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      Estimating the burden of scrub typhus: A systematic review

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          Abstract

          Background

          Scrub typhus is a vector-borne zoonotic disease that can be life-threatening. There are no licensed vaccines, or vector control efforts in place. Despite increasing awareness in endemic regions, the public health burden and global distribution of scrub typhus remains poorly known.

          Methods

          We systematically reviewed all literature from public health records, fever studies and reports available on the Ovid MEDLINE, Embase Classic + Embase and EconLit databases, to estimate the burden of scrub typhus since the year 2000.

          Findings

          In prospective fever studies from Asia, scrub typhus is a leading cause of treatable non-malarial febrile illness. Sero-epidemiological data also suggest that Orientia tsutsugamushi infection is common across Asia, with seroprevalence ranging from 9.3%–27.9% (median 22.2% IQR 18.6–25.7). A substantial apparent rise in minimum disease incidence (median 4.6/100,000/10 years, highest in China with 11.2/100,000/10 years) was reported through passive national surveillance systems in South Korea, Japan, China, and Thailand. Case fatality risks from areas of reduced drug-susceptibility are reported at 12.2% and 13.6% for South India and northern Thailand, respectively. Mortality reports vary widely around a median mortality of 6.0% for untreated and 1.4% for treated scrub typhus. Limited evidence suggests high mortality in complicated scrub typhus with CNS involvement (13.6% mortality), multi-organ dysfunction (24.1%) and high pregnancy miscarriage rates with poor neonatal outcomes.

          Interpretation

          Scrub typhus appears to be a truly neglected tropical disease mainly affecting rural populations, but increasingly also metropolitan areas. Rising minimum incidence rates have been reported over the past 8–10 years from countries with an established surveillance system. A wider distribution of scrub typhus beyond Asia is likely, based on reports from South America and Africa. Unfortunately, the quality and quantity of the available data on scrub typhus epidemiology is currently too limited for any economical, mathematical modeling or mapping approaches.

          Author summary

          Scrub typhus is a mite-transmitted infectious disease that can be life-threatening. Diagnosing this disease is difficult, requiring special techniques that are often not readily available. As the actual impact of scrub typhus on the population and its geographical distribution remains unknown, we searched systematically for available information in medical databases. Scrub typhus is common: more than every fifth person in areas where scrub typhus occurs carry antibodies as a sign of previous contact. All countries with an established surveillance system have recorded an increase in scrub typhus cases over the past 8–10 years, while reports from South America and Africa suggest a wider distribution beyond Asia. Scrub typhus is a serious disease: approximately 6% of cases die if untreated, and 1.5% if treated, but mortality can reach 13% in areas where the usual treatment does not always work well. Death rates of complications are higher, reaching 14% in brain infections, 24% with multiple organ failure, and pregnancies with scrub typhus can have poor outcomes, with high miscarriage rates. Despite many limitations on the amount and quality of available reports, we found that scrub typhus is a severely underappreciated tropical disease, affecting mainly rural populations, but increasingly urban areas as well.

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          Most cited references67

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          Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi.

          Orientia tsutsugamushi is the etiological agent of scrub typhus, an acute, mite-borne, febrile illness that occurs in the Asia-Pacific region. Historically, strain characterization used serological analysis and revealed dramatic antigenic diversity. Eyeing a recommendation of potential vaccine candidates for broad protection, we review geographic diversity and serological and DNA prevalences. DNA analysis together with immunological analysis suggest that the prototype Karp strain and closely related strains are the most common throughout the region of endemicity. According to serological analysis, approximately 50% of isolates are seroreactive to Karp antisera, and approximately one-quarter of isolates are seroreactive to antisera against the prototype Gilliam strain. Molecular methods reveal greater diversity. By molecular methods, strains phylogenetically similar to Karp make up approximately 40% of all genotyped isolates, followed by the JG genotype group (Japan strains serotypically similar to the Gilliam strain but genetically non-Gilliam; 18% of all genotyped isolates). Three other genotype groups (Kato-related, Kawasaki-like, and TA763-like) each represent approximately 10% of genotyped isolates. Strains genetically similar to the Gilliam strain make up only 5% of isolates. Strains from these groups should be included in any potential vaccine.
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            A Systematic Review of Mortality from Untreated Scrub Typhus (Orientia tsutsugamushi)

