Search Results (15)

Background: Statins are commonly used cholesterol-lowering drugs with evidence of additional chemoprotective and immunomodulatory effects resulting from the inhibition of DNA replication, cell proliferation, and TH1-cell inhibition. There are conflicting reports regarding the potential benefit of concurrent statin treatment on non-muscle invasive bladder cancer (NMIBC) and specifically on intravesical Bacillus Calmette–Guerin (BCG) outcomes. We therefore aimed to analyze the effects of concurrent BCG and statin use in patients with NMIBC. Methods: National Veterans Affairs databases were used to retrospectively identify men with NMIBC between 2000 and 2010 who were treated with BCG. Pharmacy data was interrogated, and patients were divided according to statin therapy status. Statins had to be given at the beginning of BCG treatments and continued for at least 6 months. Cox proportional hazard ratios after inverse propensity score-weighted and competing risks adjustments were calculated for recurrence, secondary events (e.g., progression), cancer-specific survival, and overall survival. Results: Among 8814 patients, with a median follow-up of 11.3 years, statins were used by 38% of the patients. Patients taking statins were older (71 vs. 68, p < 0.0001), had more comorbidities (Charlson Comorbidity Index (CCI > 2; 38.6% vs. 31.4%, p < 0.0001), and had a higher-grade disease (40.2% vs. 34.3%, p < 0.0001) compared to those not on statins. After adjusting for stage, grade, age, race, CCI, agent orange exposure, and year of diagnosis, Cox proportional hazard analysis revealed no association with recurrence (HR 1.05, 95% CI 0.97–1.15, p = 0.23), secondary events (HR 0.91, 95% CI 0.80–1.05, p = 0.189), or bladder cancer specific survival (HR 0.88, 95% CI 0.76–1.02, p = 0.09) of statin use. However, statins were associated with improved overall survival (HR 0.89, 95% CI 0.83–0.96, p = 0.002). Conclusions: Concurrent statin and BCG use in patients with NMIBC was associated with improved overall survival, but not recurrence, secondary events, or bladder cancer-specific survival. These results confirm the real-world well-established cardiovascular benefit of statin treatment and primary preventive care. However, this large population study did not find any association between statins and the outcomes of patients with NMIBC treated with BCG immunotherapy. Full article

Rickettsioses, often underreported, pose public health challenges. Rickettsia asembonensis is a potential emerging pathogen that was previously detected in humans, animals, and a variety of arthropods. While its pathogenicity in humans remains unclear, it poses a potential public health threat. Here, we present an extended epidemiological, diagnostic, and genetic analysis of the information provided in a preliminary report on the investigation of rickettsiae in Peru. In particular, we report the detection of R. asembonensis in blood specimens collected from four human patients with an acute undifferentiated fever of a seven- to nine-day duration, all of whom tested negative for other vector-borne pathogens. Additionally, we describe the replicative capacity of the R. asembonensis isolates in cell cultures. Full article

In Vietnam, the public health burden of rickettsial infections continues to be underestimated due to knowledge gaps in the epidemiology of these diseases. We conducted a systematic study among 27 hospitals from 26 provinces in eight ecological regions throughout Vietnam to investigate the prevalence, distribution, and clinical characteristics of rickettsial diseases. We recruited 1834 patients in the study from April 2018 to October 2019. The findings showed that rickettsial diseases were common among undifferentiated febrile patients, with 564 (30.8%) patients positive by qPCR for scrub typhus, murine typhus or spotted fever. Scrub typhus (484, 85.8%) was the most common rickettsial disease, followed by murine typhus (67, 11.9%) and spotted fever (10, 1.8%). Rickettsial diseases were widely distributed in all regions of Vietnam and presented with nonspecific clinical manifestations. Full article

