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To document the epidemiology, clinical features, and outcomes of murine typhus patients in the Canary Islands (Spain), we analyzed data that were retrospectively collected for 16 years for 221 patients. Murine typhus in the Canary Islands is characterized by a high rate of complications (31.6%), mainly liver, lung, kidney or central nervous system involvement.

We present 10 patients with Rickettsia typhi infection in whom next-generation sequencing of microbial cell-free deoxyribonucleic acid (mcfDNA) was used as a diagnostic tool. Rickettsia typhi mcfDNA was detected in all cases and was more rapid and specific than rickettsial serology. Rickettsia typhi mcfDNA impacted antibiotic management in 50% of patients.

Rickettsioses are neglected and emerging potentially fatal febrile diseases that are caused by obligate intracellular bacteria, rickettsiae. Rickettsia (R.) typhi and R. prowazekii constitute the typhus group (TG) of rickettsiae and are the causative agents of endemic and epidemic typhus, respectively. We recently generated a monoclonal antibody (BNI52) against R. typhi. Characterization of BNI52 revealed that it specifically recognizes TG rickettsiae but not the members of the spotted fever group (SFG) rickettsiae. We further show that BNI52 binds to protein fragments of ±30 kDa that are exposed on the bacterial surface and also present in the periplasmic space. These protein fragments apparently derive from the cytosolic GroEL protein of R. typhi and are also recognized by antibodies in the sera from patients and infected mice. Furthermore, BNI52 opsonizes the bacteria for the uptake by antigen presenting cells (APC), indicating a contribution of GroEL-specific antibodies to protective immunity. Finally, it is interesting that the GroEL protein belongs to 32 proteins that are differentially downregulated by R. typhi after passage through immunodeficient BALB/c CB17 SCID mice. This could be a hint that the rickettsia GroEL protein may have immunomodulatory properties as shown for the homologous protein from several other bacteria, too. Overall, the results of this study provide evidence that GroEL represents an immunodominant antigen of TG rickettsiae that is recognized by the humoral immune response against these pathogens and that may be interesting as a vaccine candidate. Apart from that, the BNI52 antibody represents a new tool for specific detection of TG rickettsiae in various diagnostic and experimental setups.

Rickettsia species are the etiological agents for many arthropod-borne illnesses. R. typhi is a Gram-negative obligate intracellular pathogen responsible for endemic typhus. Subunits of peptidoglycan are pattern recognition receptor ligands partially responsible for activation of the innate immune response to bacterial insult. Host detection of R. typhi cell envelope glycoconjugates remains poorly defined. In this work, peptidoglycan from R. typhi was digested and the resultant subunits were analyzed by two different, complementary, sample preparation methods each of which was subjected to LC/MS analysis to infer structure. R. typhi peptidoglycan was determined to be similar to most other Gram-negative bacteria, with mDAP-type muropeptide subunits. However, additional alanine residues were observed elongating the muropeptide stems, rather than the glycine residues usually observed in Gram-negative bacterial peptidoglycan. Despite this deviation, R. typhi, and likely all Rickettsiae, contain a murein layer that should agonize host cellular peptidoglycan receptors and be susceptible to peptidoglycan-targeting antimicrobials.

Introduction: Rickettsioses are zoonotic diseases transmitted by arthropods acting as vectors and reservoirs. Disease symptoms are nonspecific and, therefore, their clinical diagnosis is difficult. Indirect immunofluorescence (IFA) is the gold standard assay for diagnosis. The interest for conducting studies on these pathologies has resurfaced in Colombia since 2001; besides, previous studies have evidenced cases of rickettsiosis in the north of the department of Caldas. Objective: To establish the frequency of antibodies and seroconversion against Rickettsia spp. In patients consulting health institutions in Caldas, Colombia, from 2016 to 2019. Materials and methods: We conducted a quantitative, observational, and descriptive study on a non-probabilistic sample of 175 patients with symptoms compatible with rickettsiosis who consulted in different municipalities of Caldas, Colombia; IFA was performed to detect antibodies in the acute and convalescent phases against Rickettsia rickettsii, Rickettsia typhi, and Rickettsia felis. Results: The average age of the patients was 31 years. The municipalities with the highest proportion of seropositive cases were Belalcázar, Chinchiná, Filadelfia, La Dorada, La Merced, and Manizales; 66% of patients owned pets and 12% reported arthropod bites. The most frequent signs and symptoms were headache (69.7%), arthromyalgia (60%), and fever (58.2%). IgG seroprevalence was 60% for R. rickettsii, 47.9% for R. typhi, and, and 24% for R. felis. Eight patients presented seroconversion. Conclusion: We found evidence of the circulation of Rickettsia species from the spotted fever group and the typhus group associated with human cases in Caldas.Introducción. Las rickettsiosis son enfermedades zoonóticas transmitidas por artrópodos que cumplen el papel de vectores y reservorios, y cuyos síntomas son inespecíficos, por lo que su diagnóstico clínico es difícil. La inmunofluorescencia indirecta (IFI) es el método de referencia para el diagnóstico. En Colombia, ha resurgido el interés por su estudio por los casos de rickettsiosis detectados en el norte del departamento de Caldas a partir del 2001. Objetivo. Establecer la frecuencia de anticuerpos y la seroconversión contra Rickettsia spp. en pacientes atendidos en instituciones de salud del departamento de Caldas, Colombia, entre 2016 y 2019. Materiales y métodos. Se hizo un estudio de diseño cuantitativo, observacional y descriptivo, con una muestra no probabilística de 175 pacientes atendidos en diferentes municipios de Caldas, a quienes se les realizó IFI para la detección de anticuerpos en fase aguda y convaleciente contra Rickettsia rickettsii, R. typhi y R. felis. Resultados. El promedio de edad de los pacientes fue de 31 años. Los municipios con mayor proporción de seropositivos fueron Belalcázar, Chinchiná, Filadelfia, La Dorada, La Merced y Manizales. El 66 % tenía mascotas y el 12 % reportó picaduras por artrópodos. Los signos y síntomas más frecuentes fueron cefalea (69,7 %), artromialgia (60 %), y fiebre (58,2 %). La seroprevalencia por IgG fue de 60 % para R. rickettsii, 47,9 % para R. typhi y 24 % para R. felis. Ocho pacientes presentaron seroconversión. Conclusión. Se encontró evidencia de la circulación de rickettsias del grupo de las fiebres manchadas y del grupo del tifus asociada con casos humanos en el departamento de Caldas.

