| Research background:The Orientia tsutsugamushi is responsible for spreading Scrub Typhus disease,which was first discovered by Japanese scientists as early as the 19 th century.The band was successfully isolated in the 30 years of the last century.With an estimated 30 million cases reported over the past few years,scrub typhus disease is considered one of the most urgent public health problems to be addressed.More than half of the world’s population lives in areas where scrub typhus disease is endemic;and the burden of scrub typhus worm disease in rural areas is higher than in urban.There are infrequent cases of scrub typhus disease in Guangdong,Shandong,Anhui,Jiangsu,Fujian and Yunnan provinces in China,and the annual incidence of scrub typhus worm disease has been increased in the past decade in many provinces in China,but it is controlled in a sporadic state.In January 2006,to continue better surveillance of cases and take prevention and control measures,the Chinese Center for Disease Control and Prevention launched scrub typhus disease surveillance in some provinces in China.Previous reports showed that temperature,duration of sunshine,and rainfall found positively associated with Scrub typhus incidence.Meanwhile,atmospheric pressure was inversely associated with Scrub typhus occurrence,with the south has a slightly higher incidence of scrub typhus disease than the north and south-west populations.The Kawasaki type mainly causes cases of Scrub typhus disease in China,and subtypes such as Karp and Kato have begun to appear in recent years.To date,Scrub typhus is a potentially life-threatening disease that is becoming an important public health problem with its wide geographical distribution and genetic diversity of pathogens.In addition,scrub typhus is often misdiagnosed,delaying treatment and leading to more serious complications,and timely diagnosis can improve treatment success rates.There is currently no vaccine that can prevent or control scrub infection,which may be due to numerous antigen variants on the surface of the normocellular surface of scrub typhus.Therefore,more detailed molecular epidemiological studies are needed to develop more detailed strategies for prevention and control of scrub typhus disease.Objective(1)To provide insights into research activities and tendencies on the themes of Scrub typhus(ST)worldwide publications indexed in Web of Science and Scopus database.(2)To describe the case investigation reports of Scrub typhus cases from data collected through a passive surveillance system among hospitalized patients in Luhe District during the seasonal outbreak,2014 to 2017.(3)To identify the factors associated with Scrub typhus infection in Luhe District,Nanjing,provide information and evidence-based prevention and control.(4)To understand the molecular epidemiology of Scrub typhus disease among the reported cases admitted in primary health care units.Methods(1)Bibliometric analysis of Scrub typhus research productivityThe data for bibliometric analysis were downloaded from the Web of Science and Scopus databases on 30 December 2020.We use the following terms: Title:(“Orientia tsutsugamushi infection*” or “Tsutsugamushi disease*” or “Tsutsugamushi fever*” or “Scrub typhus*”)AND period of time(“all years [1990-2020]”).The bibliometric indicators and data visualization were conducted using VOSviewer v.1.6.16 software,Bibliometric(an R package),Graph Pad Prism 5,and SPSS version 19.0 for Windows(IBM SPSS,Chicago,IL,USA).The measurement data were described by mean ± standard deviation,and the t-test was analyzed;the chi-square test or Fisher accurate test was used to analyze the difference in the incidence of scrub worm disease in different ages,genders,occupations and different incomes;and multi-factor logistic regression model analysed the influencing factors of scrub disease infection,and the test level α was 0.05.(2)Scrub typhus epidemiology and disease surveillance Epidemiological data were collected using a questionnaire,clinical and laboratory data were obtained through passive surveillance from 2014 to 2017.Data were using SPSS version 19.0.