Clinical science

Br J Ophthalmol: first published as 10.1136/bjophthalmol-2017-310302 on 21 October 2017. Downloaded from http://bjo.bmj.com/ on 2 August 2018 by guest. Protected by copyright.
Significant correlation between meibomian gland
dysfunction and keratitis in young patients with
Demodex brevis infestation
Lingyi Liang,1 Yan Liu,1 Xiaohu Ding,1 Hongmin Ke,1 Chuan Chen,1 Scheffer C G Tseng2

►► Additional material is Abstract glands.11 We thus wonder if ocular demodicosis

published online only. To view
please visit the journal online
(http://d​ x.​doi.o​ rg/​10.​1136/​
bjophthalmol-​2017-​310302).
1
State Key Laboratory of
Ophthalmology, Zhongshan
Ophthalmic Center, Sun Yat-
sen University, Guangzhou,
Guangdong, China
2
Ocular Surface Clinic, Ocular
Surface Center, Miami, Florida,
USA
Correspondence to
Professor Lingyi Liang, State Key
Laboratory of Ophthalmology,
Zhongshan Ophthalmic Center,
Guangzhou 510060, China; ​
lingyiliang@q​ q.​com
Received 9 February 2017
Revised 27 August 2017
Accepted 6 October 2017
Published Online First
21 October 2017
To cite: Liang L, Liu Y,
Ding X, et al. Br J Ophthalmol
2018;102:1098–1102.
1098
Aims  To report the clinical characteristics and
correlation between meibomian gland dysfunction
(MGD) and keratitis in young patients with ocular
demodicosis.
Methods  Observational case series of 60 patients
younger than 35 years with ocular demodicosis, of
which the diagnosis was based on microscopic counting
of Demodex folliculorum and D. brevis of epilated
lashes. Severity of keratitis and MGD was graded by
photography and meibography, respectively, in a masked
fashion.
Results  MGD was detected in 54/60 (90%) patients
with the loss of meibomian gland in the upper lid more
than the lower lid (p<0.001). Blepharoconjunctivitis
and a variety of corneal pathologies were noted in
47/60 (78.3%) and 39/60 (65%) patients, respectively.
For a total of 120 eyes, normal cornea was noted
in 53 (44.2%) eyes, superficial punctate keratitis
or limbitis was noted in 17 (14.2%), while corneal
stromal infiltration was found in 50 (41.7%) eyes.
Both univariate and multivariate analyses showed that
the severity of meibomian gland loss was significantly
correlated with higher D. brevis count and more severe
keratitis (all p<0.05). Rapid resolution of keratitis and
blepharoconjunctivitis was accompanied by significant
reduction of the Demodex count in 48 patients receiving
lid scrub directed to kill mites.
Conclusions  There is a significant correlation between
MGD and keratitis in young patients with ocular
demodicosis especially inflicted by D. brevis.
Introduction
Among different species of mites, Demodex
folliculorum and D. brevis are the only two
species affecting the human skin.1–3 D. folliculorum
infests the lash follicle, while D. brevis infests the
lash’s sebaceous gland and the meibomian gland.3
Such infestation termed ocular demodicosis has
been implicated in a number of external eye diseases
such as blepharitis, eyelash disorders, conjunctivitis
and blepharoconjunctivitis.2–8
Demodicosis is highly age  dependent and gener-
ally regarded as common in asymptomatic adults,
especially in elder people, but rare in children.9–11
Meibomian gland dysfunction (MGD) is also more
prevalent in elder people but rare in children.12 In
paediatric patients, we have reported that ocular
demodicosis can be associated with chronic bleph-
aroconjunctivitis5 and chalazia especially D. brevis
infestation, another disease affecting meibomian
Liang L, et al. Br J Ophthalmol 2018;102:1098–1102. doi:10.1136/bjophthalmol-2017-310302
may also play a role in MGD. To mitigate the
concern of a high prevalence of both MGD and
demodicosis in the elder population, we decided
to conduct a prospective observational study by
focusing on young adults. As there is notable kera-
titis in this cohort resembling herpes keratitis, we
also summarise the clinical features that help differ-
entiate from herpes keratitis.
Patients and methods
Patients
Following the tenets of the Declaration of Helsinki,
we enrolled 60 patients younger than 35 years with
ocular demodicosis at the Zhongshan Ophthalmic
Center. The diagnosis of ocular demodicosis was
based on lash sampling and microscopic mite
counting as reported in all patients.5 13 14 Because
demodicosis is not as common in the paediatric
and young population,9 four instead of two lashes
per lid were removed under slit-lamp microscope
in all patients including two children (age less than
14), whose lash sampling were performed under
general anaesthesia due to their poor cooperation
as reported.5 11
All patients with demodicosis were instructed to
receive the mite-killing therapy. Because there is
no lid hygiene treatment based on tea tree oil in
China, only 48 out of 60 patients could purchase
Cliradex from Bio-Tissue (Miami, Florida, USA)
that contains the active ingredient reported to kill
Demodex mites.14 15 These 48 patients received
Cliradex lid scrub twice daily for 3 months. For
those presenting with corneal inflammation and
conjunctival injection, 0.02% fluorometholone
(Santan, Japan) was used twice daily for 3–10 days.
Artificial tears were used 4–6 times daily as needed
for patients presented with dry eye symptoms.
Diagnosis and grading of MGD
The diagnosis of MGD was made by slit-lamp
examination to detect  ≥1 lid margin abnormali-
ties (irregular lid margin, vascular engorgement,
plugged meibomian gland orifices and anterior or
posterior replacement of the mucocutaneous junc-
tion) and poor meibum expression under digital
pressure.16 The severity of MGD was graded by
meibography using Keratograph 5 M (Oculus,
Wetzlar, Germany) as reported17 to generate the
meiboscore by combining the score from both
upper and lower eyelids (see  online supplementary
figure), that is, 0 for no meibomian gland loss, 1–2
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Figure 1  Different types of corneal pathologies. Representative examples of keratitis that is classified as grade 1 with superficial punctate
keratopathy only (A) or limbitis only (B) and as grade 2 with corneal stromal involvement which might (C–E) or might not (F, G) be associated with an
epithelial defect and even perforation (H). They include phlyctenular conjunctivitis (C), of which infiltration might extend from the limbus (D) or not
extend from the limbus (E). Note that blepharitis is worse in the central part of the upper lid close to the keratitis (D).

