Orientia tsutsugamushi

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Orientia tsutsugamushi.JPG
Orientia tsutsugamushi
Scientific classification
O. tsutsugamushi
Binomial name
Orientia tsutsugamushi
(Hayashi, 1920) (Ogata, 1929) Tamura et al., 1995

Orientia tsutsugamushi (from Japanese tsutsuga meaning "illness", and mushi meaning "insect") is a mite-borne bacterium belonging to the family Rickettsiaceae and is responsible for a disease called scrub typhus in humans. [1] It is a natural and an obligate intracellular parasite of mites belonging to the family Trombiculidae. [2] [3] With a genome of only 2.4–2.7 Mb, it has the most repeated DNA sequences among bacterial genomes sequenced so far. The disease, scrub typhus, occurs when infected mite larvae accidentally bite humans. Primarily indicated by undifferentiated febrile illnesses, the infection can be complicated and often fatal.

Scrub typhus form of typhus caused by the intracellular parasite Orientia tsutsugamushi

Scrub typhus or bush typhus is a form of typhus caused by the intracellular parasite Orientia tsutsugamushi, a Gram-negative α-proteobacterium of family Rickettsiaceae first isolated and identified in 1930 in Japan.

An obligate parasite or holoparasite is a parasitic organism that cannot complete its life-cycle without exploiting a suitable host. If an obligate parasite cannot obtain a host it will fail to reproduce. This is opposed to a facultative parasite, which can act as a parasite but does not rely on its host to continue its life-cycle. Obligate parasites have evolved a variety of parasitic strategies to exploit their hosts. Holoparasites and some hemiparasites are obligate.

Intracellular parasites are microparasites that are capable of growing and reproducing inside the cells of a host. Some parasites can cause disease.


O. tsutsugamushi infection was first reported in Japan by Hakuju Hashimoto in 1810, and to the Western world by Theobald Adrian Palm in 1878. Naosuke Hayashi first described it in 1920, giving the name Theileria tsutsugamushi. Owing to its unique properties, it was renamed Orientia tsutsugamushi in 1995. Unlike other Gram-negative bacteria, it is not easily stained with Gram stain, as its cell wall is devoid of lipophosphoglycan and peptidoglycan. With highly variable membrane protein, a 56-kDa protein, the bacterium can be antigenically classified into many strains (sub-types). The classic strains are Karp (which accounts for about 50% of all infections), Gilliam (25%), Kato (less than 10%), Shimokoshi, Kuroki and Kawasaki. [4] Within each strain, enormous variability further exists.

Bacteria A domain of prokaryotes – single celled organisms without a nucleus

Bacteria are a type of biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a number of shapes, ranging from spheres to rods and spirals. Bacteria were among the first life forms to appear on Earth, and are present in most of its habitats. Bacteria inhabit soil, water, acidic hot springs, radioactive waste, and the deep portions of Earth's crust. Bacteria also live in symbiotic and parasitic relationships with plants and animals. Most bacteria have not been characterised, and only about half of the bacterial phyla have species that can be grown in the laboratory. The study of bacteria is known as bacteriology, a branch of microbiology.

Gram stain Method of staining used to differentiate bacterial species into two large groups (Gram-positive and Gram-negative)

Gram stain or Gram staining, also called Gram's method, is a method of staining used to distinguish and classify bacterial species into two large groups. The name comes from the Danish bacteriologist Hans Christian Gram, who developed the technique.

Lipophosphoglycan is a class of molecules found on the surface of some eukaryotes, in particular protozoa. A lipophosphoglycan is made up of two parts; a lipid part and a polysaccharide part. The two are linked by a phosphodiester bond, hence the name lipo-phospho-glycan.

O. tsutsugamushi is naturally maintained in the mite population by transmission from female to its eggs (transovarial transmission), and from the eggs to larvae and then to adults (transtadial transmission). The mite larvae, called chiggers, are natural ectoparasites of rodents. Humans get infected upon accidental contact with infected chiggers. A scar-like scab called eschar is a good indicator of infection, but is not ubiquitous. The bacterium is endemic to the so-called Tsutsugamushi Triangle, a region covering the Russian Far East in the north, Japan in the east, northern Australia in the south, and Afghanistan in the west. One million infections are estimated to occur annually. Antibiotics such as azithromycin and doxycycline are the main prescription drugs; chloramphenicol and tetracyclin are also effective. Diagnosis of the infection is difficult and requires laborious techniques such as Weil–Felix test, rapid immunochromatographic test, immunofluorescence assays, and polymerase chain reaction. There is no working vaccine.

Parasitism Interaction between two organisms living together in more or less intimate association in a relationship in which association is disadvantageous or destructive to one of the organisms

In evolutionary biology, parasitism is a relationship between species, where one organism, the parasite, lives on or in another organism, the host, causing it some harm, and is adapted structurally to this way of life. The entomologist E. O. Wilson has characterised parasites as "predators that eat prey in units of less than one". Parasites include protozoans such as the agents of malaria, sleeping sickness, and amoebic dysentery; animals such as hookworms, lice, mosquitoes, and vampire bats; fungi such as honey fungus and the agents of ringworm; and plants such as mistletoe, dodder, and the broomrapes. There are six major parasitic strategies of exploitation of animal hosts, namely parasitic castration, directly transmitted parasitism, trophically transmitted parasitism, vector-transmitted parasitism, parasitoidism, and micropredation.

Eschar slough or piece of dead tissue that is cast off from the surface of the skin

An eschar is a slough or piece of dead tissue that is cast off from the surface of the skin, particularly after a burn injury, but also seen in gangrene, ulcer, fungal infections, necrotizing spider bite wounds, spotted fevers and exposure to cutaneous anthrax. The term "eschar" is not interchangeable with "scab". An eschar contains necrotic tissue, whereas a scab is composed of dried blood and exudate.

Azithromycin chemical compound

Azithromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumonia, traveler's diarrhea, and certain other intestinal infections. It may also be used for a number of sexually transmitted infections, including chlamydia and gonorrhea infections. Along with other medications, it may also be used for malaria. It can be taken by mouth or intravenously with doses once per day.


