The Ocular Surface 16 (2018) 77e83

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The Ocular Surface

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Original Research

Randomized double-masked trial of eyelid cleansing treatments for

blepharitis
Justin Sung, Michael T.M. Wang, Sang H. Lee, Isabella M.Y. Cheung, Salim Ismail,
Trevor Sherwin, Jennifer P. Craig*
Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, New Zealand

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: To compare the efficacy of a dedicated eyelid cleanser and diluted baby shampoo in the
Received 31 August 2017 management of blepharitis.
Received in revised form Methods: Forty-three participants with clinical blepharitis signs were enrolled in a prospective, ran-
23 October 2017
domized, double-masked, paired-eye trial. A dedicated eyelid cleanser (TheraTears® SteriLid®) was
Accepted 31 October 2017
applied to the eyelids of one eye (randomized) and diluted baby shampoo (Johnson's® No More Tears®) to
the fellow eye, twice daily for 4 weeks. Tear film parameters, ocular surface characteristics, sympto-
Keywords:
mology and cytology markers were assessed at baseline and day 28.
Baby shampoo
Blepharitis
Results: Baseline measurements did not differ between treatments (all p > 0.05). The eyelid cleanser was
Conjunctival impression cytology preferred over baby shampoo by the majority of participants (p < 0.001). Improvements in the tear lipid
Eyelid cleanser layer, inferior lid wiper epitheliopathy (LWE), cylindrical collarettes, and MMP-9 expression were limited
Eyelid hygiene to the dedicated eyelid cleanser (all p < 0.05), and a greater decrease in SANDE symptoms score was also
Meibomian gland dysfunction observed (p ¼ 0.04). Meibomian gland capping and MUC5AC expression worsened with baby shampoo
treatment (both p < 0.05). SPEED symptoms score, superior LWE, seborrhoeic lash crusting, and trichiasis
decreased significantly following application of both treatments (all p < 0.05), but did not differ between
treatments (all p > 0.05).
Conclusion: Clinical improvements in blepharitis occurred with both treatments. However, only the
dedicated eyelid cleanser proved effective in reducing ocular surface inflammation, and was the
preferred therapy. Long term impact of decreased goblet cell function secondary to baby shampoo
treatment requires further exploration.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction observed in patients with blepharitis is thought to trigger hyper-

Blepharitis is one of the most commonly encountered
ophthalmic conditions in clinical practice [1,2] and is recognized to
have a significant impact on ocular comfort and quality of life [2,3].
It is characterized by chronic eyelid inflammation and is frequently
associated with symptoms of ocular surface irritation and dry eye
[1,2,4,5]. The inflammatory process can involve both the anterior
and posterior eyelid lamellae and affect the pericoular skin, eye-
lashes, lid margins, and meibomian glands [1,2].
The pathophysiology of blepharitis is multifactorial and has not
yet been fully established. The over-colonization of eyelid bacteria
* Corresponding author. Department of Ophthalmology, New Zealand National
Eye Centre, The University of Auckland, Private Bag 92019, Auckland, 1142, New
Zealand.
E-mail address: jp.craig@auckland.ac.nz (J.P. Craig).
sensitivity and inflammatory reactions of the ocular surface [1].
Bacterial lipolytic exoenzyme release may further promote such
inflammatory responses and disrupt tear film homeostasis through
the degradation of lipid layer constituents [6]. The potential asso-
ciation between Demodex infestation and blepharitis has also been
recognized [7].
The management of blepharitis requires both the prevention
and treatment of intermittent episodes of inflammatory exacer-
bation, which are associated with high bacterial loads [1,2,4,5].
Regular, ongoing eyelid hygiene regimens and warm compress
therapy are commonly recommended for application in the longer-
term for symptomatic relief [1,2,5]. An increasing range of dedi-
cated eyelid cleansing formulations is becoming commercially
available. Although greater subjective preference for dedicated
eyelid cleansers has previously been reported [8,9], diluted baby
shampoo continues to be frequently used [4,8,10]. However, an

https://doi.org/10.1016/j.jtos.2017.10.005
1542-0124/© 2017 Elsevier Inc. All rights reserved.
78 J. Sung et al. / The Ocular Surface 16 (2018) 77e83

