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Under the lash:
Demodex mites in human diseases
Noreen Lacey,
University of Ireland Maynooth
Kevin Kavanagh, and
University of Ireland Maynooth
Scheffer C.G. Tseng
Ocular Surface Center and Ocular Surface Research Education Foundation, Miami
Abstract
Demodex mites, class Arachnida and subclass Acarina, are elongated mites with clear
cephalothorax and abdomens, the former with four pairs of legs. There are more than 100 species
of Demodex mite, many of which are obligatory commensals of the pilosebaceous unit of
mammals including cats, dogs, sheep, cattle, pigs, goats, deer, bats, hamsters, rats and mice.
Among them, Demodex canis, which is found ubiquitously in dogs, is the most documented and
investigated. In excessive numbers D. canis causes the inflammatory disease termed demodicosis
(demodectic mange, follicular mange or red mange), which is more common in purebred dogs and
has a hereditary predisposition in breeding kennels1. Two distinct Demodex species have been
confirmed as the most common ectoparasite in man. The larger Demodex folliculorum, about 0.3–
0.4 mm long, is primarily found as a cluster in the hair follicle (Figure 1a), while the smaller
Demodex brevis, about 0.2–0.3 mm long with a spindle shape and stubby legs, resides solitarily in
the sebaceous gland (Figure 1b). These two species are also ubiquitously found in all human races
without gender preference. The pathogenic role of Demodex mites in veterinary medicine is not as
greatly disputed as in human diseases. In this article, we review the key literature and our joint
research experience regarding the pathogenic potential of these two mites in causing inflammatory
diseases of human skin and eye. We hope that the evidence summarized herein will invite readers
to take a different look at the life of Demodex mites in several common human diseases.
Keywords
Demodex; eye disease; eyelash; hair follicle; mite; skin disease
The life cycle of the Demodex mite is approximately 14–18 days from an egg to the larval
stage of protonymph to deutonymph and finally to the adult stage (see Figure 1)2. Because
all adult mites have a limited life cycle, their ability to expand in numbers in a human host
depends on successful copulation by adult male and female mites in the opening of the hair
follicle (near the skin surface). Afterwards, the gravid female moves to the sebaceous gland
to deposit eggs, each of which gives rise to a larva and then a protonymph in the sebaceous
canal. A protonymph is brought to the opening of the hair follicle and matures into a
deutonymph, which crawls on to the skin surface, then re-enters a hair follicle to become an
adult. Therefore, during a life cycle, if adults can successfully copulate and produce the next
generation, the extent of Demodex infestation will gradually increase in the host over time.
Scanning electron microscopy reveals the special piercing mouthparts of D. folliculorum as
a sharp offensive weapon capable of destroying adipose tissue. Although it has also been
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Published in final edited form as:
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. 2009 August 1; 31(4): 2–6.
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proposed that mites feed on follicular and glandular epithelial cells, sebum is thought to be
the mite’s main food source. As a result, both Demodex species often coexist at the same
skin area and gather in the face, cheeks, forehead, nose and external ear tract, where active
sebum excretion creates favourable habitats and breeding conditions. Because these mites
are susceptible to desiccation, their lifespan is limited outside the living body, and direct
contact is required for transmission of mites from one individual to another. Consequently,
an effective regimen in eradicating Demodex infestation should include killing as well as
prevention of their copulation and transmission.
Implication of Demodex mites in human diseases
Although Demodex mites have been implicated as a cause of many human skin disorders,
their pathogenic role has long been debated3. Such a concern has been raised in part because
some Demodex mites can be found in the skin of asymptomatic individuals. Most
researchers attribute some skin diseases to Demodex only when their numbers are elevated.