In the Lao People’s Democratic Republic (Laos), rickettsial infections, including scrub and murine typhus, account for a significant burden of fevers. The Mahosot Hospital Microbiology Laboratory in Vientiane, Laos, routinely performs rickettsial isolation from hospitalized patients with suspected rickettsioses using mammalian cell culture systems. We review the clinical and laboratory factors associated with successful Orientia tsutsugamushi and Rickettsia typhi isolations from this laboratory over a period of 6 years between 2008 and 2014., In the Lao People’s Democratic Republic (Laos), rickettsial infections, including scrub and murine typhus, account for a significant burden of fevers. The Mahosot Hospital Microbiology Laboratory in Vientiane, Laos, routinely performs rickettsial isolation from hospitalized patients with suspected rickettsioses using mammalian cell culture systems. We review the clinical and laboratory factors associated with successful Orientia tsutsugamushi and Rickettsia typhi isolations from this laboratory over a period of 6 years between 2008 and 2014. The overall isolation success was 7.9% for all samples submitted and 17.3% for samples for which the patient had a positive O. tsutsugamushi or R. typhi rapid diagnostic test (RDT), serology, or PCR. The frequency of successful isolation was highest for samples submitted in November, at the end of the wet season (28.3%). A longer median duration of reported illness, a positive result for a concurrent Orientia or Rickettsia spp. quantitative PCR, and the use of antibiotics by the patient in the week before admission were significantly associated with isolation success (P

Fever is a widely recognised presenting symptom of COVID-19. Consequently, other febrile illnesses may be difficult to distinguish from COVID-19—leading to delays in diagnosis and treatment. One such illness is murine typhus, a fleaborne illness with worldwide distribution caused by Rickettsia typhi. It often presents with fever, headache and myalgia, all of which have been commonly reported with COVID-19. Although the disease is usually mild with a good prognosis, there have been reports of severe illness and death. I present a case of murine typhus in a young male who had 2 weeks of headaches and daily fevers during the COVID-19 pandemic. He was ultimately tested for murine typhus when his occupation as a dog trainer was queried, and he experienced resolution of symptoms after treatment with doxycycline. During this pandemic, clinicians must be vigilant of other febrile illnesses whose symptoms overlap with COVID-19.

Bloodstream infections cause substantial morbidity and mortality. However, despite clinical suspicion of such infections, blood cultures are often negative. We investigated blood cultures that were negative after 5 days of incubation for the presence of bacterial pathogens using specific (Rickettsia spp. and Leptospira spp.) and a broad-range 16S rRNA PCR. From 190 samples, 53 (27.9%) were positive for bacterial DNA. There was also a high background incidence of dengue (90/112 patient serum positive, 80.4%). Twelve samples (6.3%) were positive for Rickettsia spp., including two Rickettsia typhi. The 16S rRNA PCR gave 41 positives; Escherichia coli and Klebsiella pneumoniae were identified in 11 and eight samples, respectively, and one Leptospira species was detected. Molecular investigation of negative blood cultures can identify potential pathogens that will otherwise be missed by routine culture. Patient management would have been influenced in all 53 patients for whom a bacterial organism was identified, and 2.3–6.1% of patients would likely have had an altered final outcome. These findings warrant further study, particularly to determine the cost–benefit for routine use, ways of implementation, and timing of PCR for organisms such as Rickettsia and Leptospira, which are important pathogens in rural Asia.

The oriental rat flea (Xenopsylla cheopis) is an ectoparasite of small mammals and a vector of many diseases for which humans are incidental hosts. This species of flea is most widely known for carrying Yersinia pestis and Rickettsia typhi, the causative agents of the plague and murine typhus, respectively. Public health issues related to X cheopis may increase in the future as global warming expands the geographic area in which the fleas can survive. A bioterrorist attack of plague also remains a threat. Extensive research is ongoing regarding X cheopis and its interaction with the bacteria it transmits to find better ways of reducing related morbidity and mortality. Traditional control measures include extermination of small mammal hosts, insecticide use to eliminate the flea itself, and use of antibiotics to control the associated diseases. The future may include targeted insecticide usage to prevent the continued development of resistance as well as new methods of reducing transmission of flea-borne diseases that could eliminate the need for chemical insecticides all together.