Recently, an intradermal inoculation of the rhesus macaque model of scrub typhus has been characterized at our institution. The current project was to establish a rhesus macaque model of scrub typhus using the naturally infected chigger challenge method that faithfully mimics the natural route of pathogen transmission to fully understand the host-pathogen-vector interactions influencing pathogen transmission. Unlike the needle-based inoculation route, Orientia tsutsugamushi-infected chiggers introduce both pathogen and chigger saliva into the host epidermis at the bite site. However, information on the interaction or influence of chigger saliva on pathogenesis and immunity of host has been limited, consequently hindering vaccine development and transmission-blocking studies. To characterize chigger inoculated O. tsutsugamushi in rhesus macaques, we determined the minimum chigger attachment time required to efficiently transmit O. tsutsugamushi to the immunocompetent hosts and preliminary assessed clinical parameters, course of bacterial infection, and host’s immunological response to identifying potential factors influencing pathogen infection. Chigger infestation on hosts resulted in: (i) Rapid transmission of O. tsutsugamushi within 1 h and (ii) antigen-specific type I and II T-cell responses were markedly increased during the acute phase of infection, suggesting that both systems play critical roles in response to the pathogen control during the primary infection. In summary, we demonstrate that O. tsutsugamushi infection in rhesus macaques via chigger challenge recapitulates the time of disease onset and bacteremia observed in scrub typhus patients. Levels of proinflammatory cytokines and chemokines were positively correlated with bacteremia. Full article

The antigenic diversity of Orientia tsutsugamushi as well as the interstrain difference(s) associated with virulence in mice impose the necessity to dissect the host immune response. In this study we compared the host response in lethal and non-lethal murine models of O. tsutsugamushi infection using the two strains, Karp (New Guinea) and Woods (Australia). The models included the lethal model: Karp intraperitoneal (IP) challenge; and the nonlethal models: Karp intradermal (ID), Woods IP, and Woods ID challenges. We monitored bacterial trafficking to the liver, lung, spleen, kidney, heart, and blood, and seroconversion during the 21-day challenge. Bacterial trafficking to all organs was observed in both the lethal and nonlethal models of infection, with significant increases in average bacterial loads observed in the livers and hearts of the lethal model. Multicolor flow cytometry was utilized to analyze the CD4+ and CD8+ T cell populations and their intracellular production of the cytokines IFNγ, TNF, and IL2 (single, double, and triple combinations) associated with both the lethal and nonlethal murine models of infection. The lethal model was defined by a cytokine signature of double- (IFNγ-IL2) and triple-producing (IL2-TNF-IFNγ) CD4+ T-cell populations; no multifunctional signature was identified in the CD8+ T-cell populations associated with the lethal model. In the nonlethal model, the cytokine signature was predominated by CD4+ and CD8+ T-cell populations associated with single (IL2) and/or double (IL2-TNF) populations of producers. The cytokine signatures associated with our lethal model will become depletion targets in future experiments; those signatures associated with our nonlethal model are hypothesized to be related to the protective nature of the nonlethal challenges. Full article

The rickettsioses of the “Far East” or Asia–Australia–Pacific region include but are not limited to endemic typhus, scrub typhus, and more recently, tick typhus or spotted fever. These diseases embody the diversity of rickettsial disease worldwide and allow us to interconnect the various contributions to this special issue of Tropical Medicine and Infectious Disease. The impact of rickettsial diseases—particularly of scrub typhus—was substantial during the wars and “police actions” of the last 80 years. However, the post-World War II arrival of effective antibiotics reduced their impact, when recognized and adequately treated (chloramphenicol and tetracyclines). Presently, however, scrub typhus appears to be emerging and spreading into regions not previously reported. Better diagnostics, or higher population mobility, change in antimicrobial policies, even global warming, have been proposed as possible culprits of this phenomenon. Further, sporadic reports of possible antibiotic resistance have received the attention of clinicians and epidemiologists, raising interest in developing and testing novel diagnostics to facilitate medical diagnosis. We present a brief history of rickettsial diseases, their relative importance within the region, focusing on the so-called “tsutsugamushi triangle”, the past and present impact of these diseases within the region, and indicate how historically, these often-confused diseases were ingeniously distinguished from each another. Moreover, we will discuss the importance of DNA-sequencing efforts for Orientia tsutsugamushi, obtained from patient blood, vector chiggers, and rodent reservoirs, particularly for the dominant 56-kD type-specific antigen gene (tsa56), and whole-genome sequences, which are increasing our knowledge of the diversity of this unique agent. We explore and discuss the potential of sequencing and other effective tools to geographically trace rickettsial disease agents, and develop control strategies to better mitigate the rickettsioses. Full article

