The Ocular Surface 15 (2017) 334e365

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TFOS DEWS II Epidemiology Report

Fiona Stapleton, MCOptom, PhD a, 1, *, Monica Alves, MD, PhD b, Vatinee Y. Bunya, MD c,
Isabelle Jalbert, OD, PhD a, Kaevalin Lekhanont, MD d, Florence Malet, MD e,
Kyung-Sun Na, MD, PhD f, Debra Schaumberg, ScD, OD g, h, Miki Uchino, MD, PhD i,
Jelle Vehof, MD, PhD j, k, l, Eloy Viso, MD, PhD m, Susan Vitale, PhD, MHS n,
Lyndon Jones, FCOptom, PhD o
a
School of Optometry and Vision Science, UNSW Sydney, Sydney, NSW, Australia
b
University of Campinas, Discipline of Ophthalmology, Faculty of Medical Sciences, Brazil
c
Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA
d
Department of Ophthalmology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
e
Pellegrin Hospital, Bordeaux, 33000, France
f
Department of Ophthalmology, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
g
Department of Epidemiology, Harvard TH Chan School of Public Health, USA
h
John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, USA
i
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
j
Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, London, United Kingdom
k
Department of Ophthalmology, King's College London, St Thomas' Hospital, London, United Kingdom
l
Departments of Ophthalmology and Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
m
Department of Ophthalmology, Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
n
Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
o
Centre for Contact Lens Research, School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada

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

Article history: The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and
Received 29 April 2017 questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of pub-
Accepted 2 May 2017 lished prevalence data estimated the impact of age and sex. Global mapping of prevalence was under-
taken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more
Keywords: variable than symptoms. There were limited prevalence studies in youth and in populations south of the
Dry eye disease
equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a
Incidence
greater increase per decade than symptoms. Women have a higher prevalence of DED than men,
Natural history
Prevalence
although differences become significant only with age. Risk factors were categorized as modifiable/non-
Quality of life modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk
Questionnaire factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological
Risk factor and physical impact of pain, are considerable, particularly costs due to reduced work productivity.
Societal cost Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence
of disease of varying severity, the incidence in different populations and potential risk factors such as
youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment
and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED,
this remains an important area for future research.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction

Epidemiological studies describe the distribution of disease,

identify factors that influence that distribution, and measure the
* Corresponding author. impact and morbidity of disease in defined populations. The 2007
E-mail address: f.stapleton@unsw.edu.au (F. Stapleton).
1 report of the Tear Film and Ocular Surface Society (TFOS) Dry Eye
Subcommittee Chair

http://dx.doi.org/10.1016/j.jtos.2017.05.003
1542-0124/© 2017 Elsevier Inc. All rights reserved.
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
Workshop (DEWS) Epidemiology subcommittee summarized the
available evidence on dry eye prevalence, incidence, risk factors,
and impact; and reviewed instruments for the diagnosis and
assessment of dry eye disease (DED) in clinical trials [1]. Key rec-
ommendations from this report for future research included;
adoption of a consensus in dry eye diagnostic criteria to improve
future epidemiological studies; implementation of well-designed
studies to estimate the incidence of disease and establish natural
history of treated and untreated disease; expansion of studies to
assess disease prevalence in additional geographic regions and to
establish the impact of race and ethnicity; initiation of prospective
studies to elucidate additional risk factors and to provide evidence
for equivocal factors in the 2007 report and, importantly, to develop
strategies to inform public and practitioner education to improve
eye and general health.
Since the publication of the 2007 report, there has been
considerable progress in many of these areas. The purpose of this
report is to review and summarize the available evidence on the
epidemiology of DED and to update the recommendations for
future needs and research opportunities.
2. Goals of the epidemiology subcommittee
The goals of the TFOS DEWS II Epidemiology subcommittee
were:
1. To assess and summarize knowledge on the prevalence and
incidence of DED from well-designed population studies carried
out in the past 10 years and to perform a meta-analyses of
existing study data to determine prevalence of DED stratified by
age and sex.
2. To assess and summarize available knowledge on risk factors of
DED from well-designed studies.
3. To evaluate data available on natural history of DED and disease
morbidity.
4. To review available instruments and determine their use/
applicability in epidemiological research.
3. Goal 1: assess and summarize knowledge on the prevalence
and incidence of dry eye
3.1. Dry eye disease (DED) definition and ascertainment
One of the major challenges historically for epidemiological
studies has been the lack of clear standardization of a disease defi-
nition and classification system for DED. This definition and classi-
fication system would need to include well-defined objective and
subjective diagnostic criteria, with good sensitivity and specificity in
differentiating dry eye from normal that could be broadly applied
across studies in different regions and populations and be sensitive to
change due to treatment or disease progression. The lack of a single
validated diagnostic test or combination of tests to confirm a diag-
nosis further complicates interpretation of epidemiological study
results. The initial TFOS DEWS Epidemiology subcommittee report
reviewed the major international epidemiological studies and
concluded that the prevalence of DED ranged from 5 to 30% in in-
dividuals over the age of 50 [1]. Their consensus was that the prev-
alence of severe disease was likely to be at the low end of this range
and that the prevalence of mild or episodic disease was closer to the
upper limit. Higher rates were generally observed with studies using
clinical criteria only, followed by questionnaire-based studies, with
lower rates amongst intention-to-treat or treatment studies.
335
Since the publication of the original TFOS DEWS report, either
meibomian gland dysfunction (MGD) or evaporative dry eye has
been accepted as the most common subtype of DED in both clinic
and population based studies [2e5], but other subtypes have been
proposed, including dry eye manifesting as either signs only or
non-obvious disease. It is worth noting that epidemiological studies
of MGD are similarly confounded by a lack of standardized defini-
tion and grading [6,7].
As a consequence, the subcommittee examined data from a
range of large cohort studies and considered different methods of
disease ascertainment and definition, including studies involving
the type, frequency and severity of symptoms, patient self-report of
a diagnosis of dry eye by an eyecare practitioner (ECP) and studies
that involved a clinical examination.
3.2. Prevalence of DED
Prevalence of a disease is a measure of the proportion of disease
within a population at a given point in time. Prevalence estimates
for DED vary with the operational definition of dry eye used and the
characteristics of the population studied. For the purpose of this
report, a search of published, peer-reviewed literature was con-
ducted using PubMed in September 2015 for articles that reported
the prevalence of dry eye. The following terms: (dry eye syndrome,
OR dry eye, OR keratoconjunctivitis sicca, OR MGD/abnormalities
OR blepharitis, NOT Sjo € gren syndrome) AND (epidemiology OR
prevalence OR incidence) were used to identify potential articles.
Only human studies published over the last 10 years (2005e2015)
were considered. Eligible studies included those reporting preva-
lence of either or both dry eye symptoms and signs. Observational
studies (cross-sectional or cohort) were included if they were
population-based, with a minimum of 500 subjects, and presented
the study outcome as dry eye versus non-dry eye. Studies were
excluded if no variance in the measure of prevalence was available
in the manuscript, or if it was not possible to calculate it from the
data presented or if the publication was an editorial or a review
article. The flowchart below describes the studies identified and
reasons for exclusion (Fig. 1).
Four hundred and thirty seven studies were identified (updated
17 Sep 2015). Estimates of the prevalence of DED from 24 large
Potentially eligible studies identified through PubMed search
(N = 437)
Excluded those that were not
Additional potentially
prevalence studies (N = 394)
eligible studies (N = 2)
Full-text articles assessed for eligibility (N = 45)
Exclusion of study reports through full-
text screening
Hospital-based population studies: 14
Non-relevant outcomes: 3
Editorial or review article: 4
Full-text articles (N = 24)
Fig. 1. Literature search outcome for DED prevalence studies.
336 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
international cohort studies, stratified by diagnostic criteria, are
summarized in Table 1 [2,7e29].
A searchable excel format of this table is available at http://dx.doi.
org/10.1016/j.jtos.2017.05.003 (Supplementary Material 1). Preva-
lence of disease for studies involving symptoms with or without
signs ranged from approximately 5% to 50%. Studies where the
diagnosis was based primarily on signs generally reported higher
and more variable rates of disease, up to 75% in certain populations.
The signs included vary between studies and some studies have
focussed on secondary outcomes, including measures of tear quality
or tear stability, and others on specific lid signs. The section below
summarizes the prevalence studies broadly grouped by diagnostic
criteria, although it should be noted that different studies do differ in
their operational definitions and it is important to consider these
differences when comparing between studies.
3.2.1. Prevalence of DED based on the Women's Health Study (WHS)
criteria
Six studies have reported rates of disease based on severe
symptoms of dryness and irritation and/or a physician's diagnosis
of dry eye, as reported by the participant (Table 1). Five of the six
studies were carried out in Asia [10e13,30], and the sixth was a
study conducted in American males, which reported the lowest age
adjusted prevalence of 4.3% [9]. In the Asian studies, the overall
prevalence of disease based on symptom report ranged between
14.4 and 24.4% [10e13,30]. Two studies evaluated high school
students in China and Japan, where symptoms of DED were re-
ported by 21e24% of participants [11,30], which was considerably
higher than rates in adults, of 9.8e11.5% in men and 18.7e19.4% in
women [10,12,13]. Women consistently had a higher prevalence
than men in all studies stratified by sex.
3.2.2. Prevalence of symptomatic disease
Population-based studies reporting the prevalence of symp-
tomatic DED are heterogeneous, not only in their population
characteristics such as age and sex but also in their definitions of
dry eye. In general, studies have defined symptomatic disease using
three different methods (below), however, even within these cat-
egories several different criteria and descriptions are used (see
Table 1).
(1) frequency of symptoms, having at least one of several
symptoms of dry eye often or all of the time, such as foreign
body sensation, dryness, irritation, itching, or burning [31].
(2) self-reported diagnosis by agreeing with a sentence that
describes dry eye that includes several symptoms,
(3) using a cut-off value of the total score of the 12 item Ocular
Surface Disease Index (OSDI) symptom questionnaire [32].
Studies performed in South East Asia used definition (1), and
these reports showed the highest prevalence rates of symptomatic
DED, ranging from 20.0 to 52.4% [14,16,17,19,20]. An exception to
this region is Singapore, where two studies showed a prevalence of
only 6.5% [18] and 12.3% [27]. Studies in Spain and USA using
similar definitions showed a prevalence of 18.4% [21] and 14.5%
[24], respectively. Two studies in the United Kingdom and Korea,
using a form of definition 1 [31], identified a similar prevalence of
symptomatic DED of around 20% [25,26]. Using definition 3 [32], a
study in France [23] showed a relatively high prevalence of
symptomatic dry eye of 39.2% using an OSDI above 22, while in Iran
a prevalence of 18.3% was found using the same cut-off value [22].
The majority of studies reported a significantly higher preva-
lence in women compared to men, ranging from 1.33 to 1.74 times
higher [16,20e24,27], except for two studies in China and Mongolia
that showed no significant sex difference [14,19] and one study in
Singapore that found a significantly lower (0.6 times) prevalence in
women [18]. Most studies were performed in people aged 40 years
and older, with only two studies reporting separate results in
younger age categories. Both showed a slightly but not significantly
lower prevalence of 10e20% symptomatic DED in those aged
20e40 years [24,25]. Despite the difficulty of comparing studies
directly because of their heterogeneity, symptomatic DED is
generally more common in women than men and more common in
Asian than Caucasian populations.
3.2.3. Prevalence of dry eye signs
There is considerable variation in the prevalence of DED diag-
nosed using clinical signs only. Some studies report a single clinical
sign and others a combination of tear stability, tear production and
ocular surface damage signs. For example, the prevalence of a tear
breakup time (TBUT) of
10 s in one or both eyes varied between
studies from 15.6 to 85.6%, of a Schirmer test score of
5 mm from
19.9 to 37%, and of a fluorescein score of 1 (based on corneal
damage graded as 0 (no staining), 1 (mild staining limited to less
than one-third of the cornea), 2 (moderate staining of less than half
of the cornea), or 3 (severe staining of half or more of the cornea))
from 5.8 to 77% [14,19e21,23,28]. Such differences in prevalence
estimates may be due not only to the variation in techniques for
measuring and interpreting conventional dry eye tests, coupled
with the lack of established cut-off values and the poor repeat-
ability of these tests, but also to the characteristics of the study
population including age, sex, ethnicity, pre-existing conditions,
medication use and lifestyle or environmental factors [33e35].
Several studies found an association between older age and an
increase in positive dry eye signs [14,19,28]. Tear instability, as
defined by a TBUT of
10 s or low tear production, such as a
Schirmer test score of
5 mm have been reported in ‘normal’
populations [36,37], thus there is likely to be some overlap between
normal and dry eye subjects. Certain signs, such as corneal staining,
may not be an intrinsic feature of dry eye but may also reflect other
conditions, however, ocular surface staining appears to have a
strong association with disease severity [38,39]. Ocular surface
homeostasis may adapt to the normal age-related reduction in tear
film and tear production. It is not well established how the path-
ological thresholds for tear instability, tear production and staining
of the cornea should be adjusted with regard to age, although the
DEWS II Diagnostic subcommittee report [40] considers a cut-off
at ± 2 standard deviations from the mean value.
Race is likely to be a confounding factor in the prevalence esti-
mates of abnormal tear function. Using the same diagnostic criteria
and similar age range, Asians have a higher prevalence of tear
instability and ocular surface staining than Caucasians (Table 1).
This may reflect geographical difference and/or differences in the
susceptibility to the disease between Asian and other populations.
A relationship between sex and objective signs of dry eye remains
controversial. Two studies reported no significant sex differences in
clinical signs [14,21]. Many topical or systemic medications and
ocular surface disorders such as MGD are associated with positive
dry eye signs both in clinic and population-based studies. Others
such as pterygia, pinguecula and punctal stenosis are associated
with positive dry eye signs in clinical studies [34,41,42], but not in
population based studies [2]. Inclusion of participants with
ocular surface disease, such as MGD or using certain medications,
may increase the prevalence of symptoms and particularly dry eye
signs. It is important to note that the ocular surface environment is
very sensitive to any external stimuli and most diagnostic tests are
fairly invasive, so that the results of sequential tests might be
affected [43].
As was previously described [1], the prevalence of DED based on
clinical testing, broadly tear stability, tear production and ocular
Table 1
Summary of population based cross sectional epidemiological studies of dry eye, stratified by diagnostic criteria and racial group.

