Clinical Practice

PEDRAM HAMRAH, MD, EDITOR

New Perspectives on Dry Eye

Definition and Diagnosis: A Consensus
Report by the Asia Dry Eye Society
KAZUO TSUBOTA, MD, PHD, 1 NORIHIKO YOKOI, MD, PHD, 2 JUN SHIMAZAKI, MD, PHD, 3
HITOSHI WATANABE, MD, PHD, 4 MURAT DOGRU, MD, PHD, 1,3
MASAKAZU YAMADA, MD, PHD, 5 SHIGERU KINOSHITA, MD, PHD, 2
HYO-MYUNG KIM, MD, PHD, 6 HUNG-WON TCHAH, MD, PHD, 7
JOON YOUNG HYON, MD, PHD, 8 KYUNG-CHUL YOON, MD, PHD, 9
KYOUNG YUL SEO, MD, PHD, 10 XUGUANG SUN, MD, PHD, 11 WEI CHEN, MD, PHD, 12
LINGYI LIANG, MD, PHD, 13 MINGWU LI, MD, PHD, 14 AND
ZUGUO LIU, MD, PHD,15 FOUNDING MEMBERS OF THE
ASIA DRY EYE SOCIETY

ABSTRACT For the last 20 years, a great amount of evidence

Accepted for publication September 2016.
From the 1Keio University School of Medicine, Tokyo, 2Kyoto Prefectural
University of Medicine, Kyoto, 3Tokyo Dental College, Ichikawa, 4Kansai
Rosai Hospital, Amagasaki, 5Kyorin University School of Medicine, Tokyo,
Japan; 6Korea University Anam Hospital, 7Ulsan University Asan Medical
Center, 8Seoul National University, Seoul National University Bundang
Hospital, 9Chonnam National University Hospital, 10Yonsei University
Severance Hospital, Korea; 11Beijing Tongren Eye Center, Beijing Institute
of Ophthalmology, 12The Affiliated Eye Hospital of Wenzhou Medical Uni-
versity, 13Zhongshan Ophthalmic Center, Sun Yat-Sen University, 14Peking
University People’s Hospital, and 15Eye Institute of Xiamen University,
China.
The Asia Dry Eye Society is partially supported by Santen Pharmaceutical
Co., Ltd. Kazuo Tsubota reports grant support and honoraria from Santen
Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and holds the
patent for the functional visual acuity measurement system by Kowa Co.
Jun Shimazaki reports honoraria and consultancies to Santen Pharmaceu-
tical Co., Ltd. and Otsuka Pharmaceutical Co., Ltd. Murat Dogru reports
grant support from Santen Pharmaceutical Co., Ltd. and Otsuka Pharma-
ceutical Co., Ltd. Shigeru Kinoshita has grant support and honoraria
from Santen Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd.,
and Senju Pharamaceutical Co. Ltd. Zuguo Liu reports grant support
from Senju Pharmaceutical Co., Ltd., and, consultancies to Santen Pharma-
ceutical Co. Ltd. The other authors report no financial disclosure.
Single-copy reprint requests to Kazuo Tsubota, MD, PhD (address below).
Corresponding author: Kazuo Tsubota, MD, PhD, Department of Ophthal-
mology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-
ku, Tokyo 160-8582 Japan. Tel: þ81-3-3353-1211. Fax: þ81-3-3358-5961.
E-mail address: tsubota@z3.keio.jp
Ó 2016 The Author(s). Published by Elsevier Inc. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/). The Ocular Surface ISSN: 1542-0124. Tsubota K,
Yokoi N, Shimazaki J, Watanabe H, Dogru M, Yamada M, Kinoshita S,
Kim H-M, Tchah H-W, Hyon JY, Yoon K-C, Seo KY, Sun X, Chen W, Liang
L, Mingwu L, Liu Z,. New perspectives on dry eye definition and diag-
nosis: a consensus report by the Asia Dry Eye Society. 2017;15(1):65-76.
has accumulated through epidemiological studies that most of
the dry eye disease encountered in daily life, especially in video
display terminal (VDT) workers, involves short tear film
breakup time (TFBUT) type dry eye, a category characterized by
severe symptoms but minimal clinical signs other than short
TFBUT. An unstable tear film also affects the visual function,
possibly due to the increase of higher order aberrations. Based
on the change in the understanding of the types, symptoms,
and signs of dry eye disease, the Asia Dry Eye Society agreed to
the following definition of dry eye: “Dry eye is a multifactorial
disease characterized by unstable tear film causing a variety of
symptoms and/or visual impairment, potentially accompanied
by ocular surface damage.” The definition stresses instability of
the tear film as well as the importance of visual impairment,
highlighting an essential role for TFBUT assessment. This paper
discusses the concept of Tear Film Oriented Therapy (TFOT),
which evolved from the definition of dry eye, emphasizing the
importance of a stable tear film.
KEY WORDS consensus, definition of dry eye, diagnosis of
dry eye, dry eye, tear film breakup time, tear film oriented
therapy
I. INTRODUCTION
he concept of tear deficiency was first proposed in
T 1903 by Schirmer, who developed the famous
Schirmer test, a modified version of which is still
in clinical use.1 Keratoconjunctivitis sicca in Sjögren syn-
drome was proposed by Sjögren in 1933.2 For many years
afterward, dry eye was considered to be equivalent to kera-
toconjunctivitis sicca, the aqueous tear deficiency.

