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: 763–772.
Watt G , Parola P , 2003. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis 16: 429–436.
Yu XJ et al., 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364: 1523–1532.
Bonell A , Lubell Y , Newton PN , Crump JA , Paris DH , 2017. Estimating the burden of scrub typhus: a systematic review. PLoS Negl Trop Dis 11: e0005838.
Li H et al., 2018. Epidemiological and clinical features of laboratory-diagnosed severe fever with thrombocytopenia syndrome in China, 2011–17: a prospective observational study. Lancet Infect Dis 18: 1127–1137.
Choi SJ et al., 2016. Severe fever with thrombocytopenia syndrome in South Korea, 2013–2015. PLoS Negl Trop Dis 10: e0005264.
Kwon JS et al., 2018. Kinetics of viral load and cytokines in severe fever with thrombocytopenia syndrome. J Clin Virol 101: 57–62.
Yun JH et al., 2019. Comparison of chest radiographic findings between severe fever with thrombocytopenia syndrome and scrub typhus: single center observational cross-sectional study in South Korea. Medicine (Baltimore) 98: e17701.
Kwon JS et al., 2021. Viral and immunologic factors associated with fatal outcome of patients with severe fever with thrombocytopenia syndrome in Korea. Viruses 13: 2351.
Balasubramanian P , Sharma N , Biswal M , Bhalla A , Kumar S , Kumar V , 2018. Critical illness scoring systems: sequential organ failure assessment, acute physiology and chronic health evaluation II, and quick sequential organ failure assessment to predict the clinical outcomes in scrub typhus patients with organ dysfunctions. Indian J Crit Care Med 22: 706–710.
Korea Disease Control and Prevention Agency , 2022. Pathogen Biosafety Collection. Available at: https://www.kdca.go.kr/board/board.es?mid=a20302111500&bid=0065. Accessed May 16, 2023.
Fajgenbaum DC , June CH , 2020. Cytokine storm. N Engl J Med 383: 2255–2273.
Park SY et al., 2018. Severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis. Clin Microbiol Infect 24: 432.e1–432.e4.
Kramme S , An le V , Khoa ND , Trin le V , Tannich E , Rybniker J , Fleischer B , Drosten C , Panning M , 2009. Orientia tsutsugamushi bacteremia and cytokine levels in Vietnamese scrub typhus patients. J Clin Microbiol 47: 586–589.
Astrup E et al., 2014. Cytokine network in scrub typhus: high levels of interleukin-8 are associated with disease severity and mortality. PLoS Negl Trop Dis 8: e2648.
Münch CCS et al., 2023. Multiple Orientia clusters and Th1-skewed chemokine profile: a cross-sectional study in patients with scrub typhus from Nepal. Int J Infect Dis 128: 78–87.
Bal M , Kar CR , Behera HK , Kar PC , Biswas S , Dixit S , Khuntia HK , Pati S , Ranjit M , 2021. Scrub typhus associated acute kidney injury: an emerging health problem in Odisha, India. J Vector Borne Dis 58: 359–367.
Sun Y et al., 2012. Host cytokine storm is associated with disease severity of severe fever with thrombocytopenia syndrome. J Infect Dis 206: 1085–1094.
Bora T , Khan SA , 2019. Evaluation of Th1 and Th2 immune response in clinical and sub-clinical scrub typhus infection. Hum Immunol 80: 503–509.
Eisermann P , Rauch J , Reuter S , Eberwein L , Mehlhoop U , Allartz P , Muntau B , Tappe D , 2020. Complex cytokine response in imported scrub typhus cases, Germany, 2010–2018. Am J Trop Med Hyg 102: 63–68.
Kwon JS et al., 2020. Factors of severity in patients with COVID-19: cytokine/chemokine concentrations, viral load, and antibody responses. Am J Trop Med Hyg 103: 2412–2418.
John SH , Kenneth J , Gandhe AS , 2012. Host biomarkers of clinical relevance in tuberculosis: review of gene and protein expression studies. Biomarkers 17: 1–8.
Ferreira AS , Baldoni NR , Cardoso CS , Oliveira CDL , 2021. Biomarkers of severity and chronification in chikungunya fever: a systemic review and meta-analysis. Rev Inst Med Trop São Paulo 63: e16.
Tramontini Gomes de Sousa Cardozo F , Baimukanova G , Lanteri MC , Keating SM , Moraes Rerreira F , Heitman J , Pannuti CS , Pati S , Romano CM , Sabino EC , 2017. Serum from dengue virus-infected patients with and without plasma leakage differentially affects endothelial cells barrier function in vitro. PLoS One 12: e0178820.
