Title
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
2
OBJECTIVES:
3
Asymptomatic infection rates of Middle East respiratory syndrome (MERS) coronavirus vary.
4
To identify rates of asymptomatic MERS infection in healthcare workers and non-healthcare
5
workers, serologic survey was conducted.
6
METHODS:
7
Study individuals were selected from the contacts based on a priority system in four MERS
8
prone-regions. Sero-epidemiological analysis was performed in 1,610 contacts (average
9
duration from exposure to test, 4.8 months), and the collected sera were tested using an
10
enzyme-linked immunospecific assay (ELISA), immunofluorscence assay (IFA), and plaque
11
reduction neutralization antibody test (PRNT). Of 1,610 contacts, there were seven ELISA-
12
positive cases. Among these seven, one exhibited positive IFA and PRNT results.
13
RESULTS:
14
Asymptomatic infection rate was 0.06% (95% confidence interval, 0.0016-0.3461%). The
15
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
18
degenerative arthritis.
19
CONCLUSIONS:
20
The asymptomatic infection was acquired via healthcare-associated transmission. Thus, it is
21
necessary to extend serological studies on inpatient contacts who have no symptoms.
22
Key words: asymptomatic infection, epidemiology, Middle East respiratory syndrome
23
coronavirus, nosocomial infections, outbreak, ELISA
24
INTRODUCTION
25
Middle East respiratory syndrome (MERS) is a severe respiratory infection caused by a
26
novel betacoronavirus [1-3]. The symptoms of MERS include fever, chills, cough, shortness
27
of breath, gastrointestinal symptoms, expectoration, wheezing, chest pain, hemoptysis, sore
28
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,
31
healthcare-associated, and travel-related [7, 8]. In South Korea, there were 186 cases, which
32
were predominantly caused by healthcare-associated transmission [7, 9-11], followed by
33
intra-familial transmission.
34
According to the International Health Regulations reported to WHO, rates of asymptomatic
35
or mild infection were 44/398 (28.6%) in Saudi Arabia, UAE, and the Islamic Republic of
36
Iran between April and June 2014, and 32/113 (28.31%) in Saudi Arabia in June 2014 [12,
37
13]. However, Oboho et al. reported that 78.79% (26/33) of initially reported asymptomatic
38
patients had at least one symptom [14]. In South Korea, among the confirmed 186 cases,
39
three asymptomatic cases were detected among healthcare workers via screening tests
40
(1.61%) [15]. In serologic studies using indirect immunofluorescence tests for healthcare
41
workers who were at MERS-affected hospitals, 2/457(0.44%) had positive results [16].
42
However, there has been no report on the asymptomatic infection rate among non-healthcare
43
workers in Korea. There is a considerable chance of human-to-human transmission, as well
44
as direct infection via the dromedary [17-19]. Therefore, it is necessary to identify
45
asymptomatic rates of MERS in healthcare workers and non-healthcare workers.
46
MATERIALS AND METHODS
47
Selection and participation of individuals
48
Based on a database of quarantined individuals provided by the epidemiological study
49
department of the Korea Centers for Disease Control and Prevention (KCDC), individuals at
50
four regions with major outbreaks—Seoul, Gyeonggi, Chungcheong, and Jeonbuk—were
51
selected. The individuals whose MERS status were diagnosed by using PCR test were
52
excluded from this study analysis. From 14,831 quarantined individuals, 7,233 (48.8%)
53
residents living in the four major MERS outbreak regions were selected. Of these individuals,
54
calls requesting research participation were made to 3,291 (45.5%) individuals according to
55
the prioritization groupings. A total of 1,610 (48.9%) individuals actually participated in the
56
study (Figure 1). Those who refused to participate are described in another study [20].
57
Study individuals were prioritized in groups according to transmission intensity of exposed
58
MERS case as follows: contact with super-spreading events (5 or more individuals
59
infected) [21], contact with spreaders who infected 1 to 4 individuals, and contact with non-
60
spreaders. We selected study subjects according to this prioritized groups; selection rates
61
were 48.8%, 16.4%, and 15.8%, respectively. We also categorized the subjects according to
62
their exposure intensity (i.e., status when they were exposed to the MERS case); patient who
63
was inpatient or outpatient of MERS affected hospital, family was people living with, or paid
64
caregiver of MERS case, visitors were those who visited the hospitalized MERS case,
65
healthcare worker was an employee at the MERS affected hospital, and colleague was a co-
66
worker in a MERS case. We selected more in family, patient, and visitors (Table 1).
67
Study performance
68
Only individuals who consented to participate in the study through telephone in each region
69
and gave written consent at the time of study initiation were subjected to surveys in the public
70
health centers of each area. From each participant, questionnaires on exposure were
71
conducted and blood samples were collected. Following the first serological test by ELISA,
72
the positive or borderline cases were tested using IFA and PRNT tests.
73
Antibody tests
74
MERS-CoV antibody for all sera collected from contacts were measured by using
75
recombinant S1 protein coated a human anti-MERS-CoV (IgG) ELISA kit (EUROIMMUN,
76
Germany), and this kit were carried out according to the manufacture’s protocol. The result of
77
tested samples was determined by calculating ratio value (OD value of sample/OD value of
78
calibrator). Ratio ≥1.1 as positive, ratio ≥ 0.8 to < 1.1 as borderline, and ratio < 0.8 was
79
considered as negative.
