Murine Typhus: A Review of a Reemerging Flea-Borne Rickettsiosis with Potential for Neurologic Manifestations and Sequalae.

Murine typhus is an acute febrile illness caused by Rickettsia typhi, an obligately intracellular Gram-negative coccobacillus. Rats (Rattus species) and their fleas (Xenopsylla cheopis) serve as the reservoir and vector of R. typhi, respectively. Humans become infected when R. typhi-infected flea feces are rubbed into flea bite wounds or onto mucous membranes. The disease is endemic throughout much of the world, especially in tropical and subtropical seaboard regions where rats are common. Murine typhus is reemerging as an important cause of febrile illness in Texas and Southern California, where an alternate transmission cycle likely involves opossums (Didelphis virginiana) and cat fleas (Ctenocephalides felis). Although primarily an undifferentiated febrile illness, a range of neurologic manifestations may occur, especially when treatment is delayed. Serology is the mainstay of diagnostic testing, but confirmation usually requires demonstrating seroconversion or a fourfold increase in antibody titer from acute- and convalescent-phase sera (antibodies are seldom detectable in the first week of illness). Thus, early empiric treatment with doxycycline, the drug of choice, is imperative. The purpose of this review is to highlight murine typhus as an important emerging and reemerging infectious disease, review its neurologic manifestations, and discuss areas in need of further study.

Bartonella spp. and Typhus Group Rickettsiae among Persons Experiencing Homelessness, São Paulo, Brazil.

Persons experiencing homelessness in São Paulo, Brazil, were seropositive for Bartonella spp. (79/109, 72.5%) and typhus group rickettsiae (40/109, 36.7%). Bartonella quintana DNA was detected in 17.1% (14/82) body louse pools and 0.9% (1/114) blood samples. Clinicians should consider vectorborne agents as potential causes of febrile syndromes in this population.

Serologic Evidence of Orientia Infection among Rural Population, Cauca Department, Colombia.

We assessed serum samples collected in Cauca Department, Colombia, from 486 persons for Orientia seroreactivity. Overall, 13.8% showed reactive IgG by indirect immunofluorescence antibody assay and ELISA. Of those samples, 30% (20/67) were confirmed to be positive by Western blot, showing >1 reactive band to Orientia 56-kD or 47-kD antigens.

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.

A Vaccine for Canine Rocky Mountain Spotted Fever: An Unmet One Health Need.

Outbreaks of life-threatening Rocky Mountain spotted fever in humans and dogs associated with a canine-tick maintenance cycle constitute an important One Health opportunity. The reality of the problem has been observed strikingly in Mexico, Brazil, Colombia, and Native American tribal lands in Arizona. The brown dog tick, Rhipicephalus sanguineus sensu lato, acquires the rickettsia from bacteremic dogs and can maintain the bacterium transtadially to the next tick stage. The subsequent adult tick can then transmit infection to a new host, as shown by guinea pig models. These brown dog ticks maintain spotted fever group rickettsiae transovarially through many generations, thus serving as both vector and reservoir. Vaccine containing whole-killed R. rickettsii does not stimulate sufficient immunity. Studies of Rickettsia subunit antigens have demonstrated that conformationally preserved outer-membrane autotransporter proteins A and B are the leading vaccine candidates. The possibility of a potentially safe and effective live attenuated vaccine has only begun to be explored as gene knockout methods are applied to these obligately intracellular pathogens.

Rickettsial Infections Causing Acute Febrile Illness in Urban Slums, Brazil.

We conducted enhanced acute febrile illness surveillance in an urban slum community in Salvador, Brazil. We found that rickettsial infection accounted for 3.5% of urgent care visits for acute fever. Our results suggest that rickettsiae might be an underrecognized, treatable cause of acute febrile illness in impoverished urban populations in Brazil.

Emerging Tickborne Bacteria in Cattle from Colombia.

Ehrlichia minasensis is a new pathogenic bacterial species that infects cattle, and Borrelia theileri causes bovine borreliosis. We detected E. minasensis and B. theileri DNA in cattle from southwestern Colombia by using PCR. E. minasensis and B. theileri should be considered potential etiologies of febrile syndrome in cattle from Colombia.