Ding YP et al., 2014. Prognostic value of clinical and immunological markers in acute phase of SFTS virus infection. Clin Microbiol Infect 20: O870–O878.
Park A et al., 2021. Molecular signatures of inflammatory profile and B-cell function in patients with severe fever with thrombocytopenia syndrome. mBio 12: e02583-20.
He Z , Wang B , Li Y , Hu K , Yi Z , Ma H , Li X , Guo W , Xu B , Huang X , 2021. Changes in peripheral blood cytokines in patients with severe fever with thrombocytopenia syndrome. J Med Virol 93: 4704–4713.
Hamilton JA , 2020. GM-CSF in inflammation. J Exp Med 217: e20190945.
Hu L et al., 2021. Early-warning immune predictors for invasive pulmonary aspergillosis in severe patients with severe fever with thrombocytopenia syndrome. Front Immunol 12: 576640.
Hu L , Kong Q , Liu Y , Li J , Bian T , Ma X , Ye Y , Li J , 2021. Time course of severe fever with thrombocytopenia syndrome virus and antibodies in patients by long-term follow-up study, China. Front Microbiol 12: 744037.
Wen S , Xu N , Wang G , 2022. Ruxolitinib for severe fever with thrombocytopenia syndrome (SFTS). Heliyon 8: e12462.
Chung H et al., 2022. Kinetics of glycoprotein-specific antibody response in patients with severe fever with thrombocytopenia syndrome. Viruses 14: 256.
Iwasaki H , Takada N , Nakamura T , Ueda T , 1997. Increased levels of macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha in sera of patients with Orientia tsutsugamushi infection. J Clin Microbiol 35: 3320–3322.
Yoon HJ , Lee MS , Ki M , Ihm C , Kim D , Kim Y , Yoo SM , 2010. Does IL-17 play a role in hepatic dysfunction of scrub typhus patients? Vector Borne Zoonotic Dis 10: 231–235.
Dai ZN et al., 2022. Effect of genomic variations in severe fever with thrombocytopenia syndrome virus on the disease lethality. Emerg Microbes Infect 11: 1672–1682.
Li MM et al., 2018. CD4 T cell loss and Th2 and Th17 bias are associated with the severity of severe fever with thrombocytopenia syndrome (SFTS). Clin Immunol 195: 8–17.
Li H et al., 2021. Single-cell landscape of peripheral immune responses to fatal SFTS. Cell Rep 37: 110039.
Soong L , 2018. Dysregulated Th1 immune and vascular responses in scrub typhus pathogenesis. J Immunol 200: 1233–1240.
Seo JW , Kim DY , Yun N , Kim DM , 2021. Clinical update of severe fever with thrombocytopenia syndrome. Viruses 13: 1213.
Seong SY , Choi MS , Kim IS , 2001. Orientia tsutsugamushi infection: overview and immune responses. Microbes Infect 3: 11–21.
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In East Asia, severe fever with thrombocytopenia syndrome (SFTS) and scrub typhus, which are common endemic tick- and mite-mediated diseases sharing common clinical manifestations, are becoming public health concerns. However, there are limited data on the comparative immunopathogenesis between the two diseases. We compared the cytokine profiles of SFTS and scrub typhus to further elucidate immune responses that occur during the disease courses. We prospectively enrolled 44 patients with confirmed SFTS and 49 patients with scrub typhus from July 2015 to December 2020. In addition, 10 healthy volunteers were enrolled as healthy controls. A cytometric bead array was used to analyze plasma samples for 16 cytokines. A total of 68 plasma samples, including 31 (45.6%) from patients with SFTS and 37 (54.4%) from patients with scrub typhus, were available for cytokine measurement. There were three cytokine expression patterns: increased levels in both SFTS and scrub typhus (interleukin 6 [IL-6], IL-10, interferon gamma induced protein 10 [IP-10], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), highest levels in SFTS (interferon alpha [IFN-α], IFN-γ, granulocyte-CSF [G-CSF], monocyte chemotactic protein 1 [MCP-1], macrophage inflammatory protein 1α [MIP-1α], and IL-8), and distinct levels in scrub typhus (IL-12p40, tumor necrosis factor alpha [TNFα], IL-1β, regulated on activation and normally T-cell expressed and secreted [RANTES], IL-17A, and vascular endothelial growth factor [VEGF]). Although patients with acute SFTS and scrub typhus exhibited partly shared expression patterns of cytokines related to disease severity, the different profiles of cytokines and chemokines might contribute to higher mortality in SFTS than in scrub typhus. Discrete patterns of helper T cell-related cytokines and VEGF might reflect differences in CD4 T-cell responses and vascular damage between these diseases.
