Seroepidemiology of spotted fever group and typhus group rickettsioses in humans, South Korea

The prevalence of spotted fever group (SFG) and typhus group (TG) rickettsioses was investigated in 3,362 sera by immunofluorescence assay. The serum samples were obtained from patients with acute febrile episodes in South Korea from December 1992 to November 1993. The number of polyvalent positive sera against SFG rickettsial agents at the level of 1: 40 dilution was 269 (8%) in Rickettsia sibirica, 482 (14.34%) in R. conorii, and 546 (16.24%) in R. akari. Many of the positive sera contained immunoglobulin (Ig) M antibodies rather than IgG antibodies. These results strongly suggest that SFG rickettsioses are prevalent in Korea. For TG rickettsial agents, the number of positive sera was 1,096 (32.60%) in R. typhi and 951 (28.29%) in R. prowazekii. Only a few epidemic typhus positive sera contained IgM antibodies. The result suggests that recent and/or primary infections of epidemic typhus were very rare in Korea during the said period. Among seven patients who had high titers (1:5,120) of IgG antibody to R. prowazekii, six were over 50 years old. The result suggests that Brill-Zinsser disease was prevalent in Korea.     

Increased Nucleosomes and Neutrophil Activation Link to Disease Progression in Patients with Scrub Typhus but Not Murine Typhus in Laos

Cell-mediated immunity is essential in protection against rickettsial illnesses, but the role of neutrophils in these intracellular vasculotropic infections remains unclear. This study analyzed the plasma levels of nucleosomes, FSAP-activation (nucleosome-releasing factor), and neutrophil activation, as evidenced by neutrophil-elastase (ELA) complexes, in sympatric Lao patients with scrub typhus and murine typhus. In acute scrub typhus elevated nucleosome levels correlated with lower GCS scores, raised respiratory rate, jaundice and impaired liver function, whereas neutrophil activation correlated with fibrinolysis and high IL-8 plasma levels, a recently identified predictor of severe disease and mortality. Nucleosome and ELA complex levels were associated with a 4.8-fold and 4-fold increased risk of developing severe scrub typhus, beyond cut off values of 1,040 U/ml for nucleosomes and 275 U/ml for ELA complexes respectively. In murine typhus, nucleosome levels associated with pro-inflammatory cytokines and the duration of illness, while ELA complexes correlated strongly with inflammation markers, jaundice and increased respiratory rates. This study found strong correlations between circulating nucleosomes and neutrophil activation in patients with scrub typhus, but not murine typhus, providing indirect evidence that nucleosomes could originate from neutrophil extracellular trap (NET) degradation. High circulating plasma nucleosomes and ELA complexes represent independent risk factors for developing severe complications in scrub typhus. As nucleosomes and histones exposed on NETs are highly cytotoxic to endothelial cells and are strongly pro-coagulant, neutrophil-derived nucleosomes could contribute to vascular damage, the pro-coagulant state and exacerbation of disease in scrub typhus, thus indicating a detrimental role of neutrophil activation. The data suggest that increased neutrophil activation relates to disease progression and severe complications, and increased plasma levels of nucleosomes and ELA complexes represent independent risk factors for developing severe scrub typhus.     

A Spatiotemporal Database to Track Human Scrub Typhus Using the VectorMap Application

Scrub typhus is a potentially fatal mite-borne febrile illness, primarily of the Asia-Pacific Rim. With an endemic area greater than 13 million km² and millions of people at risk, scrub typhus remains an underreported, often misdiagnosed febrile illness. A comprehensive, updatable map of the true distribution of cases has been lacking, and therefore the true risk of disease within the very large endemic area remains unknown. The purpose of this study was to establish a database and map to track human scrub typhus. An online search using PubMed and the United States Armed Forces Pest Management Board Literature Retrieval System was performed to identify articles describing human scrub typhus cases both within and outside the traditionally accepted endemic regions. Using World Health Organization guidelines, stringent criteria were used to establish diagnoses for inclusion in the database. The preliminary screening of 181 scrub typhus publications yielded 145 publications that met the case criterion, 267 case records, and 13 serosurvey records that could be georeferenced, describing 13,739 probable or confirmed human cases in 28 countries. A map service has been established within VectorMap (www.vectormap.org) to explore the role that relative location of vectors, hosts, and the pathogen play in the transmission of mite-borne scrub typhus. The online display of scrub typhus cases in VectorMap illustrates their presence and provides an up-to-date geographic distribution of proven scrub typhus cases.     

