• 1.

    Im JH, Baek J, Durey A, Kwon HY, Chung MH, Lee JS, 2019. Current status of tick-borne diseases in South Korea. Vector Borne Zoonotic Dis 19: 225233.

  • 2.

    Park SW, Ha NY, Ryu B, Bang JH, Song H, Kim Y, Kim G, Oh MD, Cho NH, Lee JK, 2015. Urbanization of scrub typhus disease in South Korea. PLoS Negl Trop Dis 9: e0003814.

    • Search Google Scholar
    • Export Citation
  • 3.

    Maes P 2019. Taxonomy of the order Bunyavirales: second update 2018. Arch Virol 164: 927941.

  • 4.

    Yu XJ 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364: 15231532.

  • 5.

    Liu Q, He B, Huang SY, Wei F, Zhu XQ, 2014. Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis. Lancet Infect Dis 14: 763772.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kim KH, Yi J, Kim G, Choi SJ, Jun KI, Kim NH, Choe PG, Kim NJ, Lee JK, Oh MD, 2013. Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg Infect Dis 19: 18921894.

    • Search Google Scholar
    • Export Citation
  • 7.

    Takahashi T 2014. The first identification and retrospective study of severe fever with thrombocytopenia syndrome in Japan. J Infect Dis 209: 816827.

    • Search Google Scholar
    • Export Citation
  • 8.

    Korea Center for Disease Control and Prevention, 2016. Annual Surveillance of Infectious Diseases. Available at: http://cdc.go.kr/CDC/info/CdcKrInfo0302.jsp?menuIds=HOME001-MNU1132-MNU1138-MNU0038&fid=32&q_type=&q_value=&cid=75290&pageNum=. Accessed December 1, 2017.

    • Search Google Scholar
    • Export Citation
  • 9.

    Park SW, Song BG, Shin EH, Yun SM, Han MG, Park MY, Park C, Ryou J, 2014. Prevalence of severe fever with thrombocytopenia syndrome virus in Haemaphysalis longicornis ticks in South Korea. Ticks Tick Borne Dis 5: 975977.

    • Search Google Scholar
    • Export Citation
  • 10.

    Wu YC 2016. Rapid increase in scrub typhus incidence in mainland China, 2006–2014. Am J Trop Med Hyg 94: 532536.

  • 11.

    Yoo JR, Heo ST, Kang JH, Park D, Kim JS, Bae JH, Woo JJ, Kim S, Lee KH, 2018. Mixed infection with severe fever with thrombocytopenia syndrome virus and two genotypes of scrub typhus in a patient, South Korea, 2017. Am J Trop Med Hyg 99: 287290.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wi YM, Woo HI, Park D, Lee KH, Kang CI, Chung DR, Peck KR, Song JH, 2016. Severe fever with thrombocytopenia syndrome in patients suspected of having scrub typhus. Emerg Infect Dis 22: 19921995.

    • Search Google Scholar
    • Export Citation
  • 13.

    Kim WY 2015. Nosocomial transmission of severe fever with thrombocytopenia syndrome in Korea. Clin Infect Dis 60: 16811683.

  • 14.

    Kim JY 2018. Rapid diagnosis of tick-borne illnesses by use of one-step isothermal nucleic acid amplification and bio-optical sensor detection. Clin Chem 64: 556565.

    • Search Google Scholar
    • Export Citation
  • 15.

    Kim DM, Lee YM, Back JH, Yang TY, Lee JH, Song HJ, Shim SK, Hwang KJ, Park MY, 2010. A serosurvey of Orientia tsutsugamushi from patients with scrub typhus. Clin Microbiol Infect 16: 447451.

    • Search Google Scholar
    • Export Citation
  • 16.

    Tantibhedhyangkul W, Wongsawat E, Silpasakorn S, Waywa D, Saenyasiri N, Suesuay J, Thipmontree W, Suputtamongkol Y, 2017. Use of multiplex real-time PCR to diagnose scrub typhus. J Clin Microbiol 55: 13771387.

    • Search Google Scholar
    • Export Citation
  • 17.