The earliest record of O. tsutsugamushi infection was in the 3rd century (313 CE) in China. [5] Japanese were also familiar with the link between the infection and mites for centuries. They gave several names such as shima-mushi, akamushi (red mite) or kedani (hairy mite) disease of northern Japan, and most popularly as tsutsugamushi (from tsutsuga meaning fever or harm or illness, and mushi meaning bug or insect). Japanese physician Hakuju Hashimoto gave the first medical account from Niigata Prefecture in 1810. He recorded the prevalence of infection along the banks of the upper tributaries of Shinano River. [6] The first report to the Western world was made by Theobald Adrian Palm, a physician of the Edinburgh Medical Missionary Society at Niigata in 1878. Describing his first-hand experience, Palm wrote:

Niigata Prefecture Prefecture of Japan

Niigata Prefecture is a prefecture of Japan located in the Chūbu region of Honshu. Niigata Prefecture has a population of 2,285,856 (2016) and is the fifth-largest prefecture of Japan by geographic area at 12,582 km2. Niigata Prefecture borders Toyama Prefecture and Nagano Prefecture to the southwest, Gunma Prefecture to the south, Fukushima Prefecture to the east, and Yamagata Prefecture to the northeast.

Shinano River river in Japan

The Shinano River, known as the Chikuma River in its upper reaches, is the longest and widest river in Japan and the third largest by basin area. It is located in northeastern Honshu, rising in the Japanese Alps and flowing generally northeast through Nagano and Niigata Prefectures before emptying into the Sea of Japan.

EMMS International

EMMS International is a non-denominational christian Non-governmental Organization (NGO) that provides medical aid to countries around the world and operates field offices in the UK, Malawi, India, Israel, and Nepal. Founded to provide clinical education to missionaries and medical aid to people in need in Scotland, it later expanded to the Middle East, South Asia, and Africa through sponsoring the construction of dispensaries and hospitals. It's educational mission expanded from training missionary physicians in Edinburgh to training local nurses and physicians in the countries where it works. EMMS continues to provide resource assistance at all its sites. Based in Scotland, its vision is "health for today, hope for tomorrow."

Last summer [i.e. 1877], I had the opportunity of observing a disease which, so far as I know, is peculiar to Japan, and has not yet been, described. It occurs, moreover, in certain well-marked districts, and at a particular season of the year, so that the opportunities of investigating it do not often occur. It is known here as the shima-mushi, or island-insect disease, and is so-named from the belief that it is caused by the bite or sting of some insect peculiar to certain islands in the river known as Shinagawa, which empties itself into the sea at Niigata. [7]

The aetiology of the disease was never apparent. In 1908 a mite theory of the transmission of tsutsugamushi disease was postulated by Taichi Kitashima and Mikinosuke Miyajima. [8] In 1915 a British zoologist Stanley Hirst suggested that the larvae of mite Microtrombidium akamushi (later renamed Leptotrombidium akamushi) which he found on the ears of field mice could carry and transmit the infection. [9] In 1917 Mataro Nagayo and colleagues gave the first complete description of the developmental stages such as egg, nymph, larva, and adult of the mite; and also asserted that only the larvae bites mammals, and are thus the only carriers of the parasites. [10] But then the actual infectious agent was not known, and it was generally attributed to either a virus or a protozoan. [11]

The causative pathogen was first identified by Naosuke Hayashi in 1920. Confident that the organism was a protozoan, Hayashi concluded, stating, "I have reached the conclusion that the virus of the disease is the species of Piroplasma [protozoan] in question... I consider the organism in Tsutsugamushi disease as a hitherto undescribed species, and at the suggestion of Dr. Henry B. Ward designate it as Theileria tsutsugamushi." [12] Discovering the similarities with the bacterium Rickettsia prowazekii , Mataro Nagayo and colleagues gave a new classification with the name Rickettsia orientalis in 1930. [13] [14] (R. prowazekii is a causative bacterium of epidemic typhus first discovered by American physicians Howard Taylor Ricketts and Russell M. Wilder in 1910; and described by a Brazilian physician Henrique da Rocha Lima in 1916. [15] )

The taxonomic confusion worsened. In 1931 Norio Ogata gave the name Rickettsia tsutsugamushi, [16] while Rinya Kawamüra and Yoso Imagawa independently introduced the name Rickettsia akamushi. [17] Kawamüra and Imagawa discovered that the bacteria are stored in the salivary glands of mites, and that mites feed on body (lymph) fluid, thereby establishing the fact that mites transmit the parasites during feeding. [18]

For more than 60 years there was no consensus on the choice of name – both R. orientalis and R. tsutsugamushi were equally used. Akira Tamura and colleagues reported in 1991 the structural differences of the bacterium from Rickettsia species that warranted separate genus, and proposed the name Orientia tsutsugamushi. [19] Finally in 1995, they made a new classification based on the morphological and biochemical properties, formally creating the new name O. tsutsugamushi. [20]


O. tsutsugamushi in human (U937) cells. O. tsutsugamushi in U937 cells.tif
O. tsutsugamushi in human (U937) cells.

O. tsutsugamushi belongs to Gram-negative bacteria and is a permanent (obligate) parasite in mites. A unicellular organism, it is rod shaped and measures 0.5 to 0.8 µm wide and 1.2 to 3.0 µm long. Due to similarity, it was initially categorised in the genus Rickettsia , but later assigned a separate genus, Orientia, [20] which it shares (so far) only with Candidatus Orientia chuto. [21] It is larger and broader, but shorter than other rickettsial bacteria. During reproduction, it divides (by binary fission) into two daughter cells by the process of budding. While undergoing budding, it accumulates on the host cell surface unlike other bacteria. One complete budding takes 9 to 18 hours. [22]

The bacterium is enclosed by a cell wall on the outside and cell membrane on the inside. The cell covering take up stains such as Giemsa and Gimenez stains. Although its cell wall has a classic bacterial double layer, its outer leaflet is much thicker than the inner one, which is just the opposite in Rickettsia species. [23] A capsule layer that forms a spherical halo in other bacteria is missing. The cell wall is soft and tender due to the absence of peptidoglycan, which is otherwise characteristic of the rigid cell walls of other bacteria. Classic bacterial lipophosphoglycans such as muramic acid, glucosamine, hydroxy fatty acids, heptose, and 2-keto-3-deoxyoctonic acid are also absent in the cell wall. Due to the absence of peptidoglycan, the bacterium is naturally resistant to all β-lactam antibiotics (such as penicillin), while Rickettsia species are normally sensitive to such drugs. [24] Its genome totally lacks the genes for lipophosphoglycan synthesis, but does contain those for peptidoglycan. In fact, peptidoglycan is synthesised in very small quantity that can hardly be detected and plays minor or no role in the cell wall. There are unique genes such as PBP1, alr, dapF, and murl, which are not known in other bacteria. [25] The cell membrane is also chemically different in its protein composition, and this difference gives rise to strain variations within the species itself. [26] The cytoplasm is clear and shows distinct DNA and ribosomes.