animal study suggested increased ocular inflammation associated Table 1

with diluted baby shampoo use [11], and a previous clinical study Ingredients of the dedicated eyelid cleanser (TheraTears® SteriLid®) and baby
shampoo (Johnson's® No More Tears®).
reported greater efficacy of a phospholipid-liposome solution than
baby shampoo in improving clinical signs and symptoms of dry eye Eyelid cleanser Baby shampoo
in contact lens wearers [9]. Water Water
This randomized contralateral-eye trial sought to compare the PEG-80 Sorbitan Laurate PEG-80 Sorbitan Laurate
efficacy of a dedicated eyelid cleansing formulation (TheraTears® Sodium Trideceth Sulfate Sodium Trideceth Sulfate
Cocamidopropyl Betaine Cocamidopropyl Betaine
SteriLid®) and diluted baby shampoo (Johnson's® No More Tears®)
PEG-150 Distearate PEG-150 Distearate
in blepharitis patients through the clinical assessment of ocular Sodium Chloride Sodium Chloride
surface characteristics, tear film parameters, and symptomology, Sodium Lauroamphoacetate Phenoxyethanol
and through the quantification of inflammatory marker expression Linalool Glycerin
Sodium Laureth-13 Carboxylate Citric Acid
and goblet cell function via samples collected by impression
Sodium Piperazinoethyl Acetate Sodium Benzoate
cytology. Ethylsulfonate Tetrasodium EDTA
Boric Acid Polyquaternium-10
2. Materials and methods Sodium Perborate Ethylhexylglycerin
Panthenol Sodium Hydroxide
Allantoin Potassium Acrylates Copolymer
2.1. Subjects
Cocamidopropyl PG Dimonium Chloride Yellow 6
Melaleuca Alternifolia Leaf Oil Yellow 10
This prospective, 4-week, randomized, double-masked, paired Trisodium EDTA Parfum
eye trial, followed the tenets of the Declaration of Helsinki, was Etidronic Acid
approved by the University of Auckland Human Participants Ethics Citric Acid
Sodium Hydroxide
Committee (UAHPEC-011255), and was registered as a clinical trial
(ACTRN12616000545460). Subjects were required to be 16 years or
older, with clinical signs of blepharitis on slit lamp examination
(eyelash crusting, eyelid margin/eyelash abnormalities or meibo- contamination. Unused products were returned to the investigators
mian gland capping), with no contact lens wear or use of topical/ at the end of the 28-day trial period, and weighed as a measure of
systemic medications known to affect the eye 48 h prior to baseline participant compliance.
assessment or during the treatment period. Furthermore, eligibility
required participants to report no history of major systemic, 2.3. Clinical measurements
dermatological or ocular conditions, no ocular surgery in the pre-
vious three months, and no allergies or hypersensitivity to topical The McMonnies dry eye questionnaire and Ocular Surface Dis-
medications, cleansing formulations, or shampoos. Eligible partic- ease Index (OSDI) were administered to grade the level of dry eye
ipants were enrolled after providing written informed consent and symptoms at baseline, while the Standard Patient Evaluation of Eye
were required to attend two visits, at baseline and day 28. Dryness (SPEED) and Symptom Assessment iN Dry Eye (SANDE)
A total of 43 eligible participants were recruited, exceeding the questionnaires were administered for the purpose of comparing
sample size requirements for the desired study power. Power cal- symptomology at baseline and day 28. The overall SANDE score was
culations were made with non-invasive tear film breakup time as calculated as the square root of the product of the frequency and
the designated outcome, and showed that a minimum of 41 par- severity scores [13].
ticipants was required to detect a clinically significant difference of Clinical assessments were conducted at baseline and day 28 of
5 s in pairwise comparisons, with 80% power (b ¼ 0.2) at a two- the treatment period. The investigators conducting clinical as-
sided statistical significance level of 5% (a ¼ 0.05). The SD of sessments were masked to treatment randomization. All partici-
normal values was estimated to be 8 s [12]. Sample size estimates pants were assessed at the same location, with a mean ± SD room
were determined using a uniform non-parametric adjustment, temperature of 20.8  C ± 1.4  C and a mean ± SD relative humidity
with NCSS PASS 2002 (Utah, USA). of 52.4% ± 5.1%. The measurements were conducted in ascending
order of invasiveness to minimize the impact on ocular surface or
2.2. Treatments tear film physiology for subsequent tests: tear meniscus height,
noninvasive tear film breakup time, tear film lipid layer grade,
