Mapping research trends of chronic ocular graft-versus-host disease from 2009 to 2020: a bibliometric analysis

Abstract

Purpose
To evaluate the global scientific output of research on ocular chronic Graft versus host disease (cGVHD) and explore the current status and trends in this field over the past decade by bibliometric analysis.

Methods
The bibliometric search was performed in the Web of Science Core Collection (WoSCC) database. VOSviewer v.1.6.16 was used to map the knowledge domain. The annual number of publications and citations, distribution of countries and organizations, productivity of authors and journals, international collaborations, cited references, and keywords in the field of ocular cGVHD were visualized.

Results
In total, 398 peer-reviewed publications from 2009 to 2020 on ocular cGVHD were retrieved. The United States among all countries had the highest number of publications and citations, and Keio University was the most effective institution. Dana, R ranks the highest regarding the number of publications and citations on ocular cGVHD. Cornea and Biology of Blood and Marrow Transplantation were the most-cited journals in ocular cGVHD studies from ophthalmology and hematology, respectively. The top-cited references were primarily centered on dry eye. The keywords constituted three clusters: (1) consensus criteria and epidemiology of ocular cGVHD, (2) preclinical medical research of ocular cGVHD, and (3) treatment.

Conclusion
Based on the data retrieved from WoSCC, a comparative analysis of the quantity and quality of papers on ocular cGVHD was conducted through bibliometric methods. This may contribute to better understanding of the status of ocular cGVHD study. The three major research topics shed new light on the ocular cGVHD study as well as meaningful materials for scholars to identify potential collaborators and promising partner institutions.

Full text

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https://doi.org/10.1007/s10792-022-02380-9
ORIGINAL PAPER
Mapping research trends ofchronic ocular graft‑versus‑host
disease from2009 to2020: abibliometric analysis
JiaweiXu· FangkunZhao· JianxiaFang·
MeipanShi· JunchaoPan· WenSun· ChixinDu
Received: 13 August 2021 / Accepted: 14 June 2022
© The Author(s), under exclusive licence to Springer Nature B.V. 2022
R ranks the highest regarding the number of publi-
cations and citations on ocular cGVHD. Cornea and
Biology of Blood and Marrow Transplantation were
the most-cited journals in ocular cGVHD studies
from ophthalmology and hematology, respectively.
The top-cited references were primarily centered on
dry eye. The keywords constituted three clusters:
(1) consensus criteria and epidemiology of ocular
cGVHD, (2) preclinical medical research of ocular
cGVHD, and (3) treatment.
Conclusion Based on the data retrieved from
WoSCC, a comparative analysis of the quantity and
quality of papers on ocular cGVHD was conducted
through bibliometric methods. This may contribute to
better understanding of the status of ocular cGVHD
study. The three major research topics shed new light
on the ocular cGVHD study as well as meaningful
materials for scholars to identify potential collabora-
tors and promising partner institutions.
Keywords Ocular chronic graft versus host
disease· Bibliometric analysis· Mapping knowledge
domain· VOSviewer· Hematopoietic stem cell
transplantation
Introduction
Graft versus host disease (GVHD) is a severe com-
plication that develops after hematopoietic stem cell
transplantation (HSCT), despite the advances in
Abstract
Purpose To evaluate the global scientific output of
research on ocular chronic Graft versus host disease
(cGVHD) and explore the current status and trends
in this field over the past decade by bibliometric
analysis.
Methods The bibliometric search was performed in
the Web of Science Core Collection (WoSCC) data-
base. VOSviewer v.1.6.16 was used to map the knowl-
edge domain. The annual number of publications and
citations, distribution of countries and organizations,
productivity of authors and journals, international
collaborations, cited references, and keywords in the
field of ocular cGVHD were visualized.
Results In total, 398 peer-reviewed publications
from 2009 to 2020 on ocular cGVHD were retrieved.
The United States among all countries had the high-
est number of publications and citations, and Keio
University was the most effective institution. Dana,
Jiawei Xu and Fangkun Zhao have contributed equally to
this work and share first authorship.
J.Xu· J.Fang· M.Shi· J.Pan· W.Sun· C.Du(*)
Department ofOphthalmology, The First Affiliated
Hospital, College ofMedicine, Zhejiang University, 79
Qingchun Road, Hangzhou310003, China
e-mail: duchixin@zju.edu.cn
F.Zhao
Department ofOphthalmology, The Fourth Affiliated
Hospital ofChina Medical University, Eye Hospital
ofChina Medical University, Shenyang, Liaoning, China

