eyelashes (51% vs 38%) and facial skin (38% vs 12%) was higher in individuals with allergic rhinitis (n=63) relative to controls (n=65). The authors hypothesised that allergic rhinitis could facilitate the colonisation of Demodex by adversely affecting the anatomical clearance of eyelashes, and that ocular symptoms, such as itchy eyes and tearing that frequently accompany nasal symptoms in allergic rhinitis, may facilitate the ocular localisation of Demodex mites…

Treatment:

“Synthesising data from 15 studies, the authors reported that all treatments aside from ‘usual eyelid hygiene’ decreased mite counts, with no significant difference in effect between systemic and local treatments (overall effect size: 1.68, 95% CI: 1.25 to 2.12).

Compared with pre-treatment, all interventions except for CHEO, metronidazole 2% ointment and systemic metronidazole improved mite eradication rates (overall effect size: 0.45, 95% CI: 0.26 to 0.64). All treatments were reported to reduce ocular symptoms, aside from CHEO (overall effect size: 0.76, 95% CI: 0.59 to 0.90), with no difference between local versus systemic treatment…

… Tea tree oil is the most common component of eyelid cleansing products for treating ocular demodicosis.

This essential oil derives from the leaves of the Australian Melaleuca alternifolia tree and, in addition to being toxic to Demodex, has anti-inflammatory, anti-fungal and antimicrobial properties.

Although tea tree oil has ~100 components, terpinen-4-ol has been determined as the most active pharmacological constituent for eradicating Demodex mites.

Topical products are available in a range of formulations. Higher doses can cause skin irritation, and may be toxic if ingested; the use of 100% tea tree oil is therefore discouraged.

Patch testing is recommended prior to use to avoid allergic contact dermatitis, particularly for products that have had prolonged exposure to light and/or air as sensitizers build-up over time.

Although adverse events from using topical tea tree oil are typically minor and self-limiting, they can be minimised by using an appropriately-diluted topical formulation and only using products that have been stored according to the manufacturer’s directions (e.g., used before the best-before date, and stored in a cool area (<25°C) in a light-minimising glass bottle, away from sunlight)…

… Improvement in symptoms and signs was recently reported in a small case series in which weekly 50% tea tree oil eyelid scrubs and daily tea tree oil shampoo scrubs were used for a minimum of 6 weeks in a group of patients who failed the above [standard] treatment methods.’

In contrast, the UK College of Optometrists Clinical Management Guidelines (2018) state that ‘Demodex mites can be dose-dependently killed by weekly lid cleansing with 50% tea tree oil, but this should be undertaken only by experienced practitioners as such preparations are toxic to the ocular surface. Preparations containing 4-terpineol (an active ingredient of tea tree oil) are commercially available for patient use. (GRADE*: Level of evidence =low, Strength of recommendation =weak).’ As considered below, these differences in recommendations likely relate to a need for further research to more clearly define the patient populations that would benefit from treatment, the optimal intervention(s) and duration of treatment…

… We identified four eligible studies that evaluated anti-parasitic drugs for treating ocular Demodex; three studies investigated systemic treatments and one study examined a topical, anti-parasitic agent. Only one RCT (Level II evi-topical, anti-parasitic agent. Only one RCT (Level II evidence) was identified, which examined combined oral therapy with ivermectin (two doses of 200 µgkg, 1 week apart) +metronidazole (250 mg, three times daily for 2 weeks) relative to oral ivermectin alone, in participants with treatment-resistant infestation with D. folliculurum.

Overall, combined therapy was reported to be more effective at decreasing the mean count of D. folliculorum. Two case series studies (Level IV evidence) investigated the effects of oral ivermectin in single arms of participants, diagnosed as having chronic refractory, or treatment resistant, blepharitis.

Holzchuh considered a dose of oral ivermectin (200 µgkg), repeated after seven days; Filho used oral 6 mg twice daily for one day, which was repeated after 14 days. Both studies reported a post-treatment reduction in ocular Demodex numbers relative to baseline, and reported no side effects in their respective treatment groups.

Intense pulsed light (IPL)

IPL, involving delivery of pulses of non-coherent light in the range of 500 to 1200 nanometres, is used to treat a range of dermatologic conditions, including rosacea and skin pigmentation.

More recently, IPL has been investigated as a potential intervention for treating MGD.