WHS Criteria (Severe symptoms of dryness and irritation either constantly or often, and/or a physician diagnosis of dry eye as volunteered by patient)

Authors Country N Age M:F (%, (n)) Race Sampling technique Prevalence (% [95%CI]) Prevalence (% [95%CI]) Prevalence (% [95%CI])
(mean ± SD) (Symptoms only) Physician diagnosis

Uchino 2008 [8] Japan 3433 15e18 74.4:25.6 1 Japanese high school students, 100% consent of n/a Boys 21 [20.1e21.8]; Girls Boys 4.3 [3.9e4.6]; Girls
(2848:585) those invited 24.4 [23.9e25.0] 8.0 [7.4e8.4]
Schaumberg 2009 USA 25444 50-99 100% Male 3 Participants from longitudinal Physicians Age adjusted 4.34 [4.1e4.6]; 6.8 [6.5e7.1] 3.0 [2.8e3.2]
[9] (Median 64.4) Health Studies I (N ¼ 18596) and II (N ¼ 6848). 50e54 3.90 [3.1e4.7];
All physicians in AMA invited to participate 80 < 7.67 [6.5e8.9]
Uchino 2011 [10] Japan 3294 40 46.2:53.8 1 Rural mountain town population sampled from Men 12.5 [10.7e14.5]; Men 11.5 [9.7e13.4]; Men 2.0 [1.3e3.0];
(1221:1423) residential registry. Self- administered Women 21.6 [19.5e23.9] Women 18.7 [16.7e20.8] Women 7.9 [6.6e9.5]
questionnaire distributed and later collected
from individual households
Zhang 2012 [11] China 1885 n/a 50.8:49.2 1 Multistage stratified random cluster sampling 23.7 [21.8e25.7] 23.1 [21.3e25.1] 1.3 [0.9e2.0]
of Chinese high school students
Ahn 2014 [12] South 11666 19-95 42.8:57.2 1 Stratified, multistage, clustered sampling 16 [14.6e17.3] Men > 40 10.7 14.4 [13.1e15.7] 8.0 [7.3e8.7]
Korea (49.9 ± 16.7) method based on 2009 National Resident [9.1e12.2]
demographics. Weighted prevalence calculated Women > 40 20.6
per 5th annual Korea National Health and [18.5e22.2]

F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

Nutrition Examination Survey [KNHANES V]
Um 2014 [13] South 16431 30 42.8:57.2 1 Stratified multistage probability sampling, n/a All 17.7 [17.09e18.31]; All 10.4 [9.92e10.88];
Korea (7033:9398) subjects selected from KNHANES V Men 9.84 [9.83e9.85]; Men 4.60 [4.59e4.61];
Women 19.44 [19.42 Women 12.65 [12.63
e19.46] e12.67]

Authors Country N Age M:F (%, (n)) Race Sampling technique Diagnostic criteria Prevalence (% [95%CI])
(mean ± SD)

Symptomatic disease
Lu 2008 [14] China 2632 40 56:44 1 Stratified, clustered, random sampling One or more symptoms of dry eye often 52.4 [50.2e54.7]; Men 52.1;
(56.3 ± 12.3) or all the time. Women 52.9
Moss 2008 [15] USA 2414 48-91 (63 ± 10) 44:56 3 5 and 10 year follow up examinations in Positive response to the question, “for All 21.6 [19.9e23.3]; Men 17.2;
¼ INCIDENCE Beaver Dam Eye Study population the past 3 months or longer, have you Women 25.0
STUDY had dry eyes? “foreign body sensation
with itching and burning, sandy feeling,
not related to allergy”
Jie 2009 [16] China 1957 40-84 43.2:56.8 1 From the 4439 participants in the One or more symptoms of dry eye often 21 [19.2e22.8]
(56.5 ± 9.3) (835:1112) Beijing Eye Study 2001, a random or all the time.
sample of 1957 were selected
Tian 2009 [17] China 1085 20-95 (51 ± 18) 38.6:61.4 1 6% of the target population from One or more of 6 dry eye symptoms 32.81 [30.08e35.66]
(419:666) Jiangning District, Shanghai, was often/constantly (dryness, irritation,
randomly selected (1266 subjects) burning sensation, redness, deposits,
using randomized block methods heavy eyelid sensation)
Tong 2009 [18] Singapore 3280 40e80 1576:1704 2 Age-stratified (by 10-year age group) One or more of 6 listed symptoms of 6.5 [5.7e7.4]; Men 8.2 [6.9e9.7];
random sample of the Malay population dry eye often or all the time. Women 4.9 [3.9e6.0]
residing in 15 residential districts in
Southwestern Singapore drawn from a
random list of 16,069 Malay names
provided by the Ministry of Home
Affairs
Guo 2010 [19] China 1816 40 53.3:46.7 1 Stratified, clustered, random sampling One or more of the 6 symptoms of dry 50.1 [47.8e52.4]; Men 49.9[46.8
(54.9 ± 11.7) method in Henan County China. Native eye often or all the time. e53.1]; Women 50.2[46.8e53.6]
Mongolian population living at high
altitude.
Han 2011 [20] South Korea 657 65-95 48.2:51.8 1 10% of the population chosen through One or more symptoms of dry eye often 30.3 [26.9e33.9]
(72 ± 5.9) systematic random sampling based on or all the time (dry, gritty/sandy, Men 25.6; Women 34.7
residential rosters; 1060 invited to burning, sticky, watery/tearing,
participate, 657 consented redness).

337
(continued on next page)
Table 1 (continued )

338
Authors Country N Age M:F (%, (n)) Race Sampling technique Diagnostic criteria Prevalence (% [95%CI])
(mean ± SD)

Viso 2009/Viso Spain 654 40-96 37.2:62.8 3 Age-stratified random sample of the Symptoms often or all of the time 18.4 [15.4e21.3]; Men 12.5;
2011 [2,21] (63.6 ± 14.4) (243:411) population 40 years and older was Women 21.8
drawn from the National Health Service
Registry. Part of Salnes Eye Study.
Hashemi 2014 [22] Iran 1008 40e64 41.0:59.0 6 Subsample of 5190, identified from Symptoms (OSDI score) 23 18.3 [15.9e20.6]
(413:595) 6311 subjects in Sharoud, Iran from 300
clusters derived through random
cluster sampling
Malet 2014 [23] France 915 73-94 38.7:61.3 3 Subsample of 2104 Bordeaux OSDI >22 All 39.2 [36.1e42.4]; Men 30.5 [25.9
(80.1 ± 4.4) (354:561) participants of the Three City Study of e35.5]; Women 44.7 [40.7e48.9]
vascular risk factors for dementia
2003.1450 surviving participants were
offered an eye examination between
2006 and 2008
Paulsen 2014 [24] USA 3275 21-84 (49) 45.4:54.6 3 Participants in the Beaver Dam Symptoms sometimes or more often 14.5 [13.29e15.71]; 21e49 years:
(1486:1789) Offspring Study; the adult children of and moderately bothersome or greater 14.1 [12.48e15.72]; 50 < years:
the population-based Epidemiology of (dry, gritty or burning feeling) or those 15.2 [13.39e17.01]; Men 10.5 [8.94

F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

Hearing Loss Study (EHLS) using rescue medication at least once e12.06]; Women 17.9 [16.12
per day for dry eye e19.68]
Vehof 2014 [25] England 3824 20e87 100% Female 3 Adult twins registry held at St Thomas' Have you had dry eyes in the past 3 Women 20.8 [19.5e22.1]
Hospital, London months or longer, FB sensation with
itching and burning, sandy feeling not
related to allergy
Na 2015 [26] Korea 6655 19 100% Female 1 Stratified multistage probability Eyes tend to dryness, foreign body 20 [19.01e20.99]
sampling method of participants from sensation with itching and burning or
the KNHANES V who had undergone an sandy feeling lately.
ophthalmological examination
Tan 2015 [27] Singapore 1004 15-83 44.1:55.9 6 46 of 62 train stations in Singapore McMonnies Questionnaire; at least one 12.3 [10.3e14.4]; Men 9.0 [6.5
(38.2 ± 15.5) (443:561) were randomly selected to be study of five self-reported symptoms that e12.1]; women 14.8 [12.0e18.0]
sites. Members of the public were reported as often or constantly
interviewed at stations and in nearby (soreness, scratchiness, dryness,
locations. grittiness, burning sensation)
Signs
Uchino 2006 [28] Japan 113 >60 (67.5 ± 5.7) 44.2%:55.8% 1 Twelve thousand letters were sent out Ocular surface staining with fluorescein Positive dry eye 73.5 [65.3e81.6];
(50:63) to pensioners of Chiba city, Honshu or Rose Bengal and Schirmer <5 mm or TBUT<5s 79.6 [72.2e87.1];
Island older than 60 years of age TBUT<5s. Schirmer<5 mm 39.8 [30.8e48.9];
Fluorescein staining  1 77.0 [69.2
e84.8]
Lu 2008 [14] China 2632 40 56:44 1 Stratified, clustered, random sampling TBUT
10s; Schirmer
5 mm (with TBUT
10s 35.3 [33.1e37.5]
(56.3 ± 12.3) anesthesia); fluorescein score 1 Schirmer
5 mm 24.7 [22.8e26.7];
fluorescein score 1 5.8 [4.7e6.9]
Jie 2009 [16] China 1957 40-84 43.2:56.8 1 From the 4439 participants in the Def 1: TBUT
10s or Schirmer
5 mm or Def 1: 98.5 ± 0.3; Def 2: 6.1 ± 0.5;
(56.5 ± 9.3) (835:1112) Beijing Eye Study 2001, a random fluorescein score 1 or telangiectasia; Def 3: 97.6 ± 3.3; Def 4: 1.5 ± 0.3;
sample of 1957 were selected or plugging of the gland orifices. Def 5: 36.9 ± 1.1; Def 6: 4.1 ± 0.4
Def 2: TBUT
10s and Schirmer
5 mm
and fluorescein score 1 and
telangiectasia and plugging of the gland
orifices.
Def 3: TBUT
4s or Schirmer
4 mm or
fluorescein score 2.
Def 4: TBUT
4s and Schirmer
4 mm
and fluorescein score 2
Def 5: TBUT
4s or Schirmer
4 mm
irrespective of other signs.
Def 6. TBUT
4s and Schirmer
4 mm
irrespective of other signs. (with
anesthesia)
Guo 2010 [19] China 1816 40 53.3:46.7 1 Stratified, clustered, random sampling Signs: TBUT
10s; Schirmer
5 mm TBUT
10s: 37.7 [33.5e35.9];
(54.9 ± 11.7) method in Henan County China. Native (with anesthesia); fluorescein score 1 Schirmer
5 mm: 19.9 [18.4e22.1];
Mongolian population living at high fluorescein score 1: 6.0 [4.9e7.1]
altitude.
Han 2011 [20] South Korea 657 65-95 48.2:51.8 1 10% of the population chosen through Schirmer I test score of
5 mm; Schirmer
5 mm: 27.2; TBUT
10s
(72 ± 5.9) systematic random sampling based on TBUT
10s; Fluorescein score >¼1. 85.6; Fluorescein score 1 36.0
residential rosters; 1060 invited to
participate, 657 consented
Viso 2009/Viso Spain 654 40-96 37.2:62.8 3 Age-stratified random sample of the TBUT
10s; Schirmer
5 mm (with TBUT
10s: 15.6 [12.7e18.5];
2011 [2,21] (63.6 ± 14.4) (243:411) population 40 years and older was anesthesia); fluorescein corneal Schirmer
5 mm: 37.0 [33.2e40.7];
drawn from the National Health Service staining  1; RB score  3 corneal staining  1: 7.0 [4.9e8.9];
Registry. Part of Salnes Eye Study. RB score  3: 13.0 [10.3e15.6]
Malet 2014 [23] France 915 73-94 38.7:61.3 3 Subsample of 2104 Bordeaux TBUT<5s 44.9 [41.3 to 48.5]
(80.1 ± 4.4) (354:561) participants of the Three City Study of
vascular risk factors for dementia
2003.1450 surviving participants were
offered an eye examination between
2006 and 2008
Signs and symptoms
Tian 2009 [17] China 1085 20-95 (51 ± 18) 38.6:61.4 1 6% of the target population from One or more of 6 dry eye symptoms 30.1 [27.4e32.8]; Men 24.1 [20.3
(419:666) Jiangning District, Shanghai, was often/constantly (dryness, irritation, e28.4]; Women 33.8 [30.3e37.5]

F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

randomly selected (1266 subjects) burning sensation, redness, deposits,
using randomized block methods heavy eyelid sensation) and at least 2 of
the following clinical assessments (þ):
BUT<¼5s (þþ) or <¼10s (þ);
Schirmer<¼5mm (þþ) or <¼10mm
(þ); Corneal staining >¼ grade 1 (þ)
Viso 2009/Viso Spain 654 40-96 37.2:62.8 3 Age-stratified random sample of the Symptoms often or all of the time and at All 11.0 [8.6e13.3]; Men 9.0 [5.3
2011 [2,21] (63.6 ± 14.4) (243:411) population 40 years and older was least one of:TBUT
10 s; Schirmer
e12.6]; Women 11.9 [8.8e15.1]
drawn from the National Health Service 5 mm; fluorescein corneal
Registry. Part of Salnes Eye Study. staining  grade 1; RB score 3
Hashemi 2014 [22] Iran 1008 40e64 41:59 6 Subsample of 5190, identified from Having symptoms (OSDI score 23), 8.7 [6.9e10.6]
(413:595) 6311 subjects in Sharoud, Iran from 300 and at least one of the following signs:
clusters derived through random TBUT
10 s; Schirmer score
5 mm;
cluster sampling fluorescein corneal staining  grade 1;
RB score  3
Malet 2014 [23] France 915 73-94 38.7:61.3 3 Subsample of 2104 Bordeaux Self-report dry eye and rescue med or All 10.7 [8.7e13.1]; Men 8.4 [5.8
(80.1 ± 4.4) (354:561) participants of the Three City Study of OSDI >22 (22 Based on ROC analysis). e12.0]; Women 12.3 [9.6e15.8]
vascular risk factors for dementia Signs TBUT< 5s
2003.1450 surviving participants were
offered an eye examination between
2006 and 2008
Vehof 2014 [25] England 3824 20e87 0%:100% 3 Adult twins registry held at St Thomas' Have you had dry eyes in the past 3 20.8 [19.5e22.1] for symptoms; 9.6
Hospital, London months or longer, FB sensation with [8.7e10.6] for diagnosis þ tears
itching and burning, sandy feeling not
related to allergy. Signs having a
diagnosis of DED made by a clinician
and concomitant treatment with
artificial tears.
MGD
Uchino 2006 [28] Japan 113 >60 (67.5 ± 5.7) 44.2:55.8 1 Twelve thousand letters were sent out MGD grade 1 or above per Bron 42.5 [33.4e51.6]
(50:63) to pensioners of Chiba city, Honshu classification.
Island older than 60 years of age
Jie 2009 [16] China 1957 40-84 43.2:56.8 1 From the 4439 participants in the Telangiectasia or plugging of the gland 68.3 [66.2e70.3]
(56.5 ± 9.3) (835:1112) Beijing Eye Study 2001, a random orifices
sample of 1957 were selected
(continued on next page)

