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Asymptomatic infection of Middle East respiratory syndrome coronavirus using serologic survey in Korea Running title: Asymptomatic infection of MERS in Korea Authors: Yeong-Jun Song1, Jeong-Sun Yang 1, Hee Jung Yoon, Hae-Sung Nam, Soon Young Lee, Hae-Kwan Cheong, WooJung Park, SungHan Park, BoYoul Choi, Sung Soon Kim, and Moran Ki 1

These first authors contributed equally to this article

Author affiliations: National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Republic of Korea (YJ. Song, M. Ki), The Korean Society of Infectious Diseases, Seoul, Republic of Korea (HJ. Yoon), Centers for Disease Control and Prevention, Cheongju, Republic of Korea (JS. Yang, WJ. Park, SH. Park, SS. Kim), Chungnam National University School of Medicine, Daejeon, Republic of Korea. (HS. Nam), Ajou University School of Medicine, Suwon, Republic of Korea (SY. Lee), Sungkyunkwan University School of Medicine, Suwon, Republic of Korea (HK. Cheong), Hanyang University Medical College, Seoul, Republic of Korea (BY. Choi) Corresponding author Moran Ki, MD, MPH, PhD Department of Cancer Control and Population Health, Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, 10408, Korea Phone: Office: +82-31-920-2736, Mobile: +82-10-3450-3210, Fax: +82-2-6008-6056, Email: [email protected]

1

Abstract

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OBJECTIVES:

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Asymptomatic infection rates of Middle East respiratory syndrome (MERS) coronavirus vary.

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To identify rates of asymptomatic MERS infection in healthcare workers and non-healthcare

5

workers, serologic survey was conducted.

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METHODS:

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Study individuals were selected from the contacts based on a priority system in four MERS

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prone-regions. Sero-epidemiological analysis was performed in 1,610 contacts (average

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duration from exposure to test, 4.8 months), and the collected sera were tested using an

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enzyme-linked immunospecific assay (ELISA), immunofluorscence assay (IFA), and plaque

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reduction neutralization antibody test (PRNT). Of 1,610 contacts, there were seven ELISA-

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positive cases. Among these seven, one exhibited positive IFA and PRNT results.

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RESULTS:

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Asymptomatic infection rate was 0.06% (95% confidence interval, 0.0016-0.3461%). The

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asymptomatic MERS case was a hospitalized patient with the patient zero on the same floor

16

of the hospital at the same time. The case was quarantined at home for 2 weeks after

17

discharge. The case had underlying diseases, including hypertension, angina, and

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degenerative arthritis.

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CONCLUSIONS:

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The asymptomatic infection was acquired via healthcare-associated transmission. Thus, it is

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necessary to extend serological studies on inpatient contacts who have no symptoms.

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Key words: asymptomatic infection, epidemiology, Middle East respiratory syndrome

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coronavirus, nosocomial infections, outbreak, ELISA

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INTRODUCTION

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Middle East respiratory syndrome (MERS) is a severe respiratory infection caused by a

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novel betacoronavirus [1-3]. The symptoms of MERS include fever, chills, cough, shortness

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of breath, gastrointestinal symptoms, expectoration, wheezing, chest pain, hemoptysis, sore

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throat, headache, myalgia, abdominal pain, vomiting, and diarrhea; it can also cause death in

29

severe cases [3-6].

30

The pathogen of MERS is transmitted via four modes: animal-to-human, intra-familial,

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healthcare-associated, and travel-related [7, 8]. In South Korea, there were 186 cases, which

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were predominantly caused by healthcare-associated transmission [7, 9-11], followed by

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intra-familial transmission.