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human leukocyte antigen matching [1]. The disease
is considered to be acute or chronic depending on
the timing of transplantation [2]. There have been a
great deal of publications on ocular chronic GVHD
(cGVHD) since the past years (2009–2020). Our
study utilized bibliometric techniques and mapping
knowledge domain techniques to make a thorough
inquiry of the current studies on ocular cGVHD.
Bibliometrics is a cross-disciplinary science of
quantitative analysis using mathematical and statisti-
cal methods. It is advantageously employed to iden-
tify the development, hotspots, and research frontiers
in a certain field. The mapping knowledge domain
methods are beneficial for all knowledge carriers in
order to minimize the literature and guide them in the
core field of scientific research. Moreover, co-citation
analysis of references and co-occurrence analysis of
all keywords are applied to map and build the knowl-
edge domain.
In this study, we assessed the rising tendency in
publication and citation, distribution of countries
and organizations, productivity of authors and jour-
nals on ocular cGVHD research. Scholars may ben-
efit greatly from comprehending research trends in an
academic area by analyzing publications, citations,
collaborations, co-citations, and keyword occurrence
frequency. Therefore, our study aims to adopt the
bibliometric technology to comprehensively evaluate
the development status and trends of ocular cGVHD,
so as to improve early diagnosis and detection of
cGVHD by highlighting key areas of strength and
deficiency.
Materials andmethods
Data source
The data on the literature were retrieved online from
the Science Citation Index Expanded database in the
Web of Science Core Collection (WoSCC). We took
“graft versus host disease,” “Homologous Wasting
Disease,” “ophthalmology,” “eye” and “ocular” as
topical retrieval, the document type was “all docu-
ment types.” To restrict the results, we defined the
language as “English,” the duration was “from 2009
to 2020.” In total, 398 documents met the selec-
tion criteria. We exported the data with “full record
and cited references” as “plain text.” The retrieved
findings were saved in the form of the following basic
content: country, institution, author, journal, refer-
ence, and keywords.
Analytical method
Science mapping is not only an essential procedure
of bibliometrics, but also a spatial representation of
the relationship between disciplines, fields, and docu-
ments or authors [3]. Visualization software helps
realize the visualization of the research distribu-
tions, hot topics, frontier, and international collabo-
rations by generating node-link maps. In this study,
VOSviewer v.1.6.16 (http:// www. vosvi ewer. com)
was utilized to analyze the data and map the knowl-
edge systematically. Eck and Waltman [4] developed
the literature visualization software, which is power-
ful for analyzing co-occurrence and co-citation. One
of the main advantages of VOSviewer is that it can
present the results of cluster analysis. Nodes and
links represent the analysis components in the results,
whose sizes are proportional to the weight of the
items. The thickness and distance of lines between
two nodes are proportional to the strength of the rela-
tionship between the analysis components.
Results
The annual trends of publications and citations
Based on the bibliometric retrieval results, a total
of 398 papers on ocular cGVHD were collected by
WoSCC between 2009 and 2020. The number of
publications has increased progressively in the past
12 years, from 11 to 45 papers (Fig. 1a). The ocu-
lar cGVHD-related research obtained a very slow
increase until 2015. The reason for the rapid growth
is mainly the establishment of the 2014 NIH cGVHD
Diagnosis and Staging Consensus Criteria [1], which
can also explain the increasing number of citations in
this field (Fig.1b).
The country analysis
Based on the retrieved results, 38 countries contrib-
uted to 398 publications in the ocular cGVHD field.
The top 5 countries are presented in Table 1. The
United States had the greatest number of publications