    Wang QK, Ge HM, Li ZF, Shan YF, Cui L, Wang YP, 2012. Vector research of severe fever with thrombocytopenia syndrome virus in gamasid mites and chigger mites. Chinese J Vec Biol Contr 23: 452454.

    • Search Google Scholar
    • Export Citation
  • 18.

    Blacksell SD, Bryant NJ, Paris DH, Doust JA, Sakoda Y, Day NP, 2007. Scrub typhus serologic testing with the indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to a lot of confusion. Clin Infect Dis 44: 391401.

    • Search Google Scholar
    • Export Citation
  • 19.

    Kim MC, Chong YP, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH, 2018. Differentiation of severe fever with thrombocytopenia syndrome from scrub typhus. Clin Infect Dis 66: 16211624.

    • Search Google Scholar
    • Export Citation

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Coinfection of Severe Fever with Thrombocytopenia Syndrome and Scrub Typhus in Patients with Tick-Borne Illness

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  • 1 Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus are the most common tick-borne diseases in South Korea. However, few studies have systematically examined the simultaneous presence of the two diseases. We found that two (4.9%) of 41 patients with suspected and confirmed SFTS had evidence of coinfection with scrub typhus. In addition, two (3.6%) of 55 suspected and confirmed scrub typhus patients were identified to have coinfection with SFTS. Our data suggest that diagnostic evaluation for coinfection in patients with tick-borne illness and empirical doxycycline treatment in patients with SFTS may be warranted in areas endemic for both diseases until coinfection with scrub typhus is ruled out.

Severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus are the most common tick-borne diseases in South Korea.1,2 Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus (now renamed Huaiyangshan banyangvirus) in the genus Banyangvirus, family Phenuiviridae, and order Bunyavirales,3 and was first reported in China4,5 in 2011, and in South Korea6 and Japan7 in 2013–2014. Since then, hundreds of cases have been reported annually in South Korea.8 Ticks such as Haemaphysalis longicornis have been identified as major vectors for SFTSV.9 Scrub typhus is caused by Orientia tsutsugamushi, which is transmitted by chigger mites such as Leptotrombidium species, and thousands of cases are reported annually in South Korea.8

Severe fever with thrombocytopenia syndrome and scrub typhus have similar clinical manifestations: fever, myalgia, and gastrointestinal symptoms. Moreover, the two diseases have overlapping areas of prevalence and similar risk factors, such as history of outdoor activities, farming, exposure to sward, and occasionally tick or chigger bite.5,10 In addition to the difficulty in distinguishing between SFTS and scrub typhus, coinfections are also a matter of concern in real clinical practice, in relation to laboratory evaluation and empirical doxycycline use. One case of coinfection with SFTS and scrub typhus was reported recently,11 and another study found that 17 (23%) of 74 patients with initially suspected scrub typhus were eventually diagnosed with SFTS and seven (41%) of these had high O. tsutsugamushi antibody titers.12 However, coinfections have not been systematically evaluated. We therefore investigated the frequency of coinfection of SFTS and scrub typhus.

All adult patients aged ≥ 18 years with suspected tick-borne illness in the Asan Medical Center, a 2,700-bed tertiary hospital in Seoul, South Korea, between July 2015 and October 2018 were enrolled. Of these patients, those who were diagnosed with SFTS or scrub typhus and whose blood plasma was available for further analysis were finally analyzed. Severe fever with thrombocytopenia syndrome was confirmed by detecting SFTSV RNA by reverse transcription–polymerase chain reaction (RT-PCR) analysis of a plasma sample, using a DiaStar 2× OneStep RT-PCR Pre-Mix kit (SolGent, Daejeon, South Korea), as described previously.13 To diagnose scrub typhus, we performed immunofluorescence assays (IFAs; SD Bioline Tsutsugamushi Assay; Standard Diagnostics, Yongin, South Korea) and real-time PCR for O. tsutsugamushi in plasma samples, as described previously.14 A diagnosis of scrub typhus was established if there was 1) a single positive IgG result (titer ≥ 1:320) or a 4-fold rise in IgG in serial samples by IFA,15 or 2) a positive real-time PCR result for O. tsutsugamushi.16 The study protocol was approved by the Institutional Review Board of the Asan Medical Center.