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 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al
OUTLINE
I. Introduction
II. Previously Published Definitions of Dry Eye Disease
III. Proposed New Definition of Dry Eye by The Asia Dry
Eye Society
A. Concepts Underlying New Definition
1. Introduction
2. Unstable Tear Film is the Central Feature of Dry
Eye
3. Visual Disturbances in Dry Eye
4. The Role of Inflammation in Dry Eye
B. Diagnosis of Dry Eye Disease According to the New
Definition
C. Treatment of Dry Eye Disease: Tear Film Oriented
Therapy
D. Short TFBUT-type Dry Eye
1. Characteristics
2. Possible Mechanism
IV. Future Directions
II. PREVIOUSLY PUBLISHED DEFINITIONS OF DRY EYE
DISEASE
Historically, dry eye disease (DED) was considered to be
due to either insufficient production or impaired stability of
tears. There is now evidence that any abnormality of the
ocular surface can trigger disequilibrium in all the other
components of tear dynamics. In 1995, the National Eye
Institute/Industry Workshop headed by Lemp concluded
that “Dry eye is a disorder of the tear film due to tear defi-
ciency or excessive evaporation, which causes damage to the
interpalpebral ocular surface and is associated with symp-
toms of ocular discomfort.”3 This was a very solid beginning
for establishing a consensus among dry eye researchers. Tear
deficiency was still the central concept in dry eye. In 1995,
the Japanese Dry Eye Society proposed their first definition
and diagnostic criteria.4 At that time, the Japanese definition
did not include the symptoms of DED because the ocular
surface in end-stage Stevens-Johnson syndrome patients
may be totally keratinized, resulting in absence of symp-
toms. However, such patients may still suffer from visual
disturbances, which are now considered to be among the
important symptoms of severe dry eyes. A new definition
and diagnostic criteria was proposed in 2006 as follows5:
“Dry eye is a chronic disease of tear fluid and keratoconjunctival
epithelium that results from various factors, and accompanies
ophthalmic discomfort and abnormal visual function. The diag-
nostic criteria are: 1) assessment of symptoms, 2) qualitative or
quantitative disturbance of the tear film (quantity: Schirmer I
test less than 5 mm/5 min; quality: BUT less than 5 sec), 3) ker-
atoconjunctival epithelial damage (staining score greater than 3
points). The presence of all criteria renders a diagnosis of defi-
nite dry eye and the presence of two out of the three criteria
renders a diagnosis of probable dry eye (Figure 1).”5
In 2007, a consensus on definition and diagnosis was
achieved at the first International Dry Eye WorkShop
66 THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com
(DEWS) sponsored by the Tear Film and Ocular Surface So-
ciety (TFOS), as follows6:
“Dry eye is a multifactorial disease of the tears and ocular sur-
face that results in symptoms of discomfort, visual disturbance,
and tear film instability with potential damage to the ocular sur-
face. It is accompanied by increased osmolarity of the tear film
and inflammation of the ocular surface.”6
The definition of DED in the DEWS report was similar
to the Japanese definition, but inflammation and osmolarity
were highlighted as potential risk factors for DED. The def-
initions clearly suggested that symptoms of dry eye should
be present for the diagnosis. The report proposed that if
there were no symptoms (including visual disturbances),
the condition could not be diagnosed as dry eye. However,
the report emphasized requirements of the presence of a
decreased tear volume and ocular surface damage by vital
staining for the definite diagnosis of dry eye. The report
also described the ocular surface and tear parameters to
consider when diagnosing dry eye severity, and these were
the basis for a proposed stepladder approach to treatment
(Table 1). On the other hand, short tear film breakup time
(TFBUT) with severe symptoms seems to comprise the ma-
jor type of dry eyes, so a new definition and diagnostic
criteria were needed.
In 2006, the Delphi panel proposed a new term, the
dysfunctional tear syndrome (DTS), and concluded that treat-
ment strategies should rely on symptoms and signs rather
than tests.7 The panel defined the clinical signs to be consid-
ered in assessing the severity of DTS upon which a severity-
based treatment algorithm was suggested (Figure 2).
The multinational ODISSEY European Consensus Group
aimed to establish a clear and practical algorithm for evalua-
tion and diagnosis of severe DED.8 The ODISSEY group,
comprised of 10 ophthalmologists who all contend with
ocular surface disease issues on a daily basis, was formed in
2012. The purpose of their meeting was to review clinical
and scientific challenges in diagnosis and management of se-
vere DED, and to achieve consensus agreement on a simplified
approach to evaluation of severe DED (Figure 3). A total of 14
criteria for DED severity, based on corneal fluorescein stain-
ing (CFS), tear hyperosmolarity, Schirmer test, impression
cytology, filamentary keratitis, conjunctival staining,
impaired visual function, meibomian gland disease or eyelid
inflammation, blepharospasm, TFBUT, aberrometry, in vivo
corneal confocal microscopy, inflammatory biomarkers (i.e.,
human leukocyte antigen-DR [HLA-DR], matrix metallopro-
teinase 9 [MMP9], cytokines, tear proteomics) and DED re-
fractory to standard disease treatments were discussed. The
specificity and sensitivity of these tools for diagnosing severe
DED were addressed.
The modern definitions of DED combine objective find-
ings, subjective symptoms, and mechanistic considerations,
among which hyperosmolarity and inflammation play a key
role. A second International Dry Eye Workshop commenced
in May 2015 and will generate a report by 2017, which will
revise the definition and diagnostic guidelines for DED.
 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al