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and citations in this field (198 documents and 3,021
citations), followed by Japan (48 documents and
1,213 citations) and Germany (30 documents and
1,006 citations).
Besides, the remaining 33 countries (documents,
citations) are Brazil (19, 943), South Korea (18, 255),
Canada (17, 912), China (22, 165), Switzerland (10,
120), Turkey (10, 103), Austria (8, 948), Netherlands
(7, 249), England (7, 164), Poland (6, 33), India (6,
30), Croatia (6, 16), Saudi Arabia (5, 87), Iran (4,
45), Mexico (4, 19), Australia (3, 649), Israel (3, 26),
Thailand (3, 18), Czech Republic (3, 16), Norway (3,
13), Sweden (3, 11), Denmark (3, 0), Scotland (2, 36),
Finland (2, 22), Chile (1, 56), France (1, 33), Philip-
pines (1, 7), Belgium (1, 5), Egypt (1, 2), Portugal(1,
1), Cyprus(1, 0), Russia(1, 0), and Singapore (1, 0).
The influential countries and the degree of com-
munication in countries can be evaluated by country
co-authorship analysis. The weight attribute in the
visualization as “citations” presents the number of
citations in these countries. As shown in Fig. 2, the
United States not only have the highest number of
publications and citations in the ocular cGVHD field
but also cooperate intensively with other countries,
such as Japan, Spain, China, and Brazil.
The organization analysis
Based on the retrieved results, 398 papers were pro-
duced by 494 organizations (Table2). The knowledge
domain map of research organizations in the ocular
cGVHD study is displayed in Fig.3 after co-author-
ship analysis. The weight attribute in the visualization
as “documents,” presented the number of publications
in these organizations. Keio University (Japan) has
the greatest research production, but the Fred Hutch-
inson Cancer Research Center (USA) is the most
influential organization in view of highest number of
citations.
The author analysis
Based on the retrieved results, more than 1,770
authors contributed to the ocular cGVHD study.
Dana, R (29 publications) among all authors has the
highest number of productions, followed by Ogawa,
Y (27 publications), and Tsubota, K (26 publica-
tions). Besides their productive contributions, the
citation analysis of authors indicating their relative
influence was also conducted (Table3). Dana, R (451
citations) ranked first in ocular cGVHD research, fol-
lowed by Ogawa, Y (320 citations) and Tsubota, K
(319 citations). Moreover, these three scholars owned
the largest number of citations. Thus, they were con-
sidered experts in the field of ocular cGVHD.
Co-authorship research can assess the level of
research collaboration and the research status of a
specific field [5]. Co-authorship analysis was per-
formed using the mapping knowledge domain
methods to display authors’ distribution in ocular
cGVHD research (Fig.4). The weight attribute in the
Fig. 1 The annual number of publications (a) and citations (b)
in ocular cGVHD research from 2009 to 2020, respectively
Table 1 The documents and citations from top 5 countries in
the world in ocular graft versus host disease study, 2009–2020
Rank Country Documents Country Citations
1USA 198 USA 3021
2 Japan 48 Japan 1213
3 Germany 30 Germany 1006
4 Italy 26 Austria 948
5 Spain 24 Brazil 943

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visualization as “documents,” presented the number
of publications by these authors.
The journals analysis
Based on the retrieved results, papers on the ocular
cGVHD study were spread over in 124 journals. The
Fig. 2 Distribution of
main research countries in
ocular cGVHD study. The
minimum number of docu-
ments of a country was set
as five. Of the 39 coun-
tries that were involved in
ocular cGVHD research, 19
countries met the threshold,
but 2 countries unconnected
with each other are not pre-
sented in the picture. (The
VOSviewer took China
as Peoples R China and
Taiwan mistakenly)
Table 2 The documents
and citations from top 10
organizations in the world
in ocular graft versus host
disease study, 2009–2020
Rank Organization Documents Organization Citation
1 Keio University 30 Fred Hutchinson Cancer
Research Center
1197
2 Harvard Medical School 27 Vanderbilt University 1107
3 Fred Hutchinson Cancer
Research Center
22 Dana Farber Cancer Institute 1062
4 Harvard University 15 University of Minnesota 963
5 National Cancer Institute 14 Stanford University 961
6 University of Washington 14 University of Michigan 929
7 Dana Farber Cancer Institute 11 National Cancer Center 794
8 University of Illinois 11 National Cancer Institute 430
9 University of Miami 11 Harvard University 420
10 University of Michigan 11 Keio University 360
Fig. 3 Collaboration
network of main research
organizations in ocular
cGVHD study. The mini-
mum number of documents
of an organization was set
as 5. Of the 494 organiza-
tions that were involved in
ocular cGVHD research,
37 organizations met the
threshold, but 3 organiza-
tions unconnected with
others are not presented in
the picture