The burden of scrub typhus in India: A systematic review

BackgroundScrub typhus, a vector-borne zoonotic infection caused by the bacteria Orientia tsutsugamushi, is one of the most common and clinically important rickettsial infections worldwide. An estimated one million cases occur annually with a high case fatality rate. Although scrub typhus is a major public health threat in India, the burden and distribution remains unclear. We aimed to estimate the burden of scrub typhus in India.MethodologyWe performed a systematic review of published literature on scrub typhus from India to extract information on epidemiology, morbidity, and mortality. Important databases were searched using keywords and appropriate combinations. We identified observational, interventional, and population-based studies and extracted the data to evaluate the number of cases diagnosed using serology or PCR and the number of deaths due to scrub typhus. We conducted a systematic narrative synthesis to summarize included studies.Principal findingsIn the last decade, there were 18,781 confirmed scrub typhus cases reported in 138 hospital-based studies and two community-based studies. IgM ELISA was used in 122 studies to confirm the cases in majority (89%). The proportion of scrub typhus among acute undifferentiated febrile illness (AUFI) studies was 25.3%, and community seroprevalence was 34.2%. Ninety studies had data published on multiple organ involvement out of which 17.4% of cases had multiple organ dysfunction syndromes, 20.4% patients required ICU admission, and 19.1% needed ventilation. The overall case-fatality rate was 6.3%, and the mortality among those with multi-organ dysfunction syndrome was as high as 38.9%.Conclusion/significanceScrub typhus, a common acute febrile illness in India causing severe morbidity, accounts for a large number of deaths. The burden of the disease has been underappreciated. Early diagnosis and prompt treatment can significantly reduce complications and mortality. Establishing good surveillance and instituting appropriate control measures are urgently needed.     

Strong Type 1, but Impaired Type 2, Immune Responses Contribute to Orientia tsutsugamushi-Induced Pathology in Mice

Scrub typhus is a neglected, but important, tropical disease, which puts one-third of the world''s population at risk. The disease is caused by Orientia tsutsugamushi, an obligately intracellular Gram-negative bacterium. Dysregulation in immune responses is known to contribute to disease pathogenesis; however, the nature and molecular basis of immune alterations are poorly defined. This study made use of a newly developed murine model of severe scrub typhus and focused on innate regulators and vascular growth factors in O. tsutsugamushi-infected liver, lungs and spleen. We found no activation or even reduction in base-line expression for multiple molecules (IL-7, IL-4, IL-13, GATA3, ROR-γt, and CXCL12) at 2, 6 and 10 days post-infection. This selective impairment in type 2-related immune responses correlated with a significant activation of the genes for IL-1β, IL-6, IL-10, TNF-α, IFN-γ, as well as CXCR3- and CXCR1-related chemokines in inflamed tissues. The elevated angiopoietin (Ang)-2 expression and Ang-2/Ang-1 ratios suggested excessive inflammation and the loss of endothelial integrity. These alterations, together with extensive recruitment of myeloperoxidase (MPO)-expressing neutrophils and the influx of CD3⁺ T cells, contributed to acute tissue damage and animal death. This is the first report of selective alterations in a panel of immune regulators during early O. tsutsugamushi infection in intravenously inoculated C57BL/6 mice. Our findings shed new light on the pathogenic mechanisms associated with severe scrub typhus and suggest potential targets for therapeutic investigation.     

Fulminating necrotizing amebic colitis with perforation: case report and review.

A seriously ill patient with diffuse abdominal tenderness of unknown cause is described. The diagnosis proved to be fulminating necrotizing amebic colitis with perforation. This case report serves as a reminder that amebiasis may occur in patients who have not been outside Canada, that it may readily be confused with other types of inflammatory bowel disease, and that particular care should be taken in obtaining a history of exposure. Before inflammatory bowel disease is diagnosed not only should the usual diagnostic tests such as stool examination and mucosal biopsy be done, but also serologic testing for amebiasis should be carried out.     