339
Table 1 (continued )

340
Authors Country N Age M:F (%, (n)) Race Sampling technique Diagnostic criteria Prevalence (% [95%CI])
(mean ± SD)

Tian 2009 [17] China 1085 20-95 (51 ± 18) 38.6:61.4 1 6% of the target population from Grade  1; Grade 0-no block; Grade 1- 53.2 [50.2e56.1];
(419:666) Jiangning District, Shanghai, was clear-mild milky secretion with Men 53.5 [48.7e58.2], Women 53.0
randomly selected (1266 subjects) pressure; Grade 2: thick, milky to pasty [49.2e56.8]
using randomized block methods secretion with pressure, Grade 3: no
secretion and with significant blockage.
The highest grading each eye was used
for analysis
Han 2011 [20] South Korea 657 65-95 48.2:51.8 1 10% of the population chosen through MGD definition: presence of gland 51.8 [43.6e60.0]
(72 ± 5.9) systematic random sampling based on orifice plugging (grade >¼1)
residential rosters; 1060 invited to
participate, 657 consented
Viso 2009/Viso Spain 654 40-96 37.2:62.8 3 Age-stratified random sample of the Viscous or waxy discharge expressed 30.5 [26.9e34.1]
2011 [2,21] (63.6 ± 14.4) (243:411) population 40 years and older was
drawn from the National Health Service
Registry. Part of Salnes Eye Study.
Siak 2012 [29] Singapore 3271 40-80 48.1:51.9 1 Age stratified (by 10 year age groups) Either lid margin telangiectasia, or Age standardized prevalence 56.3
(58.7 ± 11.0) (1574:1697 random sample drawn from list of orifice plugging in at least one eye of [53.3e59.4]; Men 62.9 [58.3e67.8];

F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

16069 Malay names in 15 residential each participant. Women 50.5 [46.8e54.6]
districts provided by Ministry of Home
affairs.
Viso 2012 [7] Spain 619 40-96 37.0:63.0 3 Age stratified random sample of the One or more of: 1. absent, viscous or Men 35.3 [29.4e41.7]; Men asympt
(63.4 ± 14.5) (229:390) population 40 years and older from waxy white secretion upon digital 26.5 [21.2e32.7]; Men sympt 9.0
Salnes region drawn from National expression, 2. presence of two or more [5.9e13.3]
Health Service Registry. Sample of lid margin telangiectases and 3. Women 27.5 [23.3e32.1]; Women
1155. plugging of 2 or more gland orifices. asympt 19.1 [15.5e23.4]; Women
Symptoms (dryness, grittiness, burning, sympt 8.4 [6.1e11.3]
redness, lash crusting, and eyelids
getting stuck) reported “often” (at least
once a week), and “all the time” (at least
daily)

Race allocated as follows for more than 90% of sample.

1 ¼ South East Asian.
2 ¼ North Asian (India, Pakistan, Bangladesh).
3 ¼ Caucasian.
4 ¼ Black.
5 ¼ Arabic.
6 ¼ Mixed.
Sympt ¼ symptomatic.
Asympt ¼ asymptomatic.
TBUT ¼ Tear Break Up Time.
FB ¼ Foreign Body.
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
surface staining, does not correspond to subjectively diagnosed dry
eye based on symptoms alone. The inconsistencies between signs
and symptoms could be explained by the heterogeneity of the DED
itself and the poor standardization with a lack of well-defined
diagnostic criteria of clinical tests in common use [44]. Moreover,
each dry eye test assesses only certain properties of dry eye and
certain dry eye parameters may not be evaluated by the tests
currently employed [16]. Other factors include variability in pain
thresholds, the psychosomatic component that may be present to a
variable extent in symptomatic diseases, cognitive responses to
questions about ocular sensation, and reduction in ocular surface
sensitivity as a result of the normal aging process or disease pro-
gression [1,45].
3.2.4. Prevalence of DED based on symptoms and signs
Five population-based studies reported on a combination of
symptoms and signs, with an overall prevalence ranging from 8.7 to
30.1%, however very different criteria were applied in each of the
studies [17,21e23,25]. As would be expected, based on the dis-
cussion above, it is difficult to draw conclusions given the hetero-
geneity of the disease definitions. Two studies estimated disease
prevalence based on symptoms reported often or constantly, and
either one or two clinical signs that included a TBUT
10 s,
Schirmer test score of
5 mm, fluorescein staining score of 1 and
rose bengal staining score of 3 [17,21]. Both studies included a
wide age range of randomly sampled participants; however the
study conducted in China [17] demonstrated a prevalence of almost
3x that of the study conducted in Spain [21] (30.1, 95% CI 27.4e32.8
compared with 11, 8.6e13.3). Women had 1.3e1.5x the prevalence
rate of men across all studies that include a measure of both signs
and symptoms.
3.2.5. Prevalence of MGD
Seven population-based studies reported on MGD across
different age, sex and race cohorts. The reported prevalence rates
based on clinical signs in populations over the age of 40 ranged
from 38 to 68% [7,16,17,20,21,28,29]. Broadly, rates appeared higher
in Asian population cohorts compared with Caucasian, in the two
studies with similar diagnostic criteria [7,29]. Clinical signs of MGD
frequently include telangiectasia and some measure of expressi-
bility and/or quality of meibum expressed. As with corneal staining,
it is conceivable that telangiectasia is not an intrinsic feature of
MGD but may also be present in other conditions.
The information available on the impact of sex and age on MGD
is limited because most prevalence studies fail to provide sex and
age specific data. One study showed similar rates overall for men
and women in an Asian population [17], although this appears to be
dependent on disease severity. The Singapore Malay Study [29] and
the Spanish Salnes Eye Study [7] showed a higher rate of MGD in
men. In the Spanish study, this effect of sex was limited to
asymptomatic disease and the rates for symptomatic disease were
similar between men and women [7], which is consistent with the
similar rates between men and women found in clinic-based
studies, where participants are mostly symptomatic [46]. An as-
sociation with age was found in the Salnes Eye Study, but this as-
sociation was not corroborated in the Asian study. The limited
number of studies, disparate clinical signs of MGD applied and
population differences limit the broad generalizability of these
findings and would indicate that further studies with similar
diagnostic criteria in the different population groups are required
to fully explore the prevalence of symptomatic and asymptomatic
disease in MGD, stratified by age, sex and race.
3.2.6. Global mapping of dry eye prevalence
Other than racial variations, differences in prevalence rates
341
between studies may be attributed to other geographic, climatic or
environmental variations. Information on the location (e.g. city,
region or state, country) of studies was collected for mapping and
descriptive analyses. The diagnostic criteria per Table 1 were
considered in the analysis. The locations of the populations
sampled were geo-referenced using the latitude and longitude
coordinates by cross-checking the names with Wikipedia:GeoHack
(https://www.mediawiki.org/wiki/GeoHack). The coordinates of
the midpoint of the capital of the region or country were used as a
proxy for the locations that could not be allocated exact latitude
and longitude coordinates. All the relevant information was
entered into an Excel worksheet and data were mapped using the
geographical information systems (GIS) software ArcGIS 10.3 (ESRI,
Redlands, CA) to produce maps of DED prevalence distribution
according to five diagnostic criteria (WHS definition, diagnosed dry
eye, symptomatic disease, MGD and TBUT). The prevalence maps
are shown in Figs. 2e4. A searchable Excel file of the abstracted data
and electronic geospatial ArcGIS files are available at http://dx.doi.
org/10.1016/j.jtos.2017.05.003 (Supplementary Material 2).
Overall, study locations ranged in latitude from 1.28 north
(Singapore) to 51.5 north (England) of the equator. No studies re-
ported on the prevalence of dry eye symptoms south of the equator
during the last 10-year period. Studies covered a broad range of
longitudes from 100 west (USA) to 139.7 east (Japan) of the
prime meridian. All studies included both sexes, except for the
Physicians' Health Studies results in the USA [9] (which included
males only) and the Twins UK study in England and the KNHANES-
V study in South Korea (which included females only) [25,26].
Studies were mostly conducted in adult populations, ranging in age
from 20 to 96 years. A number of Asian studies also included a
younger population aged 15e19 years [8,11,12], as does the Twins
UK study [25].
Fig. 2 displays the prevalence of dry eye according to the WHS
definition (top panel) or equivalent. This included eight studies
where dry eye was defined as the presence of either a previous
clinical diagnosis of DED or severe symptoms (both dryness and
irritation either constantly or often) [9e13,30], or self-reported dry
eye confirmed by the use of artificial tears [25] and/or OSDI greater
than 22 [23], or diagnosed DED and use of artificial tears or
symptoms, sometimes or more often, that are at least moderately
bothersome, or those who reported currently using eye drops at
least once a day for dry eyes [24]. These studies were conducted in
North America (USA), Asia (China, Japan, South Korea), and Europe
(England, France). The prevalence ranged from 4.1% to 23.7%. The
Physicians' Health Studies in the USA reported a prevalence of 4.3%
[9] and the Twins UK study in England reported a prevalence of
9.6% [25], in males and females, respectively. Seven of these eight
studies also reported the prevalence of diagnosed DED separately,
as mapped in the bottom panel of Fig. 2. The prevalence of diag-
nosed DED was generally lower, with six of seven studies reporting
prevalence at or below 11.4%. The prevalence of diagnosed DED
ranged from 1.3% in the Shouguang Chinese study [11] to 29.6% in
the Alienor study conducted in France [23].
Seventeen population studies, including many of those listed in
Fig. 2, provide data on the prevalence of symptomatic dry eye
(Fig. 3). These were conducted in North America (USA), Asia (China,
Iran, Japan, Singapore, South Korea) and Europe (England, France,
Spain). Fig. 2 includes studies where dry eye was defined as severe
symptoms (both dryness and irritation, either constantly or often)
[9e13,30], or studies where dry eye was defined as at least one
symptom of dry eye often or all the time [2,14e16,18e21,25e27], or
an OSDI score of >22 [22,23]. The average prevalence of dry eye
symptoms across these studies was 22.8 ± 13.3%, ranging from 6.5%
in the Singapore Malay Eye study [18] to 52.4% in Chinese Tibetans
[14]. All studies included both sexes, except for the Physicians'
342 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

Fig. 2. Prevalence map according to the WHS diagnostic criteria (upper panel) and self-report of clinically diagnosed dry eye (lower panel).
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365 343

Symptomatic Disease

Vehof 2014, 20.8%

Malet 2014, 39.2%
Moss 2008, 21.6%
Viso 2009 / Viso 2011, 18.4% Jie 2009, 21%
Schaumberg 2009, 6.8%
Hashemi 2014, 18.3% Lu 2008, 52.4%

Guo 2010, 50.1%

Tan 2015, 11.1%

0 3,000 6,000 12,000 Kilometers

Esri, DeLorme, GEBCO, NOAA NGDC, and other contributors

Urban Areas

Jie 2009, 21%

Han 2011, 30.3% Na 2015, 20%

Zhang 2012, 23.1% Um 2014, 13.98% Um 2014, 13.28%
Um 2014, 11.52% Um 2014, 14.8% Uchinno 2011, 15.36%
Um 2014, 16.77%
Lu 2008, 52.4% Um 2014, 11.43%
Guo 2010, 50.1%
Uchino 2008, 21.61%
Um 2014, 13.43% Um 2014, 11.77%
Um 2014, 11.63%

0 465 930 1,860 Kilometers

Esri, DeLorme, GEBCO, NOAA NGDC, and other contributors

Inset presents a magnified view of the South East Asian prevalence data

0 - 10%
11 - 20%
21 - 30%

>30%

Fig. 3. Prevalence map of symptomatic disease (upper panel) and expanded view of studies carried out in South East Asia (lower panel).
344 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
Health Studies results in the USA, the Twins UK study in England,
and the KNHANES-V study in South Korea where 6.8% of males,
20.8%, and 20.0% of females reported dry eye symptoms, respec-
tively. In studies where both values were reported, the prevalence
of dry eye symptoms was consistently higher than that of diag-
nosed dry eye.
The lower panel of Fig. 3 presents a magnified view of the re-
ported prevalence of symptoms of dry eye in nine of these studies
conducted in South East Asian countries (China, Japan, South Ko-
rea). A cartographical representation of the World Urban Areas data
was downloaded from the Natural Earth website (http://www.
naturalearthdata.com, accessed on 5 June 2016) and layered on to
the bottom panel of Fig. 3. This dataset was derived from Moderate
Resolution Imaging Spectroradiometry (MODIS), Defense Meteo-
rological Satellite Program (DMSP) nighttime lights, and gridded
population data [47].
Fig. 4 maps available data on the prevalence of MGD (top
panel) and TBUT (bottom panel) in population studies of subjects
with dry eye. The prevalence of MGD evaluated in five studies
ranged from 30.5% [21] to 68.3% [16]. The prevalence of
TBUT < 8e10 s, ranged from 15.6% [21] to 85.6% [20]. This wide
range in MGD prevalence and abnormal TBUT in the same pop-
ulations may not only reflect different diagnostic criteria. MGD is
not invariably associated with abnormal TBUT and, conversely,
abnormal TBUT may be associated with tear film deficiencies
unrelated to lipid.
Overall, the mapping of the prevalence of dry eye data shows no
clear pattern of DED prevalence with latitude. Notwithstanding the
diagnostic criteria used, the prevalence of dry eye appears slightly
higher in Asia than other continents. The mapping exercise clearly
highlights the dearth of prevalence data from the African continent
and, to a certain extent, America, where no studies to date have
looked at Central and South America.
3.2.7. Incidence of dry eye
Incidence of disease describes the rate of new or incident cases
of a disease over a period of time. A limited number of studies have
reported the incidence of DED. The Beaver Dam Eye Study estab-
lished in a Caucasian population aged 48e91 that 13.3% (95% CI
12.0e14.7%) of individuals developed symptomatic DED over 5
years and 21.6% (95% CI 19.9e23.3%) over 10 years [15]. Incidence
was higher in women (25%) than men (17.3%) over the 10-year
period after adjusting for age. Age was a risk factor for increased
incidence, with an odds ratio of 1.2x (1.1e1.3) for each 10-year
increment.
More recently, participants of the Twins UK study completed a
dry eye questionnaire in 2011 and 2013 [25], which has allowed
estimation of the incident cases of symptomatic dry eye both as
defined by the WHS criteria and as defined by the Beaver Dam Eye
Study above [15], in females aged 20e87. The incidence of dry eye
as defined by the WHS criteria was 4.4% (95% CI 3.5e5.3%) in this 2-
year period. The incidence of symptomatic dry eye as defined by the
Beaver Dam Eye Study [15], where dry eye is defined as a foreign
body sensation with itching and burning, not related to allergy and
experienced for at least 3 months, was 10.4% (95% CI 9.1e11.7%)
over the same period.
3.2.8. Meta-analysis of existing prevalence data
A meta-analysis was conducted to determine the prevalence of
dry eye for different diagnostic criteria stratified by age and sex.
Using the search strategy described above, population based
prevalence studies published since 1980 were included. Hospital
based studies were excluded. After data were abstracted, confi-
dence intervals on the measures of prevalence were estimated
using http://vassarstats.net/prop1.html. A searchable Excel file
of the abstracted data is available as Supplementary Material 3
(http://dx.doi.org/10.1016/j.jtos.2017.05.003).
Data were separated into subgroups based on diagnostic cate-
gory and, within diagnostic category, by age category. Diagnostic
subgroups were created where the diagnostic criteria were broadly
similar. In brief, subgroups comprised symptomatic disease, WHS
criteria, self-report of a prior clinical diagnosis and clinical signs
(fluorescein staining, TBUT, MGD and Schirmer test results). Studies
that could not be classified in this way were excluded from further
analysis.
For the age categorization, only studies that provided rates
within decade or finer age categories were included. Studies that
reported only overall rates (e.g. 40þ or 65þ) were not included. A
standard approach to the analysis was applied, using age categories
by decade (i.e., 20e29, 30e39, 40e49, etc), although the youngest
and oldest age categories were narrower (age 15e18) and wider
(age 80þ), respectively. For studies that had finer age categoriza-
tions that covered the entire decade, the weighted mean rate of
adjacent categories was calculated (e.g. 40e44 and 45e49 were
combined into a single rate for 40e49, and the sample size was
computed as the sum of the two 5-year sample sizes). Age cate-
gories that fell within but did not cover an entire decade were
included in that decade (e.g. if the age category was 73e80, it was
included in the “70e79” category for analysis). For one study with
10-year age categories offset by 5 years (i.e., 35e44, 45e54, etc), the
weighted average of the adjacent categories was computed and
sample size adjusted for the standard decade as follows: one-half of
the lower category's sample size plus one-half of the higher cat-
egory's sample size. For age 90þ, only 5 patients were reported, so
these results were omitted from the analysis (of age 80þ). This
approach was used for studies that reported both sexes together
and the process was repeated for studies that gave separate reports
for males and females. Some studies reported results only for one
sex, and results from those studies were only used in the sex-
specific calculations, and not in the overall analysis that reported
both sexes together.
Few studies reported standard errors for their prevalence esti-
mates; most reported 95% confidence intervals. To compute the
standard error, the formula [square root of p times q over n], where
p was the proportion with dry eye, was applied. For studies where
prevalence was 0, the exact Poisson confidence limits were
computed [48] for the proportion and the width of that interval,
divided by 3.92 to approximate the standard error.
For descriptive analyses, box plots were produced using SAS
version 9.4 (SAS Institute, Cary, North Carolina, USA). The number
of studies for most age categories within diagnosis category was
small. When there was only a single study in the category, the
prevalence was reported as originally reported by the study. If there
were two or more studies in the category, a pooled rate was
calculated by using a suite of SAS macros marandom developed by
Weir and Senn [49]. These macros include summary statistics for
the DerSimonian and Laird [50] approach. Forest plots of the results
were produced using the Weir and Senn macro maforest.
A regression analysis of the pooled prevalence estimates from
the meta-analyses on age was carried out for studies that reported
both sexes in aggregate. The prevalence estimates were weighted
by the inverse of their standard error.
1. Prevalence by age.
Fig. 5 shows the prevalence of symptomatic disease (upper
panel), WHS criteria (central panel) and clinically diagnosed dry
eye (lower panel) by age. Both a report of symptoms and a clinical
diagnosis of dry eye show a modest change below the age of 49,
with a gradual increase from aged 50 and a more marked increase
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365 345