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top 10 journals with the highest number of publica-
tions and citations on ocular cGVHD are listed in
Table 4. Investigative Ophthalmology and Visual
Science published the highest number of papers (73,
18.3%), followed by BBMT (36, 9.0%) and Cornea
(30, 7.5%). Over a third of the papers (34.9%) in this
study were published in these three journals. Com-
pared to the field of hematology (51), numbers of
publications in the field of ophthalmology (155) are
more in the top 10 main source journals, and Cornea
remains the most-cited journal for ocular cGVHD
studies. However, the number of citations of BBMT is
twice as high as that of Cornea. These results indicate
that further research on ocular cGVHD in the field of
ophthalmology is needed in the future (Table5).
The cited references analysis: a knowledge base of
ocular cGVHD study
The intellectual base of ocular cGVHD research can
be availably built by co-citation analysis of cited ref-
erences. The minimum number of citations of a cited
reference was set to 20. Of the 8511 cited references,
42 cited references satisfied the condition. The top
nine co-cited references in the three clusters are listed
in Table6. The weight attribute of the analysis in the
visualization as “citations,” influenced these papers
Table 3 The documents and citations from top 10 productive
authors and influential authors in the world in ocular graft ver-
sus host disease study, 2009–2020
Rank Author Document Cited author Citation
1 Dana, R 29 Dana, R 451
2 Ogawa, Y 27 Ogawa, Y 320
3 Tsubota, K 26 Tsubota, K 319
4 Mukai, S 15 Shikari, H 204
5 Perez, V 15 Riemens, A 184
6 Jain, S 11 Rothova, A 152
7 Kawakami, Y 11 Hamrah, P 134
8 Kheirkhah, A 10 Kheirkhah, A 130
9 Yamane, M 10 Jain, S 115
10 Amparo, F 9 Kawakita, T 114
Fig. 4 Co-authorship network of productive authors in ocu-
lar cGVHD study. The minimum number of documents of an
author was set as 5. Of the 1770 authors that were involved in
ocular cGVHD research, 69 authors met the threshold, but 29
authors unconnected with others are not presented in the pic-
ture

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(Fig.5). Moreover, the journal, keywords, key points
of the references, the first authors and their country
and organization were also listed.
The keywords analysis: hot topics of ocular cGVHD
study
The research hot topics of the ocular cGVHD study
were identified through co-occurrence analysis of
high-frequency keywords. The minimum number
of co-occurrences of a keyword was set to 5. Of the
screened 1394 keywords referring to ocular cGVHD,
113 keywords satisfied the condition, but two key-
words unconnected with others are not presented in
the picture (Fig. 6). Based on the network, the 111
keywords were divided into three groups, where simi-
lar keywords are clustered and marked as red, green,
and blue, respectively. The top 15 keywords in the
three clusters are listed in Table7.
Discussion
Global trends on ocular cGVHD research
The quantitative fluctuation in academic publications
can indicate the development trends in the field of
ocular cGVHD. In total, 398 papers were selected in
these 12years (2009–2020), and the publications on
the ocular cGVHD study fluctuated by asmallampli-
tude during the initial periods (2009–2014). Since
then, there has been a rapid increase in the number
of publications. The main reason for this growth spurt
is that the National Institutes of Health (NIH) revised
Table 4 The main source of journals with the number of papers and citations in ocular graft versus host disease study, 2009–2020
Rank Journal Count Journal Citation
1 Investigative Ophthalmology & Visual Science 73 Biology of Blood and Marrow Transplantation 1047
2 Biology of Blood and Marrow Transplantation 36 Cornea 586
3 Cornea 30 Ophthalmology 256
4 Ocular Surface 21 Investigative Ophthalmology & Visual Science 181
5 Bone Marrow Transplantation 15 Ocular Surface 152
6 Plos One 11 Bone Marrow Transplantation 150
7 American Journal of Ophthalmology 9 Blood 147
8 Eye & Contact Lens-Science and Clinical Practice 9 Molecular Vision 133
9 Graefes Archive for Clinical and Experimental
Ophthalmology
7 Plos One 128
10 Ophthalmology 6 Scientific Reports 117
Table 5 The main source
of countries with papers in
various journals in ocular
graft versus host disease
study, 2009–2020
Country Journal
England Bone Marrow Transplantation
Scientific Reports
Germany Graefes Archive for Clinical and Experimental Ophthalmology
Netherlands Biology of Blood and Marrow Transplantation
United States American Journal of Ophthalmology
Cornea
Eye and Contact Lens-Science and Clinical Practice
Investigative Ophthalmology and Visual Science
Molecular Vision
Ophthalmology
Ocular Surface
Plos One