(3)Factors associated with Scrub Typhus infectionA case-control study of 116 Scrub typhus cases(101 diagnosed positive by serological method and 15 by PCR)and 232 controls matched with cases was conducted.The Scrub typhus cases were obtained from a passive surveillance system of data retrospectively gathered from medical records obtained from the Nanjing network of the surveillance system of Nanjing Municipal Center for Disease Prevention and Control during the seasonal outbreak start from October 2015 to December 2017.Demographic characteristics of the population,living environment,outdoor agriculture activities,and human behaviors were determined.SPSS 19.0for Windows was used for data analysis.Chi-square or Fisher’s exact test(when appropriate)was used for categorical data to find a potential association between study variables.The goodness-of-fit of the model was evaluated using Hosmer＿lemes how χ2 statistics.All variables with a P-value of < 0.05 were considered for possible inclusion in a multivariate conditional logistic regression model.The adjusted Odd Ratios and the confidence interval set95%(CI)were reported to predict the dimension of factors associated with ST.An alpha value of 0.05 was considered statistically significant.(4)Molecular epidemiological of sub typhus analysis of scrub typhus diseaseThe NCBI data(https://www.ncbi.nlm.nih.gov/nuccore)Search and download the global gene sequence of scrub 56-k Da over the years,with keywords such as: "Oriental body of scrub worm disease" or "rickettsia of scrub disease" or "rickettsia of scrub disease" and "56-k Da",delete duplicate sequences,edit,compare and build sequence sets,select the best nucleotide replacement model using MEGA X 10.2.6 software,and then build a systematic evolutionary tree based on that model to analyze the evolutionary characteristics of global diseases.Genomic DNA was extracted from 13 ST-positive cases using QIAamp DNA Mini Kit(Qiagen,Valencia,CA,USA)according to the manufacture’s instruction.DNA sequencing was done by using ABI 3730 xl DNA analyzers(Biosune,Shanghai,China).MEGA 10.2.6software is used to build the system tree.Results(1)Comprehensive mapping analysis of Scrub typhus researchA bibliometric analysis was carried out to provide insights into research activities and tendencies of the global Scrub typhus from 1990 to 2020.Over the past 120 years,only 928 articles from the Web of Science Core Collection(Wo SCC)and 1389 articles from Scopus were identified.The results show that the number of publications in Scrub typhus research has increased rapidly,especially after 2000.American Journal of Tropical Medicine and Hygiene and PLOS Neglected Tropical Diseases was the most productive journal that published Scrub typhus research.Wo SCC data shows 274(29.52%)articles have been published in the “Infectious Diseases,” 250(26.94%)in the“Tropical Medicine,” and 235(25.32%)in the “Public Environmental Occupational Health.” In Scopus,1230(88.55%)articles were published in the fields of “medicine,” 348(25.05%)in“Immunology and Microbiology.” Korea,India,China,and the USA are productive countries.Wellcome Trust and the National Natural Science Foundation of China are among the top funding organizations that support Scrub typhus research.Richards AL is the most prolific author with h＿index in the field of Scrub typhus.Meanwhile,“diagnosis,” “Infection,”“female,” “male,” and “adult” keywords are new research hotspots or Scrub typhus research frontiers.Through in-depth analysis,a significant association between the citation scores and the number of authors(r=0.682,P<0.0001),between the number of documents of years since publications(r=0.873,P<0.0001),journal(r= 0.692,P<0.0001)in Wo SCC.As well as citation scores between the number of authors(r=0.455,P=0.0001)and number of documents years since publications(r=0.789,P<0.0001)and journals(r=0.630,P<0.0001)in Scopus database,respectively.(2)Scrub typhus epidemiology and disease surveillanceAmong 148 cases,64(43.2%)are male,and 84(56.8%)are females’,more commonly affected age group 75(50.7%)was at 40-59 years,and 117(79.1%)of cases are practising farming activities.Most Scrub typhus cases were reported in the first October-November and the end of December each year.The typical clinical signs and symptoms among reported cases include fever 138(93.24%),headache 128(86.48%),rash 134(90.54%),and fatigue79(53.37%).A few cases show severe signs,such as pneumonia 14(9.45%)and myocarditis18(12.2%).Mortality was not observed during the surveillance.The early diagnosis of Scrub typhus and intervention may help to establish strategies for effective prevention and management.