Revisiting scrub typhus: A neglected tropical disease

Highlights

• Scrub typhus is most common re-emerging rickettsial disease in Asia-Pacific

• There are a non- availability of cost-effective, rapid, specific and sensitive diagnostic methods.

• The knowledge about the pathogenesis of the disease will help the scientists to design and develop these methods.

Abstract

Scrub typhus is an under diagnosed re-emerging vector borne disease caused by an intracellular gram negative bacteria, Orientia. The disease is commonly prevalent in rural and hilly areas of Tsutsugumashi triangle. The diagnosis of the disease is very challenging due to similarity of its early symptoms with other febrile illnesses, like dengue and COVID 19, as well as non-availability of rapid, reliable and cost-effective methods. Moreover, the diverse clinical presentation in severe cases make it significant health problem. The occupational and behavioral risks responsible for the transmission lead to urgent need of vaccine development against the disease. The complete knowledge about its pathogenesis and the interaction with host’s immune cells may help the scientists in developing the appropriate diagnostic methods as well as the vaccines.

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.