The capacity for IPL to affect Demodex mite viability was first reported by Prieto et al. in the context of cutaneous disease. It was hypothesised that the Demodex mite could contain a chromophore that rendered it vulnerable to the energy delivered by IPL.

Furthermore, it was proposed that accumulated energy might be absorbed by the exoskeleton to induce coagulative necrosis. There is also a possibility that the heat generated from IPL pulses may directly kill Demodex mites. The optimal temperature for Demodex viability is 16 to 20°C; temperatures above 54°C are thought to be lethal.

Whether IPL, used with the intent of treating MGD, can effectively and safely kill ocular Demodex may depend on the specific device that is used and the region the light pulse is applied. For example, Craig et al. noted that while IPL can induce a local increase in skin temperature with the E-Eye device (E-SWIN, France), the effect on external skin surface, immediately after treatment, was small (an increase of <1°C). The exact temperature reached at the target tissue (within the meibomian glands), as delivered by the light pulses, is unknown. However, an in vitro evaluation using the M22 IPL device (Lumenis, USA) suggested that five consecutive IPL pulses elevated the local temperature of a glass slide to 49°C and induced death of a Demodex mite on an epilated eyelash.

Zhang et al. investigated the efficacy of facial treatments with the LumenisâM22 IPL device for reducing ocular Demodex infestation, relative to lid massage with a sterile solution of tea tree oil mixed with petroleum jelly (5%, vol vol), 15 min daily. IPL was applied to the facial area using the proprietary ‘dry eye mode’ setting, and with energy parameters based on skin type and patient tolerance and/or comfort; a total of three treatments were applied over 90 days.

The study population involved 40 participants with ocular demodicosis. These authors reported no significant inter-group differences in eyelash Demodex count, eyelid margin abnormalities, conjunctival hyperaemia, corneal staining with fluorescein, meibomian gland expressibility or tear production (quantified using the Schirmer I test). The ocular Demodex eradication rate was described to be more complete with IPL (100%) relative to the comparator group (75%).

Given this is the only currently-published RCT evaluating the efficacy of IPL as a treatment for Demodex, further research is required to corroborate this promising finding.

Conclusions:

This systematic review has captured the landscape of clinical evidence relating to the prevalence, aetiology, diagnosis
and treatment of ocular Demodex.

In terms of epidemiology, this review found high variability in the reported prevalence of ocular Demodex in different clinical populations. In this respect, there remains a need for sufficiently powered, prospective cohort studies,

in well-defined clinical populations, to more definitively ascertain whether Demodex is an aetiological factor in anterior eye conditions. Although often considered a ubiquitous, non-pathogenic parasite, Demodex may be a potential
causative agent in several ocular surface conditions, in particular blepharitis. Ocular Demodex has been relatively consistently associated with increasing age and facial rosacea.

The question around the relative pathogenicity of Demodex in ocular surface disease also relies on accurately determining the severity of infestation, given that mites can be present in healthy, asymptomatic individuals. It is therefore crucial to determine what a minimal, clinically relevant level of infestation is.

A range of diagnostic methods has been investigated for ocular Demodex, including eyelash epilation and light microscopy, eyelash manipulation and imaging of the eyelash follicle using IVCM. Once again, each method has relative strengths and limitations, and no method is currently universally considered as a gold standard.

Future research in this area should seek to further develop and improve validated diagnostic tools with enhanced sensitivity and specificity for ocular Demodex infestation. Nevertheless, the presence of blepharitis with

CD during a slit lamp examination should alert the clinician to the likelihood of associated ocular demodicosis.

Visual examination of the eyelashes, with epilation, manipulation or IVCM, is then recommended to establish a diagnosis.

In terms of interventions for treating ocular Demodex, of the 11 included RCTs, nine (82%) were published in the past two years. We also identified six unpublished RCTs on clinical trial registries (Table 5). These findings reflect growing interest in Demodex as a contributory factor to ocular surface disease and a need to consider this factor in cases that are recalcitrant to conventional therapy.

In general, topical formulations containing tea tree oil were reported to be effective in reducing the number of Demodex mites on eyelashes. Other emerging treatment options include anti-parasitic drugs and IPL, but there is currently limited high-quality evidence to ascertain the efficacy of these treatments for ocular Demodex with any certainty.

Our review highlights notable gaps in the evidence, in particular high-quality studies to inform best practice. In particular, there is still a need to clearly establish the relative efficacy of different interventions in head-to-head active comparator studies, as well as optimal dosing schedules and treatment duration.”

You can find out more details about this study here