Financial support: This study was supported by a grant from the
Authors’ addresses: Ji-Soo Kwon, Ji Yeun Kim, Hye Hee Cha, and Sung-Han Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea, E-mails: kwonjs92@hotmail.com, aeki22@naver.com, heyhe0102@naver.com, and shkimmd@amc.seoul.kr. Sun In Hong, Division of Infectious Diseases, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea, E-mail: hsun0702@hanmail.net. Taeeun Kim, Division of Infectious Diseases, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea, and Division of Infectious Diseases, Nowon Eulji University Hospital, Eulji University School of Medicine, Seoul, Republic of Korea, E-mail: sleepju@naver.com. Se Yoon Park, Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Republic of Korea, and Department of Infectious Diseases, Hanyang University Medical Center, Hanyang University College of Medicine, Seoul, Republic of Korea, E-mail: livinwill2@gmail.com. Min-Chul Kim, Seong-Ho Choi, and Jin-Won Chung, Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea, E-mails: pour-soi@hanmail.net, tobeserve@gmail.com, and drjwchung@cau.ac.kr. Seong Yeon Park, Department of Infectious Diseases, Dongguk University Ilsan Hospital, Goyang, Republic of Korea, E-mail: psy99ch@daum.net.
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: 763–772.
Watt G , Parola P , 2003. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis 16: 429–436.
Yu XJ et al., 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364: 1523–1532.
Bonell A , Lubell Y , Newton PN , Crump JA , Paris DH , 2017. Estimating the burden of scrub typhus: a systematic review. PLoS Negl Trop Dis 11: e0005838.
Li H et al., 2018. Epidemiological and clinical features of laboratory-diagnosed severe fever with thrombocytopenia syndrome in China, 2011–17: a prospective observational study. Lancet Infect Dis 18: 1127–1137.
Choi SJ et al., 2016. Severe fever with thrombocytopenia syndrome in South Korea, 2013–2015. PLoS Negl Trop Dis 10: e0005264.
Kwon JS et al., 2018. Kinetics of viral load and cytokines in severe fever with thrombocytopenia syndrome. J Clin Virol 101: 57–62.
Yun JH et al., 2019. Comparison of chest radiographic findings between severe fever with thrombocytopenia syndrome and scrub typhus: single center observational cross-sectional study in South Korea. Medicine (Baltimore) 98: e17701.
Kwon JS et al., 2021. Viral and immunologic factors associated with fatal outcome of patients with severe fever with thrombocytopenia syndrome in Korea. Viruses 13: 2351.
Balasubramanian P , Sharma N , Biswal M , Bhalla A , Kumar S , Kumar V , 2018. Critical illness scoring systems: sequential organ failure assessment, acute physiology and chronic health evaluation II, and quick sequential organ failure assessment to predict the clinical outcomes in scrub typhus patients with organ dysfunctions. Indian J Crit Care Med 22: 706–710.
Korea Disease Control and Prevention Agency , 2022. Pathogen Biosafety Collection. Available at: https://www.kdca.go.kr/board/board.es?mid=a20302111500&bid=0065. Accessed May 16, 2023.
Fajgenbaum DC , June CH , 2020. Cytokine storm. N Engl J Med 383: 2255–2273.
Park SY et al., 2018. Severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis. Clin Microbiol Infect 24: 432.e1–432.e4.
Kramme S , An le V , Khoa ND , Trin le V , Tannich E , Rybniker J , Fleischer B , Drosten C , Panning M , 2009. Orientia tsutsugamushi bacteremia and cytokine levels in Vietnamese scrub typhus patients. J Clin Microbiol 47: 586–589.
Astrup E et al., 2014. Cytokine network in scrub typhus: high levels of interleukin-8 are associated with disease severity and mortality. PLoS Negl Trop Dis 8: e2648.
Münch CCS et al., 2023. Multiple Orientia clusters and Th1-skewed chemokine profile: a cross-sectional study in patients with scrub typhus from Nepal. Int J Infect Dis 128: 78–87.
Bal M , Kar CR , Behera HK , Kar PC , Biswas S , Dixit S , Khuntia HK , Pati S , Ranjit M , 2021. Scrub typhus associated acute kidney injury: an emerging health problem in Odisha, India. J Vector Borne Dis 58: 359–367.
Sun Y et al., 2012. Host cytokine storm is associated with disease severity of severe fever with thrombocytopenia syndrome. J Infect Dis 206: 1085–1094.
