**2. Scrub typhus**

## **2.1. Epidemiology**

Although scrub typhus was known in China in the third century A.D., it was first described by Hakuju Hashimoto in 1810 in people living in the banks of the Shinano river and later

in 1879 by Baclz and Kawakami as Japanese 'flood fever'. It is widespread in the so-called 'tsutsugamushi triangle' which extends from Pakistan, India, Nepal in the West, to South Eastern Siberia, Japan, China and Korea in the North, to Indonesia, the Philippines, Northern Australia and the Pacific islands in the South. Taiwan is the centre of the tsutsugamushi triangle, and Korea has the highest reported incidence in the world [2]. About one million new cases are identified annually.

In India, the disease had occurred among troops during World War II in the state of Assam and West Bengal. Although the disease is endemic in India, epidemics have also been reported.

Epidemiological reports confirm strong existence of scrub in hilly/rain prone areas. Outbreaks reveal an autumn-winter type and a summer type of pattern. In comparison with the summer type, the autumn-winter type is less severe.

Increasing prevalence of scrub typhus reported from some Asian countries may be related to urbanization of rural areas.

#### **2.2. Pathophysiology**

Scrub typhus is caused by an obligate intracellular gram-negative bacterium called *Orientia tsutsugamushi*. Ogata in 1931 isolated the organism and named it *Rickettsia* tsutsugamushi. Now it has been renamed as *O. tsutsugamushi*. The organism lacks a cell wall. There are six important serotypes of *O. tsutsugamushi*—Gilliam, Karp, Kato, Shimokoshi, Kawasaki and Kuroki. A new strain has been isolated from a case of scrub typhus in Australia which was quite different from the classic strains and has been named as Litchfield.

The mite has four stages: egg, larva, nymph and adult. The larval forms (chiggers) transmit the disease to humans and other vertebrates. The larvae feed on rodents particularly wild rats of subgenus Rattus, The infection in humans is acquired during outdoor recreational and agricultural activities, by the bite of the larval stage of mites. The areas are usually secondary scrub growth which grows after clearance of primary forest hence the term scrub typhus. Humans are therefore accidental hosts for the pathogen. Vertical transovarial transmission occurs in mites. One case of transplacental spread has been reported in a pregnant woman, who delivered a preterm baby with scrub typhus IgM positivity.

Following the bite, the pathogen multiplies at the site of inoculation and produces both systemic and local manifestation. Infection spreads through both haematogenous and lymphatic routes. The severity of the illness depends on both host-related and pathogen-related factors. Pathogenrelated factors may be related to the different strains of *O. tsutsugamushi*. Host-related factors as seen in humans with G6PD deficiency who has a worse prognosis also play a role. Target cells for multiplication are the endothelial cells of the various systems. The immune response induced by the pathogen is a combination of humoral and cell-mediated immunity. There occurs a rise of cytokines during an acute infection. There also occurs a rise in macrophage colony stimulating factor, interferon gamma and granulocyte colony stimulating factor. Therefore, the macrophage and T-lymphocyte response may be the main factor in immunity against the infection. However, the parasite has also evolved to evade the immune response of the host. The pathogen can down-regulate the expression of glycoprotein 96, in infected macrophages and endothelial cells and thereby neutralize host immune response. This molecule plays a central role antigen presentation and antibody production [3].

Central nervous system involvement occurs in scrub typhus. It is speculated that since the pathogen is an obligatory intracellular organism, it enters the cerebrospinal fluid in a monocyte or grow through the endothelium, enter via the luminal cell membrane and release into the perivascular space [4]. The pathogen also invades and multiplies in the vascular endothelium and cause wide spread vasculitis. Autopsy specimens have shown central nervous system pathology in scrub typhus cases in the form of diffuse or focal mononuclear cell infiltration of the leptomeninges, presence of typhus nodules (clusters of microglial cells) and haemorrhages of the brain substance [4].