Fig. 4. Prevalence map of MGD (upper panel) and tear film instability (TBUT <8-10 sec) disease (lower panel).
346 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

as the slope estimate (Table 2). The prevalence increased between

2.0% (self-report of a clinical diagnosis of dry eye) and 10.5% (based
on a positive Schirmer test) by decade depending on the diagnostic
group. Generally, the increase in prevalence for signs of dry eye
showed a greater increase than for a diagnosis based on symptoms.
The prevalence of MGD increased by 5.3% per decade.

2. Prevalence by sex

Figs. 7 and 8 illustrate the prevalence of DED by sex for the

diagnostic criteria described above. There appeared to be minimal
and inconsistent sex differences in the prevalence of DED. In
symptomatic disease and clinically diagnosed DED, the differences
between sexes become clearer at ages above 50.
Fig. 8 shows the prevalence by age and sex for 40 years and
above based on disease signs, including tear stability (TBUT), tear
production (Schirmer test) and corneal damage (fluorescein stain-
ing) and MGD. In general, females show a higher prevalence with
increased age than males, although there is considerable variability.
A different trend was observed for MGD than for other dry eye
diagnostic criteria; males had a slightly higher prevalence for most
age categories, although the differences were not statistically sig-
nificant, except in the age 80þ group. However it is worth noting
that only two studies reported data for MGD prevalence that were
stratified by age and sex, therefore any conclusions may be pre-
mature and stratification would be an important consideration in
future studies.

3.2.9. Summary and recommendations

This report has summarized the results of published population
based studies of prevalence and, to a lesser degree, incidence. A
meta-analysis has enabled rational combination of studies to
evaluate the effects of age and sex on disease prevalence. Spatial
mapping has summarized the prevalence estimate by region and
electronic resources have been made available to allow further
exploration of environmental and population factors including
climate, population density, air quality index, weather, altitude and
to incorporate new data as these become available. The prevalence
mapping described here could also be used to examine overlap
with the human development index (a composite statistic of life
expectancy, education, and income per capita) and the distribu-
tions of different dry eye interventions.
Key findings are as follows:

Fig. 5. Prevalence of symptomatic disease (upper), WHS criteria (central) and clinically
diagnosed dry eye (lower panel) by age. The number of studies reporting prevalence is
shown above the x-axis.
beyond the age of 80. Symptom report prevalence shows the
greatest variability.
Fig. 6 shows the prevalence by age, for 40 years and above, based
on disease signs, including tear stability (TBUT), tear production
(Schirmer test) and corneal damage (fluorescein staining) and MGD.
Both tear signs and corneal staining show a similar pattern of
prevalence change with age, with a similar degree of variability. The
absolute values of prevalence of MGD with age do increase, however
there is wide variability in the estimates, which may be consistent
with the range of different clinical parameters used in the diagnosis.
Regression analyses by age for each diagnostic subgroup are
summarized in Table 2.
Overall for all subgroups, except for the WHS criteria, the
prevalence of dry eye increased significantly and showed a linear
association with age. For each diagnostic group the increase in
prevalence of dry eye with each decade of increasing age is shown
 While disease definitions vary between studies, which con-
founds comparisons, the rates of prevalence based on symptom
reporting are more consistent than those including signs, which
aligns with the understanding that dry eye is a symptomatic
disease. However, most studies of symptom reporting are binary
and there is a lack of recent evidence describing the prevalence
of disease by symptom severity. The measurement of dry eye
signs may be confounded by poor repeatability and technique
differences between observers and between studies. Signs may
also not always be an intrinsic feature of the disease, but may
reflect normal aging or conditions other than dry eye. The lack of
association between the prevalence of symptomatic disease and
the prevalence of signs of dry eye in population-based studies
suggests that a considerable proportion of subjects may have
asymptomatic disease.
 Prevalence appears to be higher in Asian than in Caucasian
populations.
 The prevalence of dry eye increases linearly with age. The in-
crease in prevalence by decade is greater with clinical signs of
dry eye compared with symptoms report and with self-report of
a clinical diagnosis. Similarly, the rate of MGD increases linearly
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365 347

Fig. 6. The prevalence of DED signs by age.

with age. There remains a great need for more clinical signs of
dry eye data in populations younger than 40 years.
 Perhaps surprising is the relatively high prevalence rates re-
ported in younger subjects and in school children, which would
certainly support further studies in this age group and evalua-
tion of potential risk factors such as digital device use.
 Differences in prevalence rate by sex become significant
generally only with age, although there is considerable vari-
ability, with women having a higher prevalence of dry eye than
men. As only two studies report data for MGD prevalence that
stratify by age and sex, any conclusions may be premature and
stratification would be an important consideration in future
studies.
 There have been no population-based studies from the Southern
Hemisphere published in the last 10 years. Geographical map-
ping approaches will allow future exploration of the impact of
climate, socioeconomic and environmental factors on dry eye

Table 2
Regression analysis of prevalence data by age for each diagnostic subgroup.

Diagnostic subgroup No of studies Slope estimate Std error of slope p-value (H0: slope ¼ 0) R2
(per decade of age) estimate

1. Symptoms of OSDI>22 8 3.43 0.57 0.001 0.858

2. Self-report of a clinician diagnosis of dry eye 8 2.01 0.73 0.034 0.556
3. WHS Criteria 8 0.44 0.57 0.475a 0.088
b
4. Schirmer 5 10.55 1.78 0.010 0.921
b
5. TBUT 5 9.71 1.20 0.004 0.956
b
6. Corneal staining 5 7.63 1.67 0.020 0.875
b
7. MGD 5 5.23 1.44 0.036 0.815
a
Indicates that there is no change in prevalence by age for the WHS criteria.
b
Regression analyses are based on estimates of prevalence from age 40e49 and up (i.e., missing values for prevalence for ages 15e18, 19e29, and 30e39).
348 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
Fig. 7. Prevalence of symptomatic disease (upper), clinically diagnosed dry eye (cen-
tral) and WHS criteria (lower panel) by age and sex. The number of studies reporting
prevalence is shown above the x-axis.
 There are limited studies evaluating disease incidence and ac-
cess to large population data sets from longitudinal studies
would be of value.
4. Goal 2. to assess and summarize knowledge on the risk
factors for DED
In evaluating risk factors for DED, the Epidemiology subcom-
mittee found a large number of published studies compared with
the previous report [1]. The limited number of population-based
studies included in the TFOS DEWS report of 2007 [51e57] was
supplanted by more recent robust data [9,10,12,16,18e21,23,25,26].
New studies performed in different populations around the world
provided valuable information about DED by geographic region.
However, there is still a considerable lack of the information
needed to provide a comprehensive understanding of risk factors
for DED, due partly to methodological differences between studies,
differences in population groups and diagnostic criteria. Overall, a
review of the existing data generates an extensive list of risk factors,
which is to be expected since the tear film and ocular surface form
part of a highly integrated functional unit, influenced by lifestyle,
environmental exposures, conditions such as connective tissue and
metabolic diseases and their treatment and ocular diseases, such as
MGD. However, these risk factors have been neither equally sub-
stantiated nor equally evaluated by the different studies (Table 3).
Studies on risk factors for DED can provide important informa-
tion that enables advances in diagnostic methodology, elucidation
of pathophysiological mechanisms and relationships, therapeutic
perspectives, public education and strategies to improve both
general and ocular health. For the purpose of this report, the search
strategy for risk factor publications studies used PubMed and
Scopus databases with the following terms: (Dry eye syndrome OR
dry eye OR tear dysfunction OR tear deficiency or insufficiency, OR
keratoconjunctivitis sicca OR sicca syndrome OR MGD OR ble-
pharitis) AND (epidemiology OR risk factor OR correlation OR as-
sociation OR relation). Duplicate articles were excluded and eligible
studies included those reporting either or both symptoms and
signs. Observational studies (cross-sectional, cohort, case control
study, randomized controlled trial) presenting the study outcome
as dry eye versus non-dry eye and published in the last 10 years
were included. Studies were excluded if they had a non-relevant
outcome, specifically if they did not evaluate risk factors. Risk fac-
tors were tabulated using the approach chosen in the 2007 report
as mostly consistent, probable, or inconclusive factors (Table 3).
Factors were also stratified into non-modifiable versus modifiable
risk factors, as this may inform approaches to the management of
DED. The following factors were identified and considered in the
analysis; age, sex, race, MGD, contact lens wear, hematopoietic
stem cell transplantation, Sjo € gren syndrome, environmental ex-
posures, computer use, diet and nutritional factors, affective and
somatoform disorders, heritability and genetic risk factors, lifestyle
factors, socioeconomic status, alcohol intake, smoking, caffeine
intake, allergy, autoimmune disease, cardiovascular disease, dia-
betes, hepatitis B and C infection, Herpes Simplex virus infection,
human T cell lymphotropic virus infection, human immunodefi-
ciency virus infection, Epstein-Barr virus infection, rosacea,
sarcoidosis, gout, thyroid disease, psychiatric disease, anxiety,
chronic pain, migraine, depression, post-traumatic stress disorder,
sleep disorder, hormone factors including androgen deficiency,
hormone replacement therapy, menopause, pregnancy, oral con-
traceptive use, ovarian dysfunction/menstrual irregularity, medi-
cations including anti-depressants, anti-psychotics, antihistamines,
anxiolytics, oral beta blockers, cholinergic drugs, oral diuretics,
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
Fig. 8. The prevalence of DED signs (TBUT, top left; Schirmer, top right; fluorescein staining, lower left; and MGD, lower right) by age and sex.
isotretinoin, radiotherapy, chemotherapy, pseudoexfoliation, pte-
rygium, uncorrected refractive error, ocular surgery including
cataract surgery, refractive surgery, keratoplasty, botulinum toxin
use and Demodex infestation.
The weight of evidence from large epidemiologic studies con-
firms that female sex and older age increase the risk for DED.
Other substantiated risk factors include MGD [7,29], hematopoietic
stem cell transplantation [58,59], computer use [8], Asian race
contact lens wear [21,24,25,27,60], Sjo € gren syndrome [61,62],
environmental hazardous conditions such as pollution, low hu-
midity, systemic connective diseases, and certain classes of medi-
cations including antihistamines, antidepressants, anxiolytics and
isotretinoin. Studies conducted prior to 2007 [1] had confirmed
androgen deficiency as a substantiated risk factor, however limited
studies included androgen deficiency during the current search
period. Most recently a metabolomics study has confirmed this
association between DED and low levels of circulating androgen
metabolites [63].
349
4.1. Age
As discussed in Goal 1, recent population-based studies have
reinforced age as one the most consistent risk factors for DED,
although this may vary with diagnostic criteria (See section 3.2 for
overview). The majority of studies have reported an increase in dry
eye prevalence with age [9,12e16,21,22,25,53e55,64e68], while a
smaller number of others did not find a significant association
[18,20,27,51,56].
4.2. Sex
Similarly, female sex is consistently associated with DED
[10,12,13,15,16,20e24,64e66,69e72], although some studies have
found otherwise [18,19,27,67,73]. In a population-based, cross
sectional study comprising a cohort of 3824 British female twins
aged 20e87 years [25], the prevalence of dry eye increased
significantly per age decade, with a peak increase in the 40e50
350 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

Table 3
Risk factors for dry eye disease.

