Accepted Manuscript

The Asia Cornea Society Infectious Keratitis Study: A Prospective Multicenter Study
Of Infectious Keratitis In Asia

Wei-Boon Khor, Venkatesh N. Prajna, Prashant Garg, Jodhbir S. Mehta, Lixin

Xie, Zuguo Liu, Ma. Dominga B. Padilla, Choun-Ki Joo, Yoshitsugu Inoue, Panida
Goseyarakwong, Fung-Rong Hu, Kohji Nishida, Shigeru Kinoshita, Vilavun
Puangsricharern, Ai-Ling Tan, Roger Beuerman, Alvin Young, Namrata Sharma,
Benjamin Haaland, Francis S. Mah, Elmer Y. Tu, Fiona J. Stapleton, Richard L.
Abbott, Donald Tiang-Hwee Tan

PII: S0002-9394(18)30433-1
DOI: 10.1016/j.ajo.2018.07.040
Reference: AJOPHT 10611

To appear in: American Journal of Ophthalmology

Received Date: 8 June 2018

Revised Date: 26 July 2018
Accepted Date: 28 July 2018

Please cite this article as: Khor W-B, Prajna VN, Garg P, Mehta JS, Xie L, Liu Z, Padilla MDB, Joo C-
K, Inoue Y, Goseyarakwong P, Hu F-R, Nishida K, Kinoshita S, Puangsricharern V, Tan A-L, Beuerman
R, Young A, Sharma N, Haaland B, Mah FS, Tu EY, Stapleton FJ, Abbott RL, Tiang-Hwee Tan D, for
theACSIKS GROUP, The Asia Cornea Society Infectious Keratitis Study: A Prospective Multicenter
Study Of Infectious Keratitis In Asia, American Journal of Ophthalmology (2018), doi: 10.1016/
j.ajo.2018.07.040.

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 ACCEPTED MANUSCRIPT

ABSTRACT
Purpose: To survey the demographics, risk factors, microbiology and outcomes for
infectious keratitis in Asia.
Design: Prospective, non-randomized clinical study
Methods: Thirteen study centers and 30 sub-centers recruited consecutive subjects

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over 12 - 18 months, and performed standardized data collection. A microbiological
protocol standardized the processing and reporting of all isolates. Treatment of the
infectious keratitis was decided by the managing ophthalmologist. Subjects were

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observed for up to six months. Main outcome measures were final visual acuity and the
need for surgery during infection.

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Results: A total of 6626 eyes of 6563 subjects were studied. The majority of subjects
were male (n=3992). Trauma (n=2279, 34.7%) and contact lens wear (n=704, 10.7%)
were the commonest risk factors. Overall, bacterial keratitis was diagnosed in 2521
eyes (38.0%) and fungal keratitis in 2166 eyes (32.7%). Of the 2831 microorganisms

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isolated, the most common were Fusarium species (n=518, 18.3%), Pseudomonas
aeruginosa (n=302, 10.7%) and Aspergillus flavus (n=236, 8.3%). Cornea
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transplantation was performed in 628 eyes to manage ongoing infection, but 289 grafts
(46%) had failed by the end of the study. Moderate visual impairment (Snellen vision
less than 20/60) was documented in 3478 eyes (53.6%).
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Conclusion: Demographic and risk factors for infection vary by country, but occur
predominantly in males and is frequently related to trauma. Overall, a similar
percentage of bacterial and fungal infections were diagnosed in this study. Visual
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recovery after infectious keratitis is guarded, and corneal transplantation for active
infection is associated with a high failure rate.
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THE ASIA CORNEA SOCIETY INFECTIOUS KERATITIS STUDY: A PROSPECTIVE

MULTICENTER STUDY OF INFECTIOUS KERATITIS IN ASIA
Wei-Boon Khor1,2
Venkatesh N. Prajna3
Prashant Garg4
Jodhbir S. Mehta1-2,5-6

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Lixin Xie7
Zuguo Liu8
Ma. Dominga B. Padilla9,24
Choun-Ki Joo10

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Yoshitsugu Inoue11
Panida Goseyarakwong12
Fung-Rong Hu13

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Kohji Nishida14
Shigeru Kinoshita15
Vilavun Puangsricharern16

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Ai-Ling Tan17
Roger Beuerman2,5-6
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Alvin Young18
Namrata Sharma19
Benjamin Haaland5
Francis S. Mah20
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Elmer Y. Tu21
Fiona J. Stapleton22
Richard L. Abbott23
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Donald Tiang-Hwee Tan1-2,5-6

for the ACSIKS GROUP*
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1
Singapore National Eye Centre, Singapore
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2
Singapore Eye Research Institute, Singapore
3
Aravind Eye Care System, Madurai, India
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4
LV Prasad Eye Institute, Hyderabad, India
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5
Duke-NUS Graduate Medical School, Singapore
6
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore
7
Shandong Eye Institute, Shandong, China
8
Xiemen Eye Center, Xiemen, China

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9
University of the Philippines Manila, Philippine General Hospital, Manila, the
Philippines
10
St Mary Hospital, The Catholic University of Korea, Seoul, Republic of Korea
11
Division of Ophthalmology and Visual Science, Tottori University, Faculty of Medicine,
Tottori Prefecture, Japan

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12
Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
13
Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan

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14
Osaka University Graduate School of Medicine, Osaka University Hospital, Osaka,
Japan

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15
Kyoto Prefectural University of Medicine, Kyoto, Japan
16
King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University,
Bangkok, Thailand