for less than one-third total gland loss and considered as ‘mild’,
3–4 for one-third to two-thirds total gland loss and considered
as ‘moderate’ and 5–6 for more than two-thirds total gland loss
and considered as ‘severe’.
Grading of corneal changes
We also routinely graded corneal pathologies by slit-lamp photo-
graphs as ‘0’ for no abnormal finding, ‘1’ for superficial punc-
tate keratopathy (SPK) only or limbitis only and ‘2’ for stromal
involvement such as infiltration or ulceration (figure 1). For
those presenting with corneal ulcers, standard corneal scraping
and microbiological culturing were also performed.
Statistical analysis
Grading of MGD and corneal changes was performed by two
investigators under a masked fashion. Any inconsistent grading
between the two was arbitrated by a third investigator, who had
no knowledge about the other clinical information at the time.
Meiboscore of the worse eye was used for comparison among
different patients. The Pearson’s Χ2 test and p for trend test were
used to compare categorical and ranked variables, respectively.
Univariate regression was performed to evaluate the risk factors
of keratitis and MGD. Those factors identified as probably
significant (p<0.1) by univariate regression were subjected to
multivariate regression. All statistical analyses were performed
using SPSS software V.16.0 and reported as two-tailed probabil-
ities, with p<0.05 being considered significant.
Results
The study group consisted of 60 patients (19.1±7.5 years, 22
males and 38 females) with ocular demodicosis. The history
disclosed chalazia in 29 (48.3%) patients. The Demodex count
was 5.6±3.5 including 2.5±2.4 for D. brevis and 3.1±1.9 for D.
folliculorum. Further examination revealed MGD (n=54, 90%),
lash disorders (n=51, 85%), blepharitis (n=47, 78.3%), keratitis
(n=39, 65%), allergic conjunctivitis (n=7, 11.7%) and phlyc-
tenular conjunctivitis (n=3, 5%). The keratitis of all 39 patients
had not responded to topical antiviral agents, antibiotics and
steroid for a period up to 20 years under the clinical impres-
sion of herpes simplex keratitis (HSK, n=24), bacterial keratitis
(n=3), severe dry eye (n=8), vernal keratoconjunctivitis (n=2)
and limbitis (n=2).
MGD is prevalent and worse in upper lids
MGD was common (90%) and remarkable in 35 patients (35/60,
58.4%) presenting more than one-third meibomian gland loss
(table 1). Intriguingly, MGD was worse in the upper eyelid
than the lower lid (p<0.001, figure 2, representative cases).

