Scrub typhus (Tsutsugamushi fever or Chigger borne typhus) is a chigger-borne zoonosis caused by Orientia tsutsugamushi. Humans are accidental hosts who acquire the disease by intruding into often sharply localized foci colonized by infected larval trombiculid mites (chigger mites).
The family Rickettsiaeceae currently comprises of three genera-Rickettsia, Orientia and Ehrlichia. These organisms are primarily parasites of arthropods such as lice, fleas, ticks and mites.
Causative agent
Orientia tsutsugamushi is an obligate intracellular parasite. The organism are rods approximately 0.5 µm in width and from 1.2 to 3.0 µm in length. It differs from other members of the family in its genetic make up and in the composition of its cell wall structure since it lacks lipopolysaccharides and peptidoglycan and does not have an outer slime layer.
Orientia tsutsugamushi invade host cells by induced phagocytosis and escapes from the phagosome to the cytosol. Once free in the host cytoplasm, the bacteria replicate by transverse binary fission in the perinuclear area. Organisms are released from the cell by pushing out the host cytoplasmic membrane from inside, and budding organisms accumulate at high density on the host cell from infected cells. The organism enters the cytosol of the new cell by lysing intervening host cell membranes. Organisms stain deep purple by Giemsa and characteristically are grouped in perinuclear clusters.
Antigenic structure
The major surface protein antigen of Orientia tsutsugamushi is the variable 56-kDa protein, which accounts for 10 to 15 % of its total protein. This protein is an immunodominant antigen, is reactive with group and strain specific monoclonal antibodies, and is recognized by sera from most scrub typhus patients. The other major surface proteins are 110, 47 and 25 kDa.
Habitat and Ecology
Transmission often occurs in zones where primary forest has been cleared and replaced by secondary, or scrub, vegetation, hence the name scrub typhus.
Humans are accidental hosts, acquiring Orientia tsutsugamushi during feeding of a larval trombiculid mite of the genus Leptotrombidium. These chiggers only feed on mammalian tissue fluid once in their lifetime and constitute the reservoir of infection through transovarial transmission. Mites are normally maintained in nature by feeding on a variety of wild rodents. Rodents are the key to the population density of chiggers but are not a reservoir of Orientia tsutsugamushi. Only a low proportion of chiggers acquire Orientia tsutsugamushi acquire from infected rats, and chiggers infected by feeding neither develop a generalized infection or transmit the organisms transovarially to their offspring.
Humans become infected when the accidentally encroach on a zone where the rodent-chigger cycle is taking place. Transmission depends on the seasonal activities of both chiggers and humans. Chigger activity is determined by temperature and humidity, both of which are relatively stable in tropics. In much of southeast Asia where climatic conditions are favorable throughout the year, populations of mites and maintaining rodent hosts may be high and endemic areas extensive.
Leptotrombidium deliense is the most important vector species in Southeast Asia and Southern China, where as L. akamushi, L. scutellare and L. pallidum are the main vectors in Korea and Japan.
Pathogenesis and pathology
Heparin sulfate proteoglycans contribute to the attachment of Orientia tsutsugamushi to cells, but a specific cellular receptor has not been identified. Scrub typhus bacteria have been demonstrated in a variety of cells in humans, including monocytes, macrophages, kuppfer cells, cardiac myocytes, hepatocytes and endothelial cells.
In fatal cases, the histopathology is chiefly disseminated focal vasculitis and perivasculitis, particularly in vessels of the skin, lungs, heart, and brain. Endovasculitis and focal hemorrhage may be present but are less prominent than in Rocky Mountain spotted fever and epidemic typhus. Pathologic abnormalities often correlate poorly with the clinical picture. Several series report consistent vasculitic lesions in the kidney and heart, but neither primary myocarditis nor renal failure are often seen clinically. The basic histopathological lesions, disseminated perivasculitis, and focal interstitial mononuclear infiltrates associated with edema suggest that macrophages are a more important target cell than the endothelium. Thrombotic lesions are rare, and little histologically evident vascular damage was seen in the most important histopathologic study of Orientia tsutsugamushi infection. The most important lesions are interstitial pneumonia with alveolar edema, hemorrhage, occasionally hyaline membranes, interlobular septal edema, and meningoencephalitis.