To explore the risk of antimicrobial resistant (AMR) non-typhoidal Salmonella during asymptomatic infection passage between pet dogs and human caregivers in Khon Kaen, Thailand, one hundred forty paired fecal samples (n = 280) were obtained from companion dogs and their human caregivers, interviewed from 140 households during 2019–2020. The purified Salmonella isolates were serotype-identified and tested for antimicrobial resistance against ampicillin, ciprofloxacin, chloramphenicol, nalidixic acid, streptomycin, sulfamethoxazole–trimethoprim, and tetracycline. The homologous Salmonella isolate pairs (suggesting Salmonella infections may have been due to passage between each one of the pair, or derived from the same source) were subsequently characterized by serotype screening, pulsed field gel electrophoresis (PFGE), and Synchrotron Fourier transform infrared spectroscopy (SR-FTIR). The Salmonella prevalence observed in dogs, 12.86% (18/140), was not significantly different from that observed in humans, 17.86% (25/140) using McNemar’s test. The AMR patterns (the patterns among the isolates of pet dogs and caregivers) and the serotypes (thirteen serotypes with 18 isolates from pet dogs plus thirteen serotypes with 25 isolates from humans) between pet dogs and humans were not significantly different using Pearson’s chi-squared test. The homologous Salmonella isolates from the Salmonella-present households was 5.13% (2/39). This study demonstrated that the hypothesis that there is a high risk of Salmonella infection passage between dogs and humans with close contact in Khon Kaen is doubtful. Only 5.13% of homologous Salmonella isolates from Salmonella-present households were found in Khon Kaen, Thailand, although the prevalence of Salmonella-positive samples, serotypes, and antimicrobial resistance patterns were quite similar among the two populations. Full article

Scrub typhus and its etiological agents, Orientia species, have been around for a very long time. Historical reference to the rickettsial disease scrub typhus was first described in China (313 AD) by Hong Ge in a clinical manual (Zhouhofang) and in Japan (1810 AD) when Hakuju Hashimoto described tsutsuga, a noxious harmful disease in the Niigata prefecture. Other clinicians and scientists in Indonesia, Philippines, Taiwan, Australia, Vietnam, Malaysia, and India reported on diseases most likely to have been scrub typhus in the early 1900s. All of these initial reports about scrub typhus were from an area later designated as the Tsutsugamushi Triangle—an area encompassing Pakistan to the northwest, Japan to the northeast and northern Australia to the south. It was not until the 21st century that endemic scrub typhus occurring outside of the Tsutsugamushi Triangle was considered acceptable. This report describes the early history of scrub typhus, its distribution in and outside the Tsutsugamushi Triangle, and current knowledge of the causative agents, Orientia species. Full article