To quantify the extent of Demodex infestation in the skin, a surface biopsy has been
standardized as the main method4. After cleaning the patient’s skin and a glass slide with
ether to improve adherence, a spot of cyanoacrylate adhesive (superglue) is applied on the
skin surface of interest before being overlaid with a slide. After approximately 1 minute on
the skin, the slide is gently removed and covered by one drop of immersion oil before being
mounted with a coverslip. The density of D. folliculorum is measured by counting the
number of mites on the slide in a pre-marked surface area of 1 cm2 at a magnification of ×40
and ×100 under a microscope. Because hairs together with the superficial horny layer are
sampled with minimal sebaceous glands, D. folliculorum is primarily found. Using this
method, Demodex infestation is thought to be non-existent in healthy children of less than
one decade of life, increasing in an age-dependent manner, and found probably 100% in
elderly skin, unless some eradicating measures are taken. It remains unclear whether such an
age-dependent increase is due to cumulative colonization or an increase in sebum levels with
age. This quantitative biopsy method has also been used for monitoring the efficacy of
various therapies in eradicating D. folliculorum in the skin.
Since 1932, Demodex infestation has been implied as a causative role in rosacea, a chronic
inflammatory dermatosis of the convexities of the central face characterized by the presence
of multiple small dome-shaped erythematous papules and papulopustules arising on a
background of fixed inflammatory erythema. It has been proposed that the pathogenic
potential increases if a mite density is higher than five per cm2 1. Several studies have
shown a higher mite density on the faces of rosacea patients than on those of age- and sex-
matched non-rosacea controls4. It is intriguing that Demodex numbers increase when the
outside temperature elevates in spring and summer, coinciding with the time when rosacea is
exacerbated. Demodex mites have also been implicated as a cause of other skin diseases
such as pityriasis folliculorum (typically found in older women who do not use soap but
apply large amounts of makeup), perioral dermatitis (a facial rash typically occurring around
the mouth), scabies-like eruptions, facial pigmentation, eruptions of the bald scalp, Demodex
folliculitis (an inflammatory reaction in the superficial aspect of the hair follicle),
demodicosis gravis (dermal granulomas formed because of mite remnants phagocytosed by
foreign-body giant cells) and even basal cell carcinoma. Furthermore, the above skin
demodicosis is prone to develop in patients whose local or systemic immune status is
compromised by topical or systemic administration of steroids or other immunosuppressive
agents or by diseases such as leukaemia and HIV.
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Implication of Demodex mites in human eye diseases
Contiguous to the skin, the eye can also be infested by Demodex mites. In the eye, D.
folliculorum is found in the lash follicle, whereas D. brevis burrows deep into the lash
sebaceous gland and the meibomian gland, the latter of which produces meibum as the
superficial layer of the preocular tear film. Because the eye is surrounded by such protruding
body parts as the nose, the brow and the cheek, the eyelid is not as accessible as the face to
daily cleansing hygiene. Therefore, once Demodex mite infestation establishes in the face, it
is likely to spread and flourish in the eyelid. As a matter of fact, the first disorder that was
associated with Demodex, dated as early as 1899, was blepharitis (inflammation of the lid), a
disease that has continued to be a subject of investigation ever since5. However, as in the
skin, the pathogenic potential of these mites in blepharitis had been questioned because a
low number of Demodex was found in the lashes of asymptomatic individuals.
Cylindrical dandruff (CD) in eye lashes (Figure 2a) is a common finding in some blepharitis
patients. We speculated that the controversy of whether CD can be regarded pathognomonic
for Demodex infestation originated from errors of the previously published method in
sampling and counting mites. Besides errors in randomly epilating eyelashes and mounting
the slide using a drop of oil, the most important one was that Demodex embedded in
compact and opaque CD could not be fully counted unless 100% alcohol6 or a drop of
fluorescein7 is added to stimulate them to migrate out (Figure 3). Using the modified
method, we have confirmed that CD in eye lashes is indeed a reliable clinical sign indicative
of Demodex infestation of the eyelash6. Furthermore, we observed that Demodex infestation
can still be detected in 50% of patients despite daily lid scrub with Baby shampoo (a routine
regimen) for more than 1 year. This result together with those published earlier strongly
suggests that the conventional lid scrub with baby shampoo may not eradicate Demodex,
rendering it difficult to resolve whether Demodex is pathogenic or not.