Spatiotemporal Dynamics of Scrub Typhus Transmission in Mainland China, 2006-2014

BackgroundScrub typhus is endemic in the Asia-Pacific region including China, and the number of reported cases has increased dramatically in the past decade. However, the spatial-temporal dynamics and the potential risk factors in transmission of scrub typhus in mainland China have yet to be characterized.ObjectiveThis study aims to explore the spatiotemporal dynamics of reported scrub typhus cases in mainland China between January 2006 and December 2014, to detect the location of high risk spatiotemporal clusters of scrub typhus cases, and identify the potential risk factors affecting the re-emergence of the disease.MethodMonthly cases of scrub typhus reported at the county level between 2006 and 2014 were obtained from the Chinese Center for Diseases Control and Prevention. Time-series analyses, spatiotemporal cluster analyses, and spatial scan statistics were used to explore the characteristics of the scrub typhus incidence. To explore the association between scrub typhus incidence and environmental variables panel Poisson regression analysis was conducted.ResultsDuring the time period between 2006 and 2014 a total of 54,558 scrub typhus cases were reported in mainland China, which grew exponentially. The majority of cases were reported each year between July and November, with peak incidence during October every year. The spatiotemporal dynamics of scrub typhus varied over the study period with high-risk clusters identified in southwest, southern, and middle-eastern part of China. Scrub typhus incidence was positively correlated with the percentage of shrub and meteorological variables including temperature and precipitation.ConclusionsThe results of this study demonstrate areas in China that could be targeted with public health interventions to mitigate the growing threat of scrub typhus in the country.     

Typhus-like Fevers of Unknown Ætiology,with Special Reference to the Malay States

Typhus exanthematicus, Rocky Mountain fever, and the tsutsugamushi disease have been classified in the "typhus group" by Megaw, as louse-typhus, tick-typhus, and mite-typhus. He has added a fourth-class, comprising typhus-like fevers, with unknown vectors. It is the diseases of this class with which this paper is concerned.Endemic typhus (Brill's disease) is very closely related to typhus fever; the Weil-Felix reaction is positive, typhus-like vascular lesions are present, and there is cross-immunity with typhus. In the exanthematic fever of Marseilles the relationship is more superficial; there is neither cross-immunity nor vascular lesion, and the Weil-Felix reaction is negative. Some, e.g., the scrub-typhus of Malaya (vector probably a mite), are more nearly related to tsutsugamushi than to typhus; others, e.g., Indian "tick-typhus" (vector probably a tick), to Rocky Mountain fever.All are non-contagious, non-epidemic, warm-weather diseases. They are unassociated with dirt, squalor, or lice, and are restricted to definite foci. Probably rodents or other animals are the reservoirs of the virus. On the question of identity with typhus, health authorities decide that notification is unnecessary; typhus introduced into America spreads, Brill's disease does not.These typhus-like diseases are not the same in all the countries where they occur. There are two main groups: (1) an urban group, more closely related to typhus, in which the Weil-Felix reaction is positive; (2) a rural group, more closely related to tsutsugamushi and Rocky Mountain fever, in which the Weil-Felix reaction is negative. There is a special non-indologenic strain of B. proteus, which is agglutinated in some of the fevers belonging to the second group.TROPICAL TYPHUS IN THE MALAY STATES: (1) urban form, or "shop-typhus," resembling Brill's disease; (2) rural form or "scrub-typhus." Peculiar association with oil-palms and coarse grass.     

Contrasting spatial distribution and risk factors for past infection with scrub typhus and murine typhus in Vientiane City, Lao PDR

Background

The aetiological diagnostic of fevers in Laos remains difficult due to limited laboratory diagnostic facilities. However, it has recently become apparent that both scrub and murine typhus are common causes of previous undiagnosed fever. Epidemiological data suggests that scrub typhus would be more common in rural areas and murine typhus in urban areas, but there is very little recent information on factors involved in scrub and murine typhus transmission, especially where they are sympatric - as is the case in Vientiane, the capital of the Lao PDR.

Methodology and Principal Findings

We therefore determined the frequency of IgG seropositivity against scrub typhus (Orientia tsutsugamushi) and murine typhus (Rickettsia typhi), as indices of prior exposure to these pathogens, in randomly selected adults in urban and peri-urban Vientiane City (n = 2,002, ≥35 years). Anti-scrub and murine typhus IgG were detected by ELISA assays using filter paper elutes. We validated the accuracy of ELISA of these elutes against ELISA using serum samples. The overall prevalence of scrub and murine typhus IgG antibodies was 20.3% and 20.6%, respectively. Scrub typhus seropositivity was significantly higher among adults living in the periphery (28.4%) than in the central zone (13.1%) of Vientiane. In contrast, seroprevalence of murine typhus IgG antibodies was significantly higher in the central zone (30.8%) as compared to the periphery (14.4%). In multivariate analysis, adults with a longer residence in Vientiane were at significant greater risk of past infection with murine typhus and at lower risk for scrub typhus. Those with no education, living on low incomes, living on plots of land with poor sanitary conditions, living in large households, and farmers were at higher risk of scrub typhus and those living in neighborhoods with high building density and close to markets were at greater risk for murine typhus and at lower risk of scrub typhus past infection.