Genomes of O. tsutsugamushi strains. O. tsutsugamushi genomes.tif
Genomes of O. tsutsugamushi strains.

The bacterium is highly virulent such that its isolation and cell culture are done only in a laboratory with biosafety level 3 facility. Unlike other bacteria which can easily grow on different culture media, it can be grown only in the yolk sacs of developing chicken embryos and in cultured cell lines such as HeLa, BHK, Vero, and L929 cell lines. [27] In contrast to Rickettsia species which reside in the nucleus of the host cell, it mostly grow within the cytoplasm of the host cell. [19] Genetically, it differs from other Rickettsia by only 9%. [28] Even though adaptation to obligate intracellular parasitism among bacteria generally results in reduced genome, it has a genome size of about 2.0–2.7 Mb depending on the strains, which is comparatively larger than those of other rickettsiales – two times larger than that of R. prowazekii, [29] the most well-known member. The entire genome is distributed in a single chromosome. Whole genome sequences are available only for Ikeda and Boryong strains, both from the Republic of Korea. The genome of Ikeda strain is 2,008,987 base pairs (bp) long, and contains 1,967 protein-coding genes. [30] The Boryong strain is larger with 2,127,051 bp and 2,179 protein-coding genes. [31]

Genome comparison shows only 657 core genes among the different strains. [32] With about 42-47% of repetitive sequences, O. tsutsugamushi has the most highly repeated bacterial genome sequenced so far. [33] Repeated DNA sequence includes short repetitive sequences, transposable elements (including insertion sequence elements, miniature inverted-repeat transposable elements, a Group II intron), and a greatly amplified integrative and conjugative element (ICE) called the rickettsial amplified genetic element (RAGE). [31] RAGE is also found in other rickettsial bacteria. In O. tsutsugamushi, however, RAGE contains a number of genes including tra genes typical of Type IV secretion systems and gene for ankyrin repeat–containing protein. Ankyrin repeat–containing proteins are secreted through a Type I secretion system into the host cell. The precise role of Type IV secretion system in O. tsutsugamushi is not known. It may be involved in horizontal gene transfer between the different strains. [1]

Life cycle and transmission

Chigger with its stylostome (arrowhead), the feeding apparatus. Trombicula-larva-stylostome.jpg
Chigger with its stylostome (arrowhead), the feeding apparatus.

O. tsutsugamushi is naturally transmitted in the mite population belonging to the genus Leptotrombidium . It can be transmitted from female to its eggs through the process called transovarial transmission, and from the eggs to larvae and adults through the process of transtadial transmission. Thus, the bacterial life cycle is maintained entirely in mites. Infection to rodents and humans is an accidental transmission from the bite of mite larvae, and not required for reproduction or survival the bacterium. In fact, in rodents and humans the transmission is stopped, and the bacterium meets a dead end. [26]

In rodent and human infections, Leptotrombidium deliense is the most universal vector of O. tsutsugamushi. L. pallidum, L. fletcheri and L. scutellare are also carriers in many countries. In addition, L. akamushi is an endemic carrier in Japan, L. chiangraiensis and L. imphalum in Thailand, L. gaohuensis in China, and L. arenicola in Malaysia and Indonesia. [3] In parts of India, a different mite species, Schoengastiella ligula is also a major vector. [34] The third-stage larvae, commonly referred to as chiggers, are the only ectoparasitic stage feeding on the body fluids of rodents and other opportunistic mammals. Thus, they are the only stage in the life of mites that cause infection. Wild rats of the genus Rattus are the principal natural hosts of the chiggers. [35] Chiggers feed only once on a mammalian host. The feeding usually takes 2 to 4 days. Contrary to most parasites, they do not feed on blood, but instead on the body fluid through the hair follicles or skin pores. They possess a special feeding apparatus called stylostome on their heads. Their saliva can dissolve the host tissue around the feeding site, so that they ingest the liquefied tissue. O. tsutsugamushi is present in the salivary glands of mites and is released into the host tissue during this feeding. [36]

Cellular invasion

O. tsutsugamushi initially attacks the myeloid cells (young white blood cells) in the area of inoculation, and then the endothelial cells lining the vasculature. In blood circulation, monocytes and macrophages in all organs are the secondary targets. The parasite first attaches itself to the target cells using surface proteoglycans present on the host cell and bacterial surface proteins such as TSP56 (TSA56) and ScaC. [37] These proteins interact with the host fibronectin to induce phagocytosis (the process of swallowing the bacterium). The ability to actually enter the host cell depends on integrin-mediated signaling and reorganisation of actin cytoskeleton. [38]

O. tsutsugamushi has a special adaptation for surviving in the host cell by evading the host immune reaction. Once it interacts with the host cells, it causes the host cell membrane to form a transportation bubble called a clathrin-coated vesicle by which it gets transported in the cytoplasm moves. Inside the cytoplasm, it makes an exit from the vesicle (now known as an endosome) before it is destroyed (in the process of cell-eating called autophagy) by the lysosome. [39] It then moves towards the nucleus, specifically at the perinuclear region, where it starts to grow and multiply. Unlike other closely related bacteria which use actin-mediated processes for movement in the cytoplasm (called intracellular trafficking or transport), O. tsutsugamushi is unusual in using microtubule-mediated processes similar to those employed by viruses such as adenoviruses and herpes simplex viruses. Further, the escape (exocytosis) from an infected host cell is also unusual. It forms another vesicle using the host cell membrane, gives rise to small bud, and releases itself from the host cell surface while still enclosed in the vesicle. The membrane-bound bacterium is formed by interaction between cholesterol-rich lipid rafts as well as HtrA, a 47-kDa protein on the bacterial surface. [40] However, the process of budding and importance of membrane-bound bacterium are not yet understood.