Murine typhus is an acute febrile, flea-borne disease caused by the bacteria Rickettsia typhi. The disease occurs worldwide but is likely underrecognized due to its non-specific symptoms, causing significant morbidity. A systematic review found disease complications in one-fourth of all patients and a long fever duration in those untreated. Although mortality in treated cases is estimated to be very low, some case series have shown a notably higher mortality in untreated patients. This study aimed to describe the outcomes and estimate the mortality of untreated murine typhus through a comprehensive systematic literature review. We systematically searched the literature for articles describing untreated murine typhus patients, excluding cases with no laboratory assay confirmed diagnosis, those who received efficacious treatment, had incomplete information on primary outcome and articles describing less than 10 patients and performed a narrative synthesis of the study findings. The study protocol followed the PRISMA guidelines and was part of a more extensive protocol registered at PROSPERO (CRD42018101991). Twelve studies including a total of 239 untreated patients matched the eligibility criteria. Only a single study reported one death in 28 patients, giving a patient series mortality of 3.6% and an overall mortality of 0.4% in 239 untreated patients. Complications were reported in 10 of the 12 studies and included involvement of the central nervous system, kidney and lung, with a hospitalisation rate of 70% and ICU admission rate of 27% in one study. The mean duration of fever in untreated patients was 15 days in two and 12.7 days in one study. Although the untreated mortality in this study was low, the sample size was small. Murine typhus caused significant morbidity when untreated, leading to high hospitalisation rates and highlighting the importance of early diagnosis and treatment of this neglected disease to reduce disease burden and health-care related costs., Author summary Murine typhus is an acute febrile, flea-borne bacterial disease that has been reported worldwide and continues to cause significant morbidity when untreated. The often self-limiting, non-specific clinical symptoms of the disease resemble that of common viral illnesses, suggesting that the disease is underdiagnosed. While the mortality in treated cases is estimated to be very low, disease complications in one-fourth of all patients and a prolonged duration of fever in untreated cases have been reported. We systematically searched the literature to identify articles describing laboratory diagnostically confirmed clinical cases of untreated murine typhus and summarized disease outcomes, including mortality, of patients in eligible studies. Of the 12 studies containing 239 untreated patients that matched the eligibility criteria, only one study reported a single death amongst 28 untreated patients, resulting in a patient series fatality rate of 3.6% and an overall untreated fatality rate of 0.4%. Disease complications were mentioned in 10 of 12 studies and the mean duration of fever in untreated cases was 15 days in two studies and 12.7 days in one study, demonstrating the significant morbidity caused by untreated murine typhus and highlighting the importance of early diagnosis and treatment of this neglected disease.

Lipschutz ulcers (LU) present as painful genital ulcers in nonsexually active females. Associated infections include Epstein Barr virus, Mycoplasma pneumoniae, Cytomegalovirus, and influenza. To our knowledge, this is the first report of LU occurring with murine typhus. Murine typhus is caused by Rickettsia typhi, a Gram-negative, obligate intracellular organism. Rat fleas (Xenopsylla cheopis) are the classic vector, although cat fleas (Ctenocephalides felis) found on cats, dogs, and opossums have been implicated in maintaining the life cycle of R. typhi in suburban areas. Murine typhus can have a nonspecific presentation making a strong index of suspicion crucial to its diagnosis. The most common presenting signs include fever, poor appetite, malaise, and headache. Laboratory abnormalities may include elevated C-reactive protein, elevated erythrocyte sedimentation rate, hypoalbuminemia, elevated transaminases, elevated neutrophil band count, and thrombocytopenia. The treatment of choice for R. typhi is doxycycline.

Background Assessing the burden of rickettsial infections in Ontario, Canada, is challenging since rickettsial infections are not reportable to public health. In the absence of reportable disease data, we assessed the burden of rickettsial infections by examining patient serological data and clinical information. Methods Our retrospective, cross-sectional study included patients who had Rickettsia serological testing ordered by their physician, in Ontario, from 2013 to 2018. We tested sera from 2755 non-travel patients for antibodies against spotted fever group rickettsiae (SFGR) and typhus group rickettsiae (TGR) using an indirect immunofluorescence assay (IFA) (positive IgG titers ≥1:64). We classified cases using a sensitive surveillance case definition: confirmed (4-fold increase in IgG titers between acute and convalescent sera with clinical evidence of infection), possible (single positive sera with clinical evidence) and previous rickettsial infection (single positive sera without clinical evidence). We classified cases seropositive for both SFGR and TGR as unspecified Rickettsia infections (URIs). Results Less than 5% of all patients had paired acute and convalescent sera tested, and of these, we found a single, laboratory-confirmed SFGR case, with a 4-fold increase in IgG titers and evidence of fever, maculopapular rash and headache. There were 45 possible (19 SFGR, 7 TGR, 19 URI) and 580 previous rickettsial infection (183 SFGR, 89 TGR, 308 URI) cases. The rate of positive tests for SFGR, TGR and URI combined (all case classifications) were 4.4 per 100,000 population. For confirmed and possible cases, the most common signs and symptoms were fever, headache, gastrointestinal complaints and maculopapular rash. The odds of having seropositive patients increased annually by 30% (odds ratio = 1.3, 95% confidence interval: 1.23–1.39). Conclusions The rates of rickettsial infections in Ontario are difficult to determine. Based on confirmed and possible cases, rates are low, but inclusion of previous rickettsial infection cases would indicate higher rates. We highlight the need for education regarding the importance of testing acute and convalescent sera and consistent completion of the laboratory requisition in confirming rickettsial disease. We suggest further research in Ontario to investigate rickettsial agents in potential vectors and clinical studies employing PCR testing of clinical samples.

Murine typhus is a flea-borne rickettsiosis caused by Rickettsia typhi. When severe, endothelial dysfunction can lead to acute kidney injury secondary to prerenal azotemia or acute tubular necrosis. Here, we describe an unusual cause of kidney injury during the course of murine typhus-focal segmental glomerulosclerosis.

Scrub typhus and spotted fever group rickettsioses are thought to be common causes of febrile illness in India, whereas they rarely test for murine typhus. This cross-sectional study explored the risk factors associated with scrub typhus, tick-borne spotted fever, and murine typhus seropositivity in three different geographical settings, urban, rural, and hill villages in Tamil Nadu, South India. We enrolled 1,353 participants living in 48 clusters. The study included a questionnaire survey and blood sampling. Blood was tested for Orientia tsutsugamushi (scrub typhus), Rickettsia typhi (murine typhus), and spotted fever group Rickettsia IgG using ELISA. The seroprevalence of scrub typhus, spotted fever, and murine typhus were 20.4%, 10.4%, and 5.4%, respectively. Scrub typhus had the highest prevalence in rural areas (28.1%), and spotted fever was most common in peri-forested areas (14.9%). Murine typhus was more common in rural (8.7%) than urban areas (5.4%) and absent in peri-forested hill areas. Agricultural workers had a higher relative risk for scrub typhus, especially in urban areas. For murine typhus, proximity to a waterbody and owning a dog were found to be major risk factors. The main risk factors for spotted fever were agricultural work and living in proximity to a forest. Urban, rural plains, and hill settings display distinct epidemiological pattern of Orientia and rickettsial infections. Although scrub typhus and spotted fever were associated with known risk factors in this study, the findings suggest a different ecology of murine typhus transmission compared with other studies conducted in Asia.