Figure 1. 2006 Japanese Diagnostic Criteria for Dry Eye.

III. PROPOSED NEW DEFINITION OF DRY EYE BY THE
ASIA DRY EYE SOCIETY
A. Concepts Underlying New Definition
1. Introduction
The Asia Dry Eye Society (ADES) was first established in
2012 in Tokyo by representatives from three countries: China,
Korea, and Japan. ADES was registered as an official society in
Tokyo; its founding members are listed in the acknowledge-
ments at the end of this paper. The first scientific meeting
was held in autumn 2012, and the discussions addressed cur-
rent problems in the definition of and criteria for diagnosing
dry eye. Successive meetings were held in June and November

Table 1. The 2007 International Dry Eye Workshop Report: Dry Eye Severity Grading Scheme
Dry Eye Severity Level 1 2 3 4*
Discomfort, severity & Mild and/or episodic; Moderate episodic or Severe frequent or Severe and/or
frequency occurs under chronic, stress or no constant without stress disabling and constant
environmental stress stress
Visual symptoms None or episodic mild Annoying and/or Annoying, chronic and/ Constant and/or
fatigue activity-limiting or constant, limiting possibly disabling
episodic activity
Conjunctival injection None to mild None to mild þ/ þ/þþ
Conjunctival staining None to mild Variable Moderate to marked Marked
Corneal staining None to mild Variable Marked central Severe punctate
(severity/location) erosions
Corneal/tear signs None to mild Mild debris, Ymeniscus Filamentary keratitis, Filamentary keratitis,
mucus clumping, [tear mucus clumping, [tear
debris debris, ulceration
Lid/meibomian glands MGD variably present MGD variably present Frequent Trichiasis, keratiniza-
tion, symblepharon
TFBUT (sec) Variable 10 5 Immediate
Schirmer score (mm/5 Variable 10 5 2
min)
* Must have signs AND symptoms.
TBUT, fluorescein tear break-up time; MGD, meibomian gland disease.
Reprinted from The Ocular Surface 5(2), Dry Eye Workshop. The Definition and Classification of Dry Eye Disease: Report of the Definition and
Classification Subcommittee of the International Dry Eye Workshop (2007). p. 75-92, with permission from Elsevier.

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 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al

Figure 2. The Delphi Panel Clinical Sign Recommendations in Dysfunctional Tear Syndrome in Severity Assessment. Reproduced from Behrens A,
Doyle J, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006; 25(8):900-7, with permission from
Wolters Kluwer Health, Inc.