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17
Department of Microbiology, Singapore General Hospital, Singapore
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18
Prince of Wales Hospital, The Department of Ophthalmology & Visual Sciences, The
Chinese University of Hong Kong, Hong Kong
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19
Dr. Rajendra Prasad Centre Ophthalmic Sciences, All India Institute of Medical
Sciences, New Delhi, India
20
Scripps Clinic Torrey Pines, La Jolla, California, USA
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21
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago,
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Illinois, USA
22
School of Optometry and Vision Science, University of New South Wales, New South
Wales, Australia
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23
Department of Ophthalmology, University of California San Francisco, California, USA
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St. Luke's Medical Center, Global City, Manila, the Philippines
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*
List of co-investigators in the ACSIKS Group can be found in Appendix 1
(Supplemental Material at AJO.com)

Corresponding author and Request for Reprints:

Donald TH Tan

Singapore National Eye Centre

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11 Third Hospital Avenue

Singapore 168751

Telephone: 65-62277255

E-mail: donald.tan.t.h@singhealth.com.sg

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Short Title

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The Asia Cornea Society Infectious Keratitis Study Results

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Supplemental Material
Supplemental Material available at AJO.com

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Appendix 1 (Members of the ACSIKS Group), Appendix 2 (Study Centers and
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Participating Institutions for ACSIKS), Appendix 3 (Members of the ACSIKS Council);
Appendix 4 (Guidelines for Standard Microbiological Investigations and Incubation
Conditions); Appendix 5 (Proposed Antibiotic Testing Panel For Bacterial
Microorganisms);
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Table 1 (Profile of Participating Institutions in the Asia Cornea Society Infectious

Keratitis Study); Table 2 (Profile of Participating Institutions in the Asia Cornea Society
Infectious Keratitis Study); Figure 2 (Histogram of Age of Study Subjects); Table 6
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(Laterality of the Infectious Keratitis in Study Subjects, by Country); Table 9 (Top Five
Most Common Microorganisms Isolated, by Country); Table 12 (Rates of Cornea
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Transplant Failure, by Country)

Acronyms
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ACSIKS - Asian Cornea Society Infectious Keratitis Study; ACS - Asia Cornea Society;
PI – Principal Investigator; CRF – case record forms; SCRI - Singapore Clinical
Research Institute; CH – China; IN – India; JP – Japan; KR – South Korea; PH – the
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Philippines; TW – Taiwan; TH – Thailand; SG - Singapore

Key Words: Asia Cornea Society, infectious keratitis, infective keratitis, cornea ulcer,
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antibiotic resistance, contact lens, bacterial keratitis, fungal keratitis

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INTRODUCTION
The contribution of infectious keratitis to global blindness is substantial,1-3 and has been
estimated to be the fourth leading cause of blindness worldwide.4 Complications of
infectious keratitis, such as cornea perforation and scarring, still remain major
indications for corneal transplantation in many developing countries, including India,5, 6
China,7, 8 and Thailand.9, 10 Furthermore, fungal infections feature more prominently in

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these countries, and are a more frequent indication for therapeutic corneal
transplantation than bacterial keratitis.5-10
The incidence of infectious keratitis is estimated to be much lower in the West11-13 as

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compared to developing countries,14, 15 yet epidemiological studies and research efforts
in the subject vary widely amongst Asian countries.16 The published research also
differs by case definition, methodology and patient populations, making it difficult to

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compile and compare the data between these studies. In order to guide primary care
physicians and ophthalmologists in their management decisions, it is crucial to have
local data on the possible risk factors and common pathogens for infection in their

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country. From a broader perspective, understanding the important risk factors for
infectious keratitis in each country, and in the region, may help doctors, advocates and
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policy makers to take steps to reduce or mitigate these risks.
The Asia Cornea Society Infectious Keratitis Study (ACSIKS) was initiated as a multi-
national, standardized survey of infectious keratitis in Asia, so as to establish a
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comparative baseline description of the risk factors, microbiology, and outcomes of

these infections in developed and developing Asian countries. The specific goals of
ACSIKS were as follows:
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• To develop a standardized protocol for the study of infectious keratitis that was
comprehensive and yet simple enough to be used in multiple sites and in
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different countries
• To determine the demographic profile and risk factors for infectious keratitis in
Asian countries;
•
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To depict the current medical and surgical practice patterns for infectious keratitis;
• To document the range of microorganisms causing infectious keratitis and the
patterns of antibiotic resistance for bacterial isolates;
• To establish Central Repositories for the bacterial and fungal organisms isolated,
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for subsequent studies on microbial resistance and to aid future development of

therapeutic agents.
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METHODS
Study Design
ASCIKS was conceived as a study in two phases. ACSIKS Phase 1 was designed to
be a prospective, non-randomized clinical study of infectious keratitis presenting to
multiple study centers in eight countries (India, China, Japan, South Korea, Taiwan,
Thailand, the Philippines and Singapore). Each center would recruit and evaluate all
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cases of infectious keratitis presenting over 12 months, with each study patient
observed for 6 months. ACSIKS Phase 2 would be a subsequent microbiological
initiative to study isolates from these countries and compare their antimicrobial
resistance profiles. This study adhered to the tenets of the Declaration of Helsinki. Each
study center obtained approval for the study from their respective Institutional Review
Boards and conducted the study in accordance with all local regulatory requirements,
which included full informed consent from all study patients. This trial was registered

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with the ClinicalTrials.gov website and identified as NCT01560208.
A total of 11 Study Centers were selected for Phase 1, with India, China and Japan