Participants were randomized to apply the dedicated eyelid conjunctival hyperaemia, tear film osmolarity, slit lamp examina-
cleanser (TheraTears® SteriLid®, Akorn, Illinois, USA) to one eye and tion, ocular surface staining, meibomian gland expression, infrared
the 1:10 diluted baby shampoo solution [11] prepared with distilled meibography, and conjunctival impression cytology.
water in a sterile laboratory environment (Johnson's® No More The lower tear meniscus height was assessed using high
Tears® Baby Shampoo, Johnson & Johnson, New Jersey, USA) to the magnification digital imaging captured by the Oculus Keratograph
fellow eye, twice daily, for a period of 28 days (Table 1). Participant 5M, and three measurements near the center of the lower meniscus
masking was achieved by supplying the two treatments in identical were averaged. Noninvasive tear film breakup time and tear film
48 mL foam pump bottles that were labelled with the study allo- lipid layer grade were also assessed using the Oculus Keratograph
cated eye for application. Product application was demonstrated 5M. Breakup time was recorded as the time taken following a blink
during the enrollment visit, and written instructions were also for the grid reflection to first show distortion, while the subject
provided. Participants were instructed to apply and gently massage maintained fixation and was requested to refrain from blinking.
foam from one bottle onto the pericoular skin of the closed superior Three breakup time measurements were averaged in each case [14].
and inferior eyelids of the designated eye with clean fingertips for Lipid layer grading was based on the modified Guillon-Keeler
one minute before rinsing with water, and to take care to avoid the grading system: grade 1, open meshwork; grade 2, closed mesh-
transfer of residual products to the fellow eye during cleansing and work; grade 3, wave or flow; grade 4, amorphous; grade 5, colored
drying. Participants were also instructed to avoid direct contact fringes; grade 0, non-continuous layer (non-visible or abnormal
with the ocular surface, and to clean their hands prior to using the colored fringes) [15,16]. Bulbar conjunctival hyperemia was
second bottle for the fellow eye, in order to prevent cross assessed by automated objective evaluation of high magnification
 J. Sung et al. / The Ocular Surface 16 (2018) 77e83
digital imaging using the Oculus Keratograph 5M, on the pro-
prietary JENVIS grading scale from 0 to 4. Tear film osmolarity was
evaluated, at baseline only, with a clinical osmometer (TearLab, CA,
USA), using 50 nL tear samples collected from the lower tear
meniscus. Two measurements were taken, and the higher reading
and interocular difference in readings recorded [14].
Lid margin and eyelash abnormalities, including lid margin
thickening, rounding, notching, telangiectasia, foaming, staphylo-
coccal lash crusting, seborrhoeic lash crusting, cylindrical collar-
ettes, madarosis, poliosis, trichiasis, and meibomian gland capping,
were assessed by slit lamp examination. Grading of the clinical
features was based on a four-point scale: grade 0, absent; grade 1,
mild; grade 2, moderate; grade 3, severe. Lid parallel conjunctival
folds (LIPCOF) were noted and sodium fluorescein and lissamine
green dyes were applied, in turn, to the bulbar conjunctiva to
evaluate localized corneal and conjunctival epithelial dessciation.
Staining was recorded using the modified Oxford grading scheme
[17] and lid wiper epitheliopathy (LWE) staining was evaluated
relative to Korb's grading using sodium fluorescein and lissamine
green dyes [18,19].
Inferior eyelid meibomian glands were expressed with the
Meibomian Gland Evaluator™ (TearScience®, North Carolina, USA).
The number of meibomian gland orifices yielding lipid secretions
was graded on a five-point scale: 0, more than 75%; 1, 50%e75%; 2,
25%e50%; 3, less than 25%; 4, none. The meibum viscosity and
expressibility was graded as: grade 0, clear fluid; grade 1, slightly
turbid; grade 2, thick opaque; grade 3, toothpaste like; grade 4,
complete orifice blockage [16]. Infrared meibography was then
performed using the Oculus Keratograph 5M at baseline, with the
superior and inferior eyelids everted in turn. From the captured
image, upper and lower eyelid meibomian gland drop out was
graded according to the five-point Meiboscale [20].
Subjective preference of the eyelid hygiene treatments (eyelid
cleanser, baby shampoo, or no preference) was recorded on day 28,
and participants were also asked to provide any further comments
they desired regarding the two treatments.
2.4. Laboratory investigations
