Comparative Immunology, Microbiology and Infectious Diseases
Revisiting scrub typhus: A neglected tropical disease
Introduction
Scrub typhus, also called as Bush Typhus or Tsutsugumashi disease, is a re-emerging but neglected zoonotic acute febrile illness. It affects about one million people worldwide annually with a mortality rate of about 50%, if untreated [1]. About one billion people across the world are at risk of infection with Orientae per year [2]. This is a disease caused by the obligate intracellular, gram negative bacteria, the Orientiae, the members of genus Orientia. Two species of Orientia are known to cause the disease, i.e. O. tsutsugamushi and O. chuto [3], [4]. The genus Orientia along with the other intracellular zoonotic pathogens, Anaplasma, Coxiella, Ehrlichia and Rickettsia, belong to the order rickettsiales, and has recently been separated from the genus Rickettsia [5]. The members of genus Orientia may be easily differentiated from the Rickettsia as they lack lipopolysaccharide, peptidoglycan, and the slime layer. Moreover, in contrast to the members of genus Rickettsia, the outer cell envelop of Orientiae is thicker than the inner one [5]. The Orientia tsutsugamushi is known for absence of lipopolysaccharide (LPS) and peptidoglycan layer; therefore, they are naturally resistant to all β-lactam antibiotics [6]. A recent report showed that Orientia has expressed peptidoglycan like structure and disulphide cross-linked outer membrane proteins here upon sensitive to cell wall targeting drugs and these components are required for bacterial growth, cell integrity and host cell invasion [7]. The pathogen is transmitted to humans through the bite of infected larval trombiculid mites of genera, Leptotrombidium, and Schoengastiella of family Trombiculidae. These larval mites, also known as chiggers, primarily feed on rodents, but occasionally on humans. The chiggers act as both vector as well as reservoir for the pathogen [8].
Scrub typhus was previously thought to be endemic only within an area of ∼13,000,000 km2, known as Tstsugumashi triangle, but later it was reported from outside the region also [1]. Currently, the disease is re-emerging and endemic in rural areas of Southeast Asia, Thailand, Korea, Australia, Russia, The Pacific Islands, and Japan [9]. The disease is prevalent in areas that favor the growth and reproduction of mites such as forests, mountains, deserts, and beaches [10]. Even after the re-emergence, the disease is still a neglected one among the public as well as the physicians. The symptoms of scrub typhus in early phase are similar with that of other infections, such as dengue, encephalitis, influenza and coronaviruses, causing acute febrile illness. Besides, one of the serious complications of scrub typhus, acute respiratory distress syndrome (ARDS) is similar with the symptom observed in SARS-CoV-2 infection. The earlier reports on co-infection of scrub typhus with dengue, chickangunya, H1N1 influenza indicate the possibility of its co-infection with the ongoing COVID 19 pandemic in the rainy and winter season. Thus, the negligence of scrub typhus poses the confusion and challenges in the diagnosis of the viral infections. Therefore, this review provides the complete picture of Scrub typhus including prevalence, clinical manifestation, pathogenesis, immunology, diagnosis, treatment and prophylaxis, as well as is an effort to aware the public and physicians both about the disease.
Section snippets
Prevalence of scrub typhus
In tropical areas, scrub typhus is prevalent throughout the year while in temperate regions seasonal pervasiveness has been observed [10]. In Asia, prevalence of disease occurs in rainy and winter season [11]. The seasonal prevalence of the disease is due to the fact that wet and cool season allows the attachment of more chiggers to the body of rodents [12]. The low temperature and high rainfall are the major weather factors responsible for development of the scrub typhus infection. The
Pathogenesis of Scrub Typhus
Orientia enters into human body through skin of the individual, who comes in contact with mite infested habitats, bush and grass, due to their frivolous or professional behaviors [15]. These organisms transmit to human through the bite or excreta of infected chiggers. The infected chiggers inoculate Orientia tsutsugamushi pathogens in humans during feeding. The pathogen multiplies at the entry site leading to formation of a papule that becomes necrotic and ultimately develops into an eschar [16]
Interaction of Orientia tsutsugamushi with immune cells
Orientia tsutsugamushi infection involves different cells such as endothelial cells, dendritic cells, monocytes, neutrophils, and macrophages. The interactions of the pathogen with these host cells are critical to disease progression as well as effective treatment management strategies [20]. These interactions with each type of host cell are described below.
Clinical manifestation
Clinical manifestation of scrub typhus occurs in early stage of infection. Early symptoms also include acute onset of fever with headache and myalgia. Thus, these symptoms are similar to that of dengue fever, chikungunya, paratyphoid, and pyrexia of unknown origin (PUO) [21], [37]. Sometimes, it appears as only flu- like symptoms, and creates confusion with other infections causing acute febrile illness such as influenza and coronavirus infections. The disease usually leads to gastrointestinal
Diagnosis
Scrub typhus is one of the under-diagnosed illnesses. The symptoms similar to other diseases and low positivity of the eschar, a characteristic feature of the scrub typhus in the Asian population left the physicians to rely on the laboratory tests only. In laboratories, the disease can be diagnosed by serological, molecular and microbiological methods (Fig. 2). However, there is urgent need for discovery of new simple, rapid, reliable, accessible and cost effective diagnostic methods [44].
Treatment and prophylaxis
Scrub typhus infected patient can be treated easily with antibiotic, doxycycline. The drug is a preferred choice as it is highly efficient and show quick action. The recommended dosage is 45 mg/day in two divided doses for patients below 45 kg and 200 mg/day in two divided doses for in adult individuals above 45 kg for duration of seven days [61]. The patients allergic to doxycycline may be given the 50–100 mg/kg/day chloramphenicol divided every 6 hourly, maximum 3 g/day. Although doxycline
Conclusion
Scrub typhus is most common re-emerging rickettsial disease in Asia-Pacific region, particularly in developing countries. Due to non- availability of cost-effective, rapid, specific and sensitive diagnostic methods, the disease remains under diagnosed and under reported. Further, low index of suspicion among the clinicians and limited awareness about the diseases makes it more difficult to diagnose. The symptoms of the disease similar to other febrile illnesses highlighted the significance of
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
Authors are thankful to their respective employers for providing necessary facilities.
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