Murine Typhus in Latin America: Perspectives of a Once Recognized but Now Neglected Vector-Borne Disease.

Murine typhus is an undifferentiated febrile illness. Historically recognized throughout Latin America, it has been seldom reported in recent decades. When clinicians and researchers are attuned, endemic foci have reemerged. The demonstrable seroprevalence in areas devoid of reported cases indicates murine typhus is an underappreciated infectious disease in Latin America.

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 characterization of a novel Ehrlichia chaffeensis genotype from an Amblyomma tenellum tick from South Texas, USA.

Ehrlichia chaffeensis is the causative agent of human monocytotropic ehrlichiosis (HME), a disease that ranges in severity from mild to fatal infection. Ehrlichia chaffeensis is maintained in a zoonotic cycle involving white-tailed deer (Odocoileus virginianus) as the main vertebrate reservoir and lone star ticks (Amblyomma americanum) as its principal vector. Through complete genomic analysis from human ehrlichial isolates and DNA sequences obtained from deer and tick specimens, nine strains of E. chaffeensis have been characterized. Few studies have examined the genetic diversity of E. chaffeensis in ticks, and some of these investigations have identified that the genetic sequences coincide with the circulating strains reported so far. Here, we report the first evidence of E. chaffeensis DNA from an unfed Amblyomma tenellum (formerly Amblyomma imitator) collected in South Texas. We characterized the genetic variation of this E. chaffeensis genotype using conserved gene markers such as rRNA, dsb, and groEL. We also used gene targets useful to distinguish genotypes, such as the variable length PCR target gene (VLPT) and 120-kDa gene, encoding the tandem-repeat proteins TRP32 and TRP120, respectively. Our results suggest a novel E. chaffeensis genotype that exhibited greater variability than other genotypes of E. chaffeensis and highlights the role for A. tenellum as a potential vector of E. chaffeensis.

Rickettsiosis subcommittee report to the tick-borne disease working group.

Tick-borne rickettsial infections are serious, common, and difficult to diagnose. Among the most important factors leading to failure to diagnose and treat tick-borne rickettsioses effectively is a lack of consideration of the potential diagnosis by primary caregivers and emergency department physicians in patients presenting with undifferentiated acute febrile illness during tick season. This situation exists because of insufficient primary and continuing medical education of medical students, primary care and emergency medicine residents, and practicing physicians regarding tick-borne rickettsioses specific to the region where they practice. Delayed initiation of treatment with an appropriate antibiotic is associated with adverse outcomes including increased rates of hospitalization, admission to an intensive care unit, and mortality. The earliest symptoms are nonspecific, consisting of fever, headache, myalgias, and nausea and/or vomiting. Laboratory abnormalities are typically absent at this time when the therapeutic response to an appropriate antibiotic would be optimal. There is a mistaken idea among a substantial portion of physicians that the best antibiotic available, doxycycline, should not be administered to children 8 years of age or younger or during pregnancy. For all of the above reasons, there is unnecessary morbidity and mortality caused by tick-borne rickettsioses. This report proposes measures to address these critical issues regarding tick-borne rickettsioses.

Murine Typhus Infection in Pregnancy: Case Series and Literature Review.

Murine typhus is a flea-borne disease of worldwide distribution with a recent reemergence in the United States of America. There are limited data about the presentation, treatment, and outcomes in the pregnant population. We report on two cases of murine typhus during pregnancy and review the literature to compile previously reported cases. A comprehensive search was performed via the PubMed database for published articles between 1990 and 2020. Seven articles met the criteria of symptomatic pregnant murine typhus infection. A total of 37 patients were identified. Patients frequently presented with a prolonged duration of fevers prior to presentation, headache, and elevated hepatic transaminases. The diagnosis was predominantly based on serology. Treatment varied. Overall, the pregnancy outcome was favorable. Murine typhus can mimic other pregnancy-related pathologies. More exclusive and large-scale studies are needed to learn more of murine typhus during pregnancy.

Manifestations and Management of Flea-Borne Rickettsioses.

