Pathology of Severe Fever with Thrombocytopenia Syndrome
Severe fever with thrombocytopenia syndrome (SFTS) is a novel viral infectious disease with high case fatality rate (CFR). SFTS is caused by a novel phlebovirus, SFTS virus (SFTSV). SFTS, a tick-borne viral infection, was reported to be endemic to central and northeastern China and is also endemic to South Korea and western Japan. Patients with SFTS show symptoms of fever, general fatigue, and gastrointestinal symptoms such as diarrhea, whereas those severely ill with SFTS usually show gastrointestinal hemorrhage and deteriorated consciousness. The CFR of SFTS patients ranges from 5 to 40%. Because the time from the discovery of SFTS is short, pathological studies on SFTS remain limited. However, the existing pathological studies revealed that SFTSV replicated mainly in the lymphoreticular organs such as lymph nodes, spleen, and liver. Furthermore, SFTSV antigen-positive cells showed multi-organ infiltration, including to central nervous cells, kidneys, and lungs. Virus infection-related hemophagocytic syndrome associated with cytokine storm is also seen in most severe SFTS patients, suggesting that the mechanisms behind the high CFR may be multi-organ failure induced by hemophagocytic syndrome and coagulopathy due to disseminated intravascular coagulation causing bleeding tendency. To reduce the morbidity and mortality of SFTS, understanding of the pathophysiology of SFTS is required.
KeywordsSevere fever with thrombocytopenia syndrome SFTS Pathology Multiorgan failure Hemophagocytosis Cytokine storm
The author acknowledges Drs. Toru Takahashi and Toshiaki Kamei, Yamaguchi Grand Medical Center, Yamaguchi, Japan, and Dr. Masahiko Kaneko, Department of Internal Medicine, Uwajima City Hospital, Ehime, Japan. The author also thanks Drs. Hideki Tani, Masayuki Shimojima, Shuetsu Fukushi, Tomoki Yoshikawa, and Takeshi Kurosu, Department of Virology 1, National Institute of Infectious Diseases (NIID); Drs. Hideki Hasegawa and Tadaki Suzuki, Department of Pathology, NIID; and Dr. Shigeru Morikawa, Department of Veterinary Medicine, NIID, Tokyo, Japan, for their contributions. The studies presented in this review article were performed with the support of a grant-in-aid from the Ministry of Health, Labor and Welfare, Japan (Grant-in-aid H25-Shinko-Shitei-009) and grants from the Japan Agency for Medical Research and Development (18fk0108002, 18fk0108072, 19fk0108081).
- Choi SJ, Park SW, Bae IG, Kim SH, Ryu SY, Kim HA, Jang HC, Hur J, Jun JB, Jung Y, Chang HH, Kim YK, Yi J, Kim KH, Hwang JH, Kim YS, Jeong HW, Song KH, Park WB, Kim ES, Oh MD; for Korea SFTS Clinical Network (2016) Severe fever with thrombocytopenia syndrome in South Korea, 2013–2015. PLoS Negl Trop Dis 10:e0005264CrossRefGoogle Scholar
- Ding YP, Liang MF, Ye JB, Liu QH, Xiong CH, Long B, Lin WB, Cui N, Zou ZQ, Song YL, Zhang QF, Zhang S, Liu YZ, Song G, Ren YY, Li SH, Wang Y, Hou FQ, Yu H, Ding P, Ye F, Li DX, Wang GQ (2014) Prognostic value of clinical and immunological markers in acute phase of SFTS virus infection. Clin Microbiol Infect 20:O870–O878CrossRefGoogle Scholar
