Medical Management of Blepharokeratoconjunctivitis

in Children: A Delphi Consensus

Moritz Claudius Daniel, Dr med; Michael OGallagher, MSc, FRCOphth;
Melanie Hingorani, MD, FRCOphth; Daniel F. Larkin, MD, FRCPI, FRCOphth; Stephen Tuft, MD, FRCOphth;
Annegret Dahlmann-Noor, Dr med, PhD, FRCOphth

ABSTRACT

Purpose: To describe a pragmatic approach to the
medical management of blepharokeratoconjunctivitis
in children, based on published evidence and clinical
experience.
Methods: The authors used the Delphi consensus
method to explore the preferred management pat-
terns of four senior clinicians at one institution to reach
agreement on indications and dosage schedules for
commonly used treatments. Four iterations were cre-
ated, with electronic questionnaires distributed via an
online survey platform. Initial questions were based on
recent systematic reviews and clinical experience. After
each round, a facilitator summarized the responses and
fed these back to the expert participants, together with
an invitation to complete the next round of questions.
cisions, and treatments were targeted toward specific
findings in these tissues rather than to overall disease
severity. Active keratitis was considered the main indi-
cation for high potency steroids, systemic antibiotics,
and possibly systemic immunomodulators. Other in-
dications for systemic antibiotics were chronic active
blepharitis and recurrent troublesome chalazia. Oral
antibiotics were used for their anti-inflammatory and
antimicrobial properties. There was little agreement on
the role of dietary modification, topical lubricants, and
preference for oral or topical antibiotics.
Conclusions: Detailed clinical assessment of eyelids
and ocular surface allows targeted treatment. Research
is needed to clarify disease mechanisms and to opti-
mize treatment strategies.

Results: Typical and specific eyelid, corneal, and con- [J Pediatr Ophthalmol Strabismus. 2017;54(3):156-
junctival disease features influenced management de- 162.]

INTRODUCTION dysfunction and secondary ocular surface inflamma-

Childhood blepharokeratoconjunctivitis is a tion.1,2 Blepharokeratoconjunctivitis is estimated to
common, often underdiagnosed and undertreated be the primary reason for referral to a pediatric eye
eyelid margin inflammation with meibomian gland clinic in up to 12% to 15% of cases.2,3 The mean age

From NIHR Moorfields Biomedical Research Centre, London, United Kingdom (MCD, MO, MH, DFL, ST, AD-N); and Eye Center, Medical Center,
University of Freiburg, Freiburg, Germany (MCD).
Submitted: June 1, 2016; Accepted: September 21, 2016
Drs. Dahlmann-Noor and Daniel are employed by the National Institute for Health Research (NIHR) Moorfields Biomedical Research Centre, and as
such the work was supported by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department
of Health. The remaining authors have no financial or proprietary interest in the materials presented herein.
Correspondence: Annegret Dahlmann-Noor, Dr med, PhD, FRCOphth, NIHR Moorfields Biomedical Research Centre, Moorfields Eye Hospital, 162
City Road, London EC1V 2PD, United Kingdom. E-mail: annegret.dahlmann-noor@moorfields.nhs.uk
doi:10.3928/01913913-20161013-04