A total of 44 and 107 patients with suspected tick-borne diseases were confirmed to have SFTS and scrub typhus, respectively, during the study period. Most patients with confirmed SFTS and those confirmed as having scrub typhus were initially suspected to have the corresponding diseases. Of the 44 patients with confirmed SFTS, 41 (93.2%) whose plasma samples were available for further analysis, with 20 paired samples and 21 single samples, underwent scrub typhus IFA. In addition, 32 patients whose plasma samples were available for further molecular analysis underwent scrub typhus PCR. Of these 41 patients, two (4.9%) patients had evidence of coinfection of scrub typhus. During the same study period, 107 patients met the aforementioned serologic criteria and were confirmed to have scrub typhus. Of these 107 patients with scrub typhus, 55 (51.4%) whose plasma samples were available for further molecular analysis underwent SFTSV RT-PCR. Of these 55 patients, two (3.6%) patients had evidence of coinfection of SFTS. Detailed clinical characteristics and laboratory data of these four patients with coinfection are shown in Table 1. One was a 62-year-old woman (Patient 1) diagnosed with SFTS in August 2018 whose O. tsutsugamushi IgG titer increased from ≥ 1:640 at admission to ≥ 1:5120 19 days later and who was positive for O. tsutsugamushi PCR. Another was a 64-year-old woman (Patient 2) diagnosed with SFTS in May 2016 whose acute plasma sample gave a positive scrub typhus PCR outcome; however, a subsequent single plasma sample IFA gave a negative result. Another was an 81-year-old woman (Patient 3) who was diagnosed with scrub typhus in November 2015 based on an initial high O. tsutsugamushi IgG titer (1:2,560) along with a positive O. tsutsugamushi PCR and was eventually diagnosed with SFTS based on a positive SFTSV RT-PCR result, also from her plasma sample. The last was a 73-year-old man (Patient 4) diagnosed with scrub typhus in November 2016 whose O. tsutsugamushi IgG titer increased from ≥ 1:40 at admission to ≥ 1:2,560 5 days later and was also eventually diagnosed with SFTS based on a positive SFTSV RT-PCR.