To evaluate the containment of antimicrobial-resistant (AMR) Salmonella contaminations of a HACCP slaughterhouse (HACCP SH) and a non-HACCP slaughterhouse (non-HACCPSH), 360 paired pig rectal (representing the farm pig status) and carcass samples (representing the contamination) were collected equally from the two slaughterhouses that serviced 6 and 12 farms, respectively, in Northeast Thailand (n = 720). The purified Salmonella isolates were serotype identified, antimicrobial susceptibility tested, and pulsed-field gel electrophoresis (PFGE) assessed. Four evaluations of two slaughterhouses were examined: (1) the means of slaughtering contamination rates (SCR) (to evaluate the contamination level by averaged farm SCRs): the HACCP SH decreased contamination (SCR: −48.89% ± 8.80%, n = 6), whereas the non-HACCP SH increased (SCR: 14.31% ± 9.35%, n = 12). (2) The serotype diversity: the HACCP SH decreased the diversity from the rectal group (110 isolates, 9 serotypes) to carcass group (23 isolates, 3 serotypes), whereas there was no decrease in the non-HACCP SH (rectal group (66 isolates, 14 serotypes) and carcass group (31 isolates, 10 serotypes)). (3) The AMR patterns: the HACCP SH decreased from rectal group (96 isolates, 7 patterns) to carcass group (22 isolates, 1 pattern), whereas there was no decrease from the non-HACCP SH rectal group (22 isolates, 7 patterns) to carcass group (48 isolates, 8 patterns). (4) The estimated indirect contamination rate (by serotype screening and PFGE confirmation): the HACCP SH was 60.87% (14/23), whereas the non-HACCP SH was 98.48% (65/66). This study indicates that both the slaughterhouses keep a high level of indirect contamination; the HACCP SH decreases Salmonella contaminations and reduces the AMR patterns, the non-HACCP SH increases contaminations. Full article

Kazakhstan and the United States have partnered since 2003 to counter the proliferation of weapons of mass destruction. The US Department of Defense (US DoD) has funded threat reduction programs to eliminate biological weapons, secure material in repositories that could be targeted for theft, and enhance surveillance systems to monitor infectious disease outbreaks that would affect national security. The cooperative biological research (CBR) program of the US DoD’s Biological Threat Reduction Program has provided financing, mentorship, infrastructure, and biologic research support to Kazakhstani scientists and research institutes since 2005. The objective of this paper is to provide a historical perspective for the CBR involvement in Kazakhstan, including project chronology, successes and challenges to allow lessons learned to be applied to future CBR endeavors. A project compendium from open source data and interviews with partner country Kazakhstani participants, project collaborators, and stakeholders was developed utilizing studies from 2004 to the present. An earlier project map was used as a basis to determine project linkages and continuations during the evolution of the CBR program. It was determined that consistent and effective networking increases the chances to collaborate especially for competitive funding opportunities. Overall, the CBR program has increased scientific capabilities in Kazakhstan while reducing their risk of biological threats. However, there is still need for increased scientific transparency and an overall strategy to develop a capability-based model to better enhance and sustain future research. Finally, we offer a living perspective that can be applied to further link related studies especially those related to One Health and zoonoses and the assessment of similar capability-building programs. Full article

Scrub typhus, a chigger-borne febrile illness, occurs primarily in countries of the Asia-Pacific rim and islands of the Western Pacific. The etiologic agent is the obligate intracellular rickettsial bacterium Orientia tsutsugamushi. Research on O. tsutsugamushi has relied on the availability of several prototype strains, which were isolated from human cases of scrub typhus in the 1940s and 1950s. We review the history of the three original, and most important, prototype strains, Gilliam, Karp and Kato, including information on their isolation, their culture history, their clinical characteristics, their importance within the research literature on scrub typhus, and recent advances in elucidating their molecular genomics. The importance of these strains to the research and development of clinical tools related to scrub typhus is also considered. Finally, we examine whether the strains have been genetically stable since their isolation, and whether prototype strains maintained in separate laboratories are identical, based on pairwise comparisons of several sequences from four genes. By using genetic information archived in international DNA databases, we show that the prototype strains used by different laboratories are essentially identical, and that the strains have retained their genetic integrity at least since the 1950s. The three original prototype strains should remain a standard by which new diagnostic procedures are measured. Given their fundamental position in any comparative studies, they are likely to endure as a critical part of present and future research on scrub typhus and Orientia. Full article