Background Reports of human rickettsial infection in Indonesia are limited. This study sought to characterize the epidemiology of human rickettsioses amongst patients hospitalized with fever at 8 tertiary hospitals in Indonesia. Methods Acute and convalescent blood from 975 hospitalized non-dengue patients was tested for Rickettsia IgM and IgG by ELISA. Specimens from cases with seroconversion or increasing IgM and/or IgG titers were tested for Rickettsia IgM and IgG by IFA and Rickettsia genomes using primers for Rickettsia (R.) sp, R. typhi, and Orientia tsutsugamushi. Testing was performed retrospectively on stored specimens; results did not inform patient management. Results R. typhi, R. rickettsii, and O. tsutsugamushi IgG antibodies were identified in 269/872 (30.8%), 36/634 (5.7%), and 19/504 (3.8%) of samples, respectively. For the 103/975 (10.6%) non-dengue patients diagnosed with acute rickettsial infection, presenting symptoms included nausea (72%), headache (69%), vomiting (43%), lethargy (33%), anorexia (32%), arthralgia (30%), myalgia (28%), chills (28%), epigastric pain (28%), and rash (17%). No acute rickettsioses cases were suspected during hospitalization. Discharge diagnoses included typhoid fever (44), dengue fever (20), respiratory infections (7), leptospirosis (6), unknown fever (6), sepsis (5), hepatobiliary infections (3), UTI (3), and others (9). Fatalities occurred in 7 (6.8%) patients, mostly with co-morbidities. Conclusions Rickettsial infections are consistently misdiagnosed, often as leptospirosis, dengue, or Salmonella typhi infection. Clinicians should include rickettsioses in their differential diagnosis of fever to guide empiric management; laboratories should support evaluation for rickettsial etiologies; and public policy should be implemented to reduce burden of disease.

Murine typhus, an undifferentiated febrile illness caused by Rickettsia typhi, is increasing in prevalence and distribution throughout Texas. In 2018, a total of 40 cases of murine typhus were reported in Galveston County. This increase, unprecedented since the 1940s, highlights the importance of awareness by physicians and public health officials.

Murine typhus is a neglected but widespread infectious disease that results in acute fever. The immunofluorescence assay (IFA) is the “gold standard” to identify IgM or IgG antibodies, although there is a lack of standardization in methodologies. The objective of this review is to summarize 1) the differences in published methodologies, 2) the diagnostic cutoff titers, and 3) the justification of diagnostic cutoffs. Searches were performed by combining the following search terms: “murine typhus,” “rickettsia typhi,” “immunofluorescence,” “IFA,” and “serologic” with restrictions (i.e., “rickettsia typhi” or “murine typhus,” and “IFA” or “immunofluorescence,” or “serologic*”). The search identified 78 studies that used IFA or immunoperoxidase assay (IIP) antibody cutoffs to diagnose murine typhus, 39 of which were case series. Overall, 45 studies (57.7%) provided little to no rationale as to how the cutoff was derived. Variation was seen locally in the cutoff titers used, but a 4-fold or greater increase was often applied. The cutoffs varied depending on the antibody target. No consensus was observed in establishing a cutoff, or for a single-value diagnostic cutoff. In conclusion, there is a lack of consensus in the establishment of a single-value cutoff. Further studies will need to be executed at each distinct geographic location to identify region-specific cutoffs, while also considering background antibody levels to distinguish between healthy and infected patients.

Rickettsial diseases (RDs) are major under-diagnosed causes of arthropod borne acute febrile illness (AFI) presenting with a range of symptoms from mild self-limiting fever to fatal sepsis. The spotted fever group (SFG) and typhus group (TG) are major RDs, which are commonly caused by Rickettsia conorii and Rickettsia typhi, respectively. The limited availability and role of serological tests in the acute phase of illness warrants rapid reliable molecular methods for diagnosis and epidemiological studies. Two hundred patients with AFI in whom the routine fever diagnostics were negative, were enrolled over a period of two months (April 2019 to May 2019). DNA was extracted and in-house nested PCR using primers specific for both SPG and TG pathogens was used. The positive amplified products were sequenced for species identification and phylogenetic analysis was performed using MEGA 7.0.14 software (iGEM, Temple University, Philadelphia, PA 19122, USA). The demographic details of the RD cases were documented. The prevalence of RD among AFI cases was 7% (14/200); SFG and TG were identified as the cause in 4% and 3% of AFI cases, respectively. The median age of the RD cases was 22 years (range 2–65). The median duration of fever was 3 days (range 1–12). The RD cases presented with respiratory symptoms or signs (44.44%), jaundice (22.22%), abdominal pain (22.22%), diarrhea (22.22), vesicular rash (11.11%), vomiting (11.11%), loss of appetite (11.11%), headache (11.11%), leukocytosis (88.88% with mean count 22,750/mm3), and thrombocytopenia (33.33%). The cases were treated empirically with piperacillin-tazobactam (66.66%), clindamycin (44.44%), cefotaxime (33.33%), meropenem (33.33%), metronidazole (33.33%), doxycycline (22.22%), azithromycin (22.22%), ceftriaxone (11.11%), and amoxicillin-clavulanic acid (11.11%). The mortality among the RD cases was 11.11%. The present pilot study shows that RD is not an uncommon cause of AFI in north India. The febrile episodes are usually transient, not severe and associated with heterogenous clinical presentation without documented history of tick exposure in the hospitalized patients. The transient, non-severe, febrile illness could be due to transient rickettsemia resulting from empirical antimicrobial therapy as the rickettsial organisms are expected to be more susceptible to higher doses of β-lactam antibiotics. The study emphasizes the molecular method as a useful tool to identify rickettsial etiology in AFI.