Table 1

Baseline characteristics and outcomes of the four coinfected patients

VariablesSevere fever with thrombocytopenia syndrome–suspected and confirmed patientsScrub typhus–suspected and confirmed patients
Patient 1Patient 2Patient 3Patient 4
SeasonSummerSpringFallFall
(Month)(August)(May)(November)(November)
Age (years)62648173
GenderFemaleFemaleFemaleMale
Underlying diseaseHTNNoneDiabetesHTN
DiabetesPrimary biliary cirrhosis
Asthma
Symptom duration before hospital visit (days)66105
Clinical manifestation
 Fever, febrile period (days)Yes (4)Yes (5)Yes (2)Yes (4)
 Tick- or chigger-bite woundNoneNoneYesNone
 Skin rashNoneNoneYesYes
 Bleeding eventsNoneNoneNoneNone
 MyalgiaYesYesNoneNone
 LymphadenopathyNoneNoneNoneNone
 General weaknessYesYesNoneYes
 Nausea/vomitingYesYesNoneNone
 Abdominal painNoneNoneNoneNone
 DiarrheaYesNoneNoneNone
 Cough/sputum/rhinorrheaYesNoneYesYes
 HeadacheNoneYesNoneNone
 Altered mental statusYesYesNoneNone
Initial laboratory data
 White blood cell count (/μL)1,2001,80011,8009,800
  Neutrophils (%)60648380
  Lymphocytes (%)36331313
  Monocytes (%)4247
 Platelet count (/μL)68,00062,000122,000121,000
 Hemoglobin (g/dL)14131212.6
 Prothrombin time international normalized ratio1.080.961.031.09
 Activated partial thromboplastin time (seconds)46394331
 C-reactive protein level (mg/dL)1.060.28.56.2
 BUN (mg/dL)38242118
 Creatinine (mg/dL)1.691.130.81.09
 Estimated glomerular filtration rate (mL/minutes/1.73 m2)32486966
 Aspartate aminotransferase (IU/L)3291216061
 Alanine aminotransferase (IU/L)105384958
 Alkaline phosphate (IU/L)584645182
 Total bilirubin (mg/dL)0.30.20.30.5
 Creatinine kinase (IU/L)1,4312,33989245
 Lactate dehydrogenase (IU/L)1,6411,837493356
 Myoglobin (IU/L)885348NoneNone
Central nervous system involvementYesYesNoneNone
Lung involvementYesYesYesYes
ShockYesNoneNoneNone
 Clinical course
  Intensive care unit admissionYesYesNoneNone
  Mechanical ventilationYesNoneNoneNone
  Inhospital deathNoneNoneNoneNone
  Hospital stay (days)431546
Treatment
 DoxycyclineYesYesYesYes
 RibavirinNoneYesNoneNone
 Supportive careNoneNoneNoneNone
 PlasmapheresisYesYesNoneNone
 Convalescent plasma therapyNoneNoneNoneNone
 AzithromycinNoneNoneNoneNone
Severe fever with thrombocytopenia syndrome virus reverse transcription–polymerase chain reaction (log copies/μL)Positive (3.2)Positive (4.4)Positive (1.0)Positive (1.2)
Scrub typhus PCR (log copies/μL)Positive (0.54)Positive (0.51)Positive (0.94)Negative
Scrub typhus gene sequencing resultsOrientia tsutsugamushi strain NishinoOrientia tsutsugamushi strain Inha-B697253-1Orientia tsutsugamushi strain BoryongNegative scrub typhus PCR result
Scrub typhus IgG titer initially1:640Negative1:2,5601:40
Scrub typhus IgG titer in paired sera1:5,120NegativeNone1:2,560

HTN = hypertension; PCR = polymerase chain reaction.

A previous Korean study12 found that as many as seven (41%) of 17 patients with SFTS who were initially suspected of having scrub typhus had high O. tsutsugamushi antibody titers (1:2,560). However, they did not systemically evaluate coinfections with SFTS and scrub typhus, and it is difficult to rule out the possibility that a single high titer of scrub typhus antibody is the result of past or recent infection. Actually, to our knowledge, there is only one case report of coinfection with SFTS and scrub typhus based on molecular evidence for both diseases.11 Because different vectors are involved in SFTS and scrub typhus, we thought that the true coinfection rate might be lower than 41%. We, therefore, systemically evaluated the frequency of coinfection of SFTS and scrub typhus using serologic tests and molecular analysis. We found that two (4.9%) of 41 suspected and confirmed SFTS patients had evidence of coinfection of scrub typhus, and two (3.6%) of 55 suspected and confirmed scrub typhus patients were identified to have coinfection with SFTS. These findings provide important information in terms of further diagnostic tests for SFTS in patients with scrub typhus and empirical doxycycline use in patients with SFTS. However, further studies are needed to elucidate questions concerning the mechanism of coinfection, such as whether it involves bites by different vectors or a bite from a common vector. We note that in China, SFTSV has been detected by RT-PCR in Leptotrombidium scutellare, a vector for scrub typhus.17

A rapid diagnosis of SFTS, with relatively high sensitivity, is usually made by RT-PCR for SFTSV in blood samples. However, for scrub typhus, rapid molecular diagnosis has some limitations in routine clinical use due to the relatively low bacterial loads in sera. Some workers have proposed performing PCR from buffy coat samples, but the preparation of such samples requires technical expertise. Therefore, a diagnosis of scrub typhus usually depends on serologic examinations such as IFA. However, a single IFA result does not support a definitive diagnosis, and a dynamic change in the IFA titer between paired sera is required.18 In this context, our data suggest that empirical doxycycline use is warranted until laboratory evidence rules out coinfection.