Hence, we believe that one way of determining the pathogenic potential of Demodex
infestation in blepharitis and other ocular diseases is to identify a treatment that can kill
Demodex with a good safety profile. Using an in vitro microscopic observation for a period
of 150 minutes, we found that adult D. folliculorum is resistant to a wide range of common
antiseptic solutions including 75% alcohol and 10% povidone–iodine, but can dose-
dependently be killed by tea tree oil (TTO)8. TTO, a natural essential oil steam-distilled
from the leaf of the tea tree Melaleuca alternifolia, has long been used as an aboriginal
traditional medicine in Australia for wounds and cutaneous infection. Unlike Bbaby
shampoo, lid scrub with TTO not only cleanses CD from the lash root, but also stimulates
embedded mites to migrate out to the skin (Figure 4). As a result, weekly lid scrub with 50%
TTO and daily lid scrub with tea tree shampoo is effective in eradicating ocular Demodex
infestation in vivo, as is evident by bringing the Demodex count down to zero in 4 weeks in a
majority of patients9,10. Because refractory ocular surface inflammation resolved after
significant reduction of mite counts achieved by this new lid scrub regimen, we concluded
that ocular Demodex infestation in lashes can cause the lashes to become mal-aligned
(Figure 2a), turn in to touch the cornea (trichiasis) (Figure 2b) and fall off (madarosis)
(Figure 2c). Furthermore, its infestation in meibomian glands can cause meibomian gland
dysfunction (Figure 2d), leading to disturbance and deficiency of the lipid tear film and
blurry vision9. To our surprise, inflammation derived from lashes and meibomian glands (in
the context of blepharitis) may spread over to the conjunctiva, resulting in conjunctivitis
(Figure 2e) and even to the cornea, resulting in various blinding corneal lesions (Figure
2f)9,10. The tendency of inflammation spread to the conjunctiva and cornea depends on not
only the severity of the host inflammatory response, but also the distance from the site of
mite infestation. In this regard, the intriguing finding that the rate of detecting D. brevis is
much higher in patients who developed corneal lesions10, is consistent with the notion that
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D. brevis primarily residing in meibomian glands is easier to reach the conjunctiva and the
cornea. Future studies are needed to determine whether the pathogenicity of D. brevis differs
from that of D. folliculorum. Unlike what has been reported for skin demodicosis, we
recently discovered that ocular Demodex infestation could be detected in immune non-
compromised paediatric patients inflicted with refractory blepharoconjunctivitis (Liang L,
Safran S, Gao Y, Sheha H, Li J, and Tseng SCG, unpublished work). Therefore future
studies are also needed to determine whether eyelash sampling is more sensitive than skin
surface biopsy in detecting demodicosis in paediatric patients.
Pathogenic mechanism of Demodex mites
Because a high number of Demodex mites have been observed in the skin and eyelashes of
patients with the aforementioned diseases, several pathogenic mechanisms have been
postulated to support the notion that mites alone are able to inflict significant damage to the
habitat that they live in. Mechanically, the mites may block the hair follicles and sebaceous
ducts to induce epithelial hyperplasia and hyperkeratinization. The chitinous exoskeleton of
the mites may act as a foreign body and cause granulomatous reaction. Debris or wastes
generated by mites may elicit inflammatory responses via a delayed hypersensitivity
reaction or an innate immune response11.
Nevertheless, one cannot rule out the pathogenic role of microbial agents that may be
associated with Demodex infestation. The notion that microbes are involved in pathogenesis
of mite-infested diseases has long been suggested because the skin inflammation in rosacea
can be markedly improved by topical metronidazole or oral antibiotics including
tetracycline, i.e. treatments that do not kill mites. Because TTO also may exert antibacterial,
antifungal and anti-inflammatory actions, we cannot attribute its therapeutic benefit in
treating the above eye diseases solely to its effect of killing mites. In fact, it has been
postulated that the mites may act as vectors to bring in common skin bacterial flora12.
Scanning electron microscopy showed bacteria on the mite skin surface. Staphylococcus
albus was shown to be transported by these mites from follicle to follicle. Superantigens
produced by streptococci and staphylococci that are implicated in a number of diseases may
play a role in the induction of rosacea.