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Table 6 The top 3 co-cited references in the 3 clusters in ocular graft versus host disease study, 2009–2020
Cluster Rank Title Country Organization First author Journal Keywords Citation Key points
1 (red) 1 National Institutes
of Health consen-
sus development
project on criteria
for clinical trials
in chronic graft-
versus-host disease:
I. Diagnosis and
staging working
group report
USA University of Cincin-
nati
Filipovich, AH Biology of Blood and
Marrow Transplan-
tation
Chronic graft-
versus-host
disease; Allogeneic
hematopoietic cell
transplantation;
Consensus; Diagno-
sis; Staging
116 This consensus docu-
ment was intended
to standardize the
criteria for diagnosis
of chronic GVHD,
and to propose a
new clinical scoring
system and new
guidelines for global
assessment of chronic
GVHD severity
2 Dry eye after hemat-
opoietic stem cell
transplantation
Japan Keio University Ogawa, Y British Journal of
Ophthalmology
70 Dry eye after HSCT
occurred only in
allograft recipi-
ents, and was not
evident in autograft
recipients. The severe
form of dry eye had a
tendency to develop
rapidly
3 Ocular Graft-versus-
Host Disease: A
Review
USA Massachusetts Eye
and Ear Infirmary
Shikari, H Survey of Ophthal-
mology
allogeneic bone mar-
row transplantation;
hematopoietic stem
cells; graft-versus-
host disease ocular
GVHD; ocular
surface disease; dry
eye disease
67 The etiology, patho-
physiology, clinical
manifestations, and
treatment of acute
and chronic systemic
GVHD are reviewed,
with a focus on ocu-
lar GVHD
2 (green) 1 Dry eye as a major
complication asso-
ciated with chronic
graft-versus-host
disease after hemat-
opoietic stem cell
transplantation
Japan Keio University Ogawa, Y Cornea bone marrow trans-
plantation; dry eye;
fibroblast and T-cell
interaction; graft-
versus-host disease;
hematopoietic stem
cell transplantation
59 Periductal fibroblasts
are involved in fibro-
genic and immune
processes by interact-
ing with T cells in
the lacrimal gland of
patients with chronic
GVHD, resulting in
rapidly progressive
dry eye

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Table 6 (continued)
Cluster Rank Title Country Organization First author Journal Keywords Citation Key points
2 Graft-versus-host
disease
USA University of Michi-
gan
Ferrara, JLM Lencet 57 Review the risk factors
and causes of GHVD,
the cellular and
cytokine networks
implicated in its
pathophysiology, and
current strategies to
prevent and treat the
disease
3 Ocular Graft-Versus-
Host Disease After
Allogeneic Stem
Cell Transplanta-
tion
Netherlands University Medical
Center Utrecht
Westeneng, AC Cornea ocular graft-versus-
host disease;
allogeneic stem cell
transplantation
46 Ocular GvHD devel-
oped in 54% of
patients and consisted
mainly of dry eyes
and conjunctivitis,
which increased
in severity during
follow-up; blepharitis
and uveitis were less
often encountered
3 (blue) 1 A significant role of
stromal fibroblasts
in rapidly pro-
gressive dry eye
in patients with
chronic GVHD
Japan Keio University Ogawa, Y Investigative
Ophthalmology &
Visual Science
40 Fibrosis of the glandu-
lar interstitium and an
increase in the num-
ber of CD34 + stro-
mal fibroblasts in the
periductal areas of
the lacrimal gland
from patients with
chronic GVHD. And
multilayered and
thickened basal lami-
nae of blood vessels,
ducts, and lobules in
the lacrimal gland of
patients

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Table 6 (continued)
Cluster Rank Title Country Organization First author Journal Keywords Citation Key points
2 Autologous serum
eye drops for the
treatment of severe
dry eye in patients
with chronic graft-
versus-host disease
Japan Keio University Ogawa, Y Bone Marrow Trans-
plantation
hematopoietic stem
cell transplanta-
tion; dry eye;
autologous serum
eye drops; punctal
plug; chronic graft-
versus-host disease
(cGVHD)
39 Autologous serum eye
drops are safe and
effective for treating
severe dry eye associ-
ated with cGVHD
and that more effi-
cient control of dry
eye may be achieved
by the combined use
of autologous serum
eye drops with punc-
tal plugs
3 Topical corticosteroid
therapy for cicatri-
cial conjunctivitis
associated with
chronic graft-ver-
sus-host disease
USA National Eye Institute Robinson, MR Bone Marrow Trans-
plantation
conjunctiva; corticos-
teroid therapy; stem
cell; transplantation;
graft-versus-host
disease
32 The high ocular drug
concentrations that
can be achieved with
topical corticos-
teroids compared
with systemic
administration can
promote lymphocyte
apoptosis and sup-
press cell-mediated
inflammation. The
pathogenesis of
cicatricial conjuncti-
vitis associated with
GVHD may represent
a response to tissue
injury associated with
conjunctival slough-
ing and ulceration