2013, followed by meetings in June, August, and November
2014. The final consensus meeting was held in Tokyo on
November 21, 2014, by the dry eye definition committee
members (Drs. Tsubota, Yokoi, Shimazaki, Watanabe, Kim,
Tchah, Hyon, Yoon, Seo, Sun, Chen, Liang, Li and Liu),
who agreed to the new definition as follows:
“Dry eye is a multifactorial disease characterized by unstable
tear film causing a variety of symptoms and/or visual impair-
ment, potentially accompanied by ocular surface damage.”
Recent findings in the field of epidemiology revealed that
the short TFBUT-type dry eye (unstable tear film) was more
prevalent than other types of dry eye.9 In the Osaka study,
Uchino et al conducted a dry eye survey among visual
display terminal (VDT) workers in Osaka, Japan, and re-
ported that the major type of dry eye was the short
TFBUT-type dry eye (Figure 4, revised from Table in
Uchino et al., 20139). Tong et al also reported that meibo-
mian gland dysfunction (MGD) resulted in tear instability
and DED.10 The percentage of dry eye patients with a
TFBUT <5 seconds was 94.6%, whereas 19.3% had a
Schirmer test value <5 mm in the Osaka study (Figure 4).
Figure 5 shows the distribution pattern of TFBUT and
Schirmer test values in the Osaka study,11 and these were
similar to those in Tong’s report.12
Relative to the previous definition, the new definition re-
tains the concept that dry eye is a multifactorial disease. The
most important agreement was that the condition was char-
acterized by an “unstable tear film.” It was agreed that the
unstable tear film is the pivotal mechanism of dry eye
causing symptoms and/or visual impairment. This concept
is consistent with the visual impairment in dry eye patients;
aberrations due to the unstable tear film comprise an inte-
gral feature of the deterioration of vision. This concept
also fits well with the corneal neuralgia hypothesis. The
most sensitive part of the ocular surface is the corneal
epithelium, and continuous stimulation by blink itself can
cause chronic pain in a neuralgia patient.13
Previously, vital staining of either the cornea or the con-
junctiva was considered to be critical; however, in this new
definition, ocular surface damage is not required for the def-
inite diagnosis of dry eye. In other words, just the combina-
tion of symptoms and an unstable tear film (short TFBUT)
is considered to be sufficient to make a definite diagnosis of
dry eye (Figure 6). This definition is simplistic and suggests
that since many individuals suffering from dry eye have the
short TFBUT-type dry eye, they should be treated not as dry
eye suspects but as patients with DED. This definition
clearly covers the short TFBUT-type dry eye, the major
type of dry eye, and emphasizes the importance of

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 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al

Figure 3. The ODISSEY Eu-

ropean Consensus-derived
scoring algorithm for severe
DED diagnosis. Reproduced
from Baudouin G, Aragona P,
Van Setten G, et al. Diag-
nosing the severity of dry
eye: a clear and practical al-
gorithm. Br J Ophthalmol
2014; 98:1168-76, with
permission from BMJ Pub-
lishing Group Ltd.

measuring tear film stability by TFBUT. However, if patients
have a stable tear film, even though the Schirmer test value is
5 mm, a definite diagnosis cannot be made under this defi-
nition The new definition assigns an essential role for
TFBUT assessment.
2. Unstable Tear Film is the Central Feature of Dry Eye
It is widely accepted that dry eye is a multifactorial
chronic disease. The relevant risk factors include inflamma-
tion, increased tear osmolarity, desiccated environment,
wind, meibomian gland dysfunction, aging, contact lenses,
refractive surgeries, conjunctivochalasis, blepharochalasis,
floppy eyelid syndrome, and others as stated in the interna-
tional DEWS report. Other important dynamic tear factors
include blink-associated problems such as incomplete blink,
decreased blink during VDT use, lagophthalmos, blepharo-
spasm, and nocturnal eye opening, which all finally affect
the tear film layer on the cornea. Various risk factors even-
tually affect one or more of the three layers of the tear film–
mucin, aqueous, and/or lipid layer– resulting in unstable
tear film, the central feature of dry eye (Figure 7). This
concept also provides a very simple approach for the

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 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al

> 5sec
5.4% (n=20)
≤ 5mm
Posi ve
19.3% (n=71)
24.2% (n=89)

≤ 5sec > 5mm Nega ve

94.6% (n=348) 80.7% (n=297) 75.8% (n=279)