156 Copyright SLACK Incorporated

of onset is between 3 and 4.5 years, with a second
peak in adolescence.1,3,4 Blepharokeratoconjunctivitis
may be more common in girls3 and in children of
South Asian ethnicity.5 Signs and symptoms appear
to be more severe in South Asian and Middle-Eastern
children,5,6 although a severe phenotype also occurs
in white adolescents.7 Children with blepharokera-
toconjunctivitis can develop acute sight-threatening
complications such as corneal thinning and perfo-
ration.4,6,8 Chronic changes such as corneal stromal
scarring, vascularization, and induced refractive er-
rors can result in deprivation amblyopia. The etiology
of blepharokeratoconjunctivitis is unclear; proposed
mechanisms include a delayed type hypersensitivity
response to bacterial antigens,9-11 bacterial lipases dis-
rupting the tear film and releasing inflammatory me-
diators,12-14 meibomian gland dysfunction,15-17 bac-
terial colonization of the meibomian glands and the
ocular surface,12-14 hyperosmolarity of the tear film,
and the action of pro-inflammatory cytokines.18,19
Most treatment strategies, such as topical and sys-
temic antibiotics, topical steroids, dietary modifica-
tion, tear supplements, and eyelid hygiene, are based
on studies of meibomian gland dysfunction and ro-
sacea keratitis in adults, but these may not be directly
appropriate or effective in pediatric practice. None of
these treatments has been evaluated in randomized
controlled trials in children.20-23 Published treatment
schedules recommend complex assessments and se-
verity scores to decide when to escalate treatment
strategies for children at higher risk,7,24 which may
not be practicable in photophobic and uncooperative
children. Treatment adherence can be low because
eyelid margin cleaning and instillation of eye drops
can be difficult in young children, and parents may
have concerns about the long-term administration of
oral antibiotics or immunomodulators.
In the absence of high grade evidence from
randomized controlled trials, we decided to use the
Delphi consensus approach to develop a pragmatic
approach to blepharokeratoconjunctivitis treatment
in children.
PATIENTS AND METHODS
Four clinicians experienced in the management
of pediatric external eye disease (two corneal special-
ists with adult and pediatric practice and two pedi-
atric ophthalmologists, of whom one has completed
fellowships in both pediatric ophthalmology and in
cornea/external diseases) took part in this consensus
Journal of Pediatric Ophthalmology & Strabismus Vol. 54, No. 3, 2017
finding. We used the Delphi method to allow the
specialists to anonymously express their opinions,
without being influenced by the others. We created
four iterations, which were delivered as electronic
questionnaires (www.surveymonkey.com). Analysis
of the responses was descriptive and, where appro-
priate, semi-quantitative. Our consensus threshold
was three of four participants.
The first round aimed to generate items for the
subsequent rounds, and asked participants to de-
scribe how they evaluate disease severity and which
treatment modalities they use. The subsequent
rounds used multiple-choice questions to determine
preferred management patterns. Participants could
indicate agreement with more than one answer and
add additional comments as free text. After each
round, a facilitator (MCD) analyzed the answers
and provided the participants with an anonymized
summary and the questions for the next round,
which had resulted from the analysis. After the third
round, we drew up management flowcharts and in-
vited comments. Narrowing of answer options led
to new disagreements, which were clarified in one
final iteration. We completed the four rounds be-
tween January 26 and February 29, 2016.
RESULTS
First Round: Disease Severity and Treatment
Options
The first round aimed to establish categories of
disease severity and treatment options. It became
obvious at this stage that although all four respon-
dents considered corneal involvement as a hallmark
of severe blepharokeratoconjunctivitis, they also
assessed the other tissues involved (eg, eyelid and
conjunctiva) as independent treatment targets. One
respondent also considered symptoms such as blink-
ing, photophobia, and watery eyes. Agreement on
indications for treatment options varied.
Three respondents always gave advice on eyelid
hygiene, and one only did so for cases of eyelid mar-
gin inflammation. Methods of eyelid margin clean-
ing included cotton buds/swabs or a flannel wrapped
tightly around the index finger and soaked in water,
with or without baby shampoo or bicarbonate of
soda, or commercial eyelid cleansing wipes.
Advice on dietary changes and supplements
ranged from never to always. Indications were to main-
tain control after completion of a course of oral anti-
biotics, or if parents prefer not to use oral antibiotics.
157
The use of topical lubricants also varied significantly,
ranging from never to always. Two respondents added
comments stating that they would prioritize the ad-
ministration of effective medication, such as steroids
and antibiotics, over lubricants if there was a risk of
overloading families with too many medications. Lu-
bricants used were different carmellose formulations.
Responses on the use of topical antibiotics showed
