Joint association of carrying HLA-B*13:01 gene and human herpesvirus-6 with occupational trichloroethylene hypersensitivity syndrome

  • Dianpeng Wang
  • Dafeng LinEmail author
  • Peimao Li
  • Huimin Liu
  • Yanhua Yang
  • Zhimin Zhang
  • Qiuyue Kong
  • Yanfang Zhang
  • Xianqing Huang
Original Article



Occupational trichloroethylene hypersensitivity syndrome (OTHS) clinically manifests as generalized severe rash resembling drug-induced hypersensitivity syndrome (DIHS) and afflicts predominantly HLA-B*13:01 gene carriers after their exposure to trichloroethylene. Meanwhile, OTHS may also be associated with human herpesvirus such as herpesvirus-6 (HHV6) and cytomegalovirus (HCMV) reported to participate in the pathology of DIHS. This study explored the association of carrying HHV6 and HCMV, and the joint association of carrying HLA-B*13:01 and HHV6 and HCMV with OTHS.


We recruited 30 OTHS patients and 40 trichloroethylene-exposed healthy workers as cases and controls, respectively. HLA-B*13:01 was genotyped and HHV6 and HCMV DNA were detected in the DNA extracted from whole-blood sample of each participant with PCR techniques. Positive rates of HLA-B*13:01 gene and HHV6 and HCMV DNA and their association with OTHS were then analyzed.


The OTHS cases showed significantly higher positive rates of HLA-B*13:01 gene and HHV6 DNA, but not HCMV DNA, than the controls (83.3% vs. 25.0% and 56.7% vs. 10.0%, respectively, both P < 0.001). Positive rate of HHV6 DNA was significantly higher in HLA-B*13:01 carriers than in non-carriers in the cases (68.0% vs. 0, P = 0.005), but not in the controls. Carrying HLA-B*13:01 and HHV6 had an interactive effect on OTHS (OR = 91.80, P < 0.001).


Carrying HLA-B*13:01 and HHV6 may be associated with OTHS; furthermore, carrying HLA-B*13:01 and HHV6 may be jointly associated with OTHS.


Trichloroethylene Hypersensitivity syndrome Human leukocyte antigen Human herpesvirus-6 Human cytomegalovirus 



This work was supported by the National Natural Science Foundation of China (no. 81502797) and the Discipline Layout Project of Shenzhen Science and Technology Innovation Committee (no. JCYJ20160429090813380).


This study was funded by the National Natural Science Foundation of China (no. 81502797) and the Discipline Layout Project of Shenzhen Science and Technology Innovation Committee (no. JCYJ20160429090813380).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethics approval

All procedures performed in the study involving human participants were in accordance with the ethical standards of the Ethics Committee of Shenzhen Prevention and Treatment Center for Occupational Diseases and with the 1975 Declaration of Helsinki and its later amendments or comparable ethical standards.

Supplementary material

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Supplementary material 1 (PDF 158 KB)
420_2019_1417_MOESM2_ESM.pdf (101 kb)
Supplementary material 2 (PDF 100 KB)
420_2019_1417_MOESM3_ESM.pdf (247 kb)
Supplementary material 3 (PDF 246 KB)