Conclusions

This study underscores the intense circulation of both scrub and murine typhus in Vientiane city and underlines difference in spatial distribution and risk factors involved in the transmission of these diseases.     

A Hematogenously Disseminated Orientia tsutsugamsushi-Infected Murine Model of Scrub Typhus

Orientia tsutsugamushi, the etiologic agent of scrub typhus, is a mite-borne rickettsia transmitted by the parasitic larval stage of trombiculid mites. Approximately one-third of the world''s population is at risk of infection with Orientia tsutsugamushi, emphasizing its importance in global health. In order to study scrub typhus, Orientia tsutsugamushi Karp strain has been used extensively in mouse studies with various inoculation strategies and little success in inducing disease progression similar to that of human scrub typhus. The objective of this project was to develop a disease model with pathology and target cells similar to those of severe human scrub typhus. This study reports an intravenous infection model of scrub typhus in C57BL/6 mice. This mouse strain was susceptible to intravenous challenge, and lethal infection occurred after intravenous inoculation of 1.25×10⁶ focus (FFU) forming units. Signs of illness in lethally infected mice appeared on day 6 with death occurring ∼6 days later. Immunohistochemical staining for Orientia antigens demonstrated extensive endothelial infection, most notably in the lungs and brain. Histopathological analysis revealed cerebral perivascular, lymphohistiocytic infiltrates, focal hemorrhages, meningoencephalitis, and interstitial pneumonia. Disseminated infection of endothelial cells with Orientia in C57BL/6 mice resulted in pathology resembling that of human scrub typhus. The use of this model will allow detailed characterization of the mechanisms of immunity to and pathogenesis of O. tsutsugamushi infection.     

Prion protein gene sequence of Canada's first non-imported case of bovine spongiform encephalopathy (BSE).

In May 2003, Canada became the 22nd country outside of the United Kingdom to report a case of bovine spongiform encephalopathy (BSE) in an animal not known to be imported from a country with cattle previously affected by this fatal, transmissible prion disease. Despite extensive testing of thousands of other animals that may have been exposed to contaminated feed at the same time as the affected animal, no evidence has been found for other infections. This finding leaves room for conjectures that the single confirmed case arose spontaneously, perhaps (by analogy with human Creutzfeldt-Jakob disease) as a result of a somatic protein misfolding event or a novel germline mutation. Here we present DNA sequence data from the affected animal's prion protein coding sequence that argue definitively against the latter hypothesis.     

Cellular immunity factors of tick-borne typhus patients in northern Asia

In patients with North Asian tick-borne typhus fever the deficiency of the T-system of immunity, most pronounced in the acute period of the disease, is observed, which is manifested by low values of lymphocyte blast-transformation and rosette-formation. A decrease in the number of active E-rosette-forming cells depends on the severity of the disease. The shifts in the T-system of immunity, appearing in patients with North Asian tick-borne typhus fever, are compensated for comparatively quickly, the normalization of the functional activity of T-lymphocytes occurring sooner than the restoration of their number. The specific dynamics of the characteristics of cell-mediated immunity in patients with North Asian tick-borne typhus fever is accompanied by a comparatively mild course of the disease and its favorable outcome.     

Typhus vaccine developments from the First to the Second World War (on Paul Weindling's 'between bacteriology and virology...')

After the louse transmission of epidemic typhus had been established (1909), a small microorganism (thought to belong to a new genus, Rickettsia) was shown in enormous numbers in the guts of lice that had fed on human typhus victims. Attempts at cultivating this organism on inert media failed; transfer from louse to louse without loss of virulence for the vertebrate host was successful. Some scientists were not convinced of the etiologic role of Rickettsiae, because the presence of this microbe in blood and organs of victims or of experimentally infected animals was difficult to demonstrate. This uncertainty was dispelled in 1928, when in guinea pigs infected with material from the closely related disease Tabardillo (murine typhus) abundant Rickettsiae were revealed in the tunica vaginalis. Live vaccines, derived from strains of murine typhus and deployed in French North Africa, were considered by outside observers as unsafe. Killed vaccines were derived from the masses of Rickettsiae present in louse guts, in chick embryo yolk sacs or in vertebrate lungs. These developments were not spurned by any 'upswing of virology' but by the threat of typhus in endemic areas and, after 1938, in a war-torn world. Their basis was firmly anchored in bacteriological thought styles and techniques.     