that indications were specific to eyelid, corneal, and
conjunctival signs. Eyelid abnormalities for which
topical antibiotics were prescribed included folliculi-
tis, acute/inflamed chalazion, chronic active blepha-
ritis, acute blepharoconjunctivitis, and diffuse eyelid
margin inflammation. Corneal signs were catego-
rized into punctate epithelial erosions versus stromal
involvement (vascularization, infiltrates) and ulcer-
ation. Topical antibiotics were prescribed for stromal
involvement. Non-compliance with or non-tolerance
of oral antibiotics was another indication for topical
antibiotics. The choice of antibiotics varied.
Topical steroids were suggested for active kera-
titis other than punctate corneal epithelial erosions
and for moderate to severe conjunctival inflamma-
tion. Indications for high potency versus surface-
acting or weaker steroids were identified as requiring
clarification in subsequent rounds.
The topical calcineurin inhibitor cyclosporine
A was uniformly suggested as a steroid-sparing al-
ternative after an initial treatment period with topi-
cal steroids. Indications were steroid-induced ocular
hypertension and steroid dependence in the control
of inflammation, particularly keratitis.
All respondents used systemic antibiotics for
chronic blepharitis (inflammation persistent for 6
weeks or longer), diffuse eyelid margin inflamma-
tion, recurrent troublesome chalazia, and any active
keratitis. The preferred antibiotics were erythromy-
cin and doxycycline for at least 6 to 12 weeks.
All respondents agreed that systemic immuno-
suppression should be reserved for extreme cases,
such as sight-threatening keratitis unresponsive
to topical steroids and severe keratitis with atopic
blepharoconjunctivitis. Two drugs suggested were
oral prednisolone and mycophenolate mofetil.
Second Round: Indications and Dosages of
Treatment Modalities
The second round explored indications and dos-
ages of treatment modalities. With regard to eyelid
hygiene, agreement was greatest for the statement
158
eyelid hygiene is advisable for obvious eyelid mar-
gin inflammation. All respondents agreed that if
only one step of full eyelid hygiene was tolerated, it
should be the cleaning of the eyelid margins. Three
of four respondents agreed that eyelid hygiene should
start with warm compresses, if tolerated by the child.
All agreed that any of the following methods of eye-
lid margin cleaning are acceptable: cotton bud/swab
or flannel wrapped tightly around index finger and
soaked in water, with or without baby shampoo or
bicarbonate of soda; or commercial eyelid wipes.
There was no consensus on the role of dietary
changes or supplements. Agreement was greatest for
dietary changes may be useful if parents prefer not
to use antibiotics. The lack of evidence on efficacy
was noted.
Topical lubricants were considered to be useful
when used in conjunction with anti-inflammatories
and/or antibiotics in the presence of signs of punc-
tate epithelial erosions with inflammation (conjunc-
tivitis, keratitis). One respondent noted again that
lubricants could be omitted if they distracted from
the administration of more effective treatments.
Agreement on indications for topical antibiotics,
steroids, calcineurin inhibitors, and antihistamines/
mast cell stabilizers was high throughout all rounds,
and is detailed in the final treatment flowchart (Fig-
ure 1). Diffuse eyelid margin inflammation, recur-
rent chalazia, and corneal ulceration were clear in-
dications for oral antibiotics, but one participant
would consider oral antibiotics only after a trial of
topical treatment. Erythromycin was the preferred
preparation for children younger than 12 years, and
doxycycline for patients 12 years and older. There
was no agreement on recommended treatment dura-
tion, with two participants preferring at least 6 weeks
and the other two at least 12 weeks.
As in the first round, all participants considered
keratitis unresponsive to topical steroids to be an
indication for systemic immunosuppression; two
also considered severe atopic blepharoconjunctivi-
tis with keratitis. Respondents agreed that in severe
cases, immunosuppression should be initiated with
a short course of oral prednisolone, followed by my-
cophenolate mofetil or azathioprine.
Third Round: Refinement of Agreement on
Treatment Decisions
The third round showed that there was no agree-
ment on whether oral or topical antibiotics should
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Figure 1. Summary of Delphi consensus and treatment flowchart. Treatment is guided by tissue-specific findings in eyelids, conjunctiva,
and cornea. IOP = intraocular pressure; OHT = ocular hypertension; PEE = punctate epithelial erosions; ATP = azathioprine; AZT = azithro-
mycin; CPL = chloramphenicol; CSA = cyclosporine A; DXC = doxycycline; DEX = dexamethasone (prednisolone acetate [preserved] can be
used as alternative); ERM = erythromycin; FLQ = fluoroquinolones (ofloxacin, levofloxacin, moxifloxacin); FML = fluorometholone; FCX =
flucloxacillin; FUS = fusidic acid; MYC = mycophenolate mofetil; PRED = prednisolone; RMX = rimexolone; LTP = loteprednol; OPT = opata-
nol; lub = lubricants; od = once daily; bd = twice daily; qds = four times a day; 2h = 2 hourly; G = guttae (drops); Oc = ointment; top = topical