(3)Factors associated with Scrub Typhus infectionAnalysis of risk factors associated with scrub disease infection showed no significant differences in sex,age,education and occupation between cases and control groups(P>0.05).The proportion of case groups living in townships was lower than that of the control group(73.3%)(P=0.005);the proportion of case groups living close to the grass,vegetable fields or ditches(82.8%)was significantly higher than that of the control group(61.2%)(P=0.001);37.9% of the cases lived in yards with weeds,significantly higher than that of the control group(6.0%)(P=0.001);56.9% of the cases lived in houses where mouse activity was observed/detected.Higher than the control group(45.7%).Therefore,the presence of rats in the housing environment,the presence of rat activity in the dwelling place,living in houses close to meadows,vegetable patches or ditches,the piling of weeds in the courtyards and the presence of rat activity in the housing environment are important influencing factors associated with scrub disease infection.Farmers have the highest number of diseases in the population distribution.Three factors that were significantly associated with an increased odds of having Scrub typhus infection are bundling or moving waste straw(OR: 1.94,95%CI;0.99,3 81),morning exercise in the park or field(OR: 4.74 95%CI;1.19,18.95),and working as labor in the vegetable field(OR: 1.02,95% CI: 1.02,3.19).(4)Characteristic analysis of Orientia tsutsugamushi subtypes of scrub typhus diseaseA total of 723 full-length reference gene sequences,56-k Da of tsutsugamushi disease,were downloaded and sorted.The gene sequences were mainly from Taiwan Province,South Korea,Thailand,and retrieved sequences isolated from 1989 to 2018.The phylogenetic analysis results show that the global O.tsutsugamushi 56-k Da in different countries and regions.The main epidemic subtype of O.tsutsugamushi and reported sequences were mainly from Taiwan Province,South Korea,and Thailand.The phylogenetic analysis showed that the global scrub typhus differs from the epidemic subtype,and Krap,Kato,and Boryong are the main epidemic strains.The evolutionary analysis shows that the genotypes of tsutsugamushi disease in Nanjing were mainly Karp and Kawasaki genotypes in the region.Krap,Kato,and Boryong are the main epidemic strains.Phylogenetic analyses of O.tsutsugamushi strains obtained in Nanjing are mainly Karp and Kawasaki genotypes.Conclusion(1)The bibliometric analysis provides historical insights and perspectives of Scrub typhus research during the past 120 years.Korea,India,and China were playing leading roles in the global Scrub typhus research.The study provides readers and health policy-makers with a practical guide in evaluating research output and progress made by the scientific community.(2)The clinical,epidemiological and laboratory profile of Scrub typhus patients is an indicator for early health diagnosis.Appropriate treatment is indicator for prevention and control of Scrub typhus disease in the future.(3)The study confirmed that farmers working in bundling or moving waste straw,morning exercise in the park or field,and working as labor in the vegetable field were significantly at risk with Scrub typhus infection.Therefore,protective measurements are recommended for the prevention and control of these groups.These findings could help establish screening for people at high risk of scrub worm disease in the region,reduce factors associated with scrub disease infection,further improve health planning and health care policies in communities.Contribute to the implementation of adequate health care services and lay the foundation for future evidence-based intervention strategies.(4)The gene sequences of Orientia tsutsugamushi retrieved on NCBI are mainly from Asian countries,and the subtypes of Orientia tsutsugamushi are different in different countries and regions.The predominant Orientia tsutsugamushi circulating genotypes were Karp and Kawasaki-related strains reported previously in Shandong province,China.Moreover,a continuous exhaustive genotyping in patient and host animals is needed to better understand the genetic diversity and pathogenic characteristics in Scrub typhus patients as an essential step for vaccine development and prevention of the disease.Continuous improvement in prevention and control strategies,such as rapid and accurate surveillance,improve clinicians’ initial diagnostic capacity in patients with scrub worm disease,to achieve early diagnosis and treatment,and to further strengthen the development of scrub disease vaccines and pay more attention to areas where scrub worm disease is endemic. |
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