- Hiraki T, Yoshimitsu M, Suzuki T, Goto Y, Higashi M, Yokoyama S, Tabuchi T, Futatsuki T, Nakamura K, Hasegawa H, Saijo M, Kakihana Y, Arima N, Yonezawa S (2014) Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: a pathognomonic histological feature and unique complication of SFTS. Pathol Int 64:569–575CrossRefGoogle Scholar
- Kaneko M, Shikata H, Matsukage S, Maruta M, Shinomiya H, Suzuki T, Hasegawa H, Shimojima M, Saijo M (2018) A patient with severe fever with thrombocytopenia syndrome and hemophagocytic lymphohistiocytosis-associated involvement of the central nervous system. J Infect Chemother 24:292–297CrossRefGoogle Scholar
- Kaneyuki S, Yoshikawa T, Tani H, Fukushi S, Taniguchi S, Fukuma A, Shimojima M, Kurosu T, Morikawa S, Saijo M (2016) Ulcerative lesions with hemorrhage in a patient with severe fever with thrombocytopenia syndrome observed via upper gastrointestinal endoscopy. Jpn J Infect Dis 69:525–527CrossRefGoogle Scholar
- 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 19:1892–1894Google Scholar
- Takahashi T, Maeda K, Suzuki T, Ishido A, Shigeoka T, Tominaga T, Kamei T, Honda M, Ninomiya D, Sakai T, Senba T, Kaneyuki S, Sakaguchi S, Satoh A, Hosokawa T, Kawabe Y, Kurihara S, Izumikawa K, Kohno S, Azuma T, Suemori K, Yasukawa M, Mizutani T, Omatsu T, Katayama Y, Miyahara M, Ijuin M, Doi K, Okuda M, Umeki K, Saito T, Fukushima K, Nakajima K, Yoshikawa T, Tani H, Fukushi S, Fukuma A, Ogata M, Shimojima M, Nakajima N, Nagata N, Katano H, Fukumoto H, Sato Y, Hasegawa H, Yamagishi T, Oishi K, Kurane I, Morikawa S, Saijo M (2014) The first identification and retrospective study of severe fever with thrombocytopenia syndrome in Japan. J Infect Dis 209:816–827CrossRefGoogle Scholar
- Xu B, Liu L, Huang X, Ma H, Zhang Y, Du Y, Wang P, Tang X, Wang H, Kang K, Zhang S, Zhao G, Wu W, Yang Y, Chen H, Mu F, Chen W (2011) Metagenomic analysis of fever, thrombocytopenia and leukopenia syndrome (FTLS) in Henan Province, China: discovery of a new bunyavirus. PLoS Pathog 7:e1002369CrossRefGoogle Scholar
- Yoshikawa T, Fukushi S, Tani H, Fukuma A, Taniguchi S, Toda S, Shimazu Y, Yano K, Morimitsu T, Ando K, Yoshikawa A, Kan M, Kato N, Motoya T, Kuzuguchi T, Nishino Y, Osako H, Yumisashi T, Kida K, Suzuki F, Takimoto H, Kitamoto H, Maeda K, Takahashi T, Yamagishi T, Oishi K, Morikawa S, Saijo M, Shimojima M (2014) Sensitive and specific PCR systems for detection of both Chinese and Japanese severe fever with thrombocytopenia syndrome virus strains and prediction of patient survival based on viral load. J Clin Microbiol 52:3325–3333CrossRefGoogle Scholar
- Yu XJ, Liang MF, Zhang SY, Liu Y, Li JD, Sun YL, Zhang L, Zhang QF, Popov VL, Li C, Qu J, Li Q, Zhang YP, Hai R, Wu W, Wang Q, Zhan FX, Wang XJ, Kan B, Wang SW, Wan KL, Jing HQ, Lu JX, Yin WW, Zhou H, Guan XH, Liu JF, Bi ZQ, Liu GH, Ren J, Wang H, Zhao Z, Song JD, He JR, Wan T, Zhang JS, Fu XP, Sun LN, Dong XP, Feng ZJ, Yang WZ, Hong T, Zhang Y, Walker DH, Wang Y, Li DX (2011) Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364:1523–1532CrossRefGoogle Scholar