Introduction: Rickettsioses are zoonotic diseases caused by pathogenic bacteria of the genus Rickettsia and transmitted to man by means of arthropod vectors such as ticks, fleas, mites and lice. Historically, Caldas Department has reported a significant number of cases of murine typhus to the Colombian national health surveillance system, and consequent studies of flea-borne rickettsiosis identified the circulation of Rickettsia typhi and Rickettsia felis in multiple municipalities. Our aim was to genotype species of Rickettsia detected in fleas collected from domestic and wild mammals in Caldas. Methodology: Flea samples were taken by convenience sampling from dogs, cats and wild mammals (rodents and marsupials) in 26 municipalities. Specimens were classified by current taxonomic keys and pooled for DNA extraction and molecular screening for Rickettsia spp. by PCR amplification of gltA, htrA and sca5 genes. Positive samples were genotyped by enzyme digestion (htrA) and sequencing. Results: A total of 1388 flea samples were collected. Rickettsia DNA was amplified in 818 (gltA), 883 (htrA) and 424 (sca5) flea pools. Alignment analysis with available Rickettsia DNA sequences showed greater similarity with R. asembonensis (gltA) and with R. felis (sca5 and htrA). Restriction pattern was compatible with R. felis. R. typhi was not identified. Conclusion: The present study confirms the presence and high prevalence of R. asembonensis and R. felis in fleas from domestic and wild animals in different municipalities from Caldas Department.

Objective Murine typhus (MT) is an acute zoonosis caused by Rickettsia typhi, a flea-borne rickettsiosis. The first autochthonous case was reported in 2012. Once autochthonous transmission of Rickettsia typhi was proven, we performed a prospective study to describe and raise awareness of this often-misdiagnosed disease among physicians. Patients and methods We performed a prospective observational study of MT cases in La Reunion from 2012 to 2017. MT cases were defined as clinically compatible illnesses with a specific positive serology and/or PCR. Results Sixty-one confirmed cases were collected. The main clinical features were prolonged fever (90%), asthenia (87%), and headaches (79%). The main biological abnormalities were elevated liver enzymes (84%) and thrombopenia (75%). Renal function was normal in 90% of cases; it was an important feature because leptospirosis is a frequent cause of acute renal failure. A seasonal factor was observed with 79% of cases reported in the warm season and most of them in the west and south of the island (i.e., the dry areas). Conclusion MT is an emerging disease in La Reunion, and local conditions could lead to an endemic situation. Cases of acute undifferentiated fever with headaches should guide to the diagnosis of MT especially in the warm season and dry areas. Leptospirosis is an alternative diagnosis, which differs from MT by its epidemiological characteristics and by the associated frequent renal dysfunction.

Typhus group rickettsioses (TGRs) are vector-borne diseases that include murine typhus (Rickettsia typhi) and epidemic typhus (R. prowazekii). Twentieth-century public health interventions led to dramatic decreases in incidence; little is known about the contemporary TGR prevalence because neither disease is nationally notifiable. We summarized administrative claims data in a commercially insured population to examine trends in TGR medical encounters. We analysed data from 2003 to 2016 IBM® MarketScan® Commercial Databases to identify persons with inpatient or outpatient visits with an International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification TGR-specific code. We summarized epidemiologic characteristics associated with incident diagnosis. We identified 1,799 patients diagnosed with a TGR. Patients resided in 46 states, and most were female (n = 1,019/1,799; 56.6%); the median age was 42 years (range: 0-64 years). Epidemic typhus (n = 931/1,799; 51.8%) was the most common TGRs, followed by murine typhus (n = 722/1,799; 40.1%). The majority of TGR patients were diagnosed in an outpatient setting (n = 1,725/1,799; 95.9%); among hospitalized patients, the majority received a murine typhus diagnosis (n = 67/74; 90.5%). TGRs are rarely diagnosed diseases. More patients were diagnosed with epidemic than murine typhus, even though R. prowazekii transmission requires body louse or flying squirrel exposure. Patients from all geographic regions were diagnosed with murine and epidemic typhus, despite historically recognized ranges for these diseases. The epidemiologic misalignment of insurance claims data versus historic TGRs data highlights the challenges of finding appropriate alternative data sources to serve as a proxy when national surveillance data do not exist.

Flea-borne (murine) typhus is caused by Rickettsia typhi. Infection in pregnant women can lead to adverse outcomes when diagnosis and treatment is delayed. We describe how next-generation sequencing (NGS) using the Karius® test was used to rapidly diagnose murine typhus in two pregnant women admitted to a large tertiary care center in Houston, Texas, when all initial testing was nondiagnostic.

A 39 year-old male was residing along the south coast of Texas, the USA, presented with fever, myalgias, headaches, and weight loss for ten days. Symptoms and manifestations progressed to include nuchal rigidity, photophobia, hyponatremia, thrombocytopenia, and transaminitis despite the intravenous administration of ceftriaxone and azithromycin. A lumbar puncture performed in the Emergency Department yielded pleocytosis and glucose cerebrospinal fluid/serum ratio of 0.35, suggestive of meningoencephalitis. Conglomerate data raised the suspicion of meningitis secondary to a zoonotic acquired infection, which was later confirmed to be Rickettsia typhi. Doxycycline is the drug of choice for the suspected Rickettsia disease. After doxycycline administration, the patient improved and was discharged home asymptomatic.