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According to the International Health Regulations reported to WHO, rates of asymptomatic

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or mild infection were 44/398 (28.6%) in Saudi Arabia, UAE, and the Islamic Republic of

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Iran between April and June 2014, and 32/113 (28.31%) in Saudi Arabia in June 2014 [12,

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13]. However, Oboho et al. reported that 78.79% (26/33) of initially reported asymptomatic

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patients had at least one symptom [14]. In South Korea, among the confirmed 186 cases,

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three asymptomatic cases were detected among healthcare workers via screening tests

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(1.61%) [15]. In serologic studies using indirect immunofluorescence tests for healthcare

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workers who were at MERS-affected hospitals, 2/457(0.44%) had positive results [16].

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However, there has been no report on the asymptomatic infection rate among non-healthcare

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workers in Korea. There is a considerable chance of human-to-human transmission, as well

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as direct infection via the dromedary [17-19]. Therefore, it is necessary to identify

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asymptomatic rates of MERS in healthcare workers and non-healthcare workers.

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MATERIALS AND METHODS

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Selection and participation of individuals

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Based on a database of quarantined individuals provided by the epidemiological study

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department of the Korea Centers for Disease Control and Prevention (KCDC), individuals at

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four regions with major outbreaks—Seoul, Gyeonggi, Chungcheong, and Jeonbuk—were

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selected. The individuals whose MERS status were diagnosed by using PCR test were

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excluded from this study analysis. From 14,831 quarantined individuals, 7,233 (48.8%)

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residents living in the four major MERS outbreak regions were selected. Of these individuals,

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calls requesting research participation were made to 3,291 (45.5%) individuals according to

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the prioritization groupings. A total of 1,610 (48.9%) individuals actually participated in the

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study (Figure 1). Those who refused to participate are described in another study [20].

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Study individuals were prioritized in groups according to transmission intensity of exposed

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MERS case as follows: contact with super-spreading events (5 or more individuals

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infected) [21], contact with spreaders who infected 1 to 4 individuals, and contact with non-

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spreaders. We selected study subjects according to this prioritized groups; selection rates

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were 48.8%, 16.4%, and 15.8%, respectively. We also categorized the subjects according to

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their exposure intensity (i.e., status when they were exposed to the MERS case); patient who

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was inpatient or outpatient of MERS affected hospital, family was people living with, or paid

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caregiver of MERS case, visitors were those who visited the hospitalized MERS case,

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healthcare worker was an employee at the MERS affected hospital, and colleague was a co-

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worker in a MERS case. We selected more in family, patient, and visitors (Table 1).

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Study performance

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Only individuals who consented to participate in the study through telephone in each region

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and gave written consent at the time of study initiation were subjected to surveys in the public

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health centers of each area. From each participant, questionnaires on exposure were

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conducted and blood samples were collected. Following the first serological test by ELISA,

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the positive or borderline cases were tested using IFA and PRNT tests.

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Antibody tests

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MERS-CoV antibody for all sera collected from contacts were measured by using

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recombinant S1 protein coated a human anti-MERS-CoV (IgG) ELISA kit (EUROIMMUN,

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Germany), and this kit were carried out according to the manufacture’s protocol. The result of

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tested samples was determined by calculating ratio value (OD value of sample/OD value of

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calibrator). Ratio ≥1.1 as positive, ratio ≥ 0.8 to < 1.1 as borderline, and ratio < 0.8 was

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considered as negative.

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IFA slides were coated with MERS-CoV non-infection or infection vero cells. Serum

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samples were diluted in phosphate buffered saline (PBS) by 1:10, 1:100, 1:250 and 1:1000,

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transferred to IFA slides, and incubated for 30 min at 37°C in a humidified chamber. The IFA

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slides were washed three times in PBS-T for 5 min each and incubated with FITC-conjugated

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rabbit anti-human IgG (Abcam, USA) diluted at 1:800 for 30 min at 37°C in a humidified

85

chamber. After washing with three times in PBS-T for 5 min, the slides were embedded with

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a mounting fluid, topped with a cover glass, and observed under a fluorescent microscope.