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each having 2 separate study centers. Some study centers were also responsible for
coordinating cases accrued from one or more secondary Participating Institutions
(Appendix 2; Supplemental Material at AJO.com). The study was overseen by the
ACSIKS Council, with representation by corneal specialists and ophthalmic

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microbiologists from all 8 countries involved in ACSIKS (Appendix 3; Supplemental
Material at AJO.com). Members of the ACSIKS Council would also be the Principal
Investigator (PI) for their respective study centers.
Study Procedures
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Study procedures were governed by two protocols, namely an ACSIKS Clinical Protocol
and an ACSIKS Microbiological Protocol, and are summarized below.
ACSIKS Clinical Protocol
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Consecutive patients from each site with a clinical diagnosis of presumed infectious
keratitis were recruited into the study. Infectious keratitis was defined as any
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inflammatory corneal lesion (ulcer, infiltrate or abscess) which was diagnosed to have a
likely infectious etiology. The following inclusion and exclusion criteria were used:
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Inclusion Criteria: presumed infectious keratitis in one or both eyes; all patients,
regardless of age, were included; and the ability of the patient (or in the case of minors
below 21 years of age, their parent or guardian) to give informed consent for the study.
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Exclusion Criteria: patients whom were unable or unwilling to undergo treatment at the
ACSIKS study center / participating institution. Patients who were cognitively impaired
or otherwise unable to give informed consent for the study were excluded.
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All patients had a full ocular examination at the point of recruitment and corneal
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samples were collected as guided by the ACSIKS Microbiological Protocol (see below).
A standardized Clinical Case Report Form (Clinical CRF) was used to document the
relevant clinical features, demographic profile, risk factors, and treatment prior to
presentation. Patients identified to have contact lens wear as a possible risk factor for
the infection would also complete a Contact Lens Questionnaire, with specific questions
on type of contact lens used, lens habits, and care practices.
The study did not standardize the treatment of these patients. Given the multiple
healthcare systems involved and the wide variation in access to medical care between
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the countries, a fixed treatment protocol would not have been possible. Management of
the infection was thus at the discretion of the attending ophthalmologist and in
accordance with the practice patterns and standards of care for that institution.
All subjects were followed up for six months, but could be discharged prior to the sixth
month if no further treatment was required - the final consultation was taken as the final
study visit. Follow-up visits were determined by the managing clinician and based on

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clinical necessity. Study data was obtained from regular chart reviews and documented
in the Clinical CRF, including the final diagnosis, details of medical treatment and of any
surgical intervention, and the unaided- and best corrected- visual acuity at the end of six

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months or at the last consultation, whichever came first. Surgical interventions that were
important to the study were those performed for ongoing infection, including therapeutic
and tectonic cornea transplants, as well as evisceration / enucleation due to

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overwhelming infection.
ACSIKS Microbiological Protocol
This protocol was to guide the collection of corneal samples and to standardize the

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laboratory processing, identification and reporting of microorganisms isolated during the
study. Separate Microbiology CRFs were designed to document the results of any and
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all microbiological testing, including antibiotic sensitivity and resistance patterns of
bacterial isolates.
Corneal scrapings and/or corneal biopsies were collected to identify the causative
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organism for the infection, regardless of lesion size and severity. All specimens were
incubated according to a standardized set of conditions (Appendix 4; Supplemental
Material at AJO.com). An exception was made for suspected viral infections, as these
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are typically diagnosed clinically, and identification of viruses (through cell cultures or
polymerase chain reaction testing) was not available at every study centers.
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A comprehensive antibiotic testing panel was developed for bacterial isolates,

predicated on the common topical antibiotics used in these 8 countries (Appendix 5;
Supplemental Material at AJO.com). Any and all bacterial growth was interpreted and
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reported according to this common standard, regardless of the number of colonies

present. This standard also applied to organisms that are typically considered to be
contaminants (e.g. coagulase-negative Staphylococcus) so as to allow for future
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analysis of the significance of these colonies.

Storage of Microbiological Samples
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All fungal and bacterial organisms isolated from study patients were sub-cultured and
transferred into Microbank vials (Pro-Lab Diagnostics, Round Rock, TX, USA) for
storage in dedicated ultra-low deep freezers (minus 80oC) at each study center. At least
two samples of each isolate were kept, so that by the end of the study each center
would retain one sample for their own research, while the second sample would be sent
to the ACSIKS Central Repositories.
Study Outcomes
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The following parameters were recorded to determine the outcome of the infection:
1) Visual Acuity: The visual acuity at the end of six months, or at the final consultation
during the six months, was recorded. Specifically, eyes with moderate visual impairment
or worse (best corrected or pinhole visual acuity less than Snellen 20/60) were
highlighted.

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2) Acute Surgical Interventions: Refers to ocular surgery performed before the
resolution of the infection. The type of surgery performed and the surgical outcomes
were captured.