Consistenta Probableb Inconclusivec

Non-modifiable Aging Diabetes Hispanic ethnicity

Female sex Rosacea Menopause
Asian race Viral infection Acne
Meibomian gland dysfunction Thyroid disease Sarcoidosis
Connective tissue diseases Psychiatric conditions
€gren Syndrome
Sjo Pterygium

Modifiable Androgen deficiency Low fatty acids intake Smoking

Computer use Refractive surgery Alcohol
Contact lens wear Allergic conjunctivitis Pregnancy
Hormone replacement therapy Demodex infestation
Hematopoietic stem cell transplantation Botulinum toxin injection
Environment: pollution, low humidity, sick
building syndrome
Medications: antihistamines, antidepressants, Medications: anticholinergic, diuretics, beta- Medications: multivitamins, oral contraceptives
anxiolytics, isotretinoin blockers
a
Consistent evidence implies the existence of at least one adequately powered and otherwise well-conducted study published in a peer-reviewed journal, along with the
existence of a plausible biological rationale and corroborating basic research or clinical data.
b
Suggestive evidence implies the existence of either inconclusive information from peer-reviewed publications or inconclusive or limited information to support the
association, but either not published or published somewhere other than in a peer-reviewed journal.
c
Inconclusive evidence implies either directly conflicting information in peer-reviewed publications, or inconclusive information but with some basis for a biological
rationale.

year old group, and identified immune-mediated disease, ocular
surgery and chronic pain syndromes as important risk factors in
women.
4.3. Meibomian gland dysfunction (MGD)
DED has been divided into evaporative and aqueous deficiency
subtypes [74,237], the former being frequently associated with
MGD [1,6,75]. Consistent with the findings of the previous TFOS
DEWS epidemiology report [1], the TFOS MGD epidemiology report
published in 2011 [6] found a lack of agreement for the definition
and classification of MGD, which limited the epidemiologic inves-
tigation of this disorder. In addition, they noted that there was a
lack of clarity regarding objective and subjective methods used to
diagnose and evaluate this common ocular condition. In this regard,
new analytical and descriptive techniques have shown promise
[76e81], but these procedures are not applicable to epidemiolog-
ical research so far because of their complexity and because they
are not yet standardized. This report also noted that many risk
factors implicated in DED also play a role in MGD, and the interplay
of the tear film, ocular surface and meibomian glands influence the
development and progression of both conditions [6]. In line with
this observation, MGD is associated with DED signs and symptoms
not only in clinical studies, but also in population based studies
[2,3,29,82], where signs are present in more than two thirds of
subjects with dry eye in clinic-based studies and in approximately
half in population-based studies. This overlap in clinical signs, with
the exception of Schirmer testing for tear production, might sug-
gest that MGD causes a local histopathologic effect on the ocular
surface, in contrast to the hyposecretory effect on tears associated
with certain drugs and systemic disorders [83,84]. However, more
research is needed to understand the relationship between MGD
and the ocular surface and to elucidate the basis for symptoms.
Rosacea-associated MGD is a variant of MGD, with distinct
epidemiological and clinical characteristics [85,86]. This form of
MGD deserves particular attention, especially in children, because it
is usually associated with a more severe disease, inflammatory
complications of the ocular surface, and its diagnosis may be elusive
since cutaneous signs may be minimal or absent [7,77,85e87].
Other chronic ocular surface disorders such as pinguecula or
punctal stenosis are associated with DED in clinical studies [41,42],
but not in population-based studies [2,57], which might reflect the
homeostatic ability of the lacrimal functional unit to respond and
adapt to changes in the ocular surface environment [88].
Conversely, MGD often causes tear film instability and signs of
damage to the ocular surface, although it is asymptomatic in most
patients. The presence of symptoms apparently depends on
comorbidities and other factors, and is not consistently associated
with more severe disease [7]. Although allergic conjunctivitis and
other ocular surface disorders are associated with symptoms
indistinguishable in many cases from dry eye, they are not
considered risk factors in a number of epidemiological studies
[52,54], but rather distinct clinical entities. There is evidence to
suggest that allergic diseases such as vernal and atopic kerato-
conjunctivitis and allergic conjunctivitis are associated with a
higher risk of dry eye in clinical populations [89e91], although this
has not been confirmed in population-based studies. Nevertheless,
such inflammatory diseases should be differentiated from primary
dry eye because their associated factors and management differ.
4.4. Asian race
As discussed in Goal 1, the body of evidence suggests that Asian
race is a significant risk factor for DED once gender and age are
controlled for, with an odds ratio of 1.5e2.2x that of Caucasians,
depending on the diagnostic group. However, studies carried out in
Singapore show a similar rate to Caucasians for symptomatic dis-
ease [18,27].
4.5. Contact lens wear
Contact lens (CL) wearers frequently report increased ocular
dryness compared to non-lens wearers, a decrease in daily wearing
time and ultimately discontinuation of use [92]. DED appears to be
up to 4 times more prevalent in CL wearers in population-based
studies [10,21,24,25,27,60]. CL wear was associated with a higher
prevalence of severe symptoms of DED [30].
The growing interest in the relationship between DED and CL
wear was explored in the TFOS International Workshop on Contact
Lens Discomfort (CLD) [93]. While CLD does appear to be a discrete
condition [92], this report highlighted the potential interaction
between DED and CLD and although there can be some overlap in
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
traditional signs and symptoms, specific differences are discernible.
For example, there can be distinct differences between the type and
chronicity of symptoms reported in each condition, symptoms are
ameliorated on removal of the CL and differences in the natural
history are observed. Contact lens wear impacts on normal ocular
surface homeostasis [94], and while there may be overlap in clinical
presentations, it is important to appreciate that CL wearers may
have, or develop, concurrent DED.
4.6. Hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation is widely
used as a potential curative treatment for hematologic malig-
nancies. Despite improvement in outcomes, chronic Graft Versus
Host Disease (GVHD) remains a life-threatening condition,
involving various organs and tissues, including the ocular surface.
The increased number of procedures performed and higher survival
rates has led to a large number of patients with ocular morbidity.
There are several good quality cross-sectional studies that have
articulated the prevalence and presentation of DED related to
ocular GVHD [95e102], confirming recipient sex mismatch,
regimen intensity, history of viral infection and presence of skin,
mouth and liver GVHD as associated risk factors. DED is the most
common manifestation of ocular GVHD, resulting from lacrimal
gland destruction from allogeneic T cells as well as from severe
MGD [96], resulting in symptoms and a broad range of ocular
surface manifestations. The poor accuracy of the Schirmer test used
as the National Institutes of Health criteria for ocular GVHD has
been criticized and is considered a limitation that must be
addressed [101,103]. It is crucial to provide detailed screening and
preventive strategies to avoid severe ocular discomfort as well as
irreversible vision threatening complications.
€gren syndrome
4.7. Sjo
€gren syndrome is a chronic autoimmune disorder charac-
Sjo
terized by exocrine gland dysfunction, which affects the salivary
and lacrimal glands. Sjo€ gren syndrome is associated predominantly
with aqueous-deficient dry eye, although a higher rate of evapo-
rative dry eye than in the non-Sjo €gren population has also been
reported [104]. The prevalence of Sjo €gren syndrome is estimated to
be in the order of 0.6% (0.19e1.39%) [105], although there is some
variation in prevalence, based on the definition used. The incidence
of physician diagnosed Sjo €gren syndrome in a white population in
the US has been estimated at 3.9 per 100,000 per year, with a 14x
higher rate in women than men [106]. Of 1208 participants in an
international Sjo€ gren syndrome registry, 85% reported symptoms
of dry eye [61]. Of individuals with significant aqueous deficient dry
eye, 10% are likely to have Sjo €gren syndrome [62]. In a US clinical
study, 26% of patients with either aqueous tear deficiency or
evaporative dry eye have an underlying rheumatic condition,
including Sjo€gren syndrome [107].
4.8. Environmental exposures
Several environmental factors have been suggested to impact
DED, such as air pollution, wind, low humidity and high altitude.
There has been a limited number of case-control studies performed
in selected populations (such as in India, Italy and Brazil) that
compared metropolitan areas with rural areas and showed asso-
ciations between DED and hazardous exposure [108e111]. How-
ever, despite these data, an important gap in knowledge about how
environmental factors affect DED persists. Indeed, the
351
understanding of the impact of pollution requires the challenging
integration of location-based heath data and corresponding envi-
ronmental data conditions.
Galor and colleagues demonstrated a higher risk of DED in
metropolitan areas of the USA. Subjects with DED were identified
by the International Classification of Disease (ICD-9) code 375.15.
Spatial information was determined by assessing latitude and
longitude coordinates of patients' zip codes, which were correlated
with meteorological data, such as temperature, wind speed, rela-
tive humidity, visibility and atmospheric pressure from National
Climatic Data Center and aerosol optical depth (a marker of air
pollution) extracted from National Aeronautics and Space Admin-
istration, at each point location. This large population study
comprised 606,708 subjects and demonstrated the risk of DED to be
13% higher in areas where the atmospheric pressure was one
standard deviation higher (incidence rate ratio (IRR) 1.13x) and in
areas with a higher level of aerosol optical depth (IRR 1.13x). In
addition, higher humidity and wind speed (in the presence of air
pollution) were inversely associated with the risk of DED (IRR 0.92x
and IRR 0.93x) [112]. A large population based study conducted in
Korea compared outdoor pollution measurements collected from
national monitoring stations to DED based on symptoms or a prior
clinical diagnosis, in 16,824 participants [113]. Higher ozone levels
and lower humidity were significantly associated with DED.
Low humidity occupational exposure can also lead to DED, as
shown in a study conducted with 352 clean room workers that
work in a very low humidity of under 1% [114]. Symptoms and
ocular signs were analysed during three annual examinations, and
an increased prevalence of DED of 14.8% in the first year, 27.1% in
the second year, and 32.8% in the third year was found.
4.9. Visual display use
Large cross-sectional studies have demonstrated a high preva-
lence of dry eye symptoms among visual display workers, pre-
dominantly young adults [8,60,115], It has been hypothesized that
during visual display use, a diminished blink frequency rate and
incomplete blinking contribute to accelerated tear evaporation,
leading to tear film instability, mild epithelial damage and dry eye
symptoms [116e119]. The use of visual displays has risen enor-
mously, not only among workers but also in the general population,
especially the young, due to the widespread use of home computers,
tablets and mobile devices. In addition, a recent study found that in
certain populations there is a pattern of very early and almost uni-
versal exposure to mobile media devices in young children aged 0e4
years [119]. There are limited well-controlled studies to understand
the impact of tablet/mobile device usage on DED in young pop-
ulations and this is clearly an area requiring further research.
4.10. Vitamin A deficiency/nutritional issues
Dietary vitamin A deficiency is recognized as a major health
problem in certain parts of the world, such as the African continent,
with children being more frequently affected. It is associated with a
form of DED that contributes to corneal involvement, keratomalacia
and preventable blindness [120]. Vitamin A deficiency also in-
creases susceptibility to a range of illnesses and an increased risk of
mortality. Worldwide vitamin A supplementation programs have
significantly reduced illness, blindness and death [121e123]. In
addition, similar presentations of DED may be related to other
nutritional conditions, such as eating disorders (e.g. anorexia and
bulimia), bariatric surgery, vegan diet, and malabsorption syn-
dromes [124e127].
352 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
4.11. Dietary supplementation
Accumulated evidence over the past decade has shown a po-
tential benefit of essential fatty acid (EFA) supplementation on dry
eye. There is an increasing interest in the use of nutritional sup-
plementation or dietary modification regarded EFAs on the pre-
vention and treatment of dry eye, based on the understanding that
a balance of omega-3/omega-6 is important to perform distinct and
complementary functions. EFAs may play an important role in
ocular surface heath and DED treatment. EFAs have been shown to
display anti-inflammatory properties systemically, based on their
effects on arachidonic acid metabolism, specifically the production
of prostaglandins [128e130]. In the eye, EFAs enhance the lipid
layer retarding tear evaporation and decrease apoptosis of lacrimal
gland acini and epithelial cells, also contributing to improved tear
secretion [131,132].
Well-designed and appropriately powered prospective, inter-
ventional trials have evaluated the role of EFA supplementation on
dry eye signs and symptoms [133,134]. Recently, a multicenter 12-
week intervention study comprising 1419 dry eye patients using
oral omega 3 supplementation showed improvement in their
symptoms and reported decreased use of lubricants [135]. Further
evidence is outlined in the TFOS DEWS II Management and Therapy
report [136].
It is important to note that the role of EFAs in the treatment of
DED is still not completely understood and that there is also no
consensus on the dose, composition and length of treatment [137].
Increased quality evidence on the usefulness of nutritional sup-
plements is needed to enable eye care professionals to confidently
outline specific treatment recommendations for using EFAs for
DED.
4.12. Refractive surgery
Laser in Situ Keratomileusis (LASIK) is the most commonly
performed vision correction surgery. However, signs and symptoms
of DED can occur in both early and late postoperative periods. LASIK
has been proposed to result in neuropathic dry eye [138], associated
with sensory nerve damage, reducing lacrimal gland secretion and
triggering neurogenic inflammation [139,140]. The risk of dry eye
after LASIK is significantly associated with preoperative conditions,
such as pre-existing tear dysfunction and long-term CL wear; Asian
patients have a higher incidence of dry eye after LASIK (28%)
compared to Caucasian patients (5%) [141]. Operative conditions
may also contribute to DED after LASIK. The impact of factors such
as flap hinge location (superior versus nasal) and flap width on the
development of DED are not well defined, as recent studies report
conflicting results [142,143]. Nevertheless, higher refractive cor-
rections and deeper ablations are associated with decreased
corneal sensitivity, increased postoperative dry eye symptoms, and
chronic tear dysfunction [139,144].
4.13. Diabetes
The association between dry eye and diabetes mellitus is not
significant in most population-based studies [10,21,25,102]. How-
ever, a population-based survey [145] analysing the comorbidities
of dry eye and several case control studies [102,146e148] found a
positive correlation with complicated disease. In two of these
studies, dry eye was associated with neuropathy [148] and reti-
nopathy classified according to the early treatment diabetic reti-
nopathy study (ETDRS) criteria [147]. In a study conducted with 199
type 2 diabetic patients, the prevalence of DED was 54.3% and dry
eye positively correlated with the duration of diabetes and the
presence of retinopathy [146]. Another study compared symptoms
and objective signs of DED in 104 children with type 1 diabetes
compared to 104 age and sex-matched controls, where 15.4% of
diabetic children complained of dry eye symptoms compared with
1.9% of the controls and 7.7% of diabetic children had dry eye signs
compared with 1.0% of controls. [149].
In diabetics, it is possible that the signs of DED are a conse-
quence of the reduction in corneal sensitivity and that impaired
homeostasis can occur in this population. Thus, it is conceivable
that in population studies that use self-reported symptoms as an
outcome measure, that the prevalence of DED may be under-
estimated. In the Salnes Eye Study [7] an association was found
with asymptomatic but not with symptomatic MGD. However, this
was the only sign found to be associated with diabetes in this
general population. The associations with TBUT, corneal and
conjunctival staining and the Schirmer test were not significant, in
contrast to the positive correlation found in the case control studies
described above.
4.14. Affective and somatoform disorders
Recent studies have shown an association between DED and
several affective disorders, with anxiety and depression the most
frequently reported [69,12,25,26,70,150e152]. Whether these dis-
orders precede or arise as a consequence of DED is not known,
although these circumstances are not mutually exclusive. Irre-
spective of the nature of the association, there are a number of
factors that can confound the results of these studies or the inter-
pretation of risk factors. For example, the role of anxiolytics and
antidepressants needs to be elucidated, as these medications can
also be associated with DED [15,23,57,70]. Similarly, individuals
with DED report lower self-perceived health [153], which could
bias the results of the questionnaires used to evaluate mental
health. Stress has been associated with both dry eye and mental
health and could act as a trigger in some instances [11,12,26,102].
Psychological factors and the consequent altered immune response
could increase the probability of DED associated with this disorder
[154].
Several chronic pain syndromes such as chronic widespread
pain syndrome, pelvic pain and irritable bowel syndrome have also
been associated with DED, as has migraine [12,25,153,155,156],
suggesting that these disorders could share etiopathogenic
neuropathic mechanisms with DED. Although somatisation and
increased pain sensitivity may impact on the frequency of reporting
of symptoms of dry eye, the extent to which this impacts the
prevalence of the disease remains to be elucidated.
4.15. Heritability and genetic risk factors
In addition to environmental risk factors, genetic susceptibility
is likely to be important in the etiology of DED, but relatively little is
known about the role of genes. DED has been shown to be
moderately heritable in one female twin study in the United
Kingdom [157], with heritability of approximately 30% for symp-
tomatic dry eye and of 40% for a diagnosis of DED by an ECP. The
remaining 60e70% of the variation of DED in the population was
attributed to environmental factors. Like most common diseases,
DED is complex or multifactorial, which means it is unlikely to have
a simple Mendelian inheritance pattern controlled by a single gene
locus [158].
Complex interactions between genes and the environment most
likely play a role in making genes difficult to identify. Genome-wide
association studies (GWAS) identify genetic variants by looking at
millions of common single-nucleotide polymorphisms and have
been highly successful in common eye diseases such as myopia,
glaucoma and age-related macular degeneration [159]. To date, no
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
GWAS studies on DED have been published. Two large GWAS case-
control studies on Sjo €gren syndrome have been performed
[160,161], showing associations with immune-related genes, but
not with genes encoding for salivary or lacrimal components,
secretion machinery or neuronal proteins that innervate glands
[162]. There have been several candidate gene studies in DED that
examined a few selected polymorphisms in pre-specified genes of
interest in clinic-based case-control studies. These studies sug-
gested possible associations with pro-inflammatory cytokine genes
[163], killer cell immunoglobulin-like receptor and human leuko-
cyte antigen-C genes [164,165], the tachykinin receptor 1 gene
[166] and brain-derived neurotrophic factor and vitamin D receptor
genes [167]. However, it is important to note that none of these
results were strong, they have not been (well) replicated in inde-
pendent studies, and candidate gene studies are notorious for false
positive results. Unravelling the interplay between genes and the
environment in DED using hypothesis-free GWAS has the potential
to identify new biological insights and therapeutic options and is
highly encouraged by this subcommittee. It is important to note
that sufficient statistical power using large sample sizes is critical to
success in GWAS studies, especially in a poorly defined and
multifactorial phenotype such as DED. International (gene-by-
environment) GWAS collaborations using strict and similar disease
definitions across cohorts are needed to obtain reliable results. A
standardized, quantitative phenotype with a (near) normal distri-
bution such as tear osmolarity may result in the highest power as
per outcome measure, but large sample sizes and sufficient statis-
tical power are most likely easier to obtain with a case-control
setting using questionnaire-based disease definitions, such as the
WHS questionnaire, particularly in populations that already have
GWAS data available.
4.16. Summary and recommendations
This review has generated a broad summary of risk factors,
categorized both based on whether factors are modifiable or non-
modifiable and by the level of evidence in support of the associa-
tion. However, these findings are still somewhat confounded by
methodological differences between studies, the quality of studies
in terms of the power to detect differences, differences in diag-
nostic criteria and study population differences. The review has
highlighted the need for appropriately powered hypothesis driven
studies, which address the major and important risk factors. Risk
factors may vary with different diagnostic criteria but also may vary
based on the health service provision in different jurisdictions. It
may also be useful to consider population attributable-risk per-
centage to prioritize risk factors based on their impact.
The Committee concluded that there were limited studies to
evaluate the impact of climate change, digital device use and dry
eye in youth, and that it was important to distinguish dry eye from
other symptomatic conditions, including allergic disease, infectious
diseases, inflammatory conditions and other chronic ocular surface
diseases.
5. Goal 3. to evaluate available data on the natural history of
DED and disease morbidity
5.1. Natural history of DED
Despite the significant impact of DED in the community, there
are limited published studies available which describe the natural
history of treated or untreated DED. Bron and colleagues [168]
proposed a theoretical model of progression based on the disease
evolving through three stages 1) Initiation of DED, 2) Reflex
compensation, and 3) Loss of the compensatory response. This
353
model suggests that disease may worsen without intervention and
that over time aqueous-deficient dry eye may show clinical signs of
evaporative dry eye and vice versa. The disease may also plateau at a
certain stage [168]. A counter view that not all DED is progressive is
supported by a recent retrospective study based on resurveying 784
participants from the Women's and Physicians' Health Studies in
the USA, who had previously reported a positive diagnosis of dry
eye or severe dry eye symptoms [169]. This study determined the
rate of, and risk factors for, an increase in dry eye discomfort,
worsening vision related symptoms and greater social impact.
Medical records were reviewed and a subset of participants also
underwent clinical examination [169]. The average duration of DED
was 10.5 years for men and 14.5 years for women. The most com-
mon perception of subjects was that there was no change in dry-
ness symptoms (32% unchanged, 44% improved and 24%
worsened), visual symptoms (52% unchanged, 19% improved and
29% worsened) or social impact (71% unchanged, 19% improved and
10% worsened) over time. The distribution of change in symptoms
was not related to the type of treatment or its relative level of
severity. Worsening of dryness symptoms was associated with a
high monthly dollar spend for treatment, a history of severe
symptoms and the use of systemic beta-blockers. A worsening of
vision symptoms was also associated with a history of ocular sur-
gery, depression and either MGD or blepharitis. A worsening of
social impact was associated with older age, use of systemic beta-
blockers and either MGD or blepharitis. Worsening symptoms
was not related to the probability of corneal staining [169].
While recall bias in retrospective studies may confound symp-
tom recall, these findings do support the view that DED charac-
terized by severe dry eye symptoms at diagnosis, appears to
progress irrespective of treatment. The lack of association between
progression of symptoms and signs is not unexpected. Without
reference to disease severity, a reduction in symptom reporting
over time has been established in the Twins UK study, where 37% of
subjects with symptomatic disease at baseline (using the Beaver
Dam study criteria) did not report symptomatic disease when
resurveyed two years later [25]. It is not clear whether these in-
dividuals were undergoing treatment or if this is representative of
the waxing and waning course of the disease. A recent meta-
analysis of the effects of topical 0.05% cyclosporine and artificial
tears, vehicle control or no treatment on disease signs and symp-
toms confirmed the overall efficacy of treatment in reducing signs
and symptoms, but there was heterogeneity between studies in
severity and etiology of dry eye [170].
Prospective studies are needed to determine the clinical course
of all severities of dry eye, prognostic factors in disease progression,
and the role of treatment in reducing signs and symptoms. The
subcommittee also recommends reviewing data from available
placebo/vehicle and treatment groups in randomized double-
masked controlled trials of sufficient duration to determine
changes in prevalence over time. Other sources of information
would include registry studies and claims data, although the type
and quality of data may vary.
5.2. Morbidity of dry eye
Dry eye is common throughout the world and the prevalence
increases with age. Given the aging of the population worldwide
(Source Kevin Kinsella and Wan He, “An Aging World: 2008,” U.S.
Census Bureau, International Population Reports, P95/09-1
[Washington, DC: U.S. Government Printing Office, 2009]) the
overall morbidity of dry eye is important to consider to understand
its full public health impact [12,56,171e173]. Dry eye represents the
most common reason for seeking medical eye care and thus it
represents a significant cost burden due to direct and indirect
354 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

