Epidemiology of Murine Typhus in Taiwan from 2013 to 2020.

Murine typhus is a flea-borne disease caused by Rickettsia typhi infection. The disease is a notifiable infectious disease in Taiwan. Specimens from suspected cases are required to be sent to the Taiwan Centers for Disease Control and Prevention for laboratory diagnosis. In this study, 204 cases of murine typhus were identified by bacterial isolation, real-time polymerase chain reaction, or indirect immunofluorescence assay between 2013 and 2020. The average incidence rate was 0.11/100,000 person-years (95% CI: 0.08-0.13). Murine typhus occurred throughout the year, but it was most prevalent in summer (May to August). The majority of patients were males (75%), residents of Kaohsiung city (31%), and worked in agriculture, forestry, fishing, and animal husbandry (27%). Fever was the most common symptom, present in 95.6% of patients, followed by headache (41%), myalgia (33%), and liver dysfunction (33%). Only 13% of patients had a rash. Up to 80% of cases were among hospitalized patients, and 43% of patients developed severe manifestations. Serological assays also indicated coinfection events. Seven patients showed a 4-fold increase in antibody titers against Orientia tsutsugamushi (N = 2), Coxiella burnetii (n = 2), and Leptospira (N = 3). In conclusion, murine typhus is an endemic and important zoonotic rickettsial disease in Taiwan that cannot be ignored. Further epidemiological surveillance and clinical characteristics should be continuously investigated to prevent and control murine typhus.

Cat Flea Coinfection with Rickettsia felis and Rickettsia typhi.

Purpose: Flea-borne rickettsioses, collectively referred to as a term for etiological agents Rickettsia felis, Rickettsia typhi, and RFLOs (R. felis-like organisms), has become a public health concern around the world, specifically in the United States. Due to a shared arthropod vector (the cat flea) and clinical signs, discriminating between Rickettsia species has proven difficult. While the effects of microbial coinfections in the vector can result in antagonistic or synergistic interrelationships, subsequently altering potential human exposure and disease, the impact of bacterial interactions within flea populations remains poorly defined. Methods: In this study, in vitro and in vivo systems were utilized to assess rickettsial interactions in arthropods. Results: Coinfection of both R. felis and R. typhi within a tick-derived cell line indicated that the two species could infect the same cell, but distinct growth kinetics led to reduced R. felis growth over time, regardless of infection order. Sequential flea coinfections revealed the vector could acquire both Rickettsia spp. and sustain coinfection for up to 2 weeks, but rickettsial loads in coinfected fleas and feces were altered during coinfection. Conclusion: Altered rickettsial loads during coinfection suggest R. felis and R. typhi interactions may enhance the transmission potential of either agent. Thus, this study provides a functional foundation to disentangle transmission events propelled by complex interspecies relationships during vector coinfections.

Rickettsia rickettsii and Rickettsia typhi in hospitalized children diagnosed with Pediatric Multisystemic Inflammatory Syndrome in Merida, Yucatan.

Multisystem Inflammatory Syndrome in Children (MIS-C) presents with fever, fatigue, elevated inflammatory markers (acute phase reactants), and a history of exposure to SARS-CoV-2 or positive antibodies to SARS-CoV-2. As the COVID-19 pandemic unfolded, the risk of MIS-C in the pediatric population increased. However, exposure to other viruses and the presence of SARS-CoV-2 positive antibodies in children hospitalized for various pathogen-associated illnesses will also remain common and may complicate differential diagnoses with diseases endemic to the region such as rickettsial diseases. The objective was to highlight the desirability of medical personnel systematically incorporating rickettsiosis as a differential diagnosis for MIS-C when studying a child with fever, non-specific symptoms, and elevated inflammatory markers. In conclusion MIS-C should be considered in children with elevated inflammatory markers when there is a history of COVID-19 and they also meet criteria that have already been established by international agencies, such as CDC and WHO.

Case Report: Cardiovascular Manifestations due to Flea-Borne Typhus.

Flea-borne typhus is a vector-borne disease caused by Rickettsia typhi that occurs worldwide, except in Antarctica. In the United States, most cases are restricted to California, Hawaii, and Texas. The syndrome is characterized by nonspecific signs and symptoms: fever, headache, rash, arthralgia, cough, hepatosplenomegaly, diarrhea, and abdominal pain. Although flea-borne typhus can cause pulmonary, neurological, and renal complications, the cardiovascular system is rarely affected. We present a case of endocarditis resulting from flea-borne typhus diagnosed by blood microbial cell-free DNA testing that required valve replacement and antibiotic therapy for 6 months. In addition, we review 20 cases of presumed and confirmed cardiovascular manifestations resulting from flea-borne typhus in the literature.