This study has some limitations. First, about half of the patients with confirmed SFTS did not undergo paired scrub typhus IgG serology tests because paired samples had not been stored or because they were not collected initially. In addition, about half of the patients with confirmed scrub typhus did not undergo further SFTSV RT-PCR because samples had not been available. Therefore, some selection bias may have been introduced. Second, in some patients, scrub typhus PCR was performed after doxycycline administration and may have yielded false-negative results. Third, some may be confused with our previous data14 reporting one false-positive PCR result (Patient 2 in Table 1 in the current study) for scrub typhus in 15 SFTS patients and one false-positive RT-PCR result (Patient 4 in Table 1 in the current study) for SFTS in 21 scrub typhus patients. Actually, the 41 patients with SFTS in the current study included the 15 patients with SFTS enrolled in the previous study,14 and the 55 patients with scrub typhus in the current study included 21 patients with scrub typhus enrolled in the previous study.14 However, we have described these findings as false-positive scrub typhus PCR and false-positive SFTSV RT-PCR with the specificity of 95% for scrub typhus PCR and 95% for SFTSV RT-PCR, respectively, because we did not have the concept of coinfection at the time of our previous writing. Fourth, some may argue the challenges in diagnosing scrub typhus using serologic methods. Although we used the serologic diagnostic criteria according to the 2007 Korea Center for Disease Control and Prevention guidelines,15 a single high IFA titer is insufficient for a definite diagnosis because a single positive IFA result may suggest past infection with scrub typhus.19 So, further well-designed studies with more strict serologic criteria for scrub typhus will reveal the true prevalence of coinfection in patients with suspected tick-borne illness. Last, the theoretical possibility of crossreactivity between the antibodies to SFTS and scrub typhus should be mentioned. However, to our knowledge, there are no reports of such crossreactivity.

In conclusion, our data suggest that about 3–4% of SFTS and scrub typhus patients are coinfected with scrub typhus and SFTS, respectively. Therefore, in areas endemic to both diseases, empirical doxycycline treatment may be warranted until coinfection with scrub typhus is ruled out in SFTS patients, and further diagnostic tests for SFTS in scrub typhus patients are necessary.

REFERENCES

  • 1.

    Im JH, Baek J, Durey A, Kwon HY, Chung MH, Lee JS, 2019. Current status of tick-borne diseases in South Korea. Vector Borne Zoonotic Dis 19: 225233.

  • 2.

    Park SW, Ha NY, Ryu B, Bang JH, Song H, Kim Y, Kim G, Oh MD, Cho NH, Lee JK, 2015. Urbanization of scrub typhus disease in South Korea. PLoS Negl Trop Dis 9: e0003814.

    • Search Google Scholar
    • Export Citation
  • 3.

    Maes P 2019. Taxonomy of the order Bunyavirales: second update 2018. Arch Virol 164: 927941.

  • 4.

    Yu XJ 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364: 15231532.

  • 5.

    Liu Q, He B, Huang SY, Wei F, Zhu XQ, 2014. Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis. Lancet Infect Dis 14: 763772.

    • Search Google Scholar
    • Export Citation
  • 6.

    Kim KH, Yi J, Kim G, Choi SJ, Jun KI, Kim NH, Choe PG, Kim NJ, Lee JK, Oh MD, 2013. Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg Infect Dis 19: 18921894.

    • Search Google Scholar
    • Export Citation
  • 7.

    Takahashi T 2014. The first identification and retrospective study of severe fever with thrombocytopenia syndrome in Japan. J Infect Dis 209: 816827.

    • Search Google Scholar
    • Export Citation
  • 8.

    Korea Center for Disease Control and Prevention, 2016. Annual Surveillance of Infectious Diseases. Available at: http://cdc.go.kr/CDC/info/CdcKrInfo0302.jsp?menuIds=HOME001-MNU1132-MNU1138-MNU0038&fid=32&q_type=&q_value=&cid=75290&pageNum=. Accessed December 1, 2017.

    • Search Google Scholar
    • Export Citation
  • 9.

    Park SW, Song BG, Shin EH, Yun SM, Han MG, Park MY, Park C, Ryou J, 2014. Prevalence of severe fever with thrombocytopenia syndrome virus in Haemaphysalis longicornis ticks in South Korea. Ticks Tick Borne Dis 5: 975977.