health costs and reduced work productivity [54]. This section re-
views the morbidity of DED with regard to both the social and
economic burden and health-related quality of life (QoL).
5.2.1. Economic burden of dry eye
Since the initial TFOS DEWS epidemiology report [1], an
increasing number of studies have quantified the costs incurred by
healthcare systems in association with DED [174e184]. Many of the
large cohort and population-based studies have calculated the
estimated cost of DED treatment or work productivity losses.
However, cost analyses cannot provide direct conclusions regarding
effective resource allocation for particular treatments or strategies.
Nevertheless, cost of illness analyses provide information about the
patterns of resource use for a particular condition, thereby enabling
a greater understanding of the framework within which decisions
about resource allocation are made. Although the medical insur-
ance fee and health care systems vary among countries, it has been
consistently reported that DED significantly increases the utiliza-
tion of healthcare resources.
DED affects tens of millions of individuals and carries significant
socioeconomic implications, including the expenses associated
with medications and physician visits and the effects on daily social
and physical functioning. Furthermore, increased time spent on
treatment and the avoidance of certain environments in the
workplace that aggravate dry eye symptoms can lead to a decrease
in workplace productivity.
The economic burden of DED can be attributed to direct
medical care spending, the impact of loss of productivity, and
impact on quality of life [179,181e186]. The total annual cost for
the management of DED was estimated to be USD 3.84 billion in
the United States [182], and USD 0.15 million in Singapore [180].
The annual total cost for 1000 patients with DED in Europe
managed by ophthalmologists ranged from USD 0.27 million in
France to USD 1.10 million in the United Kingdom [175]. The total

Table 4
The economic burden of dry eye disease.

Authors Methods Study Population Years Studied Cost Analysis

United States
Fiscella 2008 [183] Retrospective administrative 23,821 of dry eye patients treated 2004e2005  The total health plan for topical cyclosporine,
claims analysis with cyclosporine or punctal plugs US$3.05 million (mean cost $336/patient).
 Total health plan costs for punctal plugs
procedures, $3.28 million (mean cost $375/
patient).
Wlodarczyk 2009 [184] Meta-analysis, literature review Cohort of dry eye patients from two 2006  Systane® cost on average US$57.79/year more
and economic model for dry eye clinical trials (n ¼ 147) treated with than Refresh Tears®
either Systane® or Refresh Tears®  Assigning a quality-adjusted life year (QALY) gain
of 0.03 to responders results in an incremental
cost per QALY gain of US$5837.
Brown 2009 [174] Multicenter, randomized, € gren
877 of dry eye (270 had Sjo 2007  The societal perspective incremental cost-utility
clinical trials syndrome) ratio (CUR) for cyclosporine over vehicle ther-
apy is $34,953 per QALY and the societal
perspective average CUR is $11,199 per QALY. The
third-party-insurer incremental CUR is $37,179
per QALY, while the third-party-insurer
perspective average CUR is $34,343 per QALY.
Patel 2011 [178] Online survey 9034 of dry eye panel 2009  Approximately 31% of severe DED patients, 40
e60% loss in productivity while working; 15%
experienced 70e100% loss.
Yu 2011 [182] Survey 2171 of DED 2008  From payer's perspective:
US $783/person,
US $3.84 billion/year
 From a societal perspective:
US$11,302/person, US$55.4 billion/year
Galor 2012 [176] Survey 147 of nationally representative 2001e2006  Mean expenditure per patient per year being
subsample of US population using US$55 in 2001e2002 (n ¼ 29), US$137 in 2003
topical cyclosporine and/or e2004 (n ¼ 32), and $299 in 2005e2006.
Blephamide®
Japan
Yamada 2012 [181] Online survey 396 aged 20 years 2012  Cost of work productivity loss, US$ 799/person in
definite DED, US$ 58/person in marginal DED, and
US$ 1036/person in self-reported DED.
Mizuno 2012 [177] Estimated annual direct costs 118 of prospective cohort dry eye 2008  Drug cost was US$323 ± 219/year; Clinical cost
from outpatient medical US$165 ± 101/year; Total direct costs including
records and survey punctal plug treatment US$530 ± 384/year
Uchino 2014 [179] Survey 672 office workers 2013  The estimated cost of annual work productivity
losses: US$6160/person in the definite DED
group; US$2444/person in the probable DED
group.
Singapore
Waduthantri 2012 Retrospective chart review 54,052 patients; 132,758 patients' 2008e2009  US$1,509,372.20/year in 2008;
[180] episode (PE).  US $1,520,797.8/year in 2009.
 US $22.11/PE in 2008; US $23.59/PE in 2009.
France, Germany, Italy, Spain, Sweden, and the United Kingdom
Clegg 2006 [175] Systemic literature review and Model cohort 1000 dry eye patients 2003e2004  Annual burden of UK (~US $1100/person), Spain
interviews (~US $800/person), Italy (~US $600/person),
Germany (~US $500/per son), Sweden (~US $400/
person), and France (~US $300/person).
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
annual health plan cost per patient was estimated as USD 323 in
Japan, and USD 375 in United States [183]. Annual productivity
loss per patient associated with definite DED was estimated to be
USD 6160 in Japan [179] and the annual cost of DED from a societal
perspective, was USD 11,302 in the United States [182]. Mea-
surement of the treatment cost of DED is challenging because the
treatment options and health insurance service vary by country.
The treatment utilization includes prescription medication,
punctal plugs, and surgical management [182]. Fiscella and col-
leagues reported the mean treatment cost per patient at USD 336
for topical cyclosporine and USD 375 for punctal plugs [183].
Mizuno et al in 2012 estimated the total annual cost of prescrip-
tion drug per patient to be USD 323 and the cost of punctal plugs
per patient to be USD 42 [177].
Table 4 summarizes the healthcare costs by region [174e184]. A
recent systematic literature review has confirmed that the largest
proportion of costs are attributed to indirect costs due to reduced
productivity at work [187].
While cost analyses cannot recommend resource allocation for
particular treatments or strategies, cost of illness analyses provide
information about the patterns of resource use for a particular
condition, thereby enabling a greater understanding of the frame-
work within which decisions about resource allocation are made.
Although the medical insurance fee and health care systems vary
among countries, it is widely accepted that DED significantly in-
creases the utilization of healthcare resources. Cost savings through
improved QoL, improved productivity and reduction in healthcare
utilization costs associated with effective disease treatment should
also be modelled in future studies.
5.2.2. Quality of life (QoL) questionnaires
The currently validated dry eye specific questionnaires, the OSDI
and the Impact of Dry Eye on Everyday Life (IDEEL) are frequently
used to measure disease severity (Table 5) [12,24,26,185,188e193].
The OSDI is a DED-specific instrument that includes 12 ques-
tions assessing the frequency of dry eye symptoms and their effects
on vision-related function. The 12 OSDI questions form three
different subscales, namely ocular symptoms, vision-related func-
tions and limitations, and environmental triggers on which to
evaluate symptoms during a 1-week recall period. Each answer is
scored on the basis of symptom frequency using a 5-point scale
where 0 indicates no problem and 4 indicates a significant problem.
However, the OSDI has some limitations in that it does not assess
the psychological and social aspects of DED, therefore, it is not
widely used to evaluate the more holistic effects of DED on QoL.
The IDEEL, which is a 57-item questionnaire, comprises three
modules: dry eye symptom bothersomeness; impact on daily life
(including daily activities, emotional impact, and impact on work)
and treatment satisfaction (both effectiveness and treatment-
related bother/inconvenience). There are two items related to vi-
sual disturbance that assess the extent to which the patient is
affected by blurry vision and sensitivity to light, glare, and wind.
The strength of the IDEEL is that it covers all relevant domains of
DED and it also distinguishes the severity of DED, however, it is not
frequently used in routine clinical practice because of a long
duration of testing (typically taking over 30 min).
Perhaps the most widely used questionnaires pertaining to
general health and general eye health include the Short Form-36
(SF-36) and the 25-item National Eye Institute's Visual Function
Questionnaire (NEI VFQ-25), respectively. The SF-36 is used as a
measure of the general health status of an individual. It includes
36 items under the following subscales: Physical Functioning,
Role-Physical (role limitations due to physical problems), Bodily
Pain, General Health Perceptions, Vitality, Social Functioning,
Role-Emotional (role limitations due to emotional problems), and
355
Mental Health [194]. A 4-week recall period is used for all these
subscales, except Physical Functioning and General Health, which
reflect the health of the patient at the time of questionnaire
completion. The NEI-VFQ-25 assesses the effects of various eye
diseases on QoL [195]. The ocular pain subscale of the NEI-VFQ-25
shows the strongest overall correlation with the OSDI in in-
dividuals with Sjo€gren syndrome [196], leading some researchers
to suggest that patients with low ocular pain scores (where a
higher score reflects better function) in NEI-VFQ-25 should un-
dergo further testing for dry eye. However, with regard to the
assessment of QoL in patients with dry eye, the NEI-VFQ-25 is
limited because it is not disease-specific and needs further val-
idity and reliability testing in a dry eye cohort, lacks a specified
recall period, and requires 10 min for completion. In some in-
stances, a 14-item appendix can be administered to subjects to
enhance the reliability of the various subscales. The NEI-VFQ
comprises 39 questions with the following 12 domains or sub-
scales: (1) general health, (2) general vision, (3) ocular pain, (4)
difficulty with short distance vision activities, (5) difficulty with
long distance vision activities, (6) vision-related limitations in
social functioning, (7) mental health symptoms related to vision,
(8) vision-related role difficulties, (9) vision-related dependency,
(10) vision-related driving difficulties, (11) limitations with
color vision, and (12) limitations with peripheral vision. The
scores range from 0 to 100, with higher scores indicating better
function.
5.2.3. Effects of dry eye on quality of life
The available evidence suggests that DED has an adverse effect
on overall QoL. It causes pain and irritation and affects ocular and
general health and well-being, the perception of visual function,
and visual performance [12,24,26,185,188e193,197,198]. The
development of methods to assess DED patients in detail enables
clinicians to understand the magnitude of the effects of DED on
QoL. Some available measurement tools are specific to DED or
vision, some are generic, and some focus on work productivity or
anxiety/depression. Pain associated with DED can have psycho-
logical and physical impacts, while blurred vision may impose re-
strictions in daily life activities such as reading, driving, watching
television, and operating smartphones. Moreover, the cost of DED
treatment and the chronicity/intractability of DED symptoms affect
the social life of an individual. Collectively, all these factors affect
QoL and have an impact on public health.
Utility assessments suggest that patients with mild and severe
DED experience a reduction in QoL at a level similar to that expe-
rienced by patients with mild psoriasis and moderate-to-severe
angina, respectively [199]. In everyday activities, such as driving,
reading, carrying out professional work, using a computer, and
watching television, individuals with DED are three times more
likely, than those without DED, to report difficulties [200].
5.2.4. Impact of dry eye on quality of vision
The precorneal tear film has an important optical function. Tear
film instability and corneal surface irregularities due to epithelial
desiccation, resulting in changes in optical quality, can be visualized
and quantified using a range of techniques [200e202]. In the ma-
jority of patients with DED, the visual acuity is normal according to
standard measurements, however, instability of the tear film in-
troduces higher-order aberrations that result in a decrease in visual
quality. Early studies investigated optical fluctuations using the
double-pass method to assess changes in the modulation transfer
function after blinking [202]. Others involved the continuous
acquisition of corneal topography or videokeratoscopy images to
show that fluctuations in the tear film cause increased irregular
astigmatism [201]. Patients with DED often report vision-related
356 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