Clinical features
The chigger bite can occur on any part of the body, is painless, and is not usually remembered by the patient. An eschar forms at the bite site in about half of primary infection and in a lesser proportion of secondary infections. However eschars are often located in hard to examine areas such as the genital region or under the axilla and are often missed.
The eschar develops during the 6 to 20 day (average 10 days) incubation period and is usually well developed by the time fever appears. It begins as a small papule, enlarges, undergoes central necrosis, and acquires a blackened crust to form a lesion resembling a cigarette burn. Regional lymph node are enlarged and sometimes tender, and generalized lymphadenopathy and splenomegaly are not uncommon.
Fever and headache begin abruptly and are frequently accompanied by myalgias and malaise. Muscle tenderness is either absent or mild. A transient muscular rash may appear at the end of the first week of illness. The rash appears on the trunk, becomes maculopapular, and spreads peripherally. Hearing loss concurrent with the onset of fever occurs in about one-third of cases and is a very useful diagnostic clue. Acoustic nerve damage caused by scrub typhus has been well documented pathologically.
Cough, sometimes accompanied by infiltrates on the chest radiograph, is one of the most common presentations of scrub typhus infection. In severe cases, tachypnea progress to dyspnea, the patient become cyanotic, and full-blown ARDS may develop. Respiratory failure is the most common cause of death in severe scrub typhus infection.
Laboratory diagnosis
Diagnostic methods include
- Isolation of organism
- Serology
- Molecular methods (PCR)
As rickettsiae are highly infectious and comes under Group 3 organisms. isolation should be in laboratories equipped with appropriate safety provisions preferably Biosafety level-3 laboratory.
Rickettsia may be isolated in male guinea pigs or mice, yolk sac of chick embryos, vero cell line or MRC 5 cell lines from patients in early phase of the disease. Rickettsia grow well in 3-5 days on vero cell and MRC 5 cell coverslip cultures and can be identified by immunofluorescence using group and strain specific monoclonal antibodies.
Serological diagnosis
Several diagnostic tests are currently available for the demonstration of significant rise in titer of antibodies in the serum of patient during the course of infection and convalescence . Tests include Weil-Felix Test (WFT), Indirect Immunofluorescence (IIF), Enzyme Linked Immunosorbent Assay (ELISA), etc.
Weil-Felix Test : Test detects antibodies produced during Orientia tsutsugamushi infection that cross-react by agglutination with the OX-K antigen of an unrelated bacteria, Proteus mirabilis.
Indirect Immunofluorescence (IIF): Which use yolk sac propagated or cell culture derived Orientia tsutsugamushi antigens
Molecular methods
For PCR, blood sample is collected in tubes containing EDTA or sodium citrate. Organism can be demonstrated by standard and nested PCR. Recently, detection of Orientia tsutsugamushi quantitative real time PCR has been reported.
Treatment
Antibiotic therapy is the most effective measure of treatment. Tetracyclines and chloramphenicol are used for therapy. Doxycycline in a dose of 100 mg twice daily for 7-15 days or chloramphenicol 500 mg four times a day PO for 7-15 days (for children 150 mg/kg/day for 5 days) is recommended.
Prevention and control
Chemoprophylaxis : Should be considered for persons with anticipated intense but transient exposure to Orientia tsutsugamushi. Weekly dose of 200 mg of doxycycline can prevent infection.
Reduction in Chigger mite: Contact with chiggers can be reduced by applying repellent to the tops of boots, socks, and trouser legs and by not sitting or lying directly on the ground.
Scrub typhus vaccine: An effective vaccine for humans has not been developed till now, mainly due to serotypic heterogencity of the organism.
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