Crystal structure of Methionyl-tRNA Synthetase from Rickettsia typhi in complex with its cognate amino acid.

Rickettsia typhi is the causative agent of murine typhus (endemic typhus), a febrile illness that can be self-contained, though in some cases it can progress to death. The three dimensional structure of Methionyl-tRNA Synthetase from R. typhi (RtMetRS) in complex with its substrate l-methionine was solved by molecular replacement and refined at 2.30 Å resolution in space group P1 from one X-ray diffraction dataset. Processing and refinement trials were decisive to establish the lower symmetry space group and indicated the presence of twinning with four domains. RtMetRS belongs to the MetRS1 family and was crystallized with the CP domain in an open conformation, what is distinctive from other MetRS1 enzymes whose structures were solved with a bound L-methionine (therefore, in a closed conformation). This conformation resembles the ones observed in the MetRS2 family.

Surveillance of Flea-Borne Typhus in California, 2011-2019.

Flea-borne typhus (FBT), also referred to as murine typhus, is an acute febrile disease in humans caused by the bacteria Rickettsia typhi. Currently, cases of FBT are reported for public health surveillance purposes (i.e., to detect incidence and outbreaks) in a few U.S. states. In California, healthcare providers and testing laboratories are mandated to report to their respective local public health jurisdictions whenever R. typhi or antibodies reactive to R. typhi are detected in a patient, who then report cases to state health department. In this study, we characterize the epidemiology of flea-borne typhus cases in California from 2011 to 2019. A total of 881 cases were reported during this period, with most cases reported among residents of Los Angeles and Orange Counties (97%). Demographics, animal exposures, and clinical courses for case patients were summarized. Additionally, spatiotemporal cluster analyses pointed to five areas in southern California with persistent FBT transmission.

Severe Rickettsia typhi Infections, Costa Rica.

Murine typhus is a febrile, fleaborne disease caused by infection with Rickettsia typhi bacteria. Cases can range from mild and nonspecific to fatal. We report 2 cases of murine typhus in Costa Rica, confirming the presence and circulation of R. typhi causing severe disease in the country.

Fleaborne Typhus-Associated Deaths - Los Angeles County, California, 2022.

Fleaborne typhus (also known as murine typhus), a widely distributed vectorborne zoonosis caused by Rickettsia typhi, is a moderately severe, but infrequently fatal illness; among patients who receive doxycycline, the case-fatality rate is <1%. Fleaborne typhus is a mandated reportable condition in California. Reported fleaborne typhus cases in Los Angeles County have been increasing since 2010, with the highest number (171) reported during 2022. During June-October 2022, Los Angeles County Department of Public Health learned of three fleaborne typhus-associated deaths. This report describes the clinical presentation, illness course, and methods used to diagnose fleaborne typhus in these three cases. Severe fleaborne typhus manifestations among these cases included hemophagocytic lymphohistiocytosis, a rare immune hyperactivation syndrome that can occur in the infection setting; myocarditis; and septic shock with disseminated intravascular coagulation. Increased health care provider and public health awareness of the prevalence and severity of fleaborne typhus and of the importance of early doxycycline therapy is essential for prevention and treatment efforts.

Murine typhus is a common cause of acute febrile illness in Bandung, Indonesia.

Murine typhus (MT), an infection caused by the gram-negative bacteria Rickettsia typhi (R. typhi), is a significant cause of acute febrile illness (AFI) in Southeast Asia but is rarely reported in Indonesia. The current study aimed to describe the clinical characteristics of MT cases in Bandung, West Java. Non-confirmed AFI cases (n = 176) from a prospective cohort study of whom paired serum samples (acute (T1), midterm (T2), or convalescent (T3)) were available were screened using MT serology. IgG against R. typhi was detected in the T2 or T3 samples using an in-house ELISA. Positive IgG samples were further screened for the presence of IgM. If both IgM and IgG were positive, the endpoint titer of T1, T2, or T3 was determined. In cases with a fourfold increase in titer, real-time PCR of T1 samples was performed to detect R. typhi DNA. In total, 71/176 (40.3%) patients tested positive for IgG antibody, and 26 AFI cases were confirmed as MT (23 cases by PCR, 3 cases by fourfold titer increased IgG or IgM titer). The most common clinical symptoms in the confirmed cases were headache (80%), arthralgia (73%), malaise (69%), and myalgia (54%). In these cases, the presumptive clinical diagnoses were typhoid fever (43.2%), dengue (38.5%), and leptospirosis (19.2%). MT was not considered in any of the patients, and no patients received doxycycline. These findings confirmed that MT is an important cause of AFI in Indonesia. MT should be included in the differential diagnosis of AFI, and empirical treatment with doxycycline should be considered.

