4 Discussion
Tick-borne diseases are the main cause of vector-borne diseases and have broad global distribution. They are mainly natural epidemic diseases, most common in forests, bushes, and semi-desert grasslands(Wu, Na, Wei, Zhu, & Peng, 2013). There are at least 7 genera and 104 species of ticks in China. Northeast China has a mountainous terrain, has abundant biological resources, has geographical complexity, and has high species diversity, which provide an ecological and biological basis for the survival and reproduction of ticks. In this study, we found that the ticks distributed in the forest area of ​​Northeast China are dominated by the long-horned blood ticks. Most patients affected by SFTS live in mountainous, hilly, or dense jungle areas and have a history of working outdoors. More than 80% of the cases are farmers, and there is history of field work, livestock contact, etc., and a few patients have history of tick bites. Among all the 17 suspected SFTS patients in this study, all cases occurred from the end of March to the end of June, and 94% of the cases (16/17) were from Changbai Mountain and other mountainous areas, forests, and hills in Northeast China, It is highly consistent with the active season and regional distribution of ticks in Liaoning Province.
SFTSV strains have been isolated from ticks in South Korea, Japan, and other regions sharing borders with or adjacent to China(Park et al., 2014; Yasukawa, 2008; Yun et al., 2015). Reports from the East Asian region show that the average mortality rate of SFTSV varies greatly, from 5.3% to 16.2% in China, 20% in Japan, and 23.3% in South Korea. Among the six known A-F genotypes of SFTSV(Fu et al., 2016), genotype B has the highest morbidity and mortality rates, which are significantly higher than those of the other genotypes. The incidence of the F genotype is lower than that of the B genotype, but its mortality rate is also higher, while the A genotype has the lowest mortality rate(Yun et al., 2020). The most common genotypes in China are genotypes A, D, and F, and the mortality rate is relatively low, while the most common genotype in Japan and South Korea is B. Therefore, a comparison of viral genotypes and mortality indicates that the differences in reported case mortality may be related to the differences in the distribution of SFTSV genotypes in different countries. The number of clinical cases infected with certain SFTSV genotypes (especially reassortant genotypes) is small, which prevents the determination of the association between genotype and case mortality.
There is currently no vaccine or specific antiviral drug for SFTSV. Ribavirin is considered to be a potential antiviral drug for SFTS, but several retrospective studies have shown that ribavirin has not been effective in improving disease prognosis (Li et al., 2018; Liu et al., 2013). (Li et al., 2019) found that benidipine hydrochloride (a calcium channel blocker, CCB) can inhibit SFTSV infection by interfering with virus internalization and reducing viral genome replication. Further experiments showed that a large number of CCBs including nifedipine inhibited SFTSV infection as well, indicating that CCB therapy may be developed as an effective strategy for the treatment of SFTSV infection.
Our previous research showed that among the various pathogens carried by ticks distributed in the Changbai Mountain forest area in China, theRickettsia positivity rate was the highest, and it was close to 10% in some areas (Qi et al., 2014). TheRickettsia detected in this study is consistent with the newly discovered ”DandongRickettsia ” genotype in 2018 and has is genetically close toRickettsia Heilongjiang. This genotype belongs to the class Alphaproteobacteria, order Rickettsiales, in the spotted fever group rickettsiae of the genus Rickettsia . The disease caused byRickettsia in Heilongjiang is called the ”Far-East tick-borne Spotted Fever” (FESF) , FESF has been considered as an important emerging infectious disease in Northeast Asia for this rickettsiosis has been diagnosed in Northeast of China, east-Siberian and far-eastern regions of Russia, and Japan. Rickettsia infection usually manifests as fever, headache, and rash, as well as muscle pain and arthralgia. The typical symptom is eschar-like skin lesions formed by the bite of a tick or mite, and the mortality rate is low under reasonable treatment. However, rashes and eschar did not appear in the 17 patients in this study, which may be because the skin lesions were hidden and painless, making them difficult to observe and easy to ignore. The diagnosis of rickettsial diseases can be achieved by RT-PCR or conventional PCR detection in diseased tissues (Denison, Amin, Nicholson, & Paddock, 2014). However, sampling errors may cause false negatives, and patients with insignificant skin lesions may be completely ignored. Due to similar clinical manifestations caused by different rickettsial infections, there are cross-reactions in serological methods. Pathogen culture is difficult, and the application of molecular techniques in whole blood are limited so far. Thus, rapid and reliable molecular blood detection of rickettsial diseases are still difficult to achieve. Indirect immunofluorescence assay is considered to be the gold standard, but due to its extensive cross-reactivity, this method has limited use in the determination of species within serogroups (Paris & Dumler, 2016).
In our study, based on epidemiological data, clinical symptoms, and routine blood tests, 17 patients were initially classified as suspected SFTS patients. After molecular diagnostic testing, 5 SFTS patients were confirmed to have SFTSV. To understand whether there is a mixed infection of sftsv and rickettsia in patients bitten by ticks, From the 17 patient blood samples, 7 samples were chosen for Rickettsia -specific IgG antibody testing, and the positivity rate was 100%. Of these 7 samples, 3 samples were from patients diagnosed with SFTS and 4 samples were from SFTS negative patients. Considering that ticks carry SFTSV and ”Dandong-type Rickettsia ”, we conclude that tick-borne SFTSV and ”Dandong-type Rickettsia ” infections are endemic in forest areas in Northeast China are more common. We hypothesize that SFTSV-”Dandong-type Rickettsia” coinfection complicates patient conditions. Therefore, we believe that in diagnosing tick-borne diseases such as SFTSV, tick-borne encephalitis, and renal hemorrhagic fever syndrome, co-infection with Rickettsia will have to be considered. SFTS and other related tick-borne diseases should also be screened for patients with rickettsial infection.