O. tsutsugamushi is a diverse species of bacteria. Ida A. Bengtson of the United States Public Health Services was the first to note the existence of different strains using antigen-antibody interaction (complement fixation test) in 1944. [41] He observed that different strains had varying degree of virulence, and that the blood sera having different strains could cross react. By 1946 he established that there were three principal strains (serotypes), namely Karp (New Guinea), Gilliam (from India) and Seerangay (from British Malaya). [42] Akira Shishido discovered Kato strain, in addition to Gilliam and Karp, in Japan in 1958. [43] Since then six basic antigenic strains are recognised, namely Gilliam, Karp, Kato, Shimokoshi, Kawasaki, and Kuroki. Karp is the most abundant strain accounting for about 50% of all infections. [3] But in Korea, the major strain is Boryong. [44] So far, more than 30 different strains have been established in humans. [33] The number is much higher if the strains in rodents and mites are taken into account. For example, a study in Japan in 1994 reported 32 strains, 14 from human patients, 12 from wild rodents, and 6 from trombiculid mites. The different strains exert different levels of virulence, and the most virulent is KN-3, which is predominant among wild rodents. [45] Another study in 1996 reported 40 strains. [46] Genetic methods have revealed even greater complexity than had been previously described (for example, Gilliam is further divided into Gilliam and JG types). Due to immunological differences of the serotypes, simultaneous and repeated infection with different strains is possible. [47] [48]

Antigenic variation

O. tsutsugamushi has four major surface-membrane proteins (antigens) having molecular weights 22 kDa, 47 kDa, 56 kDa and 110 kDa. A 56-kDa protein is the most important because it is not produced by any other bacteria, and is responsible for making the genetic diversity in different strains. [49] It accounts for about 10–15% of the total cell protein. The 22-kDa, 47-kDa or 110-kDa antigens are not normally detected by sophisticated diagnostic tests. But clinical tests easily detect the 56-kDa protein, making it the main target in diagnosis. [50] The protein assists the adhesion and entry of the bacterium into host cells, as well as evasion of the host's immune reaction. It varies in size from 516 to 540 amino acid residues between different strains, and its gene is about 1,550 base pairs long. It contains four hypervariable regions, indicating that it synthesise many antigenically different protein but of the same kind. [46] There are also 11-kDa and 60-kDa protein inside the bacterium which are very similar to GroES and GroEL of the bacterium Escherichia coli , but not that of Rickettsia species. [51] GroES and GroEL are heat shock proteins belonging to the family of molecular chaperones in bacteria. DNA analysis have shown that the GroES and GroEL genes are indeed present in O. tsutsugamushi with slight variation in different strain and they produce the 11-kDa and 60-kDa proteins. [52]


O. tsutsugamushi causes a complex and dangerous infection scrub typhus. Infection starts when chiggers bite on the skin during their feeding. The bacteria are deposited at the site of feeding (inoculation), where they multiply. They cause progressive tissue damage (necrosis). Necrosis progresses to inflammation of the blood vessels called vasculitis. This in turn causes inflammation of the lymph nodes, called lymphadenopathy. Within a few days, vasculitis extends to various organs including liver, brain, kidney, meninges and the lung. [53] The disease is responsible for nearly a quarter of all the febrile (high fever) illness in endemic areas. Mortality in severe case or due to improper treatment or misdiagnosis may be as high as 30-70%. [54] About 6% of infected people die untreated, and 1.4% of the patients die even with medical treatment. Moreover, death rate can be as high as 13% where medical treatment is not properly handled. [55] In cases of misdiagnosis and failure of treatment, systemic complications rapidly develop including acute respiratory distress syndrome, acute kidney failure, encephalitis, gastrointestinal bleeding, hepatitis, meningitis, myocarditis, pancreatitis, pneumonia, septic shock, sub-acute thyroiditis, and multi-organ dysfunctions. [56] Harmful symptoms involving multiple organ failure and neurological impairment are difficult to treat, and can be lifelong debilitation or directly fatal. [56] The central nervous system is often affected and result in various complications including cerebellitis, cranial nerve palsies, meningoencephalitis, plexopathy, transverse myelitis, neuroleptic malignant syndrome, and Guillan-Barré syndrome. [57] Death rates due to complications can be up to 14% in brain infections, and 24% with multiple organ failure. [55] It is the major cause of acute encephalitis syndrome in India, where viral infection Japanese encephalitis has been regarded as the main factor. [58]


The Tsutsugamushi Triangle. Tsutsugamushi Triangle.tif
The Tsutsugamushi Triangle.

The World Health Organization in 1999 stated that:

“Scrub typhus is probably one of the most underdiagnosed and underreported febrile illnesses requiring hospitalization in the region. The absence of definitive signs and symptoms combined with a general dependence upon serological tests make the differentiation of scrub typhus from other common febrile diseases such as murine typhus, typhoid fever and leptospirosis quite difficult.” [59]

Scrub typhus is historically endemic to the Asia-Pacific region covering the Russian Far East and Korea in the north to northern Australia in the south and Afghanistan in the west, including islands of the western Pacific Oceans such as Japan, Taiwan, Philippines, Papua New Guinea, Indonesia, Sri Lanka, and the Indian Subcontinent. This geographic region is popularly called the Tsutsugamushi Triangle. [53] However, it has spread to Africa, Europe and South America. [60] One billion people are estimated to be at risk of infection at any moment and an average of one million cases occur every year in the Tsutsugamushi Triangle. In the absence of proper medical care, the case fatality rate can go beyond 30% to as high as 70% in some areas. [36] The burden of scrub typhus in rural areas of Asia is huge, accounting for up to 20% of febrile sickness in hospital, and seroprevalence (positive infection on blood test) over 50% of the population. [61] More than one-fifth of the population carry the bacterial antibodies, i.e., they had been infected, in endemic areas. South Korea has the highest level incidence (with its highest of 59.7 infection out of 100,000 people in 2013), followed by Japan, Thailand, and China at top of the list. [55]


O. tsutsugamushi infection can be treated with antibiotics such as azithromycin, chloramphenicol, doxycycline, rifampicin, roxithromycin, and tetracyclin. Doxycycline is the most commonly used and is considered as the drug of choice because of high efficacy and quick action. But in pregnant women and babies it is contraindicated, and azithromycin is the drug of choice. In Southeast Asia, where doxycycline and chloramphenicol resistance have been experienced, azithromycin is recommended for all patients. [62] A randomized controlled trial and systematic review showed that azithromycin is the safest medication. [63] [64]



Eschar due to O. tsutsugamushi infection on the shoulder (a, b) of a female and on the penis (c, d) of a male. Scrub typhus eschar.tif
Eschar due to O. tsutsugamushi infection on the shoulder (a, b) of a female and on the penis (c, d) of a male.