be used as first line treatment for chronic eyelid in-
flammation. Whereas two participants favored topi-
cal administration as first line, one suggested involv-
ing the parents/caregivers and older children in the
decision. Similarly, two participants considered that
the option of dietary modification should be deter-
mined by parent preferences and, although probably
less effective than oral antibiotics in chronic eyelid
inflammation, it was seen as inappropriate to in-
clude in a treatment algorithm because there is little
evidence that it is effective.
After the third round, we devised flowcharts for
each of the three tissues (eyelid, conjunctiva, and
cornea) and invited comments from the partici-
pants. This resulted in a widening of the discussion,
review of previous agreements, and the need for a
fourth round of questions to clarify specific details
of the flowcharts, such as the grouping of phlycte-
nule with severe conjunctival inflammation or the
preferences for topical versus oral antibiotics. After
the fourth and final round, we combined the three
flowcharts for eyelid, conjunctiva, and cornea into
one diagram (Figure 1).
DISCUSSION
The Delphi method is an established approach
to building consensus in a variety of settings, in-
cluding health care. It has been used in ophthal-
mology for the Standardization of the Uveitis No-
menclature,25 a clinical classification of age-related
macular degeneration,26 a minimum standard set
of outcomes after cataract surgery,27 consensus on
keratoconus diagnosis,28 and pediatric cataract man-
agement,29 among others.
Here, the consensus approach established that
the participating specialists target treatment to spe-
cific signs for each of the three tissues affected by
blepharokeratoconjunctivitis (ie, eyelids, conjunc-