Conjunctival impression cytology was conducted at baseline
and day 28, following topical anesthesia with one drop of oxy-
buprocaine hydrochloride 0.4% (Minims, Bausch & Lomb (NZ) Ltd,
Auckland, NZ). Bulbar conjunctival cells from the superior temporal
ocular surface were collected with the EYEPRIM™ conjunctival
impression device (OPIA, France). Conjunctival cell sample RNA
extraction and purification was performed using the PureLink® RNA
Mini Kit, and tested for the presence of inhibitors before under-
going cDNA synthesis using SuperScript® VILO cDNA Synthesis Kit
(ThermoFisher, Massachusetts, USA). A standard b-actin PCR and
gel electrophoresis was conducted on a representative selection of
the synthesized cDNA samples to confirm cDNA synthesis. Six
reference genes (GAPDH, b-actin, HPRT1, PPIA, GUSB and B2M)
were tested among the sample population for stability with b-actin
and B2M being established as the most stable according to the
Normfinder algorithm. The genes of interest (MMP-9, IL-6 and
MUC5AC) were quantified relative to the expression of reference
genes. The MIQE guidelines were followed to ensure validity of the
qPCR experiments, which were set up with QiAgility® PCR robot
with PrimeTime® Assays, and internal calibrators were used to
enable compensation for inter-run variations.
2.5. Statistics
Statistical analyses were performed using Graph Pad Prism
version 6.02 (California, USA) and IBM SPSS Statistics version 22
79
(New York, USA). Comparisons of continuous variables between
and within treatments were performed using multiplicity adjusted
Sidak's tests within a repeated measures analysis of variance
model, where normal distribution had been confirmed by the
Kolmogorov-Smirnov test (p > 0.05). Non-normally distributed
measures were logarithmically transformed before analysis, while
ordinal data and categorical data were converted to rank values
prior to undergoing multiplicity adjusted non-parametric analysis.
All tests were two-tailed and p < 0.05 was considered significant.
3. Results
The mean ± SD of the 43 enrolled participants (27 female, 16
male) was 38 ± 20 years (range, 17e77 years). Baseline character-
istics and clinical measurements are listed in Tables 2 and 3,
respectively. There were no significant differences in baseline
characteristics and measurements between treatments (all
p > 0.05). The mean ± SD amount of product use during the 28-day
treatment period was 24.1 ± 9.9 g of eyelid cleanser, and
22.4 ± 9.5 g of baby shampoo. The difference in amount of the two
products used was not significantly different (p ¼ 0.42).
3.1. Dry eye symptomology
SPEED and SANDE scores decreased with both treatments dur-
ing the 4-week period (all p < 0.01). Although no differences were
detected in the SPEED score changes between groups (p ¼ 0.94), a
significantly larger decrease in the SANDE score was observed in
the eyelid cleanser group (p ¼ 0.04; Fig. 1).
3.2. Tear film
Lipid layer grade increased significantly following 4 weeks of
eyelid cleanser treatment (p < 0.001; Fig. 2), but not with baby
shampoo (p ¼ 0.19). Tear meniscus height and non-invasive tear
film breakup time did not change significantly during the trial
period in either group (all p > 0.05).
3.3. Ocular surface
Following 4 weeks of treatment with both the eyelid cleanser
and baby shampoo, superior LWE, seborrhoeic lash crusting, and
trichiasis grades decreased significantly (all p < 0.05), and did not
vary between treatments (all p > 0.05). Significant decreases in
inferior LWE and lid cylindrical collarete grades were observed in
the eyelid cleanser group (both p < 0.01), but no changes were
detected in the baby shampoo group (both p > 0.05). Meibomian
gland capping grade increased significantly with baby shampoo
treatment (p ¼ 0.04), but not eyelid cleanser (p ¼ 0.49). There were
no significant changes in bulbar conjunctival hyperemia, ocular
Table 2
Baseline characteristics of the eyes of participants randomized to the dedicated
eyelid cleanser and diluted baby shampoo treatments. Data are presented as
mean ± SD, median (IQR), or number of participants (% of participants). Asterisks
denote statistically significant differences (p < 0.05).
Characteristic Eyelid cleanser Baby shampoo p
(n ¼ 43) (n ¼ 43)
Age 38 ± 20
Female sex 27 (63%)
McMonnies score 12.2 ± 7.4 12.4 ± 7.5 0.86
OSDI score 23.1 ± 16.5 23.2 ± 17.4 0.95
Upper eyelid meibography grade 2 (1e3) 2 (1e3) >0.99
Lower eyelid meibography grade 2 (1e3) 2 (1e3) 0.86
Tear film osmolarity (mOsmol/kg) 303 ± 13 304 ± 16 0.71
80 J. Sung et al. / The Ocular Surface 16 (2018) 77e83