Nonnegligible Seroprevalence and Predictors of Murine Typhus, Japan.

To elucidate the epidemiology of murine typhus, which is infrequently reported in Japan, we conducted a cross-sectional study involving 2,382 residents of rickettsiosis-endemic areas in Honshu Island during August-November 2020. Rickettsia typhi seroprevalence rate was higher than that of Orientia tsutsugamushi, indicating that murine typhus is a neglected disease.

Detection of Severe Murine Typhus by Nanopore Targeted Sequencing, China.

We report a case of murine typhus in China caused by Rickettsia typhi and diagnosed by nanopore targeted sequencing of a bronchoalveolar lavage fluid sample. This case highlights that nanopore targeted sequencing can effectively detect clinically unexplained infections and be especially useful for detecting infections in patients without typical signs and symptoms.

Serological cross-reactivity between spotted fever and typhus groups of rickettsia infection in Japan.

OBJECTIVES: We examined the frequency of cross-reactions to Rickettsia typhi in patients with Japanese spotted fever (JSF) and evaluated the differences between two rickettsiae using antibody endpoint titers. METHODS: Patients' immunoglobulin (Ig)M and IgG titers against Rickettsia japonica and Rickettsia typhi in two phases were measured using an indirect immunoperoxidase assay at two reference centers for rickettsiosis in Japan. Cross-reaction was defined as a higher titer against R. typhi in convalescent sera than in acute sera among patients fulfilling the criteria for JSF diagnosis. The frequencies of IgM and IgG were also evaluated. RESULTS: Approximately 20% of cases showed positive cross-reactions. A comparison of antibody titers revealed the difficulty in identifying some positive cases. CONCLUSION: Cross-reactions of 20% in serodiagnosis may lead to the misclassification of rickettsial diseases. However, with the exception of some cases, we were able to successfully differentiate JSF from murine typhus using each endpoint titer.

Increased Seroprevalence of Typhus Group Rickettsiosis, Galveston County, Texas, USA.

Whether increases in typhus group rickettsiosis in Galveston County, Texas, USA, are caused by increased recognition or true reemergence is unclear. We conducted a serosurvey that demonstrated Rickettsia typhi antibodies increased from 1.2% in 2013 to 7.8% in 2021 (p<0.001). These findings support pathogen reemergence rather than enhanced recognition alone.

Rickettsia typhi infection in a clinically-ill dog from Houston, Texas.

In 2020, Rickettsia typhi was diagnosed in a dog from Houston, Texas, USA based upon R. typhi IFA seroreactivity in both acute and convalescent sera, and PCR with DNA sequencing of 4 different gene regions, all of which were 100% identical to R. typhi. The dog was clinically ill with intermittent fever, lethargy, inappetence, and lymphadenopathy. Clinicopathological abnormalities included a mild nonregenerative anemia, neutrophilia, lymphopenia, thrombocytopenia, hypoalbuminemia, and elevated ALP. The dog rapidly recovered with doxycycline administration.

Experimental Rickettsia typhi Infection in Monodelphis domestica: Implications for Opossums as an Amplifying Host in the Suburban Cycle of Murine Typhus.