Scrub typhus threatens one billion people in the Asia-Pacific area and cases have emerged outside this region. It is caused by infection with any of the multitude of strains of the bacterium Orientia tsutsugamushi. A vaccine that affords heterologous protection and a commercially-available molecular diagnostic assay are lacking. Herein, we determined that the nucleotide and translated amino acid sequences of outer membrane protein A (OmpA) are highly conserved among 51 O. tsutsugamushi isolates. Molecular modeling revealed the predicted tertiary structure of O. tsutsugamushi OmpA to be very similar to that of the phylogenetically-related pathogen, Anaplasma phagocytophilum, including the location of a helix that contains residues functionally essential for A. phagocytophilum infection. PCR primers were developed that amplified ompA DNA from all O. tsutsugamushi strains, but not from negative control bacteria. Using these primers in quantitative PCR enabled sensitive detection and quantitation of O. tsutsugamushi ompA DNA from organs and blood of mice that had been experimentally infected with the Karp or Gilliam strains. The high degree of OmpA conservation among O. tsutsugamushi strains evidences its potential to serve as a molecular diagnostic target and justifies its consideration as a candidate for developing a broadly-protective scrub typhus vaccine. Full article

Scrub typhus is the most important rickettsial disease in the world. Its previous endemic region was considered to be in Asia, Australia and islands in the Indian and Pacific Oceans; this area was referred to as the Tsutsugamushi Triangle. Accumulation of serological, molecular, genetic, and culture data have shown that not only is scrub typhus not limited to the Tsutsugamushi Triangle, but can be caused by orientiae other than Orientia tsutsugamushi. This review describes evidence currently available that will be instrumental to researchers, healthcare providers and medical leaders in developing new research projects, performing diagnosis, and preventing scrub typhus in locations not previously thought to be endemic. Full article

Scrub typhus and the rickettsial diseases represent some of the oldest recognized vector-transmitted diseases, fraught with a rich historical aspect, particularly as applied to military/wartime situations. The vectors of Orientia tsutsugamushi were once thought to be confined to an area designated as the Tsutsugamushi Triangle. However, recent reports of scrub typhus caused by Orientia species other than O. tsutsugamushi well beyond the limits of the Tsutsugamushi Triangle have triggered concerns about the worldwide presence of scrub typhus. It is not known whether the vectors of O. tsutsugamushi will be the same for the new Orientia species, and this should be a consideration during outbreak/surveillance investigations. Additionally, concerns surrounding the antibiotic resistance of O. tsutsugamushi have led to considerations for the amendment of treatment protocols, and the need for enhanced public health awareness in both the civilian and medical professional communities. In this review, we discuss the history, outbreaks, antibiotic resistance, and burgeoning genomic advances associated with one of the world’s oldest recognized vector-borne pathogens, O. tsutsugamushi. Full article

Scrub typhus is an acute, and sometimes fatal, human febrile illness, typically successfully treated using chloramphenicol or one of the tetracyclines. Over the past several years, descriptions of strains of Orientia tsutsugamushi with reduced susceptibility to antibiotics have appeared. Because case-fatality ratios approached 50% during the pre-antibiotic era, antibiotic-resistant scrub typhus is concerning. Herein, we review the data on resistant scrub typhus, describe how the theoretical existence of such resistance is affected by interpretation of treatment outcomes, and propose a plan to further identify whether true drug resistance is present and how to deal with drug resistance if it has evolved. Limited resistance is not unambiguous, if present, and antibiotic resistance in scrub typhus is not a dichotomous trait. Rather, evidence of resistance shows a continuous gradation of increasing resistance. The availability of genomes from isolates of O. tsutsugamushi allows the search for loci that might contribute to antibiotic resistance. At least eighteen such loci occur in all genomes of O. tsutsugamushi examined. One gene (gyrA) occurs as a quinolone-resistant form in the genome of all isolates of O. tsutsugamushi. At least 13 other genes that are present in some members of the genus Rickettsia do not occur within O. tsutsugamushi. Even though reports of scrub typhus not responding appropriately to chloramphenicol or a tetracycline treatment have been in the literature for approximately 23 years, the existence and importance of antibiotic-resistant scrub typhus remains uncertain. Full article