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Trial Size and Statistical Analysis
A minimum recruitment target of 200 patients per country was set to ensure greater

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than 80% power for detecting differences in rates between countries if the actual
difference in rates was 0.15. Quantitative variables were summarized as mean
(standard deviation) or median (range), as appropriate, while categorical variables were
summarized as number (percent). Patient characteristics were compared across

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countries in the context of linear or logistic generalized estimating equations models,17
depending on whether the characteristics were quantitative or categorical, accounting
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for the association among observations from the same center. Statistical analyses were
performed in Excel 2013 (Microsoft Corp., Redmond, WA, USA), Stata 13 (StataCorp.,
College Station, TX, USA), and R 3.0.1 (R Core Team, Vienna, Austria). Statistical
significance was set at a P value of less than 0.05.
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Data Handling and Quality Assurance

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The Singapore Clinical Research Institute (SCRI) was engaged as the Clinical
Research Organization for ACSIKS. Site initiation visits were conducted in person with
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all study centers to train the study investigators on the ACSIKS protocols.
Anonymized data documented on the CRFs by the participating institutions were
entered into electronic versions of the CRF held by a centralized, web-based database
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(Oracle Clinical/Remote Data Capture systems) established by SCRI. Guidelines for

entry into this database were developed to ensure uniform data entry. During the study,
SCRI performed regular remote monitoring on protocol compliance, data entry, and
queries resolution.
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RESULTS
The first patient was recruited in April 2012. As the study progressed, an extra study
center was established in both Japan and Thailand as the incidence of infectious
keratitis in these countries appeared lower than projected, so that a total of 13 Study
Centers and 30 Participating Institutions were ultimately involved in Phase 1. At study
centers where recruitment was initially below expectations (namely the Philippines,

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South Korea, Taiwan) the recruitment period was extended from 12 months to 18
months to maximize the number of patients recruited (Table 1; Supplemental Material at
AJO.com). The final study patient was recruited on 31st March 2014, and the last study

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sites were closed in November 2014.
The profiles of each participating institutions is summarized in Table 2 (Supplemental
Material at AJO.com). Most sites were dedicated ophthalmology institutes or

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ophthalmology departments in major hospitals providing tertiary-level ophthalmic care.
The annual number of outpatient visits ranged from 12,000 patients to one million
patients. Sites in India and China served a predominantly rural/agricultural population;

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sites in Singapore, Taiwan and South Korea were in urban areas, and the remaining
institutions served a mix of urban and rural populations. Centers in India, the Philippines,
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Taiwan, Thailand and Singapore were mainly in tropical environments; the local climate
was temperate in centers in China, Japan and South Korea.
Demographic Profile
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A total of 6563 subjects were recruited into the study, of which half were recruited in
India (n=3680, 56.1%) (Table 3 and Figure 1). The majority of patients were male (n=
3992, 60.8%), although in countries such as Japan, Taiwan and Singapore there was a
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slight female preponderance (Table 4). The median age was 46.0 years old (range 0.08
– 95 years) (Figure 2, Supplemental Material at AJO.com), and was lowest in Singapore
(median 28.0, range 4.0 – 84.0) and highest in Japan (median 60.0, range 8.0 – 95.0)
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(Table 5). Only 63 study subjects (1%) had bilateral infections on presentation, giving a
total of 6626 study eyes with infectious keratitis (Table 6, Supplemental Material at
AJO.com).
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Risk Factors
The most common ocular risk factor reported by study subjects was trauma (n=2279,
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34.7%), followed by contact lens wear for refractive error (n=704, 10.7%), prior surgery
(n=445, 6.8%), and ocular surface disease (n = 277, 4.2%) (Table 7).
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Trauma was the commonest ocular risk factor reported in the Philippines (n=228,
65.5%), India (n=1547, 42.0%), Thailand (n=107, 38.2%) and China (n=219, 23.3%). Of
all the subjects that had suffered trauma, 1402 subjects (61.5%) reported mechanical /
non-vegetative injury, 816 subjects (35.8%) reported some vegetative material in the
eye and 74 subjects (3.2%) had a chemical or thermal injury.
Contact lens wear to correct for refractive error was the greatest risk factor in Singapore
(n=362, 68.2%), Taiwan (n=101, 43.3%) and Japan (n=77, 25.6%). Prior ocular surgery
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was the risk factor most commonly reported in South Korea (n=53, 21.2%), of which 25
(47.2%) were related to cornea transplantation.
When the ocular and systemic risk factors were analyzed by gender, we found that men
were more likely than women to have listed trauma as a risk factor for their infection
(relative risk 1.53, 95%CI 1.42 – 1.65), whereas women were more likely to have had
contact lens wear as a risk factor (relative risk 3.35, 95% CI 2.89 – 3.89). The remaining

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risk factors were not significantly different by gender (results not shown).
Final Diagnosis
The final diagnosis was made based on positive microbiological results, or in the

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absence of positive microbiology, on the clinical impression and response to treatment.
In clinical practice, it can be difficult to distinguish between a peripheral corneal
inflammatory infiltrate versus infectious keratitis. Subjects that were eventually given a

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final diagnosis of marginal keratitis or similar peripheral inflammatory lesion were
excluded from the study. By the end of the study period, 2521 eyes (38.0%) were
diagnosed with a bacterial keratitis, 2166 eyes (32.7%) with a fungal keratitis, and 836