    • Search Google Scholar
    • Export Citation
  • 10.

    Wu YC 2016. Rapid increase in scrub typhus incidence in mainland China, 2006–2014. Am J Trop Med Hyg 94: 532536.

  • 11.

    Yoo JR, Heo ST, Kang JH, Park D, Kim JS, Bae JH, Woo JJ, Kim S, Lee KH, 2018. Mixed infection with severe fever with thrombocytopenia syndrome virus and two genotypes of scrub typhus in a patient, South Korea, 2017. Am J Trop Med Hyg 99: 287290.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wi YM, Woo HI, Park D, Lee KH, Kang CI, Chung DR, Peck KR, Song JH, 2016. Severe fever with thrombocytopenia syndrome in patients suspected of having scrub typhus. Emerg Infect Dis 22: 19921995.

    • Search Google Scholar
    • Export Citation
  • 13.

    Kim WY 2015. Nosocomial transmission of severe fever with thrombocytopenia syndrome in Korea. Clin Infect Dis 60: 16811683.

  • 14.

    Kim JY 2018. Rapid diagnosis of tick-borne illnesses by use of one-step isothermal nucleic acid amplification and bio-optical sensor detection. Clin Chem 64: 556565.

    • Search Google Scholar
    • Export Citation
  • 15.

    Kim DM, Lee YM, Back JH, Yang TY, Lee JH, Song HJ, Shim SK, Hwang KJ, Park MY, 2010. A serosurvey of Orientia tsutsugamushi from patients with scrub typhus. Clin Microbiol Infect 16: 447451.

    • Search Google Scholar
    • Export Citation
  • 16.

    Tantibhedhyangkul W, Wongsawat E, Silpasakorn S, Waywa D, Saenyasiri N, Suesuay J, Thipmontree W, Suputtamongkol Y, 2017. Use of multiplex real-time PCR to diagnose scrub typhus. J Clin Microbiol 55: 13771387.

    • Search Google Scholar
    • Export Citation
  • 17.

    Wang QK, Ge HM, Li ZF, Shan YF, Cui L, Wang YP, 2012. Vector research of severe fever with thrombocytopenia syndrome virus in gamasid mites and chigger mites. Chinese J Vec Biol Contr 23: 452454.

    • Search Google Scholar
    • Export Citation
  • 18.

    Blacksell SD, Bryant NJ, Paris DH, Doust JA, Sakoda Y, Day NP, 2007. Scrub typhus serologic testing with the indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to a lot of confusion. Clin Infect Dis 44: 391401.

    • Search Google Scholar
    • Export Citation
  • 19.

    Kim MC, Chong YP, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH, 2018. Differentiation of severe fever with thrombocytopenia syndrome from scrub typhus. Clin Infect Dis 66: 16211624.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Sung-Han Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro-43-gil, Songpa-gu, Seoul 05505, Republic of Korea. E-mail: kimsunghanmd@hotmail.com

Financial support: This study was supported by grants from the Government-wide R&D Fund Project for Infectious Disease Research (GFID), Republic of Korea (grant no. HG18C0037) and from the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (grant no. NRF-2017R1A6A3A11031093).

Authors’ addresses: Sang Hyun Ra, Ji Yeun Kim, Hye Hee Cha, Ji-Soo Kwon, Hyun-Jung Lee, Na Young Jeon, Min Jae Kim, Yong Pil Chong, Sang-Oh Lee, Sang-Ho Choi, Yang Soo Kim, Jun Hee Woo, and Sung-Han Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, E-mails: jesus4274@naver.com, aeki22@snu.ac.kr, heyhe0102@naver.com, kwonjs92@kaist.ac.kr, silverspec@naver.com, dognaf@naver.com, nahani99@gmail.com, drchong@amc.seoul.kr, soleemd@amc.seoul.kr, sangho@amc.seoul.kr, yskim@amc.seoul.kr, yeom3477@daum.net, and kimsunghanmd@hotmail.com.

These authors contributed equally to this work.

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