The main symptom of O. tsutsugamushi infection is high (febrile) fever; however, the symptom is not unique and is similar to a group of acute undifferentiated fever, which includes those of malaria, leptospirosis, typhoid fever, murine typhus, chikungunya, and dengue fever. [65] [66] This makes precise clinical diagnosis difficult, which often leads to misdiagnosis. The initial indications are fever with chills, associated with headache, muscle pain (myalgia), sweating and vomiting. The appearance of symptoms (incubation period) takes between 6 and 21 days. [53] A useful diagnosis is the presence of an inflamed scar called eschar, which is regarded as "the most useful diagnostic clue in patients with acute febrile illness". Eschar is formed on the skin where an infected mite bit, usually seen in the armpit, groin or any abdominal area. In rare cases, it can be seen on the cheek, ear lobe and dorsum of the feet. [67] But the problem is that eschar is not always present. At the highest record, only 55% of scrub typhus patients had eschar during an outbreak in south India. [68] Also that eschar is not specific to scrub typhus, as other rickettsial diseases such as Rocky Mountain spotted fever, [69] Brazilian spotted fever, [70] and Indian tick typhus. [71] [72] Using DNA analysis by advanced polymerase chain reaction, different rickettsial infection can be identified from eschars. [73] [74]

Blood test

O. tsutsugamushi is most often detected from blood serum using Weil–Felix test. Weil–Felix test is the most simple and rapid test, but it is not sensitive and specific as it detects any kind of rickettsial infection. More sensitive tests such as rapid immunochromatographic test (RICT), immunofluorescence assays (IFA), enzyme-linked immunosorbent assay (ELISA), and DNA analysis using polymerase chain reaction (PCR) are used. [35] [27] IFA is regarded as the gold standard test, as it gives reliable result. However, it is expensive and not specific for different rickettsial bacteria. [75] ELISA and PCR can detect O. tsutsugamushi-specific proteins such as the 56-kDa protein and GroEL so that they are highly specific and sensitive. [76] On the other hand, they are highly sophisticated and expensive techniques.


No licensed O. tsutsugamushi vaccines are currently available. The first vaccines were developed in the late 1940s, but failed in the clinical trials. [77] [78] Considered an ideal target, the unique 56-kDa protein itself is highly variable in its chemical composition in different strains. An effective vaccine for one strain is not useful for another. An ideal vaccine should give protection to all the strains present locally. This complexity makes it difficult to produce a usable vaccine. [79] A vaccine targeting the 47-kDa outer membrane protein (OMP) is a promising candidate with experimental success in mice against Boryong strain. [80]


There is no complete immunity to O. tsutsugamushi infection. Enormous antigenic variation among O. tsutsugamushi strains makes the immune system unable to fully recognise them. An infected individual may develop a short-term immunity but that disappears after a few months, and immunity to one strain does not confer immunity to another. [79] An immunisation experiment was done in 1950 in which 16 volunteers still developed the infection after 11–25 months of primary infection. [81] It is now known that the longevity of immunity depends on the strains of the bacterium. When reinfection occurs with the same strain as the previous infection, there can be immunity for 5–6 years (experimentally in monkeys). [82]

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<i>Streptococcus pyogenes</i> Species of bacterium

Streptococcus pyogenes is a species of Gram-positive bacterium in the genus Streptococcus. These bacteria are aerotolerant and an extracellular bacterium, made up of non-motile and non-sporing cocci. It is clinically important for humans. It is an infrequent, but usually pathogenic, part of the skin microbiota. It is the predominant species harboring the Lancefield group A antigen, and is often called group A streptococcus (GAS). However, both Streptococcus dysgalactiae and the Streptococcus anginosus group can possess group A antigen. Group A streptococci when grown on blood agar typically produces small zones of beta-hemolysis, a complete destruction of red blood cells. It is thus also called group A (beta-hemolytic) streptococcus (GABHS), and can make colonies greater than 5 mm in size.

Rickettsia prowazekii is a species of gram-negative, alphaproteobacteria, obligate intracellular parasitic, aerobic Bacillus bacteria that is the etiologic agent of epidemic typhus, transmitted in the feces of lice. In North America, the main reservoir for R. prowazekii is the flying squirrel. R. prowazekii is often surrounded by a protein microcapsular layer and slime layer; the natural life cycle of the bacterium generally involves a vertebrate and an invertebrate host, usually an arthropod, typically the human body louse. A form of R. prowazekii that exists in the feces of arthropods remains stably infective for months. R. prowazekii also appears to be the closest free-living relative of mitochondria, based on genome sequencing.

<i>Rickettsia rickettsii</i> species of bacterium

Rickettsia rickettsii is a gram-negative, intracellular, coccobacillus bacterium that is around 0.8 to 2.0 micrometers long. R. rickettsi is the causative agent of Rocky Mountain spotted fever. R. rickettsii is one of the most pathogenic Rickettsia strains. It affects a large majority of the Western Hemisphere and small portions of the Eastern Hemisphere.

Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually the host they are infecting or living in. Adhesins are a type of virulence factor.

The Weil–Felix test is an agglutination test for the diagnosis of rickettsial infections. It was first described in 1916. By virtue of its long history and of its simplicity, it has been one of the most widely employed tests for rickettsia on a global scale, despite being superseded in many settings by more sensitive and specific diagnostic tests.

<i>Orientia</i> genus of bacteria

Orientia is a genus of bacteria in family Rickettsiaceae. They are obligate intracellular, Gram-negative bacteria found in insects and mammals. They are spread through the bites or feces of infected insects.

A rickettsiosis is a disease caused by intracellular bacteria.

Ehrlichia is a genus of rickettsiales bacteria that is transmitted to vertebrates by ticks. These bacteria cause the Ehrlichiosis infection, which is considered zoonotic, because the main reservoirs for the disease are animals.

Rickettsia akari is a species of Rickettsia which causes rickettsialpox.