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eyes (12.6%) with a viral keratitis. In 944 eyes (14.2%), the cause of the infection
remained undetermined (Table 8).
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Naturally, there were country-specific differences. In India, fungal keratitis was the most
common diagnosis (n=1694, 45.6%) followed closely by bacterial keratitis (n=1423,
38.3%). In China, viral keratitis was the top diagnosis (n=434, 46.2%); 229 (24.4%) of all
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infections were diagnosed to be due to herpes simplex and 163 (17.3%) from herpes
zoster. Finally, bacterial keratitis was the most common diagnosis in South Korea
(n=107, 42.8%) and Singapore (n=224, 41.3%), although these centers also had
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substantial number of patients with no specified diagnosis at the end of the study (100
eyes and 270 eyes, respectively).
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Microbiological Results
The study isolated 2831 unique microorganisms. The five most commonly isolated
organisms were Fusarium species (n=518, 18.3%), Pseudomonas aeruginosa (n=302,
10.7%), Aspergillus flavus (n=236, 8.3%), non-sporulating moulds (n=190, 6.7%) and
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Streptococcus pneumonia (n=177, 6.3%). Fungal organisms were by far the most
common microorganisms isolated in China and India, with Fusarium species being the
most common pathogen in China (n=63, 30.9%) and India (n=432, 25.7%). In the
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remaining countries, the most common microorganism isolated were typically bacterial,
such as Pseudomonas aeruginosa in the Philippines (n=26, 12.5%), Taiwan (n=23,
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31.9%), Thailand (n=43, 32.1%) and Singapore (n=97, 42.2%), and Propionibacterium
acnes in Japan (n=59, 33.0%) and South Korea (n=13, 10.8%) (Table 9, Supplemental
Material at AJO.com). Of the parasitic infection, 64 subjects were positive for
Acanthamoeba spp. and 5 were positive for microsporidial keratitis.

Clinical Outcomes
One of the outcomes documented in this study was the response to medical therapy
(Table 10). In summary, medical treatment alone was sufficient to clear the infection in
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3644 of the study eyes (55.0%), 50 eyes (0.8%) still had the infection even after 6
months of medical treatment, and 961 (14.5%) required surgical intervention whilst the
infection was still active. A large proportion of study eyes (n=1887, 28.5%) were lost to
follow-up before the infection was documented to have healed, and these subjects were
predominantly from India (1537 eyes).
Ultimately, 68 eyes required enucleation or evisceration; this was generally an

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uncommon outcome, but accounted for almost a third of the surgeries performed in
Thailand and the Philippines (Table 11).
By far the most common surgical intervention performed to manage infection was

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therapeutic / tectonic cornea transplantation, with 628 transplants documented (Table
11). By volume, India had the largest numbers reported (351 grafts) followed by China
(184 grafts) and the Philippines (52 grafts). However, in terms of percentage of study

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eyes that required transplantation, 19.6% of eyes from China required transplantation,
followed by the Philippines (14.9%) and then India (9.5%). Unsurprisingly, cornea graft
failure in these infected eyes was extremely high, with 289 grafts (46%) having lost

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cornea clarity by the end of the 6 month study period (Table 12, Supplemental Material
at AJO.com).
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The best-corrected Snellen visual acuity for each study eye, at the end of the 6 month
follow-up period or at the final consultation (whichever was earlier), was recorded in
6489 eyes. Moderate visual impairment or worse was documented in 3478 study eyes
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(53.6%), and this percentage ranged from 64.8% (n=598) in China to 8.1% (n=44) in
Singapore (Table 13).
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DISCUSSION
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Over the course of this study, ACSIKS recruited more than 6500 subjects with infectious
keratitis, making this one of the largest prospective clinical studies on infectious keratitis
ever conducted in Asia. The majority of patients in this study were male and the
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commonest risk factor documented was ocular trauma. We found a statistically

significant association between the male gender and trauma, a finding that has been
established in previous surveys of ocular trauma.18 A male preponderance was seen in
countries where trauma was the commonest risk factor for infectious keratitis (China,
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India and the Philippines). Conversely, contact lens wear was the commonest risk factor
for documented in countries where the majority of patients were female (Japan, Taiwan
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and Singapore). Studies of contact lens-associated keratitis have noted a greater

proportion of female patients,12, 19 even though male gender has been reported to be an
independent risk factor for infection20; this may be due to the greater popularity of
contact lens wear amongst women. We are currently reviewing the data on patients with
contact lens wear as a risk factor, and we will examine the associations between
demographics, clinical features and the microbiology of contact lens-related infectious
keratitis with the treatment outcomes.

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There were an almost equal number of eyes that were diagnosed with bacterial and
fungal keratitis in ASCIKS; this finding reflects the large number of eyes with fungal
keratitis managed in the study centers in India (1694 eyes) and to a lesser extent, China
(284 eyes). It has been postulated that the high incidence of fungal keratitis in India and
China may be due to climate, socioeconomic development in the country, and trauma
as a risk factor for infection.16, 21-24 Fungal keratitis remains uncommon in most of the
other study centers, where bacterial infections predominate. Pseudomonas aeruginosa

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and Streptococcus pneumonia were the most common bacterial organisms isolated, in
keeping with previous reports from this region.16, 23 However, there were also multiple
instances of Propionibacterium acnes and coagulase-negative Staphylococcus isolated

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from subject eyes. Whether these bacteria are merely contaminants, or are true
pathogens will require further study. ACSIKS Phase 2, currently underway, will have
antimicrobial resistance data from all the bacteria and fungi isolated from our study

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patients and may shed some light on these findings.
Interestingly, the commonest diagnosis in China was viral keratitis (47.7%),
predominantly herpes simplex and herpes zoster. Herpes simplex was previously

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thought to be an uncommon cause of corneal blindness in developing countries.23
However, a recent population-based survey in China estimated the prevalence of
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herpes simplex keratitis to be 0.11%, similar to the USA and France.15 Herpes simplex
keratitis was also found to be the most common infectious cause for cornea perforation
in Shandong,25 and the second commonest indication for penetrating keratoplasty after
fungal keratitis.7 While the high incidence of herpes simplex is in keeping with some of
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the published data, herpes zoster keratitis was not reported in the afore-mentioned
population survey. However, our results are not comparable to an epidemiological
study, and the incidence of herpes zoster may be a reflection of the referral pattern and
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the specific population served by our two study centers in China.