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The neutralizing antibodies for serum samples were measured by PRNT. PRNT procedures

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were performed as follows: In briefly, 1/10 diluted sera were heat-inactivated at 56°C for 30

89

min. Heat-inactivated sera were diluted serial four-fold. After an equal volume of virus

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(MERS-CoV/Kor/KNIH/002_05_2015) added to volume of serum dilutions, these mixtures

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were incubated at 37°C for 2 h. The mixtures were added to each well of 24-well plate

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cultured Vero cells. The plate was incubated at 37°C for 60 min and then added 1 mL of 1.5%

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carboxymethylcellulose (CMC) overlay medium. After incubated for 3-4 days, cell staining

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was performed by crystal violet. The titer of neutralizing antibody by PRNT50 was calculated

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using Kärber formula as described previously [22]. Above 1:20 of titer was interpreted as a

96

positive. All sera with positive or borderline reaction by ELISA were tested by IFA and

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PRNT assay for the confirmation and positive case from any of two assays was determined as

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an anti-MERS positive.

99

This study received approval from the Bioethics Committee of the KCDC (2015-08-EXP-

100

03-P-A) and the Institutional Review Board of the National Cancer Center (NCC2016-0058).

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Informed consents were obtained from study participants or their parent or legal guardian in

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the case of children under 14.

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RESULTS

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Among the 3,291 selected individuals, response rates of contact with super-spreading events

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(5 or more individuals infected), contact with spreaders who infected 1-4 individuals, and the

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contacts with non-spreaders were 39.8% (552/1,388), 40.3% (139/345), and 59.0%

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(919/1,558), respectively. According to their status when they were exposed to the MERS

108

case, the response rates were higher in healthcare workers (99.4%), and family (97.1%),

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followed by visitors (75.8%), colleague (49.0%) and patient (36.8%) (Table 1).

110

Seropositive rate using ELISA was 1.05% (6/574) in patients, 0.33% (1/307) in healthcare

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workers, and 0.43% (7/1,610) overall. Among 7 ELISA-positive individuals, 3 had contact

112

with a super-spreading event (patient zero, case #1) who infected 28 individuals [23], one

113

had contact with a spreader (case #118) who infected 2 individuals, and 3 had contact with a

114

non-spreader (case #89). Among the ELISA-positive individuals, only one was both IFA- and

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PRNT-positive. Therefore, the confirmed asymptomatic rates of MERS were 0.17% in

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patients, and 0.06% (95% confidence interval, 0.0016% - 0.3461%) overall (Table 1).

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The confirmed asymptomatic case, patient zero, and 11 secondary MERS patients were

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hospitalized on the same floor of the hospital at the same time [23, 24]. The asymptomatic

119

case was quarantined at home for 2 weeks after discharge. The case had underlying diseases

120

that included hypertension, angina, and degenerative arthritis. The case reported no fever,

121

cough, myalgia, or gastrointestinal symptoms during hospitalization or quarantine (Table 2).

122

DISCUSSION

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MERS-CoV seroprevalence among populations other than confirmed MERS cases are

124

limited. Saudi Arabian data showed that the seroprevalence of MERS-CoV IgG among the

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general population was 0.15% [25], suggesting that a number of cases of asymptomatic or

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mild infection may be present in the general population.

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Despite a high prevalence of 186 confirmed MERS cases during the outbreak of MERS in

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South Korea, the rate of asymptomatic infection (1.6%) [15] was not as high as expected.

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Rates of asymptomatic infection using IFA and PRNT in the present study were 0.06%

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(1/1,610) for the total contacts and 0.17% (1/574) for patients group. In comparison to 0.27%

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(2/737) among healthcare workers, and 0.44% (2/457) among healthcare workers of the

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MERS-affected hospitals in Korea [16], these rates presented herein were much lower.

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Moreover, the rate of asymptomatic or mild infection in Saudi Arabia, UAE, and the Islamic

134

Republic of Iran was approximately 28% [12, 13, 18].