Bora T , Khan SA , 2019. Evaluation of Th1 and Th2 immune response in clinical and sub-clinical scrub typhus infection. Hum Immunol 80: 503–509.
Eisermann P , Rauch J , Reuter S , Eberwein L , Mehlhoop U , Allartz P , Muntau B , Tappe D , 2020. Complex cytokine response in imported scrub typhus cases, Germany, 2010–2018. Am J Trop Med Hyg 102: 63–68.
Kwon JS et al., 2020. Factors of severity in patients with COVID-19: cytokine/chemokine concentrations, viral load, and antibody responses. Am J Trop Med Hyg 103: 2412–2418.
John SH , Kenneth J , Gandhe AS , 2012. Host biomarkers of clinical relevance in tuberculosis: review of gene and protein expression studies. Biomarkers 17: 1–8.
Ferreira AS , Baldoni NR , Cardoso CS , Oliveira CDL , 2021. Biomarkers of severity and chronification in chikungunya fever: a systemic review and meta-analysis. Rev Inst Med Trop São Paulo 63: e16.
Tramontini Gomes de Sousa Cardozo F , Baimukanova G , Lanteri MC , Keating SM , Moraes Rerreira F , Heitman J , Pannuti CS , Pati S , Romano CM , Sabino EC , 2017. Serum from dengue virus-infected patients with and without plasma leakage differentially affects endothelial cells barrier function in vitro. PLoS One 12: e0178820.
Ding YP et al., 2014. Prognostic value of clinical and immunological markers in acute phase of SFTS virus infection. Clin Microbiol Infect 20: O870–O878.
Park A et al., 2021. Molecular signatures of inflammatory profile and B-cell function in patients with severe fever with thrombocytopenia syndrome. mBio 12: e02583-20.
He Z , Wang B , Li Y , Hu K , Yi Z , Ma H , Li X , Guo W , Xu B , Huang X , 2021. Changes in peripheral blood cytokines in patients with severe fever with thrombocytopenia syndrome. J Med Virol 93: 4704–4713.
Hamilton JA , 2020. GM-CSF in inflammation. J Exp Med 217: e20190945.
Hu L et al., 2021. Early-warning immune predictors for invasive pulmonary aspergillosis in severe patients with severe fever with thrombocytopenia syndrome. Front Immunol 12: 576640.
Hu L , Kong Q , Liu Y , Li J , Bian T , Ma X , Ye Y , Li J , 2021. Time course of severe fever with thrombocytopenia syndrome virus and antibodies in patients by long-term follow-up study, China. Front Microbiol 12: 744037.
Wen S , Xu N , Wang G , 2022. Ruxolitinib for severe fever with thrombocytopenia syndrome (SFTS). Heliyon 8: e12462.
Chung H et al., 2022. Kinetics of glycoprotein-specific antibody response in patients with severe fever with thrombocytopenia syndrome. Viruses 14: 256.
Iwasaki H , Takada N , Nakamura T , Ueda T , 1997. Increased levels of macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha in sera of patients with Orientia tsutsugamushi infection. J Clin Microbiol 35: 3320–3322.
Yoon HJ , Lee MS , Ki M , Ihm C , Kim D , Kim Y , Yoo SM , 2010. Does IL-17 play a role in hepatic dysfunction of scrub typhus patients? Vector Borne Zoonotic Dis 10: 231–235.
Dai ZN et al., 2022. Effect of genomic variations in severe fever with thrombocytopenia syndrome virus on the disease lethality. Emerg Microbes Infect 11: 1672–1682.
Li MM et al., 2018. CD4 T cell loss and Th2 and Th17 bias are associated with the severity of severe fever with thrombocytopenia syndrome (SFTS). Clin Immunol 195: 8–17.
Li H et al., 2021. Single-cell landscape of peripheral immune responses to fatal SFTS. Cell Rep 37: 110039.
Soong L , 2018. Dysregulated Th1 immune and vascular responses in scrub typhus pathogenesis. J Immunol 200: 1233–1240.
Seo JW , Kim DY , Yun N , Kim DM , 2021. Clinical update of severe fever with thrombocytopenia syndrome. Viruses 13: 1213.
Seong SY , Choi MS , Kim IS , 2001. Orientia tsutsugamushi infection: overview and immune responses. Microbes Infect 3: 11–21.
Past two years | Past Year | Past 30 Days | |
---|---|---|---|
Abstract Views | 4191 | 2618 | 821 |
Full Text Views | 161 | 74 | 9 |
PDF Downloads | 151 | 52 | 4 |