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The low incidence of acanthamoeba keratitis in ACSIKS does appear to be consistent

with the epidemiology of acanthamoeba infection, which is largely associated with
contact lens wear and reported to be in the range of 1 - 33 cases per million contact
lens wearers.26 The numbers of microsporidial keratitis in ACSIKS is probably lower
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than expected, given the increasing incidence of the condition in countries such as
Singapore and India. This may be due to a referral bias; as these patients generally
have milder symptoms and respond well to empiric treatment, they may have been
misdiagnosed or treated by general ophthalmologists without referral to our ACSIKS
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study centers.
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Cornea transplantation was the most common surgery performed whilst the infectious
keratitis was still active. The numbers are significant, whether judged in terms of
absolute numbers (351 eyes from the 2 study centers in India), or by percentage (20%
of eyes with infectious keratitis in China required a transplant). Unfortunately, this
disproportionately affects countries that already have limited access to corneal
transplantation, with an estimated 2 million in China and 7 million in India waiting for a
transplant.27 In these situations, surgeons may opt to utilize cornea tissue that is rated

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at a lower grade than those used for optical transplants, contributing to the high rate of
graft failure documented in this study.
Given the magnitude of the problem, the costs of medical and surgical treatments, and
the often poor visual outcomes, prevention may be one of the few feasible public health
strategies available. Our study found trauma to be a major risk factor for cornea
infections, particularly in the developing countries of Asia. While the use of protective

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eyewear in industrial and agricultural activity can prevent ocular injury, the actual usage
of such protective eyewear by workers has been found to be consistently low, even in
industrialized countries with robust workplace safety legislation in place. Realistically,

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early secondary prevention may be the solution to reducing the incidence of infectious
keratitis after trauma. Village health workers in Nepal were taught to identify a traumatic
corneal abrasions and to dispense 1% chloramphenicol ointment just three times a day
for three days; this trial found that none of the patients given prophylaxis within 18 hours

SC
of injury developed an ulcer.28 Further studies using 1% chloramphenicol ointment were
subsequently initiated in villages in three countries in South East Asia – Bhutan,29
Burma,30 and India.31 Remarkably, all of the patients who had prophylactic treatment

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healed without infection.
AN
We acknowledge the potential limitations of this study. Given the wide differences
between the eight countries in terms of demographic profile, socioeconomic
development, climate and geography, the ACSIKS study centers are not always
representative of each country. In part, these study centers were chosen because they
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were tertiary eye care institutions with the clinical expertise and internationally-
accredited laboratory facilities capable of conducting this study. Thus infections
encountered in ACSIKS are likely to be more severe compared to those treated in the
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community. The ideal epidemiological approach, to study infectious keratitis in

randomly selected communities throughout Asia, would result in a better representation
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of the incidence and burden of infectious keratitis in each country, but would be outside
the scope and intent of ACSIKS.
The scale of the ACSIKS protocol also meant that we were unable to identify suitable
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study centers in certain countries, such as Indonesia, Malaysia and Vietnam, with the
resources to conduct the study during that time. What we do hope is that other centers
in Asia will adopt the ACSIKS protocols when studying infectious keratitis, and in so
doing allow ophthalmologists to build up a more complete picture of infectious keratitis
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in the region.
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There is also a wide variation in the incidence of infections in the eight countries, and
we see that India and China will be over-represented in our results. Pooled data from
ACSIKS will need to be interpreted with this in mind, although it this does reflect the
real-world burden of infectious keratitis in Asia.
The visual acuity results for this study may also be poorer than what they potentially
could have been. Subjects with pre-existing or co-existing pathology were not excluded
from this study, so some visual loss may already have been present prior to the
infection. Rigid gas permeable lenses may also have corrected some of the irregular
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astigmatism from corneal scarring, but routine rigid gas permeable lens correction to
assess post-infection visual acuity was not feasible for this study. Finally, the six-month
follow-up period meant that most of our subjects with corneal transplantation would still
have had sutures in; potentially, the vision in patients with healthy grafts may have been
better if followed for a longer period of time and after selective suture removal.
The management of infectious keratitis was not standardized in ACSIKS, and medical

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and surgical treatment was determined by the individual ophthalmologist based on their
institutions’ practice. This is can be seen as a limitation of our study, but it also
acknowledges that there is no single standard of care that can be applied throughout

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Asia.
Finally, although there is an abundance of data presented in this paper, we are not yet
able to determine the demographic, clinical or microbiological factors that may

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predispose to a poor outcome in infectious keratitis. Future papers on the microbiology
of ACSIKS, and on specific populations such as contact lens wearers, may provide
further insights into this study population. Undoubtedly, socioeconomic development

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and access to care will also have an impact, and we suspect that an individualized risk
factor analysis will be needed for each country in order to identify the associations with
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the treatment outcomes.
In spite of these limitations, it is hoped that the data presented here will guide
ophthalmologists in these countries in the assessment and initial management of
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infectious keratitis, serve as a baseline for describing and understanding corneal

infections in this region, and ultimately contribute towards reducing corneal blindness in
Asia.
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ACKNOWLEGEMENTS

a. Funding / Support: Funding support was provided by the following organizations:

Asia Cornea Foundation, Singapore
Alcon, TX, USA

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Allergan, Ireland
Bausch & Lomb, NY, USA
Santen Pharmaceutical, Japan

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Project Orbis, NY, USA
None of the sponsors or funding organizations had a role in the study design; in the
collection, analysis and interpretation of data; in the writing of the report; nor in the

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decision to submit the article for publication.

b. Ma. Dominga B. Padilla : speakers bureau for Santen and Allergan; speakers bureau

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and advisory board for Bausch and Lomb, Philippines.
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Yoshitsugu Inoue : research funding from Santen Pharmaceutical, Senju
Pharmaceutical, Alcon Japan Ltd, Novartis Pharmaceutical Co. Ltd, Kowa
Pharmaceutical Co. Ltd, Kowa Pharmaceutical Co. Ltd, Pfizer Japan Inc, Otsuka
Pharmaceutical Co. Ltd and Bayer Yakuhin Ltd; consultant for Senju Pharmaceutical
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Companny and M’s Science Corporation.