Table 3
Baseline and day 28 clinical measurements and subjective reports of the eyes of participants randomized to the dedicated eyelid cleanser and diluted baby shampoo treat-
ments. Data are presented as mean ± SD, median (IQR), or number of participants (% of participants). Asterisks denote statistically significant differences (p < 0.05).

Measurement Eyelid cleanser Baby shampoo p

(n ¼ 43) (n ¼ 43)

Dry eye symptomology

SPEED score Baseline 14.7 ± 7.9 15.1 ± 7.5 0.57
Day 28 10.4 ± 6.5 10.8 ± 7.1 0.41
p <0.001* <0.001*
Difference 4.3 ± 6.8 4.3 ± 5.9 0.94
SANDE score Baseline 4.0 ± 2.8 4.1 ± 2.7 0.84
Day 28 2.1 ± 1.8 2.7 ± 2.3 0.03*
p <0.001* 0.002*
Difference 2.0 ± 2.5 1.4 ± 2.4 0.04*
Tear film
Tear meniscus height (mm) Baseline 0.25 ± 0.10 0.26 ± 0.10 0.25
Day 28 0.25 ± 0.10 0.25 ± 0.10 0.82
p 0.94 0.36
Difference 0.0 ± 0.07 0.0 ± 0.07 0.82
Lipid layer grade Baseline 3 (2e4) 3 (2e4) 0.41
Day 28 4 (3e5) 3 (3e4) 0.12
p <0.001* 0.19
Noninvasive tear film breakup time (s) Baseline 12.2 ± 8.6 14.5 ± 12.2 0.18
Day 28 14.2 ± 12.2 13.7 ± 14.2 0.79
p 0.22 0.50
Difference 2.0 ± 7.5 0.8 ± 13.3 0.15
Ocular Surface
Lid margin thickening grade Baseline 0 (0e1) 0 (0e1) >0.99
Day 28 0 (0e0) 0 (0e0) >0.99
p 0.73 >0.99
Lid margin rounding grade Baseline 0 (0e0) 0 (0e0) >0.99
Day 28 0 (0e0) 0 (0e0) >0.99
p >0.99 >0.99
Lid margin notching grade Baseline 0 (0e0) 0 (0e0) 0.50
Day 28 0 (0e0) 0 (0e1) 0.13
p >0.99 0.77
Lid margin telangiectasia grade Baseline 0 (0e0) 0 (0e0) >0.99
Day 28 0 (0e0) 0 (0e0) >0.99
p >0.99 >0.99
Lid margin foaming grade Baseline 0 (0e0) 0 (0e0) 0.75
Day 28 0 (0e0) 0 (0e0) 0.38
p 0.44 0.79
Bulbar conjunctival hyperaemia Baseline 0.8 ± 0.4 0.8 ± 0.4 0.26
Day 28 0.8 ± 0.4 0.8 ± 0.4 0.65
p 0.78 0.28
Sodium fluorescein staining score (out of 55) Baseline 4.9 ± 5.6 4.8 ± 5.6 0.81
Day 28 3.8 ± 3.4 4.2 ± 4.6 0.39
p 0.27 0.41
Lissamine green staining score (out of 55) Baseline 2.2 ± 3.8 2.7 ± 4.2 0.31
Day 28 1.9 ± 1.8 2.1 ± 2.6 0.66
p 0.84 0.39
Lid parallel conjunctival folds grade Baseline 1 (0e3) 1 (0e3) 0.98
Day 28 1 (0e3) 1 (0e3) 0.33
p 0.16 0.64
Superior lid wiper epitheliopathy grade Baseline 3 (1e4) 2 (1e4) 0.71
Day 28 0 (0e0) 0 (0e0) 0.13
p <0.001* <0.001*
Inferior lid wiper epitheliopathy grade Baseline 2 (0e3) 2 (0e3) 0.45
Day 28 1 (0e2) 1 (0e2) 0.68
p <0.001* 0.21
Staphylococcal lash crusting grade Baseline 0 (0e0) 0 (0e0) >0.99
Day 28 0 (0e0) 0 (0e0) >0.99
p >0.99 >0.99
Seborrhoeic lash crusting grade Baseline 1 (0e1) 1 (0e1) 0.11
Day 28 0 (0e1) 0 (0e1) 0.23
p <0.001* <0.001*
Cylindrical lash collarettes grade Baseline 0 (0e1) 0 (0e1) 0.72
Day 28 0 (0e0) 0 (0e0) 0.32
p 0.01* 0.28
Madarosis grade Baseline 0 (0e1) 0 (0e1) >0.99
Day 28 0 (0e1) 0 (0e1) >0.99
p 0.29 0.48
Poliosis grade Baseline 0 (0e0) 0 (0e0) 0.50
Day 28 0 (0e0) 0 (0e0) 0.26
p >0.99 >0.99
Trichiasis grade Baseline 0 (0e1) 0 (0e1) >0.99
Day 28 0 (0e0) 0 (0e0) >0.99
p 0.02* 0.003*
 J. Sung et al. / The Ocular Surface 16 (2018) 77e83 81