Cytokine Network in Scrub Typhus: High Levels of Interleukin-8 Are Associated with Disease Severity and Mortality

Background

Scrub typhus, caused by Orientia tsutsugamushi, is endemic in the Asia-Pacific region. Mortality is high if untreated, and even with treatment as high as 10–20%, further knowledge of the immune response during scrub typhus is needed. The current study was aimed at comparing plasma levels of a variety of inflammatory mediators in scrub typhus patients and controls in South India in order to map the broader cytokine profile and their relation to disease severity and clinical outcome.

Methodology/Principal Findings

We examined plasma levels of several cytokines in scrub typhus patients (n = 129) compared to healthy controls (n = 31) and infectious disease controls (n = 31), both in the acute phase and after recovery, by multiplex technology and enzyme immunoassays. Scrub typhus patients were characterized by marked changes in the cytokine network during the acute phase, differing not only from healthy controls but also from infectious disease controls. While most of the inflammatory markers were raised in scrub typhus, platelet-derived mediators such as RANTES were markedly decreased, probably reflecting enhanced platelet activation. Some of the inflammatory markers, including various chemokines (e.g., interleukin-8, monocyte chemoattractant peptide-1 and macrophage inflammatory protein-1β) and downstream markers of inflammation (e.g., C-reactive protein and pentraxin-3), were also associated with disease severity and mortality during follow-up, with a particular strong association with interleukin-8.

Conclusions/Significance

Our findings suggest that scrub typhus is characterized by a certain cytokine profile that includes dysregulated levels of a wide range of mediators, and that this enhanced inflammation could contribute to disease severity and clinical outcome.     

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.     

Burden of Disease Measured by Disability-Adjusted Life Years and a Disease Forecasting Time Series Model of Scrub Typhus in Laiwu,China

Background

Laiwu District is recognized as a hyper-endemic region for scrub typhus in Shandong Province, but the seriousness of this problem has been neglected in public health circles.

Methodology/Principal Findings

A disability-adjusted life years (DALYs) approach was adopted to measure the burden of scrub typhus in Laiwu, China during the period 2006 to 2012. A multiple seasonal autoregressive integrated moving average model (SARIMA) was used to identify the most suitable forecasting model for scrub typhus in Laiwu. Results showed that the disease burden of scrub typhus is increasing yearly in Laiwu, and which is higher in females than males. For both females and males, DALY rates were highest for the 60–69 age group. Of all the SARIMA models tested, the SARIMA(2,1,0)(0,1,0)₁₂ model was the best fit for scrub typhus cases in Laiwu. Human infections occurred mainly in autumn with peaks in October.

Conclusions/Significance

Females, especially those of 60 to 69 years of age, were at highest risk of developing scrub typhus in Laiwu, China. The SARIMA (2,1,0)(0,1,0)₁₂ model was the best fit forecasting model for scrub typhus in Laiwu, China. These data are useful for developing public health education and intervention programs to reduce disease.     

Laboratory animal models for human scrub typhus

A wide variety of animals have been utilized in an attempt to provide the information necessary to bring scrub typhus to the point where it is no longer a threat to man. The laboratory mouse is usually the animal of choice for the study of this disease. The discovery that certain strains of inbred mice are genetically resistant to Rickettsia tsutsugamushi, the agent of scrub typhus, has opened new avenues in the study of the immune response to the disease. The cynomolgus monkey, Macaca fascicularis, appears to be the best animal model for the study of scrub typhus as it occurs in humans and should be useful in the development of an efficacious vaccine.     

Typhus infection (Brill's disease) in the environment of a large city

The data on the epidemiological analysis of 675 cases of infection of the typhus nature, detected in Leningrad in 1974-1986, are presented. The seasonal morbidity curve, the age structure of patients, the character of the clinical course of the disease and other data gave a reason for the diagnosis of Brill's disease. The comparison of the relative data on morbidity rates in typhus at different periods of the current century was made.