Hu Fung Rong : grants from the Ministry of Science and Technology of Taiwan
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Government.
Shigeru Kinoshita : consultant for Santen Pharmaceutical Co, Ltd, Osaka, Japan.
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Tan Ai Ling : honorarium for lecture from the Singapore Association of Pharmaceutical
Industries.
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Fiona Stapleton : research funding from Tear Science and Coopervision; and consultant
for Zeiss.
Richard L. Abbott : consultant for Santen, Inc; and stock ownership in MacRegen.
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Jodhbir S. Mehta and Donald TH Tan : inventors of the EndoGlide, have financial
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interests in the device (AngioTech, Reading, Pennsylvania, USA/Network Medical

Products, North Yorkshire, UK).
The following authors have no financial disclosures: Wei-Boon Khor, Venkatesh N.
Prajna, Prashant Garg, Lixin Xie, Zuguo Liu, Panida Goseyarakwong, Kohji Nishida,
Choun-Ki Joo, Vilavun Puangsricharern, Roger Beuerman, Alvin Young, Namrata
Sharma, Benjamin Haaland, Francis S. Mah, Elmer Y. Tu.
c. Other acknowledgments – Nil.
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16. Shah A, Sachdev A, Coggon D, Hossain P. Geographic variations in microbial

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20. Stapleton F, Carnt N. Contact lens-related microbial keratitis: how have

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21. Xie L, Zhong W, Shi W, Sun S. Spectrum of fungal keratitis in north China.
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24. Leck AK, Thomas PA, Hagan M, et al. Aetiology of suppurative corneal ulcers in
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25. Xie L, Zhai H, Dong X, Shi W. Primary diseases of corneal perforation in
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Whitcher JP. Corneal ulceration in South East Asia. I: a model for the prevention of
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30. Maung N, Thant CC, Srinivasan M, et al. Corneal ulceration in South East Asia. II:
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Ophthalmol 2006; 90(8): 968-70.

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CAPTIONS

Figure 1. Percentage Distribution of Study Subjects Recruited, by Country.

IN – India; CH – China; SG - Singapore; PH – The Philippines; JP – Japan; TH –
Thailand; KR – South Korea; TW – Taiwan

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Figure 2. Histogram of Age of Study Subjects.

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Table 3. Number of Study Subjects Recruited, by Country.

Number

Country of

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Subjects %

India 3680 56.1

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China 940 14.3

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Singapore 531 8.1

The Philippines 348 5.3

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Japan 301 4.6
AN
Thailand 280 4.3

South Korea 250 3.8

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Taiwan 233 3.6

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Total 6563 100.0

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Table 4. Gender Distribution of Study Subjects, by Country.

Gender (%)
Country Total
Male Female

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2385 1295 3680
India
(64.8%) (35.2%)

RI
614 326 940
China

SC
(65.3%) (34.7%)

236 295 531

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Singapore
(44.4%) (55.6%)
AN
236 112 348
The Philippines
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(67.8%) (32.2%)

141 160 301

D

Japan
(46.8%) (53.2%)
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143 137 280

Thailand
(51.1%) (48.9%)
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133 117 250

South Korea
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(53.2%) (46.8%)
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104 129 233

Taiwan
(44.6%) (55.4%)

3992 2571 6563

Total
(60.8%) (39.2%)
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Table 5. Age Distribution of Study Subjects, by Country.

Mean Median

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Standard Min. Max.
Country Age Age
Deviation (years) (years)
(years) (years)

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India 45.2 17.8 46. 0 0.1 93.0

SC
China 50.4 16.3 54. 0 1.0 91.0

Singapore 31.6 13.8 28.0 4.0 84.0

The
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AN
42. 9 17.9 43.0 0.7 91.0
Philippines

Japan 55.1 22.6 60. 0 8.0 95.0

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Thailand 45.4 20.9 45.5 0.4 88.0

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South
50.5 19.5 53. 0 10.0 89.0
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Korea

Taiwan 42.9 21.9 39. 0 3.0 88.0

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Total 45.3 18.6 46.0 0.1 95.0

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Table 7. Distribution of Major Risk Factors for Infectious Keratitis, by Country

Total Risk Factor

Number Contact Ocular

Country Prior Ocular

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of Trauma (%) Lens Wear Surface
Surgery (%)
Subjects (%) Disease (%)

RI
India 3680 1547 28 191 128

SC
(42.0%) (0.8%) (5.2%) (3.5%)

China 940 219 4 34 8

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(23.3%) (0.4%) (3.6%) (0.9%)
AN
Singapore 531 46 362 17 40

(8.7%) (68.2%) (3.2%) (7.5%)

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The
348 228 44 21 12
D

Philippines

(65.5%) (12.6%) (6.0%) (3.4%)

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Japan 301 53 77 55 37
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(17.6%) (25.6%) (18.3%) (12.3%)

Thailand 280 107 53 36 23

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(38.2%) (18.9%) (12.9%) (8.2%)

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South
250 42 35 53 25
Korea

(16.8%) (14.0%) (21.2%) (10.0%)

Taiwan 233 37 101 38 4

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(15.9%) (43.3%) (16.3%) (1.7%)

Total 6563 2279 704 445 277

(34.7%) (10.7%) (6.8%) (4.2%)

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Table 8. Final Diagnosis of Infectious Keratitis in Subject Eyes, by Country.