135 136

The confirmed asymptomatic case presented in this study was of a patient at the same hospital as the confirmed MERS cases and, unlike in previous studies, was neither an intra-

137

familial infection nor an infection given to a child [26, 27]. The low rate of asymptomatic

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infection in South Korea is attributable to the different transmission pathway of MERS

139

infection compared to the Middle East. In Korea, most of the MERS cases are healthcare

140

associated infection and no case from animal. The low rate of asymptomatic infection is also

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attributable to the extensive epidemiological investigation conducted in Korea, including

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close monitoring of contacts with MERS patients; this has helped identify almost all MERS

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patients. This may also be attributable to promotion of proactive identification of patients via

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mass media and the establishment of communication networks by the government, leading to

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voluntary reports by people, active quarantine, and countermeasures to public health

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crises [10, 28, 29].

147

ELISA is appropriate as a screening tool as it is 10-fold more sensitive than IFA. However,

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it may cross-react with seasonal human coronavirus antibodies, and IFA, which is a spike

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protein-specific IFA, is required for confirmation. PRNT is a definitive test when ELISA and

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IFA have inconclusive results [25]. Only 10% of ELISA-positive results are positive on

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neutralization assay [25]. In our study, 1/7 patients with borderline or positive ELISA results

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also had positive results in PRNT. Therefore, the results obtained in our study are accurate

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because ELISA, IFA, and PRNT were used.

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A previous study predicted the pandemic potential of MERS-CoV to be ≤5%; however, this

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does not indicate that the risk has abated [30]. Prerequisites to reducing the risk are

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improvement of surveillance, active contact tracing, and initiation of animal host

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searching [30, 31]. Regarding the outbreak in South Korea, MERS was classified as a

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notifiable infectious disease and was subjected to surveillance [32]. Since MERS is an

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imported disease for South Korea, it is recommended that precautions be taken before travel

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and that returning time from travel and incubation period be considered.

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This study showed a low seropositivity in the quarantined population due to contact with the

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MERS cases. However, there is a possibility that it was underestimated for the following

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reasons. Firstly, participants of the present study were mostly non-healthcare worker and

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were relatively healthy. Thus, the risk of infection is low. Secondly, the overall participation

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rate was 48.9%, while it was 36.8% in the patient group at higher risk of infection. Moreover,

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we only surveyed 10.9% of the quarantined individuals. Therefore, the actual rate of

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asymptomatic infection may be higher than that in the present study.

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Lastly, the present study may have been conducted at a later time point. MERS-CoV ELISA

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results in a previous study indicated that antibody response was highest after 3 weeks from

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symptom onset [33]. Although there are no reports on the duration of antibody in the MERS

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patients regardless of their symptoms, recent study of SARS and MERS reported that

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antibodies of some patients exist for up to 2-3 years after infection [34, 35]. The present

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study was performed on contacts between October and December 2015, while the confirmed

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case occurred between May and July 2015 (a gap of 5 months). This could cause a loss of

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MERS-CoV antibody titer despite actual asymptomatic infections; therefore, the actual rate

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of asymptomatic infection may be higher than the rate in this report.

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In conclusion, among 1,610 contacts, only one non-healthcare worker who was a patient in

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the MERS-affected hospital had asymptomatic MERS-CoV infection. To understand new

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emerging infectious diseases like MERS, more intensive epidemiologic research is needed,

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which includes the characteristics of asymptomatic infection.

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ACKNOWLEDGEMENTS

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The authors would like to thank Hee-Dong Jung, and Jeong-Gu Nam (Korea Centers for

183

Disease Control and Prevention) for laboratory assistance and technical support in production

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of the manuscript. Additionally, we would like to thank all the administrative and laboratory

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staff of Korea Centers for Disease Control and Prevention who participated in the MERS-

186

CoV outbreak control in South Korea.