Table 3 (continued )

Measurement Eyelid cleanser Baby shampoo p

(n ¼ 43) (n ¼ 43)

Meibomian gland capping grade Baseline 1 (0e1) 1 (0e1) 0.30

Day 28 1 (1e1) 1 (1e1) 0.74
p 0.72 0.04*
Meibomian gland secretion grade Baseline 3 (2e3) 3 (2e4) 0.13
Day 28 3 (2e4) 3 (2e4) 0.31
p 0.32 0.87
Expressed meibum grade Baseline 1 (0e4) 2 (0e4) 0.31
Day 28 1 (0e4) 1 (0e3) >0.99
p 0.97 0.12
Inflammatory Markers
MMP-9 expression Baseline 6.70 ± 3.95 8.42 ± 5.39 0.34
Day 28 0.54 ± 2.84 6.23 ± 3.71 0.12
p 0.04* 0.79
IL-6 expression Baseline 1.69 ± 5.62 1.41 ± 5.38 0.22
Day 28 1.80 ± 7.56 1.29 ± 2.41 0.86
p 0.19 0.42
MUC5AC expression Baseline 7.86 ± 4.78 9.07 ± 9.04 0.61
Day 28 9.01 ± 15.96 6.18 ± 4.83 0.58
p 0.76 0.02*
Subjective reports
Overall treatment preference 23 (53%) 4 (9%) <0.001*
Easier application/foaming 4 (9%) 0 (0%) 0.12
Unpleasant smell 7 (16%) 2 (5%) 0.16
Ocular stinging on application 5 (12%) 18 (42%) 0.003*
Excessive eyelid drying 1 (2%) 3 (7%) 0.62