A previously healthy 50-year-old man presents with a 4-day history of fevers to 39 °C, chills, night sweats, headache, and myalgias. He describes the headache as continuous, dull, and pounding. The illness began during his travel home to the United States after a 4-week stay in Ecuador for the purpose of Spanish language immersion. He stayed with a local family who owns a small, rural cacao and banana plantation. The family had dozens of domestic cats to help control the rodent population around their farm. The man noted that he attempted to avoid the cats because they were heavily flea infested but awoke one morning last week to find one of the cats on his bed and dozens of flea bites on his lower extremities. He does not recall seeing or being bitten by mosquitoes or other insects, attributing their scarcity to the lack of rainfall during “dry season.” On physical examination, the patient appears moderately ill. His temperature is 38.7 °C. Other vital signs are normal. His neck is supple. He has no conjunctivitis. His mucous membranes are slightly dry, but his oropharyngeal exam is otherwise normal. He has normal heart sounds, and his lungs are clear. His abdomen is soft, without organomegaly. A complete neurological exam is normal. Initial laboratory results show mild leukopenia and thrombocytopenia, elevated hepatic transaminases, and elevated biomarkers of inflammation. A full battery of diagnostic studies is sent to the laboratory searching for the cause of his illness. Based on the history and initial laboratory test results, you treat the patient empirically with doxycycline for possible rickettsial infection. When he returns for follow-up 2 days later, he reports that the fevers and night sweats have resolved and that the headache is no longer constant. Results of serologic testing for rickettsial infection are suggestive of infection with Rickettsia typhi, the cause of endemic typhus. When the patient is seen again 3 weeks later, his illness has completely resolved. Repeat serologic testing for R. typhi showed the expected fourfold rise in titer between the initial result (acute) and subsequent result (convalescent), thereby confirming the diagnosis of endemic typhus.

The highest-risk activities for scrub/murine typhus laboratory-acquired infections were working with infectious laboratory animals. Eight scrub typhus deaths occurred during the preantibiotic era. Risk-based biosafety approaches would improve efficiencies of in vitro/in vivo growth of scrub/murine typhus., This study examined the literature on laboratory-acquired infections (LAIs) associated with scrub typhus (Orientia tsutsugamushi) and murine typhus (Rickettsia typhi) research to provide an evidence base for biosafety and biocontainment. Scrub typhus LAIs were documented in 25 individuals, from 1931 to 2000 with 8 (32%) deaths during the preantibiotic era. There were 35 murine typhus LAI reports and no deaths. Results indicated that the highest-risk activities were working with infectious laboratory animals involving significant aerosol exposures, accidental self-inoculation, or bite-related infections. A risk-based biosafety approach for in vitro and in vivo culture of O. tsutsugamushi and R. typhi would require that only high-risk activities (animal work or large culture volumes) be performed in high-containment biosafety level (BSL) 3 laboratories. We argue that relatively low-risk activities including inoculation of cell cultures or the early stages of in vitro growth using low volumes/low concentrations of infectious materials can be performed safely in BSL-2 laboratories within a biological safety cabinet.

Presently, few studies have investigated the role of domestic cats (Felis catus) in the recrudescence of flea-borne rickettsioses in California and the southern United States. In this study, we aimed to investigate the presence of Rickettsia typhi or Rickettisa felis in domestic cats (F. catus) and the fleas (primarily Ctenocephalides felis, the cat flea) associated with these cats in Riverside County, California. Thirty cats and 64 pools of fleas collected from these cats were investigated for rickettsial infections. Three cats and 17 flea pools (from 10 cats) tested positive for rickettsial infections. polymerase chain reaction and DNA sequencing indicated that one of the cats was positive for R. felis infections, whereas two were positive for Candidatus Rickettsia senegalensis infection. In addition, 12 of the flea pools were positive for R. felis, whereas five were positive for Ca. R. senegalensis. By contrast, no cats or their associated fleas tested positive for R. typhi. Finally, eight sera from these cats contained spotted fever group Rickettsia (SFGR) antibodies. The detection of R. felis and SFGR antibodies and the lack of R. typhi and TGR antibodies support R. felis as the main rickettsial species infecting cat fleas. The detection of Ca. R. senegalensis in both fleas and cats also provides additional evidence that cats and their associated fleas are infected with other R. felis–like organisms highlighting the potential risk for human infections with R. felis or R. felis–like organisms.

Objectives: This study examined individuals with Rickettsia typhi infection in the Lao People's Democratic Republic (Lao PDR) to (a) investigate humoral immune dynamics; (b) determine the differences in reference diagnostic results and recommend appropriate cut-offs; (c) determine differences in immune response after different antibiotic treatments; and (d) determine appropriate diagnostic cut-off parameters for indirect immunofluorescence assay (IFA). Methods: Sequential serum samples from 90 non-pregnant, adults were collected at seven time-points (days 0, 7, 14, 28, 90, 180 and 365) as part of a clinical antibiotic treatment trial. Samples were tested using IFA to determine IgM and IgG antibody reciprocal end-point titres against R. typhi and PCR. Results: For all 90 individuals, reciprocal R. typhi IgM and IgG antibody titres ranged from Conclusions: This study suggests suitable diagnostic cut-offs for local diagnostic laboratories and other endemic settings and highlights antibody persistence following acute infection. Further studies are required to validate and define cut-offs in other geographically diverse locations.

Typhus group rickettsiosis is caused by the vectorborne bacteria Rickettsia typhi and R. prowazekii. R. typhi, which causes murine typhus, the less severe endemic form of typhus, is transmitted by fleas; R. prowazekii, which causes the severe epidemic form of typhus, is transmitted by body lice. To examine the immunology of human infection with typhus group rickettsiae, we retrospectively reviewed clinical signs and symptoms, laboratory changes, and travel destinations of 28 patients who had typhus group rickettsiosis diagnosed by the German Reference Center for Tropical Pathogens, Hamburg, Germany, during 2010-2017. Immunofluorescence assays of follow-up serum samples indicated simultaneous seroconversion of IgM, IgA, and IgG or concurrence in the first serum sample. Cytokine levels peaked during the second week of infection, coinciding with organ dysfunction and seroconversion. For 3 patients, R. typhi was detected by species-specific nested quantitative PCR. For all 28 patients, R. typhi was the most likely causative pathogen.