80
IFA slides were coated with MERS-CoV non-infection or infection vero cells. Serum
81
samples were diluted in phosphate buffered saline (PBS) by 1:10, 1:100, 1:250 and 1:1000,
82
transferred to IFA slides, and incubated for 30 min at 37°C in a humidified chamber. The IFA
83
slides were washed three times in PBS-T for 5 min each and incubated with FITC-conjugated
84
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
86
a mounting fluid, topped with a cover glass, and observed under a fluorescent microscope.
87
The neutralizing antibodies for serum samples were measured by PRNT. PRNT procedures
88
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
90
(MERS-CoV/Kor/KNIH/002_05_2015) added to volume of serum dilutions, these mixtures
91
were incubated at 37°C for 2 h. The mixtures were added to each well of 24-well plate
92
cultured Vero cells. The plate was incubated at 37°C for 60 min and then added 1 mL of 1.5%
93
carboxymethylcellulose (CMC) overlay medium. After incubated for 3-4 days, cell staining
94
was performed by crystal violet. The titer of neutralizing antibody by PRNT50 was calculated
95
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
97
PRNT assay for the confirmation and positive case from any of two assays was determined as
98
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).
101
Informed consents were obtained from study participants or their parent or legal guardian in
102
the case of children under 14.
103
RESULTS
104
Among the 3,291 selected individuals, response rates of contact with super-spreading events
105
(5 or more individuals infected), contact with spreaders who infected 1-4 individuals, and the
106
contacts with non-spreaders were 39.8% (552/1,388), 40.3% (139/345), and 59.0%
107
(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%),
109
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
111
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
115
PRNT-positive. Therefore, the confirmed asymptomatic rates of MERS were 0.17% in
116
patients, and 0.06% (95% confidence interval, 0.0016% - 0.3461%) overall (Table 1).
117
The confirmed asymptomatic case, patient zero, and 11 secondary MERS patients were
118
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
123
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
125
general population was 0.15% [25], suggesting that a number of cases of asymptomatic or
126
mild infection may be present in the general population.
127
Despite a high prevalence of 186 confirmed MERS cases during the outbreak of MERS in
128
South Korea, the rate of asymptomatic infection (1.6%) [15] was not as high as expected.
129
Rates of asymptomatic infection using IFA and PRNT in the present study were 0.06%
130
(1/1,610) for the total contacts and 0.17% (1/574) for patients group. In comparison to 0.27%
131
(2/737) among healthcare workers, and 0.44% (2/457) among healthcare workers of the
132
MERS-affected hospitals in Korea [16], these rates presented herein were much lower.
133
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
138
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
141
attributable to the extensive epidemiological investigation conducted in Korea, including
142
close monitoring of contacts with MERS patients; this has helped identify almost all MERS
143
patients. This may also be attributable to promotion of proactive identification of patients via
144
mass media and the establishment of communication networks by the government, leading to
145
voluntary reports by people, active quarantine, and countermeasures to public health
146
crises [10, 28, 29].
147
ELISA is appropriate as a screening tool as it is 10-fold more sensitive than IFA. However,
148
it may cross-react with seasonal human coronavirus antibodies, and IFA, which is a spike
149
protein-specific IFA, is required for confirmation. PRNT is a definitive test when ELISA and
150
IFA have inconclusive results [25]. Only 10% of ELISA-positive results are positive on
151
neutralization assay [25]. In our study, 1/7 patients with borderline or positive ELISA results
152
also had positive results in PRNT. Therefore, the results obtained in our study are accurate
153
because ELISA, IFA, and PRNT were used.
154
A previous study predicted the pandemic potential of MERS-CoV to be ≤5%; however, this
155
does not indicate that the risk has abated [30]. Prerequisites to reducing the risk are
156
improvement of surveillance, active contact tracing, and initiation of animal host
157
searching [30, 31]. Regarding the outbreak in South Korea, MERS was classified as a
158
notifiable infectious disease and was subjected to surveillance [32]. Since MERS is an
159
imported disease for South Korea, it is recommended that precautions be taken before travel
160
and that returning time from travel and incubation period be considered.
161
This study showed a low seropositivity in the quarantined population due to contact with the
162
MERS cases. However, there is a possibility that it was underestimated for the following
163
reasons. Firstly, participants of the present study were mostly non-healthcare worker and
164
were relatively healthy. Thus, the risk of infection is low. Secondly, the overall participation
165
rate was 48.9%, while it was 36.8% in the patient group at higher risk of infection. Moreover,
166
we only surveyed 10.9% of the quarantined individuals. Therefore, the actual rate of
167
asymptomatic infection may be higher than that in the present study.
168
Lastly, the present study may have been conducted at a later time point. MERS-CoV ELISA
169
results in a previous study indicated that antibody response was highest after 3 weeks from
170
symptom onset [33]. Although there are no reports on the duration of antibody in the MERS
171
patients regardless of their symptoms, recent study of SARS and MERS reported that
172
antibodies of some patients exist for up to 2-3 years after infection [34, 35]. The present
173
study was performed on contacts between October and December 2015, while the confirmed
174
case occurred between May and July 2015 (a gap of 5 months). This could cause a loss of
175
MERS-CoV antibody titer despite actual asymptomatic infections; therefore, the actual rate
176
of asymptomatic infection may be higher than the rate in this report.
177
In conclusion, among 1,610 contacts, only one non-healthcare worker who was a patient in
178
the MERS-affected hospital had asymptomatic MERS-CoV infection. To understand new
179
emerging infectious diseases like MERS, more intensive epidemiologic research is needed,
180
which includes the characteristics of asymptomatic infection.
181
ACKNOWLEDGEMENTS
182
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
184
of the manuscript. Additionally, we would like to thank all the administrative and laboratory
185
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