Fig. 1. Differences in SANDE score following 4-week treatment with the dedicated
eyelid cleanser and diluted baby shampoo treatments. Each bar represents the mean
difference in SANDE score. Error bars represent the standard deviation. Asterisks
denote statistically significant differences (p < 0.05).
staining, LIPCOF, lid margin signs, staphylococcal lash crusting,
madarosis, poliosis, meibum and meibomian gland secretion
grades in either group during the trial period (all p > 0.05).
3.4. Inflammatory markers
MMP-9 expression levels decreased following eyelid cleanser
(p ¼ 0.04, Fig. 3), but not baby shampoo, treatment (p ¼ 0.79). A
significant reduction in MUC5AC expression was detected in eyes
randomized to baby shampoo treatment (p ¼ 0.02), but not eyelid
cleanser (p ¼ 0.76). IL-6 expression levels did not change in either
group during the 4-week period (both p > 0.05).
3.5. Treatment preference
A significantly higher proportion of participants preferred the
Fig. 2. Tear film lipid layer grade of eyes randomized to dedicated eyelid cleanser and
diluted baby shampoo treatments at baseline and day 28. Each point represents the
lipid layer grade of an individual eye. Bars represent the median lipid layer grade. Error
bars represent the interquartile range. Asterisks denote statistically significant differ-
ences (p < 0.05).
eyelid cleanser over the diluted baby shampoo treatment (53% vs.
9%, p < 0.001; Fig. 4). The proportion of participants reporting
ocular stinging following application of baby shampoo was greater
than with eyelid cleanser (42% vs. 12%, p ¼ 0.003). No further
adverse events were reported during this study.
4. Discussion
The results of this study demonstrate objective and subjective
clinical improvements in blepharitis patients following a 4-week
treatment with both the dedicated eyelid cleanser and diluted
baby shampoo. Significant decreases in SPEED and SANDE symp-
tomology scores, superior LWE, seborrhoeic lash crusting and
82 J. Sung et al. / The Ocular Surface 16 (2018) 77e83
Fig. 3. Relative MMP-9 expression levels in eyes randomized to dedicated eyelid
cleanser and diluted baby shampoo treatments at baseline and day 28. Each bar rep-
resents the mean relative MMP-9 expression level. Error bars represent the standard
deviation. Asterisks denote statistically significant differences (p < 0.05).
Fig. 4. Treatment preference of participants. Each bar represents the percentage of
participants that reported preference for the dedicated eyelid cleanser, dilute baby
shampoo, or no preference. Error bars represent the 95% confidence interval. Asterisks
denote statistically significant differences (p < 0.05).
trichiasis grades were observed with both treatments. These find-
ings are consistent with previous reports, which have described
improvements in blepharitis signs and symptoms following eyelid
hygiene regimens with both dedicated eyelid cleansers and diluted
baby shampoo [4,8,9,21]. However, improvements in inferior LWE
and cylindrical collarette grades were limited only to the eyelid
cleanser treatment, and a significantly greater reduction in the
SANDE score was also detected. This suggests that the eyelid
cleanser may be more effective than diluted baby shampoo. The
improvement in cylindrical collarettes, which are pathognomonic
for Demodex infestation, with eyelid cleanser application may
potentially be related to its tea tree oil constituent [2]. These trends
are comparable to the results of a previous study, which reported
greater clinical efficacy of a phospholipid-liposome solution than
baby shampoo in contact lens wearers with blepharitis [9].
The clinical findings were supported by the quantification of
inflammatory markers. A significant reduction in MMP-9 expres-
sion levels was observed following 4-week treatment with the
eyelid cleanser, but not with baby shampoo. MMP-9 is an important
matrix-degrading enzyme in normal physiological processes of
tissue remodelling [22]. However, it is also understood to play a
pathological role in inflammatory responses, whereby the cleavage
of tight junction proteins including occludin and ZO-1 can
contribute towards the disruption of epithelial cell layers [23]. The
release of MMP-9 can also result in the activation of other media-
tors, creating a feedback loop which upregulates a cycle of pro-
gressive inflammation [24,25]. Elevated levels of MMP-9 have
previously been reported in dry eye patients [22,26], and its release
from corneal epithelial cells can be triggered by tear film
hyperosmolarity-induced stress-activated protein kinase (SAPK)
signalling cascades [27]. The decrease in MMP-9 expression with
eyelid cleanser treatment therefore suggests that it may be more
effective in reducing ocular surface inflammation than is diluted
baby shampoo.
Levels of MUC5AC expression were observed to decrease in eyes
randomized to the baby shampoo treatment, while no significant