Murine typhus is an acute undifferentiated febrile illness caused by Rickettsia typhi. In the United States, its reemergence appears to be driven by a shift from the classic rat-rat flea cycle of transmission to one involving opossums (Didelphis virginiana) and cat fleas. Little is known of the ability of opossums to act as a reservoir and amplifying host for R. typhi. Here, we use Monodelphis domestica (the laboratory opossum) as a surrogate for D. virginiana. Opossums were inoculated via the intraperitoneal (IP) or intradermal (ID) route with 1 × 106 viable R. typhi. Blood and tissues were collected on days 6, 13, 20, and 27 or if moribund. Although one ID-infected opossum died, the remainder did not appear ill, whereas half of the IP-inoculated animals succumbed to infection. Rickettsemia was demonstrated in all animals through week 2 of infection and sporadically in weeks 3 and 4. Rickettsia typhi DNA was detected in all tissues, with most animals demonstrating the presence of bacteria into weeks 3 and 4. Histopathology and immunohistochemistry demonstrated typical findings of rickettsial infection. Akin to infection in rats, the demonstration of disseminated infection, typical inflammation, and prolonged rickettsemia with relatively few clinical effects (especially in the more natural route of ID inoculation) supports the potential of opossums to act as a competent mammalian reservoir and component of the zoonotic maintenance cycle of R. typhi. Understanding the dynamics of infection within opossums may have implications for the prevention and control of murine typhus.

Genetic typing of isolates of Rickettsia typhi.

Murine typhus, which is caused by Rickettsia typhi, has a wide range of clinical manifestations. It has a low mortality rate but may result in meningoencephalitis and interstitial pneumonia in severe cases. Comparisons of complete genome sequences of R. typhi isolates from North Carolina, USA (Wilmington), Myanmar (B9991PP), and Thailand (TH1527) identified only 26 single nucleotide polymorphism (SNP) and 7 insertion-deletion (INDEL) sites in these highly syntenic genomes. Assays were developed to further define the distribution of these variant sites among 15 additional isolates of R. typhi with different histories from Asia, the USA, and Africa. Mismatch amplification mutation assays (MAMA) were validated for 22 SNP sites, while the 7 INDEL sites were analyzed directly on agarose gels. Six SNP types, 9 INDEL types, 11 total types were identified among these 18 isolates. Replicate DNA samples as well as comparisons of isolates with different passage and source histories gave consistent genetic typing profiles. Comparison of the SNP and INDEL markers to R. typhi's nearest neighbor Rickettsia prowazekii demonstrated that the majority of the SNPs represent intra-species variation that arose post divergence of these two species while several INDEL sites also exhibited intraspecies variability among the R. prowazekii genomes that have been completely sequenced. The assays for the presence of these SNP and INDEL sites, particularly the latter, comprise a low technology gel method for consistently distinguishing R. typhi and R. prowazekii as well as for differentiating genetic types of R. typhi.

Delayed correlation between the incidence rate of indigenous murine typhus in humans and the seropositive rate of Rickettsia typhi infection in small mammals in Taiwan from 2007-2019.

Murine typhus is a flea-borne zoonotic disease with acute febrile illness caused by Rickettsia typhi and is distributed widely throughout the world, particularly in port cities and coastal regions. We observed that murine typhus was an endemic disease (number of annual indigenous cases = 29.23±8.76) with a low incidence rate (0.13±2.03*10-4 per 100,000 person-years) in Taiwan from 2007-2019. Most (45.79%, 174/380) indigenous infections were reported in May, June, and July. The incidence rates in both May and June were statistically higher than those in other months (p<0.05). Correspondingly, sera collected from small mammals (rodents and shrews) trapped in airports and harbors demonstrated anti-R. typhi antibody responses (seropositive rate = 8.24±0.33%). Interestingly, the ports with the highest seropositivity rates in small mammals are all inside/near the areas with the highest incidence rates of indigenous murine typhus. In addition, incidence rates in humans were positively correlated with the 1-month and 2-month prior seropositive rates in small mammals (R = 0.31 and 0.37, respectively). As early treatment with appropriate antibiotics for murine typhus could effectively shorten the duration of illness and reduce the risk of hospitalization and fatality, flea-related exposure experience should be considered in clinics during peak seasons and the months after a rise in seropositivity rates in small mammals. Surveillance in small mammals might be helpful for the development of real-time reporting or even early reminders for physicians of sporadic murine typhus cases based on the delayed correlation observed in this study.

Zoonotic Pathogens in Wildlife Traded in Markets for Human Consumption, Laos.

We tested animals from wildlife trade sites in Laos for the presence of zoonotic pathogens. Leptospira spp. were the most frequently detected infectious agents, found in 20.1% of animals. Rickettsia typhi and R. felis were also detected. These findings suggest a substantial risk for exposure through handling and consumption of wild animal meat.