<i>Bacillus anthracis</i> species of bacteria, causes anthrax

Bacillus anthracis is the etiologic agent of anthrax—a common disease of livestock and, occasionally, of humans—and the only obligate pathogen within the genus Bacillus. B. anthracis is a Gram-positive, endospore-forming, rod-shaped bacterium, with a width of 1.0–1.2 µm and a length of 3–5 µm. It can be grown in an ordinary nutrient medium under aerobic or anaerobic conditions.

Leptotrombidium is a genus of mites in the family Trombiculidae, that are able to infect humans with scrub typhus through their bite. The larval form feeds on rodents, but also occasionally humans and other large mammals. They are related to the harvest mites of the North America and Europe.

African tick bite fever spotted fever that has material basis in Rickettsia africae, which is transmitted by ticks

African tick bite fever (ATBF) is a bacterial infection spread by the bite of a tick. Symptoms may include fever, headache, muscles pains, and a rash. At the site of the bite there is typically a red skin sore with a dark center. Onset usually occur 4–10 days after the bite. Complications are rare, however may include joint inflammation. Some people do not develop symptoms.

Rickettsia helvetica, previously known as the Swiss Agent, is a bacterium found in Dermacentor reticulatus and other ticks which has been implicated as a suspected but unconfirmed human pathogen. First recognized in 1979 in Ixodes ricinus ticks in Switzerland as a new member of the spotted fever group of Rickettsia, the Rickettsia helvetica bacterium was eventually isolated in 1993. Although R. helvetica was initially thought to be harmless in humans and many animal species, some individual case reports suggest that it may be capable of causing a non-specific fever in humans. In 1997 a man living in eastern France seroconverted to Rickettsia 4 weeks after onset of an unexplained febrile illness. In 2010, a case report indicated that tick-borne R. helvetica can also cause meningitis in humans.

Rickettsia felis is a species of bacterium, the pathogen that causes cat-flea typhus in humans. In cats the disease is known as flea-borne spotted fever. Rickettsia felis also is regarded as the causative organism of many cases of illnesses generally classed as fevers of unknown origin in humans in Africa.

<i>Rickettsia sibirica</i> species of bacterium

Rickettsia sibirica is a species of Rickettsia. This bacterium is the etiologic agent of North Asian tick typhus, which is also known as Siberian tick typhus. The ticks that transmit it are primarily various species of Dermacentor and Haemaphysalis.

This is a timeline of typhus, describing major events such as epidemics and key medical developments.