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Total Country

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Final
Number of

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Diagnosis IN CH SG PH JP TH KR TW
Eyes (%)

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Bacterial 2521 1423 144 224 185 144 150 107 144

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(38.0%) (38.3%) (15.3%) (41.3%) (53.2%) (47.8%) (50.5%) (42.8%) (61.8%)

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Fungal 2166 1694 284 4 94 19 27 25 19

(32.7%) (45.6%) (30.2%) (0.7%) (27.0%) (6.3 %) (9.1%) (10.0%) (8.2%)

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Parasitic 159 78 8 7 20 15 12 3 16

(2.4%) (2.1%) (0.9%) (1.3%) (5.7%) (5.0%) (4.0%) (1.2%) (6.9%)

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Viral 836 255 434 38 7 50 18 15 19
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(12.6%) (6.9%) (46.2%) (7.0%) (2.0%) (16.6%) (6.1%) (6.0%) (8.2%)

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Infectious
944 264 70 270 42 73 90 100 35
keratitis
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(Not
(14.2%) (7.1%) (4.4%) (49.7%) (12.1%) (24.3%) (30.3%) (40.0%) (15.0%)
Specified)

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Total 6626 3714 940 543 348 301 297 250 233

RI
SC
IN – India; CH – China; SG - Singapore; PH – the Philippines; JP – Japan; TH – Thailand; KR – South Korea; TW –

Taiwan

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Table 10. Outcomes of Medical Treatment for Infectious Keratitis in Subject Eyes,

by Country.

Medical Treatment Outcomes (%)

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Infection
Infection Infection not Infection not
Lost to

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resolved resolved, resolved, but resolved Total
follow-up
Country without need acute acute and no Number
before
for acute surgical surgical surgery of Eyes

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infection
surgical intervention intervention performed
resolved
intervention required still required upon exit

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of study
India 1650 484 23 20 1537 3714
AN
(44.4%) (13.0%) (0.6%) (0.5%) (41.4%)
China 550 317 33 3 36 939
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(58.6%) (33.8%) (3.5%) (0.3%) (3.8%)

Singapore 437 7 3 2 94 543
D

(80.5%) (1.3%) (0.6%) (0.4%) (17.3%)

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The 120 70 8 8 139 345

Philippines (34.8%) (20.3%) (2.3%) (2.3%) (40.3%)
Japan 271 9 0 1 20 301
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(90.0%) (3.0%) (0.0%) (0.3%) (6.6%)

Thailand 216 51 1 12 15 295
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(73.2%) (17.3%) (0.3%) (4.1%) (5.1%)

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South 175 22 3 4 46 250

Korea (70.0%) (8.8%) (1.2%) (1.6%) (18.4%)
Taiwan 225 1 7 0 0 233
(96.6%) (0.4%) (3.0%) (0.0%) (0.0%)
Total 3644 961 78 50 1887 66201
(55.0%) (14.5%) (1.2%) (0.8%) (28.5%)
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1
Missing data – 6 eyes

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Table 11. Type of Surgery Performed During Ongoing Infection, by Country.

Type Of Surgery (%)

PT
Total Number
Amniotic
Country Corneal Cornea Conjunctival Evisceration/ of Surgeries

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membrane
biopsy transplant flap Enucleation Performed

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transplant

India 3 351 10 0 16 380

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AN
(0.8%) (92.4%) (2.6%) (0.0%) (4.2%)

China 47 184 84 36 5 356

M
(13.2%) (51.7%) (23.6%) (10.1%) (1.4%)

D
Singapore 2 7 0 1 1 11

(18.2%) (63.6%)
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(0.0%) (9.1%) (9.1%)
EP
The Philippines 0 52 0 1 23 76

(0.0%) (68.4%) (0.0%) (1.3%) (30.3%)

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Japan 1 8 0 0 1 10

(10.0%) (80.0%) (0.0%) (0.0%) (10.0%)

Thailand 11 17 11 1 19 59
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(18.6%) (28.8%) (18.6%) (1.7%) (32.2%)

South Korea 0 4 13 5 3 25

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(0.0%) (16.0%) (52.0%) (20.0%) (12.0%)

Taiwan 0 5 3 1 0 9

RI
(0.0%) (55.6%) (33.3%) (11.1%) (0.0%)

SC
Total 64 628 121 45 68 926

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(6.9%) (67.8%) (13.1%) (4.9%) (7.3%)

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Table 13. Distribution of Subject Eyes with Moderate Visual Impairment, by

Country

Country Number of Number of Eyes with

PT
Subject Moderate Visual

Eyes1 Impairment (%)

RI
India 3666 2208 (60.2%)

SC
China 923 598 (64.8%)

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Singapore 541 AN 44 (8.1%)

The Philippines 335 206 (61.5%)

Japan 277 78 (28.2%)

M

Thailand 280 150 (53.6%)

D

South Korea 234 111 (47.4%)

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Taiwan 233 83 (35.6%)

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Total 6489 3478 (53.6%)

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1
Number of Eyes without Visual Acuity data = 137 eyes
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RI
U SC
AN
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