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the diagnostic criteria of ocular cGVHD in 2014, and
removed the Schirmer’s test values from the scoring
form in the current recommendations [1].
As shown in Table 1, the most productive and
influential countries were the United States, followed
by Japan. On analyzing the distribution of research
organizations (Table2), Keio University (Japan) pre-
sents the highest number of publications (30), while
the FredHutchinsonCancer Research Center (USA)
presents the highest number of citations (1197). These
results demonstrate that the United States and Japan
are the most international academic centers on ocular
cGVHD research. Cooperation within the groups was
also identified (Figs.2 and 3), which can reflect the
degree of communication in this field. The thick and
adjacent lines between the USA and Japan or their
organizations show that they have set upclose aca-
demic cooperationandfrequent personnel exchanges
Fig. 5 Co-citation network
of cited references in ocular
cGVHD study. The mini-
mum number of citations
of a cited reference was set
as 20
Fig. 6 Co-occurrence
network of keywords in
ocular cGVHD study. The
minimum number of occur-
rences of a keyword was set
as 5. Of the 1394 keywords
that were involved in ocular
cGVHD research, 113
keywords met the threshold,
but 2 keywords uncon-
nected with each other are
not presented in the picture

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in the field of ocular cGVHD. This indicates that they
are central to the entire study network. Moreover,
researchers can obtain possible cooperation oppor-
tunities through a co-authorship network knowledge
map. There are two author clusters, one cluster (red-
colored) centered at Prof. Ogawa, Y (University of
Maryland Baltimore, USA), and the other cluster
(green-colored) centered at Prof. Dana, R (Harvard
Medical School, USA).
The core journals were determined by the distribu-
tion analysis of academic journals in a certain field.
For this purpose, Investigative Ophthalmology &
Visual Science (73, 18.3%) and BBMT (36, 9%) are
the most prolific journals on ocular cGVHD in the
field of ophthalmology and hematology, respectively.
Regarding academic influence, BBMT (1047, 19.2%)
and Cornea (586, 10.8%) presented the highest num-
ber of citations in the field of hematology and oph-
thalmology, respectively. This indicates that much
more in-depth studies on ocular cGVHD studies
have been focusing on hematology in these 12years.
Therefore, strengthening the cooperation between
ophthalmology and hematology is conducive to
broadening the research prospects of cGVHD in the
field of ophthalmology.
Intellectual base
The co-citation relationship between the two papers
is established when they appear simultaneously in
another paper’s citations [6]. A large number of cited
references can demonstrate the academic setting of a
specific domain through co-citation analysis, which
chooses representative literature as the analysis
object, and then divides them into several clusters by
the network analysis method. Therefore, cluster anal-
ysis was conducted to explore the main topics in the
ocular cGVHD study. It was shown that the top nine
cited references in three clusters mainly presented
dry eyesymptoms in patients with cGVHD (Table6).
Cluster # 1 (red) represents the progression and diag-
nosis of ocular cGVHD, cluster # 2 (green) represents
pathological studies in ocular cGVHD, and cluster #
3 (blue) represents the treatmentof the disease.
As shown in Fig.5, the paper represented by the
largest red-colored node belonging to cluster #1 was
published by Filipovich, AH (2,005). His paper titled
‘‘National Institutes of Health consensus develop-
ment project on criteria for clinical trials in chronic
graft-versus-host disease: I. Diagnosis and staging
working group report’’ ranks first in frequency cita-
tion weight, which is considered central to the whole
knowledge map. It standardized the criteria for the
diagnosis of cGVHD, proposed a new clinical scoring
system (0–3), and guidelines for global assessment of
cGVHD severity [2]. The other paper in cluster #1,
titled “Dry eye after hematopoietic stem cell trans-
plantation” determined the occurrence and progres-
sion of dry eye after hematopoietic stem cell trans-
plantation through a prospective survey.
Table 7 The analysis of top
15 keywords co-occurrence
in the 3 clusters in ocular
graft versus host disease
study, 2009–2020
Cluster1 Cluster2 Cluster3
Dry eye 86 Dry eye disease 32 Graft-versus-host Disease 53
Bone-marrow-transplantation 78 Expression 19 keratoconjunctivitis sicca 27
Stem-cell transplantation 75 Inflammation 16 Management 27
Versus-host-disease 60 Corneal 13 Ocular surface 27
Diagnosis 55 Lacrimal gland 13 Transplantation 24
Consensus development project 52 Dry eye patients 10 Severe dry eye 21
Clinical-trials 46 Tears 9 Therapy 19
Criteria 41 Conjunctiva 8 Ocular surface disease 16
Risk-factors 30 Regulatory t-cells 8 Autologous serum 15
Quality-of-life 21 Dendritic cells 7 Dry eye syndrome 12
Manifestations 18 In-vitro 7 Efficacy 12
Severity 13 Meibography 7 Sjogrens-syndrome 11
Prevalence 11 Biomarkers 6 Safety 8
complications 10 Cytokines 6 Eyedrops 7
Total-body irradiation 10 Cytokine 5 Trial 7