Table 5
Health-related Quality of Life and dry eye.

Authors Country Instruments Subjects Analysis

Mertzanis 2005 United States IDEEL, SF-36 32 with SS, 130 with non-SS KCS, 48 - Non-SS KCS patients had lower Role-Physical (effect size [ES] ¼ -0.07),
[188] controls Bodily Pain (ES ¼ 0.08), and Vitality (ES ¼ 0.11) scores.
- All SF-36 scale scores except Mental Health (ES ¼ 0.12) were lower in
the SS group than the adjusted norm.
- Mild patients consistently had lower Role-Physical and Bodily Pain
scores than the norm, suggesting impact on daily roles (ES < 0.2).
- The group with severe disease scored lower than the norm across all
domains (ES range: 0.14 to 0.91) except Role-Emotional
(ES ¼ 0.13) and Mental Health (ES ¼ 0.23).
Rajagopalan United States SF-36,EQ-5D, IDEEL 130 with non-SS KCS, 32 with SS, 48 - Significant differences between severity levels were found with most
2005 [189] controls SF-36 scales (P < 0.05), all EQ-5D scales (P < 0.05), and all IDEEL scales
(P < 0.0001), except for Treatment Satisfaction.
- IDEEL scales consistently outperformed the generic QoL measures
regardless of the severity criterion used. Most SF-36 scales out-
performed the EQ-5D QoL scale, but the EQ-5D visual analog scale
outperformed the SF-36 scales, except for General Health Perceptions.
Paulsen 2014 United States NEI-VFQ 25, SF-36 The Beaver Dam Offspring Study - Dry eye was also associated with lower scores on the Medical
[24] (BOSS) (2005e2008), participants Outcomes Study Short Form 36 (b ¼ 3.9, P < 0.0001) as well as on
(N ¼ 3285), aged 21e84 years the National Eye Institute 25-Item Visual Function Questionnaire (NEI
VFQ-25) (b ¼ 3.4, P < 0.0001) when controlling for age, sex, and
comorbid conditions.
Abetz 2011 United States, IDEEL, SF-36, EQ-5D The focus groups had 6 to 10 - Significantly different (p < 0.0001) mean scores were observed
[185] Canada participants in each; the total between different levels of severity in all the IDEEL dimensions
population consisted of 45 patients: except Satisfaction with Treatment Effectiveness.
30 with non-SS KCS and 15 with SS. - For the SF-36, significant differences between the various severity
levels were noted in the Physical Component Scale scores across the 3
different severity criteria.
- In observing the EQ-5D results, significant differences in mean
dimension scores at the varying severity levels were also consistently
noted across all criterion measures.
Hackett 2012 United Improved Health 69 subjects with SS from specialist - Significantly poorer functional ability in SS compared with controls
[190] Kingdom Assessment clinical service. 69 age and sex across all domains; Functional impairment specifically associated in
Questionnaire matched controls. Functional ability univariate analysis with physical fatigue, pain, depression, symptom
assessed burden, disease activity, quality of life, dryness, daytime somnolence,
anxiety score and circulating C-reactive protein level.
Buchholz 2006 United NEI VFQ-25. OSDI Dry eye disease (N ¼ 44) of whom - There was a statistically significant difference between the mean VFQ-
[191] Kingdom had mild/moderate disease (N ¼ 24) 25 score for patients who rated themselves as mild or moderate (78.1,
and severe disease (N ¼ 20). N ¼ 24) and for those who rated themselves as severe (64.5, N ¼ 20
[p-value ¼ 0.005])
- OSDI scores strongly correlated to VFQ-25 scores (Pearson
correlation coefficient: 0.7495, p-value<0.0001)
Na 2015 [26] South Korea EQ-5D, EQ VAS Korea National Health and - Significant different (p < 0.05) value of pain/discomfort (EQ_4), and
Nutrition Examination Survey anxiety/depression (EQ_5) in both clinically diagnosed DED and
(KNHANES)(2010e2011), symptoms of DED compare to normal controls.
(N ¼ 3285), women aged over 19
years
Ahn 2014 [12] South Korea EQ-5D, EQ-VAS Korea National Health and - Means of pain, discomfort/anxiety, depression dimensions, and EQ-
Nutrition Examination Survey VAS in the EQ-5D were significantly higher in the group diagnosed
(KNHANES)(2010e2011), with DES than in the normal group (all P < 0.01)
(N ¼ 11,666), aged 19e95.
Belenguer 2005 Spain SF-36 110 patients (105 women and 5 - Comparison between patients with primary SS and the control
[192] men, mean age of 56 years) with population showed lower scores in SS in all SF-36 scales (p < 0.001)
primary SS
Mizuno 2010 Japan VFQ-25, SF8 158 with DED (30 with SS, 128 with - Some patients recorded extremely low VFQ-25 scores
[193] non-SS) - VFQ-25 and SF-8 scores were not significantly different between the
SS and non-SS patients.

difficulties during daily activities, resulting in a decreased QoL and
these changes are often related to depression and anxiety [203].
There are two categories of vision-related QoL instruments.
Generic instruments are designed for a broad spectrum of visual
disorders and ocular diseases, while disease-specific instruments
are designed and validated for a specific ocular disorder [196].
Generic instruments provide broader and more general vision-
related information, whereas disease-specific instruments pro-
vide more sensitive results on vision-related QoL. Most studies
assessing the vision-related QoL of patients with DED used both
generic (e.g. NEI-VFQ-25) and disease-specific instruments (e.g. the
vision-related functions and limitations subscale of the OSDI)
[200e205].
5.2.5. Impact of dry eye on mental health
€ gren syndrome on mental
The effects of DED associated with Sjo
health status have been widely reported, although the impact on
DED more broadly has not been evaluated. Patients with Sjo € gren
syndrome experience significant symptoms of fatigue, autonomic
dysfunction, and excessive sleepiness in addition to sicca-related
symptoms. The overall impact of these symptoms on the func-
tional ability of individuals is considered to have a significant
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
negative impact on psychological well-being [190,197,206,207].
Because most previous studies on autoimmune-related DED did not
assess the burden of dry eye separately from that of other systemic
symptoms and signs of Sjo €gren syndrome, there is limited infor-
mation of the impact of DED. Hackett and colleagues reported that
patients with primary Sjo €gren syndrome experienced greater
functional impairment than controls (Improved HAQ total scores:
mean ± SD 24 ± 25 for primary SS versus 9 ± 19 for controls;
p ¼ 0.0002) across all domains of activity, including physical fa-
tigue, pain, depression, total symptom burden, systemic disease
activity, quality of life, dryness, daytime somnolence, anxiety score,
and C-reactive protein (CRP) level [190]. Patients with primary
€gren syndrome showed similar scores compared with those
Sjo
with systemic lupus erythematosus, using the Zung Self-rating
Anxiety/Depression Scales [208].
Recently, population-based studies indicated a relationship
between depression/anxiety and DED [25,70,150,151,209e211].
Ocular pain and discomfort without a definitely impaired tear film
may also be associated with depression, anxiety, and psycholog-
ical stress [186,200,201,203,205,212,213]. DED affects vision
quality through tear-related changes in aberrations, and an
impaired visual performance can likewise lead to depression and
impaired QoL. An awareness of such associations between dry eye
symptoms and depression is important for ECP, who may serve as
the starting point for medical care. Although the precise mecha-
nisms underlying the effects of DED on mental health remain
unclear, one possible explanation is that DED results in neuro-
pathic disease, resulting in chronic pain and negatively affecting
the patient's QoL, function, and daily activities and work, even-
tually leading to depression and/or anxiety. A further consider-
ation is the use of medications for these conditions which may
increase the risk of dry eye.
5.2.6. New methods for measurement of dry eye related QoL
Because there is no “gold standard” diagnostic test for DED, a
combination of signs and symptoms is commonly used as diag-
nostic criteria. Most methods for assessing dry eye-related QoL are
time consuming, and their ability to quantify changes in symptoms
is limited. Therefore, the development of a simple, reproducible,
reliable, and quantitative instrument is critical for the diagnosis,
treatment, and follow-up of DED patients.
A short questionnaire based on a visual analog scale (VAS) to
quantify the frequency and severity of dry eye symptoms has been
developed. This is known as the Symptom Assessment in Dry Eye
(SANDE) questionnaire [214], which comprises two questions
assessing the frequency and severity of dry eye symptoms. Each of
these two items is assessed using a 100-mm VAS and scored from
0 to 100. The total SANDE score is calculated as the square root of
the product of the two scores and ranges from 0 to 100, with higher
scores indicating greater disability [214]. The SANDE questionnaire
has been validated against the OSDI instrument in a clinic popu-
lation and the SANDE scores have shown negligible differences
from OSDI scores [215], suggesting that the SANDE may be used in
clinical practice as a short, quick, and reliable measure of disease
symptoms.
In 2013, the Dry Eye-Related Quality-of-Life Score (DEQS)
questionnaire was developed and validated in Japan [216]. The
diagnostic criteria conformed to those defined by the Japanese Dry
Eye Society in 2006. The questionnaire comprises 15 items under
an Overall Summary scale and two multi-item subscales, namely
Impact on Daily Life and Bothersome Ocular Symptoms. When the
results were compared with those of the SF-8 and NEI-VFQ-25, the
DEQS questionnaire was valid and reliable for evaluating the
multifaceted effects of DED on the daily lives of patients, including
their mental health [216]. This suggests that this instrument may be
357
used in routine clinical practice, although the questionnaire is time
consuming and the generalizability to other populations has not
been reported.
5.2.7. Future research directions
With the development of electronic devices and transmission
technology, monitoring symptoms and the burden of disease in
individuals with DED is changing rapidly compared with existing
measurement tools. Smartphone based applications, such as elec-
tronic diaries or electronic data capture systems may be used to
translate and validate the prevalence of disease effect of chronicity
and treatment and the effect of DED on quality of life.
6. Goal 4: review of instruments and their use/applicability in
epidemiological research
Although clinical tests have shown a wide variability in their
ability to detect many cases of DED [40,217,218], conducting a
battery of tests could provide information on risk factors in the
absence of symptoms, as recent research has suggested [7,21,56].
Evaporimetry and interferometry and other investigational tech-
niques may be useful and specific diagnostic tools, but they lack
standardization and are not yet applicable to epidemiological
research.
Symptoms alone or in combination with signs are present in
many definitions of dry eye used in published epidemiological
studies. Since the initial TFOS DEWS report, MGD or evaporative
dry eye has been identified as the most common cause of dry eye
[2e5] and MGD is more frequently asymptomatic than symp-
tomatic [7], which perhaps challenges the use of current symp-
toms instruments. The definition of dry eye in the current
workshop includes both signs and symptoms, although symptoms
or signs may be absent in a single subject where there is a
disturbance or a lack of tear film homeostasis. There has been
increasing focus on non-obvious disease, characterized by signs in
the absence of symptoms [7,237]. The report of the TFOS DEWS II
Diagnostic Methodology subcommittee [40] has described a bat-
tery of tests suitable to diagnose and monitor dry eye and the
grading of disease severity includes both signs and symptoms.
While the relationship between signs and symptoms may be ab-
sent in early or mild disease, the assessment of both symptoms
and signs is clearly important in grading disease severity, under-
standing the natural history and in monitoring response to
treatment.
In 2007, the initial TFOS DEWS report summarized the available
instruments for DED [1]. In the previous report, the focus was on
questionnaires that had been used in randomized clinical trials or
epidemiologic studies [1]. This report will similarly focus on those
instruments used in epidemiological studies in disease ascertain-
ment or determination of severity.
We searched PubMed using the terms ‘dry eye’ and ‘question-
naire’ and we limited the language to ‘English’ and the use as ‘hu-
man’. We also reviewed existing data regarding validation and
utility of each questionnaire. In the present report, we discuss
seventeen questionnaires. The first twelve questionnaires have
been validated using various methods, while the last five ques-
tionnaires have not yet been validated.
The twelve validated questionnaires are reviewed below and are
summarized in Table 6. The first five questionnaires (OSDI, IDEEL,
NEI-VFQ, SANDE, and DEQS) are described in the quality of life
section above, and the remainder are described below.
1) Ocular Surface Disease Index (OSDI) [219].
2) Impact of Dry Eye on Everyday Life (IDEEL) [189].
 358
Table 6
Summary of questionnaires.