  1. 1 2 Salje, J.; Kline, K.A. (2017). "Orientia tsutsugamushi: A neglected but fascinating obligate intracellular bacterial pathogen". PLOS Pathogens. 13 (12): e1006657. doi:10.1371/journal.ppat.1006657. PMC   5720522 . PMID   29216334.
  2. Watt, G.; Parola, P. (2003). "Scrub typhus and tropical rickettsioses". Current Opinion in Infectious Diseases. 16 (5): 429–436. doi:10.1097/01.qco.0000092814.64370.70 (inactive 2019-02-09). PMID   14501995.
  3. 1 2 3 Kelly, D.J.; Fuerst, P.A.; Ching, W.M.; Richards, A.L. (2009). "Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi". Clinical Infectious Diseases. 48 Suppl (Suppl): S203–S230. doi:10.1086/596576. PMID   19220144.
  4. Yamamoto, S.; Kawabata, N.; Tamura, A.; Urakami, H.; Ohashi, N.; Murata, M.; Yoshida, Y.; Kawamura A, Jr. (1986). "Immunological properties of Rickettsia tsutsugamushi, Kawasaki strain, isolated from a patient in Kyushu". Microbiology and Immunology. 30 (7): 611–620. doi:10.1111/j.1348-0421.1986.tb02988.x. PMID   3095612.
  5. Fan, M.Y.; Walker, D.H.; Yu, S.R.; Liu, Q.H. (1987). "Epidemiology and ecology of rickettsial diseases in the People's Republic of China". Reviews of Infectious Diseases. 9 (4): 823–840. doi:10.1093/clinids/9.4.823. PMID   3326129.
  6. Kawamura, R. (1926). Studies on tsutsugamushi disease (Japanese Blood Fever). Cincinnati, OH (USA): Spokesman Printing Company. p. 2.
  7. Palm, T.A. (1878). "Some account of a disease called "shima-mushi," or "island-insect disease," by the natives of Japan; peculiar, it is believed, to that country, and hitherto not described". Edinburgh Medical Journal. 24 (2): 128–132. PMC   5317505 . PMID   29640208.
  8. Miyajima, M.; Okumura, T. (1917). "On the life cycle of the "Akamushi" carrier of Nippon river fever". Kitasato Archives of Experimental Medicine. 1 (1): 1–14.
  9. Hirst, S. (1915). "On the Tsutsugamushi (Microtrombidium akamushi, Brumpt), carrier of Japanese river fever". Journal of Economic Biology. 10 (4): 79–82.
  10. Nagayo, M. (1917). "On the nymph and prosopon of the tsutsugamushi, Leptotrombidium akamushi, N. Sp. (Trombidium akamushi Brumpt), carrier of tsutsugamushi disease". Journal of Experimental Medicine. 25 (2): 255–272. doi:10.1084/jem.25.2.255. PMC   2125768 .
  11. Lalchhandama, K. (2018). "The saga of scrub typhus with a note on the outbreaks in Mizoram". Science Vision. 18 (2): 50–57. doi:10.33493/scivis.18.02.01.
  12. Hayashi, N. (1920). "Etiology of tsutsugamushi disease". The Journal of Parasitology. 7 (2): 52–68. doi:10.2307/3270957. JSTOR   3270957.
  13. Nagayo, M.; Tamiya, T.; Mitamura, T.; Sato, K. (1930). "On the virus of tsutsugamushi disease and its demonstration by a new method". Jikken Igaku Zasshi (Japanese Journal of Experimental Medicine). 8 (4): 309–318.
  14. Nagayo, M.; Tamiya, T.; Mitamura, T.; Sato, K. (1930). "Sur le virus de la maladie de Tsutsugamushi [On the virus of tsutsugamushi]". Comptes Rendus des Séances de la Société de Biologie. 104: 637–641.
  15. da Rocha Lima, H. (1916). "Untersuchungen über fleckfleber [Reseraches on typhus]". Münchener Medizinische Wochenschrift. 63 (39): 1381–1384.
  16. Ogata, N. (1931). "Aetiologie der Tsutsugamushi-krankheit: Rickettsia tsutsugamushi [Aetiology of the tsstsugamushi disease: Rickettsia tsutsugamushi". Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. 122: 249–253.
  17. Kawamüra, R.; Imagawa, Y. (1931). "Ueber die Proliferation der pathogenen Rickettsia im tierischen organismus bei der tsutsugamushi-krankheit [The multiplication of the Rickettsia pathogen of tsutsugamushi disease in animals]". Transactions of the Japanese Society of Pathology. 21: 455–461.
  18. Kawamüra, R.; Imagawa, Y. (1931). "Die feststellung des erregers bei der tsutsugamushikrankheit [Confirmation of the infective agent in tsutsugamushi disease]". Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. 122 (4/5): 253–261.
  19. 1 2 Tamura, A.; Urakami, H.; Ohashi, N. (1991). "A comparative view of Rickettsia tsutsugamushi and the other groups of Rickettsiae". European Journal of Epidemiology. 7 (3): 259–269. doi:10.1007/BF00145675. PMID   1909244.
  20. 1 2 Tamura, A.; Ohashi, N.; Urakami, H.; Miyamura, S. (1995). "Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. nov., as Orientia tsutsugamushi comb. nov". International Journal of Systematic Bacteriology. 45 (3): 589–591. doi:10.1099/00207713-45-3-589. PMID   8590688.
  21. Izzard, L (2010). "Isolation of a novel Orientia species (O. chuto sp. nov.) from a patient infected in Dubai". Journal of Clinical Microbiology. 48 (12): 4404–4409. doi:10.1128/JCM.01526-10. PMC   3008486 . PMID   20926708.
  22. Moree, M.F.; Hanson, B. (1992). "Growth characteristics and proteins of plaque-purified strains of Rickettsia tsutsugamushi". Infection and Immunity. 60 (8): 3405–3415. PMC   257328 . PMID   1379212.
  23. Silverman, D.J.; Wisseman, C.L. Jr. (1978). "Comparative ultrastructural study on the cell envelopes of Rickettsia prowazekii, Rickettsia rickettsii, and Rickettsia tsutsugamushi". Infection and Immunity. 21 (3): 1020–1023. PMC   422098 . PMID   101465.
  24. Amano, K.; Tamura, A.; Ohashi, N.; Urakami, H.; Kaya, S.; Fukushi, K. (1987). "Deficiency of peptidoglycan and lipopolysaccharide components in Rickettsia tsutsugamushi". Infection and Immunity. 55 (9): 2290–2292. PMC   260693 . PMID   3114150.
  25. Atwal, S.; Giengkam, S.; Chaemchuen, S.; Dorling, J.; Kosaisawe, N.; VanNieuwenhze, M.; Sampattavanich, S.; Schumann, P.; Salje, J. (2017). "Evidence for a peptidoglycan-like structure in Orientia tsutsugamushi". Molecular Microbiology. 105 (3): 440–452. doi:10.1111/mmi.13709. PMC   5523937 . PMID   28513097.
  26. 1 2 Lalchhandama, K. (2017). "Rickettsiosis as a critical emerging infectious disease in India". Science Vision. 17 (4): 250–259. doi:10.33493/scivis.17.04.09.
  27. 1 2 Koh, G.C.; Maude, R.J.; Paris, D.H.; Newton, P.N.; Blacksell, S.D. (2010). "Diagnosis of scrub typhus". The American Journal of Tropical Medicine and Hygiene. 82 (3): 368–370. doi:10.4269/ajtmh.2010.09-0233. PMC   2829893 . PMID   20207857.
  28. Ohashi, N.; Fukuhara, M.; Shimada, M.; Tamura, A. (1995). "Phylogenetic position of Rickettsia tsutsugamushi and the relationship among its antigenic variants by analyses of 16S rRNA gene sequences". FEMS Microbiology Letters. 125 (2–3): 299–304. doi:10.1111/j.1574-6968.1995.tb07372.x. PMID   7875578.