changes were detected with the eyelid cleanser. MUC5AC is a mucin
specific to goblet cells, and its expression levels are a marker of
goblet cell density and function within the conjunctival epithelium
[28e30]. Ocular surface inflammation and hyperosmotic stress can
compromise goblet cell integrity and consequently result in a
reduction of MUC5AC expression [31]. The fall in MUC5AC
expression following 4 weeks of baby shampoo treatment suggests
the potential presence of pro-inflammatory agents within the
formulation. An earlier animal study also suggested inflammatory
effects of baby shampoo formulations on the ocular surface [11].
Fragrances present within shampoo formulations are known to be
skin irritants [32,33], while associations between phenoxyethanol
and reduced tear film stability have been reported [34]. However, it
is currently unknown whether these baby shampoo ingredients are
directly responsible for inducing ocular surface inflammation.
Nevertheless, this may provide some explanation in regard to the
clinical findings of the current study, whereby the therapeutic ef-
fects of the baby shampoo application may be partially offset by
pro-inflammatory constituents, which contributed to a lesser
reduction of blepharitis signs and symptoms than occurred with
the eyelid cleanser treatment. The worsening meibomian gland
capping observed in the baby shampoo group may also be poten-
tially related to inflammation-induced gland orifice epithelializa-
tion. Furthermore, it must be noted that the preparation of the
diluted baby shampoo solution was performed accurately and in
sterile laboratory conditions. Such precision is unlikely to be
reproduced by patients at home, and dilution may potentially be
conducted with unsterilized tap water. This may introduce risks of
contamination and insufficient dilution, and it is unknown whether
this could further reduce potential clinical efficacy or result in more
pronounced adverse effects. Moreover, the length of time for which
diluted baby shampoo solutions can be safely stored has not been
established, and it is not known whether the storage of pre-diluted
solutions may be associated with additional undesirable outcomes.
As blepharitis is a chronic condition, regular and long-term use
of eyelid hygiene regimens is required to achieve sustained
symptomatic relief. However, the therapeutic potential of any self-
applied therapy will be limited by patient compliance. Patient
preference, perceived efficacy, convenience and adverse effects are
likely to influence compliance levels [35]. In the current double-
masked study, a significantly higher proportion of participants
expressed preference for the dedicated eyelid cleanser than diluted
baby shampoo. A greater reduction in overall SANDE symptomol-
ogy scores was observed in eyes randomized to the eyelid cleanser,
 J. Sung et al. / The Ocular Surface 16 (2018) 77e83
and a larger proportion of participants reported ocular stinging
with baby shampoo application than with eyelid cleanser. Although
the eyelid cleanser is available commercially in foam pump bottles,
the undiluted baby shampoo bottles do not have an associated
foaming mechanism. Patients using baby shampoo for eyelid hy-
giene will therefore need to dilute and lather the formulation prior
to application. The relatively more time-consuming nature of the
diluted baby shampoo treatment may be associated with perceived
inconvenience, conceivably partially offsetting the difference in
financial costs of the two treatments. Overall, these factors would
appear to favor superior long-term compliance levels with eyelid
cleanser treatment over baby shampoo.
5. Conclusions
Of note, a 4-week treatment with both the dedicated eyelid
cleanser and the diluted baby shampoo preparation effected im-
provements in blepharitis signs and symptoms. However, clinical
assessment and inflammatory marker analysis point towards a
superior ability of the dedicated eyelid cleanser to reduce inflam-
mation, and it was also the preferred treatment option among
study participants. The long-term impact of decreased goblet cell
function secondary to baby shampoo treatment requires further
exploration.
Disclosure statements
The authors have no commercial or proprietary interest in any
concept or product described in this article. The funding sources
had no role in study design; the collection, analysis and interpre-
tation of data; the writing of the report; or the decision to submit
the article for publication.
Sources of support
This research was funded with the aid of a Maurice and Phyllis
Paykel Trust Project Grant, New Zealand. The researchers are
grateful to Akorn Pharmaceuticals for product donation (Ther-
aTears) and supply of unused bottles for masking purposes.
Trial registration number
ACTRN12616000545460.
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