Journal of Pediatric Ophthalmology & Strabismus Vol. 54, No. 3, 2017 159
tiva, and cornea). We found that there was much
agreement on the grading of disease severity and the
use of topical antibiotics, topical steroids, and eyelid
hygiene. Active corneal inflammation is the main in-
dication for high potency steroids, systemic antibiot-
ics, and, in rare cases, systemic immunomodulators.
Chronic active blepharitis and recurrent troublesome
chalazia are also treated with systemic antibiotics;
in blepharokeratoconjunctivitis, erythromycin and
doxycycline are used for their anti-inflammatory and
antimicrobial properties. Severe conjunctival inflam-
mation, particularly phlyctenular conjunctivitis, may
warrant high-potency topical steroids. In this study,
we included dexamethasone in the Delphi process,
although prednisolone acetate would be a reasonable
alternative. Steroid-induced ocular hypertension, in-
ability to measure the intraocular pressure, or pro-
longed need for topical steroids can be addressed by
treating with surface-acting or weaker steroids, or
with calcineurin inhibitors such as cyclosporine A.
Cyclosporine A is not in common use for blepharo-
keratoconjunctivitis, although it has been described
in previous studies.7,24,30 It has been available for
years as a veterinary ophthalmic ointment; in 2015,
the European Medicines Agency granted a market-
ing authorization for cyclosporine A 0.1% eye drops
for the treatment of severe keratitis in adults with dry
eye disease.
Our study has several methodological limita-
tions that affect the external validity of this work.
The main concern is that we only involved four ex-
perts, and that these experts all practice at the same
institution. A full Delphi consensus should include
experts from different institutions and representa-
tives of all stakeholders, such as patients, caregiv-
ers, and family physicians. However, there is no
agreement in the literature on optimal panel size or
composition.31 For this initial study, we restricted
the participants to our specialists to clarify the pre-
ferred medical approach before extending the scope.
Blepharokeratoconjunctivitis has been reported to
be more severe in South Asian and Middle-Eastern
children.4 Although blepharokeratoconjunctivitis is
a common ophthalmological diagnosis in children,
gaining experience and expertise in the treatment
of children with blepharokeratoconjunctivitis can
be challenging in institutions where its prevalence
is lower and the patient population is of less ethni-
cally diverse backgrounds. Our institution is one of
the largest childrens eye care facilities in the world
160
and a tertiary referral center, with several hundred
children with blepharokeratoconjunctivitis attend-
ing our clinics every year. We therefore felt ideally
placed to begin the consensus process locally.
Few other treatment protocols for pediat-
ric blepharokeratoconjunctivitis have been pub-
lished.4,5,7,24,30 An important difference between our
study and earlier work is that rather than following
an overall severity grading approach, our partici-
pants differentiated eyelid, conjunctival, and corne-
al findings and tailored the prescribed treatment to
each of these tissues. This explains why our consen-
sus did not result in a staircase-shaped algorithm, but
rather in flowcharts for each tissue. Our approach is
pragmatic in that the presence or absence of signs is
sufficient to guide treatment; detailed assessment of
corneal vascularization as a proportion of circumfer-
ence and distance to the visual axis and quantifica-
tion of corneal punctate epithelial erosions4,5,7 may
be difficult to assess in a photophobic child.
Another important finding is the lack of agree-
ment on the use of treatment options where the evi-
dence base is particularly weak, such as the use of di-
etary modification, eyelid hygiene, topical lubricants,
and the choice between topical and oral antibiotics.
Other published treatment protocols have recom-
mended daily eyelid hygiene and topical lubricants re-
gardless of the degree of ocular surface inflammation,
and essential fatty acids for all cases of meibomian
gland dysfunction, chalazion, or hordeolum.7,24,30
All treatment schedules agree that topical steroids
are indicated for active inflammation and corneal
involvement, but do not necessarily specify route of
administration or dose.24,30 With regard to the use of
oral doxycycline in children, we follow standard rec-
ommendations to avoid tetracycline adverse effects in
children younger than 12 years. This differs from a
previous treatment schedule that recommended oral
tetracycline in children from the age of 2 years.7 Topi-
cal azithromycin is a new addition to the treatment
spectrum and, due to its long tissue half-life, there
is particular uncertainty about its role and optimum
dosage in blepharokeratoconjunctivitis. Only one
study of the use of topical azithromycin in childhood
blepharokeratoconjunctivitis is available, which sug-
gested a 6-month course with increasing intervals be-
tween short 3-day cycles of treatment.32 Trials will be
required to confirm the most effective dosage.
Finally, our inclusion of coexisting atopic or
other allergic eye disease (atopic eyelid dermatitis
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and chronic atopic conjunctivitis) is novel, a poten-
tial confounding factor when designing treatment
protocols. There was lack of agreement on this point
among our respondents. Patients with atopic der-
matitis are known to have increased bacterial skin
colonization,33 and increased staphylococcal ocu-
lar surface colonization has been shown in dogs34
and humans,35 factors that are suspected to make a
significant contribution to the pathophysiology of
blepharokeratoconjunctivitis. Although vernal kera-
toconjunctivitis is more common, atopic keratokon-
junctivitis also occurs in children and is frequently
associated with blepharitis. It can be postulated that
in some individuals both atopic and blepharitic in-
flammatory mechanisms may contribute to the de-
velopment of the ensuing keratopathy.36 The clini-
cian can usually determine from clinical symptoms
and signs the relative contribution of these two con-
ditions to tailor the management of individual cases.
All flowcharts and treatment algorithms can
only provide general recommendations for clinical
management. It is up to the practitioner to assess
the clinical signs, determine their relative weighting,
and design a management strategy. We agreed that
the treatment schedule may work well for our pa-
tient population and those in similar settings, but
may require modification elsewhere.
We present a pragmatic treatment algorithm
to assist in the management of blepharokeratocon-
junctivitis in children based on evidence and clinical
experience. Further work will evaluate the efficacy
of this approach in the management of blepharo-
keratoconjunctivitis. It is clear that studies in bleph-
arokeratoconjunctivitis published thus far report
observations and treatment outcomes in case series
and that trials to establish effective and safe inter-
ventions are needed.
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