Table 1  Correlative analysis of potential predictors of meibomian gland loss and corneal changes
Meiboscore Keratitis grading
0 1, 2 3, 4 5, 6
Normal (n=9) Mild (n=16) Moderate (n=13) Severe (n=22) p Value Grade 0 (n=21) Grade 1 (n=9) Grade 2 (n=30) p Value
Age (years) 20.8±9.2 22.6±8.6 18.4±7.5 18.4±7.4 0.16* 23.2±8.6 14.9±5.4 19±7.5 0.72*
Gender (M:F) 6:3 5:11 2:11 9:13 0.09† 9:12 4:5 9:21 0.08†
Disease duration (years) 1.8±1.4 2.2±2.3 2.9±3.1 4.0±5.1 0.17* 1.8±1.2 2.6±3 3.9±4.8 0.56*
Demodex brevis count 0.3±0.7 2±0.1 3.2±1.8 4.3±2.4 <0.001* 1.2±0.9 2.1±1.3 4.2±2.2 <0.001*
Demodex folliculorum 3.7±1.4 2.8±1.8 2.7±2.0 3.5±2.3 0.50* 3.2±1.6 2.1±1.8 3.3±2.2 0.79*
count
Blepharitis, cases (%) 8 (88.9) 7 (43.8) 10 (76.9) 21 (95.5) 0.08† 15 (71.4) 5 (55.6) 27 (90) 0.06†
Keratitis grading 0±0 0.4±0.5 1.5±0.8 2±0.2 <0.001*
Meiboscore – 1.0±1.1 2.6±1.3 5±1.1 <0.001*
*p For trend test.
†Χ2 test.

Liang L, et al. Br J Ophthalmol 2018;102:1098–1102. doi:10.1136/bjophthalmol-2017-310302 1099

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Figure 2  Association between keratitis grading and meibomian gland loss. The corresponding meibography of different severity of keratitis from
grade 0 (A), 1 (B) to 2 (C and D). Compared with the meibography of grade 0 (E) and grade 1 keratitis cases (F), those with grade 2 keratitis (G and H)
had more severe meibomian gland loss. Note that the meibomian gland loss was more evident in the upper lid.