Tear breakup me (BUT) Schirmer test value Ocular surface staining

Figure 4. Distribution of TFBUT, Schirmer test value, and ocular surface staining in dry eye patients in the Osaka study. Of 368 people who had a
diagnosis of dry eye syndrome, the number of subjects with abnormal TFBUT (94.6%) is more than that with abnormal Schirmer test value (19.3%) and
with ocular surface staining positive (24.2%). Data from Uchino M, et al, 2013.9

treatment of dry eye, in which the most important point of
action is to stabilize the precorneal tear film.
In the “Treatment” section of this paper, we will discuss
in detail the concept of tear film oriented therapy, which
evolved from the definition of dry eye and shows the impor-
tance of a stable tear film. This approach emphasizes the
importance of tear film as a target of the treatment.
3. Visual Disturbances in Dry Eye
It is well known that the very severe cases of dry eye,
such as in Stevens-Johnson syndrome, ocular cicatricial
pemphigoid, or advanced Sjögren syndrome, affect visual
function.14,15 However, dry eye without any corneal damage
was considered to be just a symptomatic disease not
affecting the visual function. The last 20 years of research
have revealed that dry eye with unstable tear film affects
the quality of vision in clinical measurements as well as in
daily life.12,15-23 The tear film is the first entry point of light,
and for the formation of sharp images, a smooth tear film
layer is mandatory. When the eye is opened after a blink,
diquafosol sodium eye drop, has been reported to stabilize
the tear film layer, which also can improve the functional vi-
sual acuity.25 Thus, treating visual deterioration by targeting
the unstable tear film is one of the important goals of treat-
ment of dry eye, in addition to improvement of
discomfort.26
4. The Role of Inflammation in Dry Eye
Inflammation is an important risk factor and/or a conse-
quence of dry eye.27 Desiccation stress has been shown to
induce Th1 type cytokines on the ocular surface, leading
to Th-17-associated corneal epithelial barrier disruption in
experimental mice studies.28,29 Severe types of dry eye, like
79.9% 0.8%
40
35
30
㎜)

the tear film is formed and the patient may see well momen-
Schirmer test value(㎜

25
tarily. This instant visual acuity can be maintainable even in
the dry eye patient with an unstable tear film. Normal visual 20
acuity measurement, however, cannot detect the visual
15
impairment of the dry eye patient, because it measures the
maximal visual acuity at the time of eye opening. In daily 10
life, patients keep their eyes open for a certain period of
5
time, during which the tear film layer becomes irregular 4.6%
and the visual acuity may not be maintained. Measurements 0
of functional visual acuity can detect such deteriorated vi- 0 2 4 6 8 10 12
14.7%
sual acuity over one minute (Figure 8). Since visual acuity BUT(sec)
is the most important parameter of visual function, it is Figure 5. Four subtypes of dry eye patients in the Osaka study. Top left
now believed that dry eye is a vision-affecting disease. quadrant: TFBUT5 sec, Schirmer test value >5 mm; bottom left
Treatment of dry eye by various methods is expected to quadrant: TFBUT5 sec, Schirmer test value 5 mm; bottom right
improve TFBUT and functional visual acuity. Kaido et al re- quadrant: TFBUT>5 sec, Schirmer test value 5 mm; top right quadrant:
ported that punctal occlusion stabilizes the tear film layer, TFBUT>5 sec, Schirmer test value >5 mm. The majority of dry eye
subtype (79.9%) is TFBUT5 sec, Schirmer test value >5 mm. Data from
extends the TFBUT, and improves the functional visual acu- Yokoi, et al, 2015.11
ity at the same time.24 A new mucin and water secretagogue,