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The paper represented by the largest green-colored
node belonging to cluster #2 was published by Ogawa,
Y (2003). His paper “Dry Eye as a Major Complica-
tion Associated with Chronic Graft-Versus-Host Dis-
ease after Hematopoietic Stem Cell Transplantation”
reported that stromal fibroblasts had a critical func-
tion in the pathogenic processes of cGVHD-related
dry eye [7]. Publication titled “Graft-versus-Host
Disease” mainly reviewed the advances made in the
pathophysiology of this major HCT complication [8].
The papers represented by the largest blue-
colored node belonging to cluster #3 were published
by Ogawa. His paper “Autologous serum eye drops
for the treatment of severe dry eye in patients with
chronic graft-versus-host disease” concluded that
autologous serum eye drops were safe and effective
for treating severe cGVHD-related dry eye [9]. The
paper titled “Topical corticosteroid therapy for cica-
tricial conjunctivitis associated with chronic graft-
versus-host disease” identified the positive effect of
topical ocular corticosteroids for treating cicatricial
conjunctivitis associated with cGVHD (2004) [10].
As scientists look deeper into molecular or basic
research, the study of topicalmedicaltherapy will be
in astronguptrend.
Research frontiers
The co-occurrence of keywords can reflect the
research hot topics and frontiers effectively in a spe-
cific field, which provides additional information
for researchers [11]. A total of 1381 keywords were
obtained from 398 ocular cGVHD-related papers.
Among them, 603 (43.7%) keywords appeared only
once, indicating that the knowledge boundary of vis-
ual cGVHD is worth further expanding on. The top-
ics of ocular cGVHD are mainly divided into three
clusters, where similar keywords in research topics
are classified together (Fig.6). The size of the node
and vocabulary fonts is proportional to the weight. A
shorter distance between two nodes generally reveals
a stronger relation [12]. The thicker the line, the more
frequent the co-occurrence. Combined with the fea-
tures and status of the ocular cGVHD study, the three
clusters were analyzed as follows:
Cluster # 1 (red) represented primary keywords
for the consensus criteria and epidemiology of ocu-
lar cGVHD, including prevalence, diagnosis, risk
factors, manifestations, and quality of life. They
matched the content of papers in cluster #1 in co-
citation analysis, which emphasized the diagnosis and
prognosis of ocular cGVHD before 2009. The key-
word “dry eye” has the highest frequency (86), fol-
lowed by “bone-marrow-transplantation” (78), and
“stem-cell transplantation” (75). The top three high-
frequency keywords in cluster # 1 outdistanced every
keyword in the other two clusters. Thus, the keywords
in cluster # 1 are expected to be the core theme in
the entire research field. It is common for cGVHD
patients to develop ocular symptoms, which accounts
for over 50% [13]. The diagnostic criteria for ocular
cGVHD include new ocular sicca documented by
a low Schirmer’s test with a mean value of 5mm at
5 min or new onset of keratoconjunctivitis sicca by
slit-lamp examination with mean Schirmer’s test val-
ues of 6–10mm [1]. Evaluation by an ophthalmolo-
gist, especially baseline evaluation post-transplant
(approximately day 100), is recommended for eye-
specific clinical trials [14]. The Schirmer’s test, which
is useful for diagnosis, was removed from the severity
scoring form in the 2014 NIH consensus [1]. Due to
poor correlation with symptom change, the numerical
values of Schirmer’s test are not useful for follow-up
of ocular GVHD. The risk factors related to ocular
cGVHD differ according to the time of onset of ocu-
lar cGVHD concerning the development of systemic
cGVHD [13]. Sun etal. [13] clarified that female sex,
more severe acute cGVHD, and higher dosages of
prednisone were independent risk factors for ocular
cGVHD in the early stage of the disease. Recently,
Wang et al. [15] found that patients with systemic
cGVHD who exhibited lung and gastrointestinal
tract involvement were more likely to develop severe
ocular cGVHD. The most frequent ocular symptoms
include a sensation of dryness, irritation, redness,
and photophobia. Patients with moderate or severe
cGVHD reported worse quality of life, lower perfor-
mance status, and a higher symptom burden com-
pared to those with resolved cGVHD [16]. Moreover,
vision-related quality of life is strongly associated
with symptoms of ocular dryness and is modestly
associated with the degree of corneal epitheliopathy
[17].
Cluster # 2 (green) represented primary key-
words for the preclinical medical research of
ocular cGVHD, including expression, inflam-
mation, conjunctiva, dendritic cells, and others.
They match the content of papers in cluster # 2 in