To reconcile the apparently disparate findings of increased numbers of D. folliculorum
mites, perifollicular inflammation and response of papulopustular rosacea to selective
antibiotic therapy in some patients, we have recently isolated Bacillus oleronius inside
Demodex mites from one patient with papulopustular rosacea13. We discovered further that
this bacterium produced antigens capable of stimulating proliferation of peripheral blood
mononuclear cells in patients with rosacea in a significantly higher frequency than in control
subjects13. The pooled serum from six patients with papulopustular rosacea exhibited
positive immunoreactivity to two pro-inflammatory 62-kDa and 83-kDa proteins produced
by this bacterium13. Lately, our collaborative and prospective study of 59 patients disclosed
further a strong correlation among positive serum immunoreactivity to these two bacillus
proteins, ocular Demodex infestation, facial rosacea and blepharitis (Li J, O’Reilly N, Sheha
H, Katz R, Raju VK, Kavanagh K, and Tseng SCG, unpublished work). If such a strong
correlation signifies a causative relationship, a new pathogenic paradigm emerges to link
both Demodex infestation and microbial infection through symbiotic Bacillus oleronius in
causing skin and ocular surface inflammation. Such co-morbidity between mites and
Bacillus rests in the symbiosis of the latter in the former, a scenario first reported in the
hindgut of a termite. This paradigm explains that the large numbers of dying mites in the
follicles or glands may increase the release of the 83-kDa and 62-kDa bacterial antigen load
to a critical level to trigger a cascade of host inflammatory responses. Furthermore, it also
predicts why such a host immune-inflammatory response might be modified or exaggerated
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in certain individuals who are allergic or immune-sensitive to mites as alluded to above11.
Because ocular surface inflammation is notably reduced by lid scrub with TTO, but not by
conventional treatments including lid hygiene with Bbaby shampoo, topical steroids and
antibiotics or systemic doxycycline in some rosacea patients that present with corneal
lesions10, the mite’s role in stirring up host inflammatory response cannot be ruled out. In
short, the co-morbidity based on a symbiotic relationship of B. oleronius in Demodex mites
also justifies the consideration of a therapeutic strategy directed to killing the symbiotic
bacterium via oral antibiotics such as tetracycline and to killing and preventing mating/
reinfestation of Demodex mites, e.g. lid scrub with TTO and general hygiene at the same
time. Future investigation into this co-morbidity between mites and microbes may shed new
light not only on the understanding of the pathogenesis of this century-old common ailment
of the skin and eye, but also other similar unresolved human diseases.
Acknowledgments
Dr Tseng has filed two patents for the use of TTO and its ingredients for treating demodicosis. Studies described in
this article are supported in part by a research grant 1R43 EY019586-01 from the National Institutes of Health,
National Eye Institute.
Biographies
Noreen Lacey is a graduate of National University of Ireland Maynooth, where she received
her BSc in Biology (2004) and PhD (2007). Her PhD research was focused on investigating
the factors involved in the induction and persistence of papulopustular rosacea, under the
supervision of Dr K. Kavanagh. Results from this study demonstrated a potential role for
Demodex mite-related bacterial antigens in the pathogenesis of rosacea. She is currently a
postdoctoral researcher at the UCD Clinical Research Centre at the Mater Misericordiae
University Hospital, Dublin. Her research interests remain focused on investigating the role
of Demodex mites in the biology of human skin. Noreen.lacey@ucd.ie
Kevin Kavanagh is a Senior Lecturer in the Department of Biology at the National
University of Ireland Maynooth. His research is focused on understanding the mechanisms
employed by microbes to regulate the innate immune response of the host to facilitate their
continued persistence. He also has interests in exploring the structural and functional
similarities between the immune system of vertebrates and invertebrates.