Murine typhus is one of the most prevalent rickettsial infections in the world, caused by the bacterial genus Rickettsia. Though the disease manifests a relatively benign clinical course with fever, rash, and headache being the 3 classic symptoms, neurological complications may arise in patients that could become permanent. In this case study, a patient with a brain abscess caused by R typhi infection is described. Based upon the recent reemergence of arthropod-borne disease, the findings in this case are significant; R typhi can cause a brain abscess that mimics a brain tumor, which delays the diagnosis and appropriate management of the disease. Murine typhus should always be considered when performing the differential diagnosis of brain abscesses in South Korea.

In this paper, we present a historical review of rickettsiosis in Central America and also the most recent findings of Rickettsia in ectoparasites. All countries of Central America have records of rickettsiosis. Regarding the typhus group rickettsioses, there is clinical or serological evidence of Rickettsia prowazekii in Guatemala, Rickettsia typhi in Panama, Guatemala, and Costa Rica and unidentified species of the typhus group in El Salvador. Concerning spotted fever group rickettsiosis, there is serological evidence of infection by Rickettsia akari in Costa Rica and confirmed cases involving Rickettsia rickettsii in Panama and Costa Rica. There are also reports of spotted fever group rickettsiosis in acute patients from Guatemala, Honduras, and Nicaragua. Serological studies in Central America show reactivity of Rickettsia ambyommatis, Rickettsia bellii, Rickettsia felis, Rickettsia rhipicephali, and R. rickettsii in domestic and wild mammals. Eight species of Rickettsia have been detected in ectoparasites from Central America: R. africae (or very similar), R. amblyommatis, R. asembonensis, R. bellii, R. felis, R. parkeri, R. rhipicephali, and R. rickettsii, in addition to undescribed strains such as Atlantic Rainforest, Colombianensi, IbR/CRC, Barva, Aragaoi, and Candidatus "Rickettsia nicoyana;" the latter being the only one associated with Argasidae (Ornithodoros knoxjonesi). R. amblyommatis is the most common species in Central America, seeing as it has been reported in 10 species of ticks and one of fleas in five of the seven countries of the region. In this study, we demonstrate that the genus Rickettsia is widely distributed in Central America and that rickettsiosis could be an underestimated problem in the absence of greater diagnostic efforts in undetermined febrile cases.

Rickettsia spp. has been detected in dog fleas in Bangkok, Thailand. With the intent of collecting evidence to confirm the presence of rickettsioses in dogs and to assess the level of associated potential for accidental human infection, human buffy coat from patients with fever of unknown origin (n = 168), whole blood samples from dogs (n = 353), and 19 flea groups from our dog sample population were studied during the 2012 to 2014 study period. The presence of Rickettsia was investigated by molecular detection of 23S rRNA gene of Rickettsia genus, citrate synthase (gltA) gene, and 17-kDa outer membrane gene. All positive samples were confirmed by DNA sequence analysis. Using phylogenetic analysis, three groups of Rickettsia were detected, as follows: Rickettsia felis in 8 patients and 8 dogs; R. felis-like sp. in 2 patients, 5 dogs, and 11 flea samples; and Rickettsia typhi in 3 patients. In addition to confirming the presence of R. felis in Thai patients, the findings of this study suggest that R. felis-like sp. isolated from fleas that were symbiotically coexisting with dogs that we evaluated in this study can transmit and cause disease in dogs and humans in Bangkok.

Scrub and murine typhus are common, treatable causes of undifferentiated febrile illnesses in hospitalized patients., We conducted a yearlong prospective study of febrile patients admitted to a tertiary referral hospital in Chittagong, Bangladesh, to assess the proportion of patients with rickettsial illnesses and identify the causative pathogens, strain genotypes, and associated seasonality patterns. We diagnosed scrub typhus in 16.8% (70/416) and murine typhus in 5.8% (24/416) of patients; 2 patients had infections attributable to undifferentiated Rickettsia spp. and 2 had DNA sequence–confirmed R. felis infection. Orientia tsutsugamushi genotypes included Karp, Gilliam, Kato, and TA763-like strains, with a prominence of Karp-like strains. Scrub typhus admissions peaked in a biphasic pattern before and after the rainy season, whereas murine typhus more frequently occurred before the rainy season. Death occurred in 4% (18/416) of cases; case-fatality rates were 4% each for scrub typhus (3/70) and murine typhus (1/28). Overall, 23.1% (96/416) of patients had evidence of treatable rickettsial illnesses, providing important evidence toward optimizing empirical treatment strategies.

Rickettsia typhi and Rickettsia felis are flea-borne pathogens, which cause murine typhus and flea-borne spotted fever, respectively. Recently, two other flea-borne rickettsiae (phylogenetically similar to R. felis) have been discovered-Rickettsia asembonensis and Candidatus Rickettsia senegalensis. Currently, species-specific identification of detected organisms requires sequencing- or probe-based PCR assays. Our aim was to develop an efficient and inexpensive method to differentiate R. felis and R. felis-like organisms through restriction fragment length polymorphism (RFLP) analysis. Outer membrane protein B sequences of the aforementioned flea-borne rickettsiae were analyzed using DNASTAR Lasergene Core software to focus on the region amplified by the primers 120.2788 and 120.3599. Restriction enzyme digestion sites were identified, and in silico digestions of each species were compared through simulated agarose gels. The enzyme NlaIV was determined to be the most effective at creating a unique banding pattern within the area of interest. To confirm the predicted performance of NlaIV digestion, we tested the DNA of known PCR positive Ctenocephalides felis fleas collected from cats and opossums within Galveston, Texas. DNA from these fleas was amplified using the sca5 primer set 120.2788 and 120.3599. The PCR products were then digested with NlaIV, subjected to polyacrylamide gel electrophoresis, and visualized through ethidium bromide staining. The banding patterns were then compared with the computer-generated digestion patterns. All samples demonstrated a banding pattern consistent with the predicted pattern for the known species, as confirmed by previous sequencing. This RFLP assay was developed to be an efficient and cost-effective method to screen samples for R. felis, R. asembonensis, and Candidatus R. senegalensis. We believe this assay can aid in the epidemiological and ecological studies of flea-borne rickettsiae.