Consequently, the tear breakup time was 2.5±1.3 s in these Improvement of keratitis after lid scrub with Cliradex
patients. Meiboscore was significantly correlated with D. brevis We then investigated the possible correlation between demodi-
count and keratitis grading (both p<0.001) but not correlated cosis and keratitis in 48 of 60 patients who underwent Demodex
with D. folliculorum count, age, gender, blepharitis and disease mite-killing therapy. Results showed that both keratitis and
duration (all p>0.05, table 1). ocular surface inflammation rapidly resolved within 2–3 weeks
(Figures 3,4), including the two eyes with corneal perfora-
Keratitis is prevalent and severe tion. At the end of 3 months of treatment, the Demodex count
We then looked deeper into keratitis and noted different forms
in 67 eyes of 39 study patients, including grade 1, that is, SPK
only (figure 1A) or limbitis (figure 1B) in 17 eyes and grade 2,
that is, corneal stromal involvement in 50 eyes (figure 1C-H).
The corneal stromal involvement was associated with (19 eyes,
figure 1C–E) or without (29 eyes, figure 1F–G) an epithelial defect
and could be presented with perforation (two eyes, figure 1H),
corneal neovascularisation (36 eyes) or scar (17 eyes). Keratitis
was bilateral (76.9%) more than unilateral (23.1%) and located
at inferior (32 eyes), central (25 eyes), diffusive (seven eyes) and
superior (three eyes) corneas. For the 50 eyes with grade 2 kera-
titis, the stromal lesion extended to the limbus in all except two
eyes (figure 1E). The microbial results of 19 cases presenting
with corneal ulcers were all negative for aerobic microbes. An
overwhelming majority, that is, 57 of 67 eyes (85.1%) with kera-
titis also presented with blepharitis, which was more evident in
the central upper lid in 51 of 57 (89.5%) patients (figure 1D,
representative cases). The severity of keratitis was significantly
correlated with D. brevis count and meiboscore (both p<0.001)
but not with D. folliculorum count, age, gender, blepharitis and
disease duration (all p>0.05, table 1).

Significant correlation between MGD and keratitis

When the worse eye of each patient were compared, we noted
a significant correlation between meiboscore and keratitis scores
in 60 study patients (Spearman's rho=0.97, p<0.001) (Figure 2,
representative case 1). Multivariate regression analysis of the
three variables that were found to be significant in univariate
regression, that is, D. brevis count, keratitis grading and meibo-
score, disclosed that both D. brevis count (OR 1.56; 95% CI
1.09 to 2.23, p=0.01) and higher keratitis scores (OR 8.72;
95% CI 3.21 to 23.67, p<0.001) were the two predictors of
meiboscore, but meiboscore was the predictor of keratitis score
(see online supplementary table). These results strongly indi-
cated that patient with a higher D. brevis count tended to have
more severe MGD, which was significantly correlated with kera-
titis severity.
1100
Figure 3  Representative case 1: asymmetric corneal changes and
meibomian gland dysfunction. (A) The right eye presented with grade
2 keratitis with an epithelial defect associated with stromal infiltration
and lid margin changes that were pronounced in the same location as
the keratitis (marked by two vertical lines). (B) The left eye presented
with inferior superficial punctate keratopathy. (C and D) After treatment,
both keratitis and lid margin changes resolved in both eyes. The
meibomian gland loss judged by meibography was more severe in right
eye, especially the upper lid (E) than that of the left eye (F).
Liang L, et al. Br J Ophthalmol 2018;102:1098–1102. doi:10.1136/bjophthalmol-2017-310302