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co-citation analysis, which emphasized on patho-
logical research in ocular cGVHD before 2009.
Epithelial-mesenchymal transition is partially
responsible for conjunctival and lacrimal gland
fibrosis in patients with cGVHD [18]. Recently, it
was reported that senescent cells with the senes-
cence-associated secretory phenotype or cells with
stress-induced senescent features contribute to the
pathogenesis of cGVHD in the lacrimal glands [19].
Increased dendritic cells activation with higher den-
dritic cells density and larger cells with more den-
drites were noted in cases with cGVHD, which may
help in assessing the activity of the immune system
and the inflammatory response [20]. The correlation
of these dendritic cells or dendritic cells changes to
severity of cGVHD will be a great research direc-
tion in the future.
Cluster # 3 (blue) represented primary keywords
for the treatment of ocular cGVHD, which included
management, transplantation, autologous serum eye
drops, and others. They matched the content of papers
in cluster # 3 in the co-citation analysis. The ther-
apy regimes of ocular cGVHD are comparable with
those of severe dry eye disease, initially based on
preservative-free lubricant eye drops and ointments,
while cleaning the lid margins. With the increase in
the inflammatory activity of the ocular surface, topi-
cal corticosteroids, cyclosporine, and tacrolimus were
prescribed [20]. In more severe cases, scleral contact
lenses or autologous serum eye drops (ASED) were
prescribed [21]. It is known that topical cyclosporine
0.05% at a frequency of 3 to 4 times daily can be ben-
eficial to patients with severe inflammatory forms of
dry eye disease such as ocular cGVHD [22]. Moreo-
ver, 100% ASED could significantly improve visual
acuity, corneal staining, and ocular surface disease
index without any side effects [23]. However, Tahmaz
etal. [24] found that cyclosporine and mycophenolic
acid in the ASED, which were administered orally
for the treatment of systemic cGVHD, might affect
topical therapy of ocular cGVHD. Moreover, punctal
plug placement for the treatment of dry eye disease
secondary to ocular cGVHD can help improve ocular
surface parameters [25].
Combined with co-citation analysis and occur-
rence analysis of keywords, we conclude that the
intellectual base before 2009 somewhat corresponds
with the research status after 2009. The core hotspots
remain unchanged, but an in-depth study has been
carried out, and the boundaries of knowledge have
been pushedback gradually.
Before NIH proposes the new cGVHD diagnosis
and staging consensus criteria in 2014, the hotspots
were bone marrow transplantation, stem cell trans-
plantation, and dry eye (Table 8). Since 2015, dry
eye has topped all the keywords, followed by bone
marrow and stem cell transplantation. Therefore, we
can conclude that the ocular symptoms in cGVHD
patients have been taken seriously by researchers and
ophthalmologists in these years.
Conclusion
We built a range of scientific maps of the annual pub-
lication and citation number, the productivity and col-
laborations of countries, organizations, authors, and
journals, the co-citation of references, and the occur-
rences of keywords in the ocular cGVHD study. The
data may help to choose suitable journals for submis-
sion, infusive institutes, or scholars for cooperation.
The screened keywords help the researcher ascer-
tain novel topics and predict directions for further
research. Nevertheless, this study has several short-
comings. First, the literature data were retrieved from
WoSCC from 2009 to 2020, which may be insufficient
to represent the entire topic of the ocular cGVHD
study. Second, the primary data were extracted from
WoSCC, excluding data extracted using other search
engines, such as PubMed, Scopus, or Google Scholar.
Third, there may have been a linguistic bias because
most papers in the WoSCC were in English.
Acknowledgements The authors thank all reviewers for their
valuable comments and support.
Table 8 The top 3 keywords in ocular graft versus host dis-
ease study for the periods 2009–2014 and 2015–2020
Keywords Count (%)
2009–2014 Bone-marrow transplantation 27 (4.7)
Stem-cell transplantation 24 (4.2)
Dry eye 23 (4.0)
2015–2020 Dry eye 63 (5.9)
Bone-marrow transplantation 51 (4.8)
Stem-cell transplantation 51 (4.8)

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Funding This study was funded by Higher Education Institu-
tions Scientific Research Project of Liaoning Province (Grant
No. LJKZ0773) and Medical Science and Technology Project
of Zhejiang Province (Grant No. 2021KY157).
Declarations
Conflict of interest Non-financial interest (such as personal
or professional relationships, affiliations, knowledge or beliefs)
in the subject matter or materials discussed in this manuscript.
Ethics approval This article does not contain any studies with
human participants or animals performed by any of the authors.
Informed consent This article does not contain any studies
with human participants.
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