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 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al
keratoconjunctivitis sicca, accompany inflammation. The
proinflammatory cytokines were increased in the tear fluid
from patients with severe type of dry eye, as in Sjögren syn-
drome and graft-versus-host disease.30 There is accumu-
lating evidence that inflammation is one of the key
components of dry eye, and the DEWS definition also
stresses the role of inflammation.
The ADES committee discussed whether or not inflam-
mation should be included in the definition of dry eye.
Various supportive comments were addressed, especially
by the Korean members, who noted that cyclosporine A is
available and the control of inflammation is considered to
be an important therapeutic strategy.31,32 However, it was
pointed out that inflammation may be one of the risk fac-
tors, not the central core mechanism related to the defini-
tion. Inflammation may affect all three tear film layers,
but in VDT users, dry eye is not due to inflammation but
develops due to the suppressed blink and increased evapora-
tion, resulting in a short TFBUT. In this type dry eye, the
inflammation will also present in some patients if their
tear film has not recovered quickly. The ADES consensus
group also discussed the role of tear osmolarity in DED.
Hyperosmolarity of the tear fluid was reported to be a suit-
able marker to assess DED.33-35 It has been reported that an
increase in tear evaporation and a decrease in tear produc-
tion induces an increase in tear osmolarity, but due to the
variations of the measurement, controversial reports exist
suggesting that this methodology is difficult for practical
clinical application.36 The ADES consensus group
concluded that further studies are necessary to investigate
the relationship of osmolarity to dry eye conditions. Thus,
tear osmolarity has not been emphasized in the definition
of dry eyes at this time.
B. Diagnosis of Dry Eye Disease According to the New
Definition
The consensus group discussed practical diagnosis of dry
eye according to the new definition. First of all, patients
should have symptoms of either discomfort or visual distur-
bance, which necessitates the evaluation of symptoms.
Applicability of a variety of methods, including direct or
validated questionnaires, was considered. The consensus
group concluded that relevant dry eye questionnaires out-
lined in the DEWS report, such as Ocular Surface Disease
Index (OSDI),37 McMonnies questionnaire,38 Women’s
THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com
Figure 6. Dry eye disease is
diagnosed by the combina-
tion of symptoms and un-
stable tear film.
Health Study Questionnaire,16 or the recently reported dry
eye-related QOL score (DEQS),39 are useful tools, but ques-
tionnaires assessing the visual impairment in daily life may
provide additional and helpful information in the context of
this new definition.
Since the unstable tear film is pivotal in the definition of
dry eye with this proposal, the measurement of TFBUT is
mandatory. TFBUT is measured using a fluorescein dye as
a standard method. To minimize the effect on the tear vol-
ume and TFBUT, a small quantity of the dye (less than
2 mL) should be administered with a pipette or wetted fluo-
rescein strip.40-42 After the dye is instilled, the subject is
instructed to blink three times to ensure adequate mixing
of the dye with the tears. The time interval between the
last blink and appearance of the first dark spot on the cornea
is measured by stopwatch. The mean value of the three mea-
surements should be used.
The consensus members adopted a cutoff value of less
than 5 seconds for the diagnosis of dry eye. Any tear TFBUT
value greater than or equal to 5 seconds cannot be consid-
ered as dry eye according to this proposal. Although it is
not mandatory to check the ocular surface damage and
tear production by the Schirmer test, they are important
for the diagnosis of aqueous deficiency type dry eye and
evaluation of the ocular damage, which may potentially
lead to epithelial defects and infection. In order to validate
Static risk factors
Abnormality of mucin, aqueous and/or oily layers
Unstable Tear Film
Dynamic risk factors
Conjunctivochalasis, incomplete blink,
decreased blink during VDT work,
blepharospasm, lagophthalmos, nocturnal eye
opening
Figure 7. Various risk factors affect precorneal tear film.
71
 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al

Figure 8. Comparison of functional visual acuity for non-dry eye and short TFBUT-type dry eye.

the cut-off value of 5 seconds, cross-sectional and longitudi-
nal studies on dry eyes are being planned.
C. Treatment of Dry Eye Disease: Tear Film Oriented
Therapy
According to the definition and diagnostic criteria, a
new concept of treatment strategy was developed by the Jap-
anese and the Asian Dry Eye Societies. Since the new defini-
tion proposes a very important role of a “normal precorneal
tear film” for a healthy ocular surface and an unstable tear
film is the key factor for the diagnosis of dry eye, attention
should be paid to tear film stability. This led to development
of a new strategy called “tear film oriented therapy” (TFOT
[Figure 9]).
As previously mentioned, the tear film consists of
three layers: lipid, aqueous, and mucin. When one of
the three layers becomes abnormal, the tear film layer
becomes unstable, possibly leading to the development
of dry eye. The TFOT concept is as follows: It is possible
to determine which tear layer is affected. For example, if a
patient has mucin deficiency, the mucin secretion should
be recovered first, and prescribing a mucin secretagogue
such as diquafosol sodium43 or rebamipide eye drops
would be appropriate. This concept is easy to understand.
If there is an abnormal layer, the layer should be targeted
for treatment. When the lipid layer is affected, such as in
MGD, then it may be appropriate to treat meibomian
glands, first by lid hygiene or warm compresses.44-47
The International Workshop report on the management
of MGD emphasized a severity-based treatment
algorithm that entails the use of lid warming and hygiene,
artificial tears, topical/systemic antibiotics, topical lipid
formulations, and intake of omega 3 fatty acid
supplements.48

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Figure 9. The concept of TFOT (Tear Film Oriented Therapy). *Diquafosol sodium may increase the function of the tear film lipid layer by promoting
spreading of the lipid layer through lipid and tear fluid secretion. **Rebamipide may suppress the inflammation of the ocular surface in dry eye by its
anti-inflammatory action. Figure provided by Dry Eye Society Japan.