Figure 4  Representative case 2: recurrence in a different eye. The right
eye presented with grade 2 keratitis with an epithelial defect associated
with stromal infiltration/scarring and vascularisation and lid margin and
conjunctival inflammation (A). Similar to case 1, blepharitis appeared
to be worse in the upper lid at the same corresponding position as
keratitis. The left eye was quiet except malalignment of lashes and mild
irregular lid margin (B). At the time of recurrence, the right eye remained
quiet (C) but the left cornea presented with inferior SPK, stromal
infiltration and neovascularisation (D). Meibography showed that
meibomian gland loss was more evident in both upper lids (E and F).
was significantly reduced to 0.5±0.7 (range 0–3, p<0.001).
However, corneal scar remained in 35 eyes. Forty-six patients
were followed up for at least 12 months, during which time four
patients developed recurrent keratitis at 6, 8, 10 and 13 months,
respectively, after discontinuation of treatment. They were all
successfully controlled by the second run of Cliradex lid scrub.
Interestingly, recurrent keratitis was noted in the ‘quiet’ fellow
eye of three patients (representative case 2, figure 4).
The remaining 12 patients received baby shampoo lid hygiene
and topical steroid and lubricants if needed. After treatment, the
lid margin became clean and ocular surface inflammation was
controlled temporarily, while Demodex count remained almost
the same.
Representative case 1: coexistence of MGD and keratitis in
one eye
A 6-year-old girl complained of redness and irritation in both
eyes for 1 year. She was treated as HSK but failed to respond
to antiviral and antibiotic therapies. On examination, her
visual acuity was 20/300 and 20/40, respectively. Lash sampling
revealed two D. brevis. The right eye had more blepharitis in
the upper lid that was in contact with the corneal epithelial
defect associated with stromal infiltrate and neovascularisation
(Figure 3A). The left eye had milder blepharitis also worse in the
Liang L, et al. Br J Ophthalmol 2018;102:1098–1102. doi:10.1136/bjophthalmol-2017-310302
Clinical science
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upper lid with meibomian gland orifice plugging and inferior
corneal SPK (Figure 3B). Meiboscore was four in the right eye
(Figure 3E) and three in the left eye (Figure 3F). Inflammation
was subsided in both eyes 2 weeks after lid scrub with Cliradex
(Figure 3C; Figure 3D) together with healing of the keratitis and
regression of vessels in the right eye (Figure 3C) and resolution
of SPK in the left eye (Figure 3D). Her vision in both eyes was
improved to 20/40 and 20/30, respectively. After 3 months of
treatment, the Demodex count was 0 while both eyes were quiet.
Representative case 2: recurrence in a different eye
A 19-year-old woman complained of redness and irritation in
both eyes and decreased vision in the right eye for 5 years. She
was treated as HSK but failed to respond to antiviral and anti-
biotic therapies. On examination, her vision was 20/200 and
20/20, respectively. Lash sampling detected six D. brevis and two
D. folliculorum. The right eye had blepharitis located at the same
location of the corneal epithelial defect with stromal infiltration
(figure 4A). The left eye was unremarkable except lash malalign-
ment and irregular lid margin (figure 4B). Meibography showed
meibomian gland loss that was more evident in both upper lids
(figure 4E, F). After 2 weeks of treatment, the right keratitis and
blepharitis subsided with dramatic regression of corneal vessels
(figure 4C). Both eyes remained non-inflamed for 13 months
until 1 day when the right eye remained stable while the left
cornea presented with inferior stromal infiltration (figure 4D).
Lash sampling revealed three D. brevis. This recurrent keratitis
was controlled after 1 week of lid scrub with Cliradex.
Discussion
Because both demodicosis and MGD are common in the elderly
population,3 4 13 18 the potential causal relationship between
the two is hard to resolve. Therefore, we focused on a cohort
of young patients where both demodicosis and MGD are rela-
tively rare. Our observational case series study discloses a strong
correlation between ocular demodicosis especially by D. brevis
and MGD and keratitis in young patients.
Univariate and multivariate analyses show that the severity of
MGD was significantly correlated with demodicosis by D. brevis
but not D. folliculorum in these young patients. This finding is
consistent with the notion that D. brevis resides in sebaceous
and meibomian glands and has been found to be significantly
correlated with chalazia.11 We were surprised to note that
demodicosis was associated with severe MGD that presented
with more than 1/3 meibomian gland loss, especially in the
upper lid, in such a young population. To further understand the
impact of demodicosis on meibomian gland, a carefully designed
case–control study or cohort study and disease animal model are
warranted.
In six cases with ocular demodicosis, Kheirkhah et al,6 for
the first time, reported corneal changes including superficial
corneal vascularisation, marginal corneal infiltration, superficial