  1. Bilenoğlu O, Altındiş M, Öz E, Yücel-Öz Y, İrigül-Sönmez Ö, Ünal CB (2015) Detailed polymorphism study on cytomegalovirus DNA polymerase gene to reveal the most suitable genomic targets for quantitative real-time PCR. Bosn J Basic Med Sci 15:28–34CrossRefGoogle Scholar
  2. Cao K, Hollenbach J, Shi X, Shi W, Chopek M, Fernández-Viña MA (2001) Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes in the five major ethnic groups of the United States reveals high levels of diversity in these loci and contrasting distribution patterns in these populations. Hum Immunol 62:1009–1030CrossRefGoogle Scholar
  3. Chen JZ, Liang SH, Wu QF, Li LY, Li ZG (2008) Study on the clinical skin pathology of medicamentose-like dermatitis induced by trichloroethylene. Zhong Guo Zhi Ye Yi Xue 35:128–130 (in Chinese) Google Scholar
  4. Dai Y, Chen Y, Huang H, Zhou W, Niu Y, Zhang M, Bin P, Dong H, Jia Q, Huang J, Yi J, Liao Q, Li H, Teng Y, Zang D, Zhai Q, Duan H, Shen J, He J, Meng T, Sha Y, Shen M, Ye M, Jia X, Xiang Y, Huang H, Wu Q, Shi M, Huang X, Yang H, Luo L, Li S, Li L, Zhao J, Li L, Wang J, Zheng Y (2015) Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome. Sci Rep 20:12169CrossRefGoogle Scholar
  5. De Paschale M, Agrappi C, Manco MT, Clerici P (2010) Positive predictive value of anti-HCMV IgM as an index of primary infection. J Virol Methods 168:121–125CrossRefGoogle Scholar
  6. Fishman JA (2013) Overview: cytomegalovirus and the herpesviruses in transplantation. Am J Transplant Suppl 3:1–8 (quiz 8) Google Scholar
  7. Hua M, Zhu GH, Xia LH, Zheng QL, Huang WX (2010) Analysis of causes of death and intervention measures of occupational medicamentose-like dermatitis due to trichloroethylene. Zhong Hua Lao Dong Wei Sheng Zhi Ye Bing 28:54–55 (in Chinese) Google Scholar
  8. Huang H, Kamijima M, Wang H, Li S, Yoshikawa T, Lai G, Huang Z, Liu H, Chen J, Takeuchi Y, Nakajima T, Li L (2006) Human herpesvirus 6 reactivation in trichloroethylene-exposed workers suffering from generalized skin disorders accompanied by hepatic dysfunction. J Occup Health 48:417–423CrossRefGoogle Scholar
  9. Ishida T, Kano Y, Mizukawa Y, Shiohara T (2014) The dynamics of herpesvirus reactivations during and after severe drug eruptions: their relation to the clinical phenotype and therapeutic outcome. Allergy 69:798–805CrossRefGoogle Scholar
  10. Kamijima M, Hisanaga N, Wang H, Nakajima T (2007) Occupational trichloroethylene exposure as a cause of idiosyncratic generalized skin disorders and accompanying hepatitis similar to drug hypersensitivities. Int Arch Occup Environ Health 80:357–370CrossRefGoogle Scholar
  11. Kamijima M, Wang H, Yamanoshita O, Ito Y, Xia L, Yanagiba Y, Chen C, Okamura A, Huang Z, Qiu X, Song X, Cai T, Liu L, Ge Y, Deng Y, Naito H, Yoshikawa T, Tohyama M, Li L, Huang H, Nakajima T (2013) Occupational trichloroethylene hypersensitivity syndrome: human herpesvirus 6 reactivation and rash phenotypes. J Dermatol Sci 72:218–224CrossRefGoogle Scholar
  12. Lautenschlager I, Razonable RR (2012) Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: review. Transpl Int 25:493–502CrossRefGoogle Scholar
  13. Li H, Dai Y, Huang H, Li L, Leng S, Cheng J, Niu Y, Duan H, Liu Q, Zhang X, Huang X, Xie J, Feng Z, Wang J, He J, Zheng Y (2007) HLA-B*1301 as a biomarker for genetic susceptibility to hypersensitivity dermatitis induced by trichloroethylene among workers in China. Environ Health Perspect 115:1553–1556CrossRefGoogle Scholar
  14. Liu Z, Chen G, Kang X, Han M, Chen R, Chen C, Wang H (2016) A multiplex allele-specific real-time polymerase chain reaction assay for HLA-B*13:01 genotyping in four Chinese populations. HLA 88:164–171CrossRefGoogle Scholar
  15. Lyall EG, Cubie HA (1995) Human herpesvirus-6 DNA in the saliva of paediatric oncology patients and controls. J Med Virol 47:317–322CrossRefGoogle Scholar
  16. Pavlos R, Mallal S, Ostrov D, Buus S, Metushi I, Peters B, Phillips E (2015) T cell-mediated hypersensitivity reactions to drugs. Annu Rev Med 66:439–454CrossRefGoogle Scholar
  17. People’s Republic of China (2007) Diagnostic criteria of occupational medicamentose-like dermatitis due to trichloroethylene. National Standards for Occupational Health. People's Medical Publishing House Co., LTD, Beijing, ChinaGoogle Scholar
  18. Saito S, Ota S, Yamada E, Inoko H, Ota M (2000) Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens 56:522–529CrossRefGoogle Scholar
  19. Tohyama M, Hashimoto K, Yasukawa M, Kimura H, Horikawa T, Nakajima K, Urano Y, Matsumoto K, Iijima M, Shear NH (2007) Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome. Br J Dermatol 157:934–940CrossRefGoogle Scholar
  20. Watanabe H, Tohyama M, Kamijima M, Nakajima T, Yoshida T, Hashimoto K, Iijima M (2010) Occupational trichloroethylene hypersensitivity syndrome with human herpesvirus-6 and cytomegalovirus reactivation. Dermatology 221:17–22CrossRefGoogle Scholar
  21. White KD, Chung WH, Hung SI, Mallal S, Phillips EJ (2015) Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Allergy Clin Immunol 136:219–234 (quiz 235) CrossRefGoogle Scholar
  22. Williams F, Meenagh A, Darke C, Acosta A, Daar AS, Gorodezky C, Hammond M, Nascimento E, Middleton D (2001) Analysis of the distribution of HLA-B alleles in populations from five continents. Hum Immunol 62:645–650CrossRefGoogle Scholar
  23. Xu X, Yang R, Wu N, Zhong P, Ke Y, Zhou L, Yuan J, Li G, Huang H, Wu B (2009) Severe hypersensitivity dermatitis and liver dysfunction induced by occupational exposure to trichloroethylene. Ind Health 47:107–112CrossRefGoogle Scholar
  24. Zhang JX, Li N, Wang H, Shen T, Zhu QX (2017) The immune response in trichloroethylene hypersensitivity syndrome: a review. Toxicol Ind Health 33:876–883CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Clinical LaboratoryShenzhen Prevention and Treatment Center for Occupational DiseasesShenzhenChina
  2. 2.Poisoning Detection CenterShenzhen Prevention and Treatment Center for Occupational DiseasesShenzhenChina
  3. 3.Hebei North UniversityHebeiChina

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