kevin.kavanagh@nuim.ie
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Scheffer Tseng was a chaired professor at Bascom Palmer Eye Institute University of Miami
School of Medicine until 2002, when he became Chief Scientific Officer leading a research
team of 12 people of Bio-Tissue, Inc., a leading tissue engineering company. He has been
specialized in ocular surface diseases and surgical reconstruction using stem cells and
amniotic membrane, and received research support from NIH, National Eye Institute for
over 25 years. For the last 5 years, he has been interested in understanding the pathogenic
role of Demodex mites. stseng@ocularsurface.com
References
1. Baima B, Sticherling M. Acta Derm. Venereol 2002;82:3–6. [PubMed: 12013194]
2. Rufli T, Mumcuoglu Y. Dermatologica 1981;162:1–11. [PubMed: 6453029]
3. Pena GP, Andrade Filho JS. Rev. Inst. Med. Trop. Sao Paulo 2000;42:171–173. [PubMed:
10887379]
4. Forton F, Seys B. Br. J. Dermatol 1993;128:650–659. [PubMed: 8338749]
5. Norn MS. Dan. Med. Bull 1971;18:14–17. [PubMed: 5110952]
6. Gao Y-Y, Di Pascuale MA, Li W, et al. Invest. Ophthalmol. Visual Sci 2005;46:3089–3094.
[PubMed: 16123406]
7. Kheirkhah A, Blanco G, Casas V, Tseng SC. Cornea 2007;26:697–700. [PubMed: 17592319]
8. Gao Y-Y, Di Pascuale MA, Li W, et al. Br. J. Ophthalmol 2005;89:1468–1473. [PubMed:
16234455]
9. Gao Y-Y, Di Pascuale MA, Elizondo A, Tseng SC. Cornea 2007;26:136–143. [PubMed: 17251800]
10. Kheirkhah A, Casas V, Li W, et al. Am. J. Ophthalmol 2007;143:743–749. [PubMed: 17376393]
11. Bevins CL, Liu FT. Nat. Med 2007;13:904–906. [PubMed: 17680001]
12. Wolf R, Ophir J, Avigad J, et al. Acta Derm. Venereol 1988;68:535–537. [PubMed: 2467494]
13. Lacey N, Delaney S, Kavanagh K, Powell FC. Br. J. Dermatol 2007;157:474–481. [PubMed:
17596156]
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Figure 1.
Microscopic features of adult D. folliculorum(a) and D. brevis (b). D. folliculorum tends to
gather as a group in the follicle area of the hair or lash (a). In contrast, D. brevis tends to be
in solitude and reside in the sebaceous gland. As a result, D. brevis is not readily detected
during sampling of the lash. Under scanning electron microscopy, several D. folliculorum
mites are together next to the hair follicle
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Figure 2.
Clinical features of Demodex infestation in the eye. The most common finding is CD on the
skin surface where lashes emit (a). As mites reside close to the follicle, the orientation of
lashes become disorganized (a), can turn in to touch the ocular surface (trichiasis) (b), and in
the extreme cases results in the loss of lashes (madarosis) (c). Besides lashes, meibomian
glands can be involved to manifest plugging of the orifices (d). The inflammation derived
from lashes or meibomian glands of the lid margin can be spill over to the conjunctiva (e)
and cause a number of corneal lesions, including nodular scar (f)
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Figure 3.
Unmasking embedded mites in CD by fluorescein solution. A representative lash with CD
(a), in which embedded mites are revealed only after application of a drop of an aqueous
solution containing fluorescein (b). An arrow marks the hidden mites (a) that are revealed by
fluorescein drops. Note that this procedure of dissolving CD frequently generates air
bubbles, and the change of colour is due to the presence of fluorescein
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Figure 4.
Migration of Demodex by lid scrub with TTO. In this eye with diffuse CD found in the
lashes before treatment (a), lash to be epilated (marked by arrow) showed a fragment of CD
attached to the lash and abundant Demodex embedded close to the lash follicle (d). After lid
scrub in the orifice with 50% TTO, the lashes became clean and totally free of CD, but tails
of Demodex were protruding from the lash roots (b, arrow). At 3 minutes after lid scrub, free
Demodex was found on the trunk close to the skin surface, i.e. away from the lash follicle in
the epilated lash (e). Rotating these lashes (shown in b) before epilation allowed us to detect
a group of Demodex migrating along the lash trunk (f and g). If no lid scrub was carried out
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at home for one week, CD returned to the lashes 1 week later (c). With permission from Br.
J. Ophthalmol.8
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