            Background Scrub typhus, a bacterial infection caused by Orientia tsutsugamushi, is increasingly recognized as an important cause of fever in Asia, with an estimated one million infections occurring each year. Limited access to health care and the disease’s non-specific symptoms mean that many patients are undiagnosed and untreated, but the mortality from untreated scrub typhus is unknown. This review systematically summarizes the literature on the untreated mortality from scrub typhus and disease outcomes. Methodology/Principal Findings A literature search was performed to identify patient series containing untreated patients. Patients were included if they were symptomatic and had a clinical or laboratory diagnosis of scrub typhus and excluded if they were treated with antibiotics. The primary outcome was mortality from untreated scrub typhus and secondary outcomes were total days of fever, clinical symptoms, and laboratory results. A total of 76 studies containing 89 patient series and 19,644 patients were included in the final analysis. The median mortality of all patient series was 6.0% with a wide range (min-max) of 0–70%. Many studies used clinical diagnosis alone and had incomplete data on secondary outcomes. Mortality varied by location and increased with age and in patients with myocarditis, delirium, pneumonitis, or signs of hemorrhage, but not according to sex or the presence of an eschar or meningitis. Duration of fever was shown to be long (median 14.4 days Range (9–19)). Conclusions Results show that the untreated mortality from scrub typhus appears lower than previously reported estimates. More data are required to clarify mortality according to location and host factors, clinical syndromes including myocarditis and central nervous system disease, and in vulnerable mother-child populations. Increased surveillance and improved access to diagnostic tests are required to accurately estimate the untreated mortality of scrub typhus. This information would facilitate reliable quantification of DALYs and guide empirical treatment strategies.
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              Isolation of a novel Orientia species (O. chuto sp. nov.) from a patient infected in Dubai.

              In July 2006, an Australian tourist returning from Dubai, in the United Arab Emirates (UAE), developed acute scrub typhus. Her signs and symptoms included fever, myalgia, headache, rash, and eschar. Orientia tsutsugamushi serology demonstrated a 4-fold rise in antibody titers in paired serum collections (1:512 to 1:8,192), with the sera reacting strongest against the Gilliam strain antigen. An Orientia species was isolated by the in vitro culture of the patient's acute blood taken prior to antibiotic treatment. The gene sequencing of the 16S rRNA gene (rrs), partial 56-kDa gene, and the full open reading frame 47-kDa gene was performed, and comparisons of this new Orientia sp. isolate to previously characterized strains demonstrated significant sequence diversity. The closest homology to the rrs sequence of the new Orientia sp. isolate was with three strains of O. tsutsugamushi (Ikeda, Kato, and Karp), with a nucleotide sequence similarity of 98.5%. The closest homology to the 47-kDa gene sequence was with O. tsutsugamushi strain Gilliam, with a nucleotide similarity of 82.3%, while the closest homology to the 56-kDa gene sequence was with O. tsutsugamushi strain TA686, with a nucleotide similarity of 53.1%. The molecular divergence and geographically unique origin lead us to believe that this organism should be considered a novel species. Therefore, we have proposed the name "Orientia chuto," and the prototype strain of this species is strain Dubai, named after the location in which the patient was infected.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                25 September 2017
                September 2017
                : 11
                : 9
                : e0005838
                Affiliations
                [1 ] Oxford University Clinical Research Unit, National Hospital of Tropical Diseases, Hanoi, Vietnam
                [2 ] Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand
                [3 ] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
                [4 ] Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos
                [5 ] Centre for International Health, University of Otago, Dunedin, New Zealand
                [6 ] Department of Medicine, Swiss Tropical and Public Health Institute, Basel, Switzerland
                [7 ] Faculty of Medicine, University Basel, Basel, Switzerland
                University of California Davis, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-4743-5987
                Article
                PNTD-D-17-00222
                10.1371/journal.pntd.0005838
                5634655
                28945755
                dfc57081-cdb9-435d-b165-49bb570b734d
                © 2017 Bonell et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 March 2017
                : 28 July 2017
                Page count
                Figures: 2, Tables: 4, Pages: 17
                Funding
                Mahidol Oxford Tropical Medicine Research Unit (MORU), Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU) and Oxford University Clinical Research Unit Vietnam (OUCRU) are in part supported by the Wellcome Trust, UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Typhus
                Scrub Typhus
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Fevers
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Fevers
                People and Places
                Geographical Locations
                Asia
                India
                Medicine and Health Sciences
                Epidemiology
                Disease Surveillance
                Infectious Disease Surveillance
                Medicine and Health Sciences
                Infectious Diseases
                Infectious Disease Control
                Infectious Disease Surveillance
                Biology and Life Sciences
                Population Biology
                Population Metrics
                Death Rates
                Research and Analysis Methods
                Research Design
                Clinical Research Design
                Case Series
                Medicine and Health Sciences
                Public and Occupational Health
                Global Health
                Medicine and Health Sciences
                Epidemiology
                Custom metadata
                vor-update-to-uncorrected-proof
                2017-10-10
                All relevant data are within the paper and its Supporting Information file.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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