  29. Bishop-Lilly, K.A.; Ge, H.; Butani, A.; Osborne, B.; Verratti, K.; Mokashi, V.; Nagarajan, N.; Pop, M.; Read, T.D.; Richards, A.L. (2013). "Genome sequencing of four strains of Rickettsia prowazekii, the causative agent of epidemic typhus, including one flying squirrel isolate". Genome Announcements. 1 (3): e00399–13. doi:10.1128/genomeA.00399-13. PMC   3695431 . PMID   23814035.
  30. Nakayama, K.; Yamashita, A.; Kurokawa, K.; Morimoto, T.; Ogawa, M.; Fukuhara, M.; Urakami, H.; Ohnishi, M.; et al. (2008). "The Whole-genome Sequencing of the Obligate Intracellular Bacterium Orientia tsutsugamushi Revealed Massive Gene Amplification During Reductive Genome Evolution". DNA Research. 15 (4): 185–199. doi:10.1093/dnares/dsn011. PMC   2575882 . PMID   18508905.
  31. 1 2 Cho, N.-H.; Kim, H.-R.; Lee, J.-H.; Kim, S.-Y.; Kim, J.; Cha, S.; Kim, S.-Y.; Darby, A. C.; et al. (2007). "The Orientia tsutsugamushi genome reveals massive proliferation of conjugative Type IV secretion system and host-cell interaction genes". Proceedings of the National Academy of Sciences. 104 (19): 7981–7986. doi:10.1073/pnas.0611553104. PMC   1876558 . PMID   17483455.
  32. Batty, E.M.; Chaemchuen, S.; Blacksell, S.; Richards, A.L.; Paris, D.; Bowden, R.; Chan, C.; Lachumanan, R.; et al. (2018). "Long-read whole genome sequencing and comparative analysis of six strains of the human pathogen Orientia tsutsugamushi". PLOS Neglected Tropical Diseases. 12 (6): e0006566. doi:10.1371/journal.pntd.0006566. PMC   6005640 . PMID   29874223.
  33. 1 2 Viswanathan, S.; Muthu, V.; Iqbal, N.; Remalayam, B.; George, T (2013). "Scrub typhus meningitis in South India—a retrospective study". PLOS One. 8 (6): e66595. doi:10.1371/journal.pone.0066595. PMC   3682970 . PMID   23799119.
  34. Tilak, R.; Wankhade, U.; Kunwar, R.; Tilak, V.W. (2011). "Emergence of Schoengastiella ligula as the vector of scrub typhus outbreak in Darjeeling: Has Leptotrombidium deliense been replaced?". Indian Journal of Public Health. 55 (2): 92–99. doi:10.4103/0019-557X.85239. PMID   21941043.
  35. 1 2 Luce-Fedrow, A.; Lehman, M.; Kelly, D.; Mullins, K.; Maina, A.; Stewart, R.; Ge, H.; John, H.; Jiang, J.; Richards, Allen (2018). "A review of scrub typhus (Orientia tsutsugamushi and related organisms): then, now, and tomorrow". Tropical Medicine and Infectious Disease. 3 (1): 8. doi:10.3390/tropicalmed3010008. PMC   6136631 . PMID   30274407.
  36. 1 2 Xu, G.; Walker, D.H.; Jupiter, D.; Melby, P.C.; Arcari, C.M.; Day, N.P. (2017). "A review of the global epidemiology of scrub typhus". PLOS Neglected Tropical Diseases. 11 (11): e0006062. doi:10.1371/journal.pntd.0006062. PMC   5687757 . PMID   29099844.
  37. Ge, Y.; Rikihisa, Y. (2011). "Subversion of host cell signaling by Orientia tsutsugamushi". Microbes and Infection. 13 (7): 638–648. doi:10.1016/j.micinf.2011.03.003. PMID   21458586.
  38. Cho, B. A.; Cho, N. H.; Seong, S. Y.; Choi, M. S.; Kim, I. S. (2010). "Intracellular invasion by Orientia tsutsugamushi is mediated by integrin signaling and actin cytoskeleton rearrangements". Infection and Immunity. 78 (5): 1915–1923. doi:10.1128/IAI.01316-09. PMC   2863532 . PMID   20160019.
  39. Ko, Y.; Choi, J.H.; Ha, N.Y; Kim, I.S.; Cho, N.H.; Choi, M.S.; Bäumler, A. J. (2013). "Active escape of Orientia tsutsugamushi from cellular autophagy". Infection and Immunity. 81 (2): 552–559. doi:10.1128/IAI.00861-12. PMC   3553808 . PMID   23230293.
  40. Kim, M.J.; Kim, M.K.; Kang, J.S. (2013). "Involvement of lipid rafts in the budding-like exit of Orientia tsutsugamushi". Microbial Pathogenesis. 63: 37–43. doi:10.1016/j.micpath.2013.06.002. PMID   23791848.
  41. Bengston, I.A. (1945). "Apparent serological heterogeneity among strains of Tsutsugamushi disease (scrub typhus)". Public Health Reports. 60 (50): 1483–1488. PMID   21004496.
  42. Bengston, I.A. (1946). "A serological study of 37 cases of tsutsugamushi disease (scrub typhus) occurring in Burma and the Philippine Islands". Public Health Reports. 61 (24): 887–894. PMID   20987857.
  43. Shishido, A.; Ohtawara, M.; Tateno, S.; Mizuno, S.; Ogura, M.; Kitaoka, M. (1958). "The nature of immunity against scrub typhus in mice i. the resistance of mice, surviving subcutaneous infection of scrub typhus rickettsia, to intraperitoneal reinfection of the same agent". Japanese Journal of Medical Science and Biology. 11 (5): 383–399. doi:10.7883/yoken1952.11.383.
  44. Jang, M.S.; Neupane, G.P.; Lee, Y.M.; Kim, D.M.; Lee, S.H. (2011). "Phylogenetic analysis of the 56 kDa protein genes of Orientia tsutsugamushi in southwest area of Korea". The American Journal of Tropical Medicine and Hygiene. 84 (2): 250–254. doi:10.4269/ajtmh.2011.09-0601. PMC   3029177 . PMID   21292894.
  45. Yamashita, T.; Kasuya, S.; Noda, N.; Nagano, I.; Kang, J.S. (1994). "Transmission of Rickettsia tsutsugamushi strains among humans, wild rodents, and trombiculid mites in an area of Japan in which tsutsugamushi disease is newly endemic". Journal of Clinical Microbiology. 32 (11): 2780–2785. PMC   264159 . PMID   7852572.
  46. 1 2 Ohashi, N.; Koyama, Y.; Urakami, H.; Fukuhara, M.; Tamura, A.; Kawamori, F.; Yamamoto, S.; Kasuya, S.; Yoshimura, K. (1996). "Demonstration of antigenic and genotypic variation in Orientia tsutsugamushi which were isolated in Japan, and their classification into type and subtype". Microbiology and Immunology. 40 (9): 627–638. doi:10.1111/j.1348-0421.1996.tb01120.x. PMID   8908607.
  47. Bakshi, D.; Singhal, P.; Mahajan, S.K.; Subramaniam, P.; Tuteja, U.; Batra, H.V. (2007). "Development of a real-time PCR assay for the diagnosis of scrub typhus cases in India and evidence of the prevalence of new genotype of O. tsutsugamushi". Acta Tropica. 104 (1): 63–71. doi:10.1016/j.actatropica.2007.07.013. PMID   17870041.
  48. Parola, P.; Blacksell, S.D.; Phetsouvanh, R.; Phongmany, S.; Rolain, J.M.; Day, N.P.; Newton, P.N.; Raoult, D. (2008). "Genotyping of Orientia tsutsugamushi from humans with scrub typhus, Laos". Emerging Infectious Diseases. 14 (9): 1483–1485. doi:10.3201/eid1409.071259. PMC   2603112 . PMID   18760027.
  49. Tamura, A; Ohashi, N; Urakami, H; Takahashi, K; Oyanagi, M (1985). "Analysis of polypeptide composition and antigenic components of Rickettsia tsutsugamushi by polyacrylamide gel electrophoresis and immunoblotting". Infection and Immunity. 48 (3): 671–675. PMC   261225 . PMID   3922893.
  50. Stover, CK; Marana, DP; Carter, JM; Roe, BA; Mardis, E; Oaks, EV (1990). "The 56-kilodalton major protein antigen of Rickettsia tsutsugamushi: molecular cloning and sequence analysis of the sta56 gene and precise identification of a strain-specific epitope". Infection and Immunity. 58 (7): 2076–2084. PMC   258779 . PMID   1