Murine typhus and flea-borne spotted fever are undifferentiated febrile illnesses caused by Rickettsia typhi and Rickettsia felis, respectively. These organisms are small obligately intracellular bacteria and are transmitted to humans by fleas. Murine typhus is endemic to coastal areas of the tropics and subtropics (especially port cities), where rats are the primary mammalian host and rat fleas (Xenopsylla cheopis) are the vector. In the United States, a cycle of transmission involving opossums and cat fleas (Ctenocephalides felis) are the presumed reservoir and vector, respectively. The incidence and distribution of murine typhus appear to be increasing in endemic areas of the US. Rickettsia felis has also been reported throughout the world and is found within the ubiquitous cat flea. Flea-borne rickettsioses manifest as an undifferentiated febrile illness. Headache, malaise, and myalgia are frequent symptoms that accompany fever. The incidence of rash is variable, so its absence should not dissuade the clinician to consider a rickettsial illness as part of the differential diagnosis. When present, the rash is usually macular or papular. Although not a feature of murine typhus, eschar has been found in 12% of those with flea-borne spotted fever. Confirmatory laboratory diagnosis is usually obtained by serology; the indirect immunofluorescence assay is the serologic test of choice. Antibodies are seldom present during the first few days of illness. Thus, the diagnosis requires acute- and convalescent-phase specimens to document seroconversion or a four-fold increase in antibody titer. Since laboratory diagnosis is usually retrospective, when a flea-borne rickettsiosis is considered, empiric treatment should be initiated. The treatment of choice for both children and adults is doxycycline, which results in a swift and effective response. The following review is aimed to summarize the key clinical, epidemiological, ecological, diagnostic, and treatment aspects of flea-borne rickettsioses.

RAPID DEVELOPMENT OF IATROGENIC CUSHING SYNDROME IN A PATIENT ON RITONAVIR: THE ADVERSE METABOLIC CONSEQUENCE OF TOPICAL STEROID USE.

OBJECTIVE: Topical steroid use is common, but its association with Cushing syndrome is rare. We report the rapid development of iatrogenic Cushing syndrome in a patient on ritonavir who applied a moderate-potency topical steroid cream, triamcinolone, on his genital mucosa for treatment of phimosis. METHODS: Clinical and diagnostic challenges associated with topical steroid use are presented and discussed. RESULTS: A 41-year-old man with human immunodeficiency virus infection on stable antiretroviral therapy that included ritonavir, a cytochrome P450 3A4 inhibitor, presented with new onset diabetes and development of overt cushingoid features over a 4-week period. He reported no known history of steroid use. A midnight salivary cortisol using a quantitative enzyme immunoassay was obtained and reported at >15.0 µg/dL (normal, <0.112 µg/dL). However, free cortisol in a 24-hour urine collection was undetectable by high-performance liquid chromatography and morning plasma cortisol was also unexpectedly low at 1.1 µg/dL (normal, 4.5 to 23.0 µg/dL). Further investigation revealed that the patient had been applying a topical cream with triamcinolone acetonide (0.1%) on the glans penis for treatment of phimosis. The salivary enzyme immunoassay for cortisol appears to have detected the absorbed triamcinolone, a compound known to cross-react with cortisol in this assay. CONCLUSION: This case raises awareness on the severe metabolic consequence resulting from the seemingly benign use of a topical steroid medication when applied to the genital mucosa in the setting of stable therapy with ritonavir and illustrates the limitations of salivary cortisol enzyme immunoassays for the evaluation of Cushing syndrome in this setting.

Flea-borne Rickettsia species in fleas, Caldas department, Colombia.

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.

Pharmacological approaches to the treatment of COVID-19 patients.

The current COVID-19 pandemic has presented unprecedented challenges to the world community. No effective therapies or vaccines have yet been established. Upon the basis of homologies to similar coronaviruses, several potential drug targets have been identified and are the focus of both laboratory and clinical investigation. The rationale for several of these drug candidates is presented in this review. Emerging clinical data has revealed that severe COVID-19 disease is associated with heightened inflammatory responses and a procoagulant state, suggesting that patient treatment strategies must extend beyond antiviral agents. Effective approaches to the treatment of vulnerable patients with comorbidities will render COVID-19 substantially more manageable.