Patients with rickettsial infection usually present with a febrile illness, headache, arthromyalgia and various biochemical abnormalities. Neurologic involvement is rare in murine typhus. Here, we report a case of a patient who presented with status epilepticus secondary to Rickettsia typhi infection. Keywords: Meningoencephalitis, Murine typhus, Rickettsial meningitis, Aseptic meningitis, Rickettsial neurological manifestations

1. Kelly Kovaric, MD* 2. Coburn H. Allen, MD† 1. *Department of Pediatrics, St. David’s Children’s Hospital, Austin, TX 2. †Department of Pediatric Infectious Disease, Dell Children’s Medical Center of Central Texas, Austin, TX A 17-year-old previously healthy boy presents with scleral icterus for 1 day. For approximately 10 days previously, he has had fever, arthralgias, and headache. He additionally complains of eye pain with movement, stiff neck, excessive thirst (drinking 64 oz of water a day), back pain, and nausea. He denies rash, sore throat, cough, and congestion. He has not traveled anywhere. He has been taking approximately 8 g of acetaminophen daily for the past 2 weeks for joint pain. On physical examination the patient's vital signs are normal except for fever (to 101.7°F [38.7°C]). He has scleral icterus, no periorbital swelling or edema, no meningismus, no hepatomegaly or splenomegaly, no swelling of the joints, and insect bites on his ankles but no rash. Laboratory evaluation reveals the following values: sodium, 126 mEq/L (126 mmol/L); white blood cell count, 14,600/μL (14.6 × 109/L), with 75.5% neutrophils and 22% lymphocytes; hemoglobin, 12.6 g/dL (126 g/L); platelet count, 79,000 × 103/μL (79,000 × 109/L); acetaminophen level, less than 2 μg/mL (

We report a surface-enhanced Raman scattering (SERS)-based immunoassay platform for the rapid diagnosis of scrub typhus and murine typhus, which are the most common acute febrile diseases in South Korea. A microarray device, composed of multiple gold nanopopcorn substrates capable of detecting ultra-sensitive biomarkers, was used as a multiplex SERS-based assay platform. Sequentially diluted titers of Orientia tsutsugamushi and Rickettsia typhi specific human IgG/IgM antibodies, which are biomarkers of two typhus diseases, were analyzed by Raman spectroscopy, and the peak intensity was plotted against the different titer concentration range (0-2048 and 0-1024 for O. tsutsugamushi IgG/IgM and 0-8192 and 0-256 for R. typhi IgG/IgM) to generate calibration curves. The sensitivities and limits of detection (LODs) determined for four different IgG/IgM antibodies were significantly lower than those for the ELISA method. The LODs of titer concentrations for O. tsutsugamushi IgG/IgM and R. typhi IgG/IgM are determined to be 20.4, 7.03, 16.8 and 12.5, respectively. The LOD values were all lower than the cut-off values (256, 16, 128, and 64) used for clinical diagnosis, which means that this assay platform can diagnose two typhus diseases with high sensitivity. When the microarray sensors are combined with portable Raman spectrophotometers, which are commercially available worldwide, it is also possible to directly diagnose a patient in the field without sending their blood sample to a hospital.

Background Scrub typhus (ST) and murine typhus (MT) are common but poorly understood causes of fever in Laos. We examined the spatial and temporal distribution of ST and MT, with the intent of informing interventions to prevent and control both diseases. Methodology and principle findings This study included samples submitted from 2003 to 2017 to Mahosot Hospital, Vientiane, for ST and MT investigation. Serum samples were tested using IgM rapid diagnostic tests. Patient demographic data along with meteorological and environmental data from Laos were analysed. Approximately 17% of patients were positive for either ST (1,337/8,150 patients tested) or MT (1,283/7,552 patients tested). While both diseases occurred in inhabitants from Vientiane Capital, from the univariable analysis MT was positively and ST negatively associated with residence in Vientiane Capital. ST was highly seasonal, with cases two times more likely to occur during the wet season months of July-September compared to the dry season whilst MT peaked in the dry season. Multivariable regression analysis linked ST incidence to fluctuations in relative humidity whereas MT was linked to variation in temperature. Patients with ST infection were more likely to come from villages with higher levels of surface flooding and vegetation in the 16 days leading up to diagnosis. Conclusions The data suggest that as cities expand, high risk areas for MT will also expand. With global heating and risks of attendant higher precipitation, these data suggest that the incidence and spatial distribution of both MT and ST will increase., Author summary These data from Laos strongly support the hypothesis that murine typhus and scrub typhus are more urban and rural diseases, respectively. Risks of scrub typhus were associated with visiting rice fields and forests, with surface flooding and higher vegetation density. Risks of murine typhus were living in Vientiane City and not having visited rice fields and forests. Homes of patients with scrub typhus were consistently further away from the city centre and from roads than for those of patients with murine typhus. With the outward spread of higher house density with city expansion during the study, murine typhus spread outwards whilst scrub typhus receded. Temporal trends in incidence were associated, for murine typhus, with higher temperature and, for scrub typhus, with higher rainfall, humidity and flooding. In areas where both diseases are found, these data suggest that residence, occupational and climatic differential risks are useful for assisting with identifying patients. The data also suggest that as cities further enlarge, high risk areas for murine typhus will expand. With global heating and risks of attendant higher precipitation, these data also suggest that the incidence and spatial distribution of both murine typhus and scrub typhus will increase.