When the aqueous layer is affected, as in a Sjögren syn-
drome patient, then strategies to increase of tear volume,
e.g., punctal occlusion49,50 or tear secretagoques,51 would
be used. Based on this concept, interesting associations
were detected. Once one layer deteriorates, there seems to
be a compensation mechanism to stabilize the tear film
layer. For example, when MGD occurs and the lipid layer
is affected, the aqueous production appears to increase to
compensate for the lack of lipid layer.52 This phenomenon
has not only been observed in the clinic52 but also in animal
models of MGD (Inaba et al, unpublished data).
In the context of TFOT strategy, the control of inflamma-
tion is also important, because it improves the three layers
altogether. Suppression of inflammation may increase the
mucin secretion and aqueous secretion and improve the
MGD. The corneal and conjunctival epithelium may cease
secreting transmembrane and secretory mucins when inflam-
mation persists.53,54 However, according to the concept of
TFOT, the control of inflammation is not the central strategy
of dry eye treatment; rather, producing a healthy stable tear
film is the primary treatment target. Although inflammation
is not a central concept of TFOT, anti-inflammatory drugs
are frequently used in the care of dry eye patients.
D. Short TFBUT-type Dry Eye
1. Characteristics
We have originally reported that short TFBUT-type dry
eye with minimally decreased tear production and minimal
vital staining may be associated with severe symptoms
(Figure 10 from Toda et al).55 Since patients with short
TFBUT-type dry eye have almost no vital staining and normal
tear production, it is difficult to understand why such dry eye
patients suffer from symptoms similar to those seen in the tear
deficient-type of dry eye with ocular surface damage.
Shimazaki-Den et al reported a subgroup of younger VDT-
user dry eye patients without MGD who had severe dry eye
symptomatology (compared to patients with aqueous defi-
cient dry eye) with short TFBUT and no interpalpebral stain-
ing.56 The authors suggested that severe symptomatology
might relate to the abundance of sensory corneal nerves in
the younger individuals. Differences in tear clearance may
also play a role in terms of symptomatology. For the last
20 years, a great amount of evidence has accumulated showing
that the short TFBUT-type dry eye is an important disease
category with severe symptoms, although the clinical signs
are minimal. Yokoi et al also recently reported that the short
TFBUT-type is associated with severe symptomatology in
VDT users.11 The emerging concept of functional visual acu-
ity, which measures the continuous visual acuity over one
minute, revealed that an unstable tear film affects the visual
function, possibly due to the increase of higher order aberra-
tions,57-59 which may be why the short TFBUT-type dry eye
patients often report visual related symptoms, such as ocular
fatigue.11,54,60
2. Possible Mechanism
In addition to increased higher order aberrations and
deteriorated functional visual acuity, there is another

THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com 73

 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al
Short BUT-type
Ocular fatigue Ocular fatigue
Foreign body
Heavy sensation
sensation
Discomfort Dryness
Dryness Discomfort
Pain Pain
Foreign body
sensation Heavy sensation
Brightness Brightness
Redness Discharge
Discharge Redness
Mean number of
complaints/patients = 4.5
Other Other
0 10 20 30 40 50 60 70 80
possible mechanism to explain the discrepancy between the
lack of severe signs but presence of severe symptoms. One
possibility is neuralgia, which has been proposed by Rosen-
thal13 and Battat et al.61 This hypothesis suggests that the
development of dry eye requires two factors, one being neu-
ralgia or corneal hypersensitivity, and the other being the
unstable tear film. A short TFBUT produces evaporative
decrease of corneal temperature,62,63 which is insignificant
for normal people, but causes pain in neuralgia patients. If
the tear film is stabilized and reaches a certain level of
threshold, then the pain system is suppressed. This hypoth-
esis was recently confirmed by Kaido et al, who found that
short TFBUT-type dry eye had corneal sensitivity and the
pain was higher in the short TFBUT than to the normal
controls.64 The neuropathic pain component is important
for the pathogenesis of dry eye, and this hypothesis should
be further studied.
Another possibility involves the effect of accommoda-
tion on symptoms in dry eye patients. In that regard, the
high frequency components of accommodation are related
to the severe symptoms in short TFBUT-type dry eye, sug-
gesting that an unstable tear film places a great burden on
the ciliary muscle to compensate for the optical aberrations
due to the unstable tear film with each blink (Kaido et al,
unpublished data).
Lemp et al proposed the concept of corneal desiccation
despite normal tear volume.65 They have shown that
Stevens-Johnson syndrome or ocular cicatricial pemphigoid
patients with severe ocular surface disease can develop an
unstable tear film due the lack of proper mucin secretion.
Since the mucin anchors the tear film on the ocular surface
epithelium, mucin deficiency is definitely the possible cause
of unstable tear film.66,67 In addition to very severe mucin
deficiency as seen in Stevens-Johnson or Sjögren syndrome,
MUC5AC mucin deficiency in VDT users has been reported
to be related to an unstable tear film and ocular symptoms.68
The original short TFBUT report by Toda et al also
74 THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com
Staining type
Figure 10. Symptoms of
short TFBUT-type and
staining-type dry eye. The
symptoms were comparable
for the two groups, suggest-
ing that patients with short
TFBUT-type dry eye suffer
greatly, despite the lack of
ocular surface damage.
Reprinted from Toda I, Shi-
Mean number of
complaints/patients = 5.6 mazaki J, Tsubota K
Ophthalmology 1995;102(2):
302-9, with permission from
0 10 20 30 40 50 60 70 80 Elsevier.55
suggested that the chronic inflammation in allergic conjunc-
tivitis might contribute to such decrease.55 Thus, a relative
mucin deficiency may be the cause of short TFBUT-type
dry eye. Deficiency of the lipid layer due to MGD may be
another reason for short TFBUT. In MGD, a compensa-
tional mechanism has been suggested to be activated to sta-
bilize the tear film by increasing the tear production.52
When the compensational mechanism fails, the tear film
stability is affected. Practically, combined disturbance of
the mucin and lipid layers may be the real reason for short
TFBUT-type dry eye, but further studies are necessary.
IV. FUTURE DIRECTIONS
In this report, the Asia Dry Eye Society has proposed a
new definition of dry eye. The concept is an extension from
the 1996 and 2007 definitions of dry eye, but it emphasizes
the importance of tear film and subjective complaints. Since
dry eye is a sociomedical disease and the fundamental mech-
anism of the disease is still unknown, we expect that our
proposal will be revised in the future. At the same time,
we need a global consensus about dry eye in addition to
the Asian agreement. In the near future, such an integrated
consensus meeting will be necessary to form a global agree-
ment. The classification of dry eye should also be considered
depending on the concept of TFOT. From the concept of
TFOT and our proposed definition, tear deficiency type of
dry eye is in an independent category. However, evaporative
DED may be categorized as oil deficient (MGD) variant.
Although mucin deficiency cannot be evaluated easily in
daily practice, the short TFBUT-type dry eye may be the
major type of mucin deficiency dry eye. Further diagnostic
methods in this direction need to be developed.
With regard to severity grading, the previous concept
attempted to coordinate the severity of ocular surface dam-
age and severe symptoms. However, as we have discussed in
this proposal, there is a discrepancy between severe symp-
toms and severe signs (ocular surface damage) in short
 CONSENSUS ON DRY EYE BY ASIA DRY EYE SOCIETY / Tsubota, et al
TFBUT-type dry eye. The unstable tear film affecting the vi-
sual function may explain the discrepancy between the signs
and symptoms from the point of corneal hypersensitivity or
accommodative stress. These directions should be studied
extensively in the near future. Since the understanding of
the fundamentals of dry eye is expanding, we hope we can
shed more light on the mechanisms of DED and develop
useful prevention and treatment strategies for our modern
societies.
ACKNOWLEDGMENTS
Founding members of Asia Dry Eye Society:
CHINA
Zuguo Liu, Xuguang Sun, Wei Chen, Yingping Deng, Jing Hong, Ying
Jie, Mingwu Li, Ying Li, Lingyi Liang, Hong Qi, Hua Wang, Xiaoming Yan,
Wenzhao Yang, Yufeng Ye, Jin Yuan, Hong Zhang, Hui Zhan, Mingchang
Zhang, Shaozhen Zhao.
KOREA
Hyo-Myung Kim, Hungwon Tchah, Chul Young Choi, Eui-Sang
Chung, Joon Young Hyon, Hyun-Seung Kim, Mee Kum Kim, Myoung-
Joon, Tae-Im Kim, Do-Hyung Lee, Hyung-Keun Lee, Kyoung Yul Seo,
Jong Suk Song, Kyung-Chul Yoon.
JAPAN
Kazuo Tsubota, Norihiko Yokoi, Shiro Amano, Reiko Arita, Murat
Dogru, Yuichi Hori, Tetsuya Kawakita, Motoko Kawashima, Shizuka
Koh, Kohji Nishida, Yoko Ogawa, Jun Shimazaki, Hitoshi Watanabe, Masa-
kazu Yamada, Masahiko Yamaguchi.
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