Number Instrument Description Category Number items Domains sampled Recall frequency Utility
Title

1 McMonnies Key questions in a dry eye history Symptoms and risk factors 15 1) Symptoms; Not specified Clinical studies
2) Environment;
3) Review of systems
2 OSDI The Ocular Surface Disease Index Symptoms and HRQL 12 1 week Clinical studies
3 IDEEL Impact of Dry Eye on Everyday Life Symptoms and HRQL 57 1) Daily Activities 2 weeks Epidemiological and clinical
2) Treatment Satisfaction studies

F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365

3) Symptom Bother
4 WHS Women's health study questionnaire Symptoms 3 1) Ocular symptoms Not specified Epidemiological studies
2) History of DED
5 DEQ Dry Eye Questionnaire Symptoms and bothersomeness 21 1) Prevalence Not specified Epidemiological and clinical
2) frequency, diurnal severity studies
and intrusiveness
6 UNC DEMS North Carolina Dry Eye Management HRQL 1 Symptom bothersomeness 1 week Clinical studies
Scale
7 SPEED Standard Patient Evaluation of Eye Symptoms 4 Symptoms (type, frequency, 3 months Epidemiological studies,
Dryness severity) clinical practice
8 SESoD Subjective Evaluation of Symptom of Symptoms 3 Symptoms Not specified Clinical practice
Dryness
9 DEQS Dry Eye-Related Quality-of-Life Score Symptoms and HRQL 15 Symptoms (frequency and 1 week Clinical practice
Questionnaire severity)
10 SANDE Symptom Assessment in Dry Eye Symptoms 2 (visual analog Symptoms (frequency and Not specified Clinical practice
scale) severity)
11 DEEP Dry Eye Epidemiology Projects Symptoms 19 Symptoms (frequency) Not specified Screening
12 NEI-VFQ National Eye Institute Visual Function Visual functioning; HRQL 25 Symptoms (frequency and Not specified Clinical researcha
Questionnaire severity), impact
13 CANDEES Canadian Dry Eye Epidemiology Study Symptoms 13 Symptoms severity, risk factors Not specified Prevalence study
Questionnaire
14 SEE Salisbury Eye Evaluation Symptoms 6 Symptoms (frequency) Not specified Prevalence study
15 Melbourne VIP Melbourne Visual Impairment Project Symptoms 6 Symptoms (severity) Not specified Epidemiological studies
16 Bjerrum Symptoms 14 Symptoms Not specified Clinical practice
questionnaire
17 Japanese dry Symptoms 30 Symptoms Not specified Prevalence study; clinical
eye awareness practice (self-diagnosis)
study

HRQL ¼ Health related quality of life.

a
Useful for group-level comparisons of vision-targeted, health-related QoL.
 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
3) National Eye Institute-Visual Function Questionnaire (NEI-
VFQ) [220].
4) Symptom Assessment in Dry Eye [214,221,222].
5) Dry Eye-Related Quality-of-Life Score Questionnaire (DEQS)
[216].
6) McMonnies Dry Eye Questionnaire [223,224].
7) Women's Health Study Questionnaire [53].
8) Dry Eye Questionnaire (DEQ) [225].
9) North Carolina Dry Eye Management Scale (UNC DEMS)
[226].
10) Subjective Evaluation of Symptom of Dryness (SESoD) [227].
11) Standard Patient Evaluation of Eye Dryness (SPEED) [228].
12) Dry Eye Epidemiology Project Questionnaire (DEEP) [222].
13) Canada Dry Eye Epidemiology Study (CANDEES) [229].
14) Salisbury eye evaluation [230].
15) Melbourne visual impairment project [52].
16) Bjerrum questionnaire [231].
17) Japanese dry eye awareness study [232].
6.1. McMonnies Dry Eye Questionnaire
The McMonnies Dry Eye Questionnaire consists of 12 items, of
which most are dichotomous (yes/no) [223]. This questionnaire has
been used for dry eye screening in dry eye clinic populations
[25,27]. Items include age, sex, contact lens wear, previous diag-
nosis of dry eye, and triggers (environment, swimming, alcohol). It
also assesses the frequency of symptoms dryness, grittiness, sore-
ness, redness, tiredness (never, sometimes, often, constantly), and
medications used (arthritis, dry mouth, thyroid status) [224].
6.2. Women's Health Study (WHS) questionnaire
The WHS questionnaire has been used widely in population
based studies of dry eye (Table 1). It consists of the following 3
items:
1) Previous diagnosis of dry eye from clinician? (yes or no).
2) How often eyes feel dry (not wet enough)? (constantly, often,
sometimes, or never)
3) How often eyes feel irritated? (constantly, often, sometimes, or
never)
An individual is considered positive for dry eye with reported
rates of disease based on symptoms of dryness and irritation
at least often and/or a physician's diagnosis of dry eye, as
reported by the participant. The WHS has been reported to
have similar sensitivity and specificity as a 16 item instrument
[233], comprising symptoms including: sandy or gritty, burning
or stinging pain, itching, light sensitivity, blurry vision, tiredness,
soreness, scratchiness, redness, stickiness, achy feeling watery
eyes and swollen eyelids. In addition, it has been validated
against a standardized clinical exam [53].
6.3. Dry eye questionnaire (DEQ)
The DEQ has 21 items and includes questions about contact lens
wear, age, and sex. It includes categorical scales of prevalence,
frequency, diurnal severity and intrusiveness of symptoms in a
typical day over a one-week recall period. It also assesses the fre-
quency (never, infrequent, frequent, constantly) and intensity (from
0; none to 5; very intense) of the following symptoms of comfort,
dryness, blurry vision, soreness and irritation, grittiness and
scratchiness, burning and stinging, foreign body sensation, light
sensitivity, and itching. The DEQ also includes questions regarding
359
the time of day of worsening, the effect on daily living activities,
medications, allergies, dry mouth, nose, or vagina, treatments,
and patient global assessment [234]. The short version of
DEQ comprising 5 questions only (DEQ-5) is sensitive to disease
severity [235] and is one of two instruments recommended by the
TFOS DEWS II diagnostic methodology report [40].
6.4. North Carolina Dry Eye Management Scale (UNC DEMS)
The UNC DEMS has 1 item, which asks about the severity of dry
eye symptoms (pain, burning, tearing, grittiness, feeling like
something is in your eye, and sensitivity to light), and how symp-
toms affect daily life. The answer uses a 10-point scale over a one
week of recall period. It has been validated using dry eye patients
and non-dry eye patients, and appears to be highly correlated with
the longer OSDI [226].
6.5. Subjective Evaluation of Symptom of Dryness (SESoD)
The SESoD consists of a three-item questionnaire to evaluate
a patient's perception of ocular discomfort related to dryness
for the purpose of clinical practice. Key questions are frequency
of symptoms [31], the presence of discomfort [32], and
interference with activity. The SESoD assesses dry eye using a 5-
point scale where 0 ¼ no dryness to 4 ¼ severe dryness.
This questionnaire has been validated against the
SPEED, OSDI, DEQ, and McMonnies Dry Eye History question-
naires [227].
6.6. Standard Patient Evaluation of Eye Dryness (SPEED)
The SPEED questionnaire is a four-question survey to assess the
frequency and severity of patient dry eye symptoms. Specifically, it
monitors diurnal and longer-term symptom changes over the
course of three months. The SPEED questionnaire has been shown
to exhibit good validity, unidimensionality, objectivity and consis-
tency when compared with the DEQ, McMonnies questionnaire,
OSDI and SESoD questionnaires [236].
6.7. Dry Eye Epidemiology Project (DEEP)
The DEEP questionnaire consists of 19 questions and is used, as a
phone interview-screening questionnaire, to screen for DED. The
resulting sensitivity/specificity values are reasonably high (60%/
94%). It surveys the use of eye washes, compresses, drops, fre-
quency of symptoms such as itchy, sore, dry, scratchy, gritty,
burning, irritated, watering, photophobia, red, sticky, achy (never,
sometimes, often, constantly). In addition, it surveys the presence
of dry mouth, ocular allergies, the frequency of contact lens wear
and whether a physician has made a diagnosis of dry eye [222].
6.8. Summary/recommendations - utility for patients/patient
acceptance
Although there are many questionnaires to evaluate DED, more
research is required to better reflect symptom reporting in dry eye
and define normative data and clinically significant changes. The
symptoms that patients frequently report are missing from many
questionnaires e e.g. photophobia; menthol (cold sensation);
burning, which needs to be addressed in questionnaire develop-
ment. Further evidence is needed to identify the best methods for
self-monitoring or in communicating with practitioners, and
methods of capture of symptoms including electronic data capture/
electronic diaries.
360 F. Stapleton et al. / The Ocular Surface 15 (2017) 334e365
7. Conclusions and recommendations
This report has considered the epidemiology of DED based on
diagnostic criteria, including symptoms and/or signs, and one that
based on a prior diagnosis of DED made by an ECP. While disease
definitions vary between studies, the prevalence of disease in-
creases with age and females are more frequently affected, with the
exception of MGD where sex effects are more equivocal. Limited
studies have been carried out in youth and there remains a need for
studies in populations below 40 years of age. Prevalence appears to
be higher in Asian than in Caucasian populations, although studies
have not been conducted in major geographic regions. However, it
does appear from scientific abstracts presented since September
2015 that studies are/have been carried out in some of these re-
gions identified. Geographical mapping approaches will facilitate
future exploration of the impact of climate, socioeconomic and
environmental factors on dry eye. There are limited studies of both
disease incidence and the natural history of treated and untreated
disease, both of which remain future needs for this field.
While modifiable and non-modifiable risk factors have been
summarized, the report has identified a need for appropriately
powered hypothesis driven studies, which address the major and
important risk factors and emerging factors such as associations
with other conditions, youth, screen use, air quality, climate change
and environmental factors. Overlap of dry eye with (or misdiag-
nosis of) other chronic ocular surface conditions including allergy
has confounded study of their contribution to, or as risk factors for,
dry eye. A better appreciation of the contribution of allergic or in-
flammatory disease to dry eye would advance this field.
The economic burden of DED is considerable, particularly
related to indirect costs such as those attributed to loss of pro-
ductivity and impact on QoL. Future studies should also consider
cost savings associated with treatment. The wide-ranging impact of
dry eye on QoL has been summarized and the limitations of many
existing instruments are recognized, particularly in sensitivity to
detect changes in symptoms. Future exploration of the impact of
dry eye on quality of life may be facilitated by real time
smartphone-based electronic data capture approaches.
Instruments used in epidemiological studies in disease ascer-
tainment or determination of severity were reviewed. Future
questionnaire design and development should focus on defining
normative data and ensuring sufficient sensitivity to detect clini-
cally significant changes in both the natural history of disease and
in response to treatment, and on determining recommendations
for patients for self-monitoring and in communicating with prac-
titioners. Improved public and practitioner awareness will result in
both eye and general health improvement.
Financial disclosures
F. Stapleton: Alcon Laboratories, Allergan, CooperVision, John-
son & Johnson Vision Care, Stiltec (F); Nidek (C);
M. Alves: Prior to date: Genom eUniao Química Brasil and Alcon
Brasil.
V.Y. Bunya: National Eye Institute (R01-EY026972), Research to
Prevent Blindness, Bausch & Lomb (F)
I. Jalbert: MD Foundation (F)
K. Lekhanont: None.
F. Malet: Laboratoires Thea (F)
K-S. Na: None.
D. Schaumberg: Mimetogen (I); Shire (SARcode)
M. Uchino: None.
J. Vehof: None.
E. Viso: None.
S. Vitale: None.
L. Jones: Advanced Vision Research, Alcon, Allergan, Contamac,
CooperVision, Essilor, Inflamax, Johnson & Johnson Vision Care,
Ocular Dynamics, Oculus, Safilens, TearLab, TearScience (F); Alcon,
CooperVision, Johnson & Johnson Vision Care (C) (R)
F (Financial Support, I (Personal Financial Interest), E (Employ-
ment), C (Consultant), P (Patent), R (Recipient), N (No Commercial
Relationship), S (non-remunerative)
Acknowledgments
Rebecca Petris for her participation in the subcommittee
meeting.
Appendix I. Questionnaires not yet validated
Canada Dry Eye Epidemiology Study (CANDEES)
CANDEES is a 13-item questionnaire. The assessment of fre-
quency and intensity of symptoms are combined, with patients
asked to rate each using the following categories: occasional and
mild, occasional and moderate, constant and mild, constant and
moderate, and severe. This questionnaire also evaluates medica-
tions, time of day, allergies, dry mouth, and itchy/swollen/red
eyelids [229].
Salisbury eye evaluation
The Salisbury eye evaluation is a standardized 6-item ques-
tionnaire that assesses the frequency of symptoms and 3 signs
(Answers: Rarely, Sometimes, Often, All of the time). This ques-
tionnaire has been used for a self-reported population-based
prevalence survey in the elderly for clinical and subjective evidence
of dry eye [230].
Melbourne visual impairment project
The questionnaire used in the Melbourne visual impairment
project assesses self-reported dry eye symptoms elicited by an
interviewer-administered questionnaire [52].
Bjerrum questionnaire
The Bjerrum questionnaire is a three-part questionnaire, which
includes an ocular part with fourteen questions. It has been used to
€gren syndrome dry eye, diagnosis of dry eye,
evaluate QoL due to Sjo
and the epidemiology of Sjo€gren syndrome [231].
Japanese dry eye awareness study
This questionnaire consists of thirty questions relating to
symptoms and knowledge of dry eye. It has been used for a
population-based, self-diagnosis study to assess public awareness
and symptoms of dry eye [232].
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jtos.2017.05.003.
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