187 188 189

CONFLICT OF INTEREST The authors have no conflicts of interest to declare for this study.

190 191

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respiratory

syndrome

coronavirus

infections.

New

England

Journal

of

Medicine

283 284 285 286 287 288 289 290 291

Tables

292 293

Table 1. Study subjects and seropositives by characteristics of exposed MERS case, and

294

status of subjects when they exposed to the MERS case in 2015 Korean outbreak

Characteristics of exposed MERS case Quarantined subjects

Selected subjects

Study participants

Subjects with seropositve, ELISA (IFA / PRNT)

Status* of subjects when they exposed to MERS

Selection†or Responserate (%)

Patient

Family

Visitor

Healthcare worker

Colleague

Unknown

Total

1141

71

417

558

3

657

2847

1067

64

364

198

35

375

2103

Non-spreaders

3489

321

1613

1260

453

2745

9881

Total

5697

456

2394

2016

491

3777

14831

744

60

254

115

3

212

1388

48.8

191

10

105

10

0

29

345

16.4

Non-spreaders

626

101

281

184

101

265

1558

15.8

Total

1561

171

640

309

104

506

3291

22.2

27.4

37.5

26.7

15.3

21.2

13.4

22.2

252

53

152

94

1

0

552

39.8

60

4

62

12

0

1

139

40.3

Non-spreaders

262

109

271

201

50

26

919

59.0

Total

574

166

485

307

51

27

1610

48.9

Response rate (%)

36.8

97.1

75.8

99.4

49.0

5.3

48.9

Spreaders with 5 or more cases

2 (1)

Spreaders with 1 to 4 cases

1 (0)

1 (0)

Non-spreaders

3 (0)

3 (0)

Total

6 (1)

1 (0)

7 (1)

Seropositive rate (%)

1.05 (0.17)

0.33 (–)

0.43 (0.06)

Spreaders with 5 or more cases Spreaders with 1 to 4 cases

Spreaders with 5 or more cases Spreaders with 1 to 4 cases

Selection rate (%) Spreaders with 5 or more cases Spreaders with 1 to 4 cases

1 (0)

3 (1)

295

*Patient who was inpatient or outpatient of MERS affected hospital, family was people living

296

with or paid caregiver of MERS case, visitors were those who visited the hospitalized MERS

297

case, healthcare worker was an employee at the MERS affected hospital, and colleague was a

298

co-worker in a MERS case.

299

†Selection

300

intensity) or status of subjects (i.e. exposure intensity).

rates were different by characteristics of exposed MERS case (i.e. transmission

301

Table 2. Characteristics of MERS seropositive subjects by ELISA, IFA and PRNT in South

302

Korea

Subj

Expos

Sampli

ect

ure

ng

No.

date

date

1 2

3

4

May.1 5 May.1 6 May.1 5 Jun.9

Status at exposur e

Expos ed MERS case

Underlying disease

Symptom

ELISA

IFA

PRNT

s after exposure

Ratio

Result

no.*

Nov.1

patient

#1

angina

none

0.996

borderline

positive

positive

Nov.2

patient

#1

none

none

2.078

positive

negative

negative

#1

none

fatigue

1.640

positive

negative

negative

hypertensi

blurred

on

vision

1.116

positive

negative

negative

none

0.916

borderline

negative

negative

fatigue

1.724

positive

negative

negative

0.985

borderline

negative

negative

healthc Nov.2

are worker

Oct.31

patient

#118

hypertensi 5

Jun.4

Nov.8

patient

#89

ve heart disease lumbar

6

Jun.5

Nov.9

patient

#89

spinal stenosis

fatigue 7

Jun.11

Nov.8

patient

#89

none

and blurred vision

303

*The patient zero (#1) infected 28 cases (super-spreading event transmit 5 or more cases),

304

case #118 infected 2 cases, and case #89 did not transmit MERS to anyone during 2015

305

Korean MERS outbreak.