corneal opacity, nodular corneal scar and phlyctenule-like lesion,
suggesting the potential corneal involvement. Surprisingly, D.
brevis is detected in four out of these six cases.6 Herein, we noted
a variety of corneal changes in 39 out of 60 young patients with
ocular demodicosis. Besides the aforementioned pathologies, we
also detected SPK, limbitis, central infiltration and ulceration
and even perforation. Hence, we surmise that ocular demod-
icosis should be considered in young patients presenting with
sight-threatening keratitis.
The severity of keratitis was significantly correlated with
that of MGD in our patients (figure 2 and table 1). Presumably,
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 Clinical science
because of its predominant asymmetrical presentation (eg,
figures 2 and 4), such keratitis could prompt one to suspect HSK
as revealed in their histories. Our study disclosed the following
clinical pearls that may help differentiate keratitis caused by
demodicosis and that by herpetic infection. First, the history
would suggest a refractory nature to antiviral, antimicrobial and
topical steroid therapies but a rapid response by mite-killing lid
scrub. Second, keratitis associated with demodicosis was strongly
associated with ipsilateral blepharitis, lash malalignment and
MGD, of which the upper lid tended to be worse than the lower.
Third, keratitis associated with demodicosis, if recurred, could
be in the contralateral eye.
The keratitis rapidly resolved after lid scrub with Cliradex,
which contains terpinen-4-ol identified as the most active
ingredient to kill mites.15 Recent studies revealed a potential
microbial role in demodicosis. First, the mites may work as a
vector carrying bacteria such as Staphylococci and Streptococ-
ci.19Second, mites can harbour symbiotic microbes in its intestine
such as Bacillus oleronius, which can trigger a host immune reac-
tion by producing proinflammatory proteins that can stimulate
proliferation of peripheral blood mononuclear cells in patients
with rosacea.20 We have reported a strong correlation among
positive serum immunoreactivity to the 83 kDa and 62 kDa
bacillus proteins, ocular Demodex infestation, facial rosacea and
blepharitis.8 21 The microbial role is disclosed in ‘meibomitis-re-
lated keratoconjunctivitis’ reported by Suzuki and Kinoshita22 23
that exhibits similar clinical features such as blepharitis, chalazia,
subepithelial corneal infiltration, corneal neovascularisation
and conjunctival hyperaemia. They detected Propionibacterium
acnes which normally inhabits human sebaceous follicles, in
60% of patients but 23.5% age-matched normal control subjects.
Although systemic antimicrobial therapy is effective for curing
ocular inflammation in meibomitis-related keratoconjuncti-
vitis,22 23 refractory cases have also been reported. Their study
did not disclose whether culture of P. acnes became negative
on resolution of inflammation and whether there was concom-
itant demodicosis. Although we did not subject specimens to
anaerobic microbial cultures, a number of our patients had not
responded to systemic and/or topical antibiotics. Further study
on the impact of demodicosis on the ocular surface microbiome
and the potential pathogenic role between mites and microbes
is warranted.
Conclusions
In summary, this prospective study demonstrates a strong
correlation between ocular demodicosis especially by D. brevis
and MGD and keratitis in young patients. Furthermore, we also
summarise that the unique characteristics of MGD and keratitis
associated with demodicosis can be differentiated from HSK.
Contributors  LL and SCGT designed the study and reviewed the manuscript. LL,
YL and HK researched and collected the data. LL, YL and XD wrote and edited the
manuscript. XD analysed the data. CC contributed to discussion and reviewed the
manuscript.
Funding  This study is supported in part by a grant (81770892) from the National
Natural Science Foundation of China, a grant (2014B020226003) from the
Technological Project Foundation of Guangdong Province, a grant (201510010219)
from the Technological Project Foundation of Guangzhou and a grant (R44 EY019586)
from the National Eye Institute, the National Institutes of Health (to SCGT).
1102 Liang L, et al. Br J Ophthalmol 2018;102:1098–1102. doi:10.1136/bjophthalmol-2017-310302
Br J Ophthalmol: first published as 10.1136/bjophthalmol-2017-310302 on 21 October 2017. Downloaded from http://bjo.bmj.com/ on 2 August 2018 by guest. Protected by copyright.
Disclaimer  The sponsors or funding organisations had no role in the design or
conduct of this research; collection, management, analysis and interpretation of the
data and preparation, review or approval of the manuscript.
Competing interests  SCGT has filed two patents for the use of tea tree oil
and its ingredients for treating demodicosis. Cliradex is formulated by inclusion of
the active ingredient identified through the support of grant R43 EY019586 (NEI,
NIH).
Ethics approval  This study is approved by the Ethics Committee of the Zhongshan
Ophthalmic Center (Guangzhou, China).
Provenance and peer review  Not commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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