306 307 308 309 310 311 312 313 314

Figure legend Figure 1. Flowchart of participating population in serologic survey for MERS, Korea. * Major MERS outbreak areas including Seoul, Gyeonggi, Chungcheong, and Jeonbuk in Korea.

14

1

Tables

2 3

Table 1. Study subjects and seropositives by characteristics of exposed MERS case, and

4

status of subjects when they exposed to the MERS case in 2015 Korean outbreak

Characteristics of exposed MERS case Quarantined subjects

Selected subjects

Study participants

Subjects with seropositve, ELISA (IFA / PRNT)

Status* of subjects when they exposed to MERS

Selection†or Responserate (%)

Patient

Family

Visitor

Healthcare worker

Colleague

Unknown

Total

1141

71

417

558

3

657

2847

1067

64

364

198

35

375

2103

Non-spreaders

3489

321

1613

1260

453

2745

9881

Total

5697

456

2394

2016

491

3777

14831

744

60

254

115

3

212

1388

48.8

191

10

105

10

0

29

345

16.4

Non-spreaders

626

101

281

184

101

265

1558

15.8

Total

1561

171

640

309

104

506

3291

22.2

27.4

37.5

26.7

15.3

21.2

13.4

22.2

252

53

152

94

1

0

552

39.8

60

4

62

12

0

1

139

40.3

Non-spreaders

262

109

271

201

50

26

919

59.0

Total

574

166

485

307

51

27

1610

48.9

Response rate (%)

36.8

97.1

75.8

99.4

49.0

5.3

48.9

Spreaders with 5 or more cases

2 (1)

Spreaders with 1 to 4 cases

1

1

Non-spreaders

3

3

Total

6 (1)

1

7(1)

Seropositive rate (%)

1.05 (0.17)

0.33 (–)

0.43 (0.06)

Spreaders with 5 or more cases Spreaders with 1 to 4 cases

Spreaders with 5 or more cases Spreaders with 1 to 4 cases

Selection rate (%) Spreaders with 5 or more cases Spreaders with 1 to 4 cases

1

3 (1)

5

*Patient who was inpatient or outpatient of MERS affected hospital, family was people living

6

with or paid caregiver of MERS case, visitors were those who visited the hospitalized MERS

7

case, healthcare worker was an employee at the MERS affected hospital, and colleague was a

8

co-worker in a MERS case.

9

†Selection

10

rates were different by characteristics of exposed MERS case (i.e. transmission

intensity) or status of subjects (i.e. exposure intensity).

Table 2. Characteristics of MERS seropositive subjects by ELISA, IFA and PRNT in South Korea

Subj

Expos

Sampli

ect

ure

ng

No.

date

date

1 2

3

4

May.1 5 May.1 6 May.1 5 Jun.9

Status at exposur e

Expos ed MERS case

Underlying disease

Symptom

ELISA

IFA

PRNT

s after exposure

Ratio

Result

no.*

Nov.1

patient

#1

angina

none

0.996

borderline

positive

positive

Nov.2

patient

#1

none

none

2.078

positive

negative

negative

#1

none

fatigue

1.640

positive

negative

negative

hypertensi

blurred

on

vision

1.116

positive

negative

negative

none

0.916

borderline

negative

negative

fatigue

1.724

positive

negative

negative

0.985

borderline

negative

negative

healthc Nov.2

are worker

Oct.31

patient

#118

hypertensi 5

Jun.4

Nov.8

patient

#89

ve heart disease lumbar

6

Jun.5

Nov.9

patient

#89

spinal stenosis

fatigue 7

Jun.11

Nov.8

patient

#89

none

and blurred vision

*The patient zero (#1) infected 28 cases (super-spreading event transmit 5 or more cases), case #118 infected 2 cases, and case #89 did not transmit MERS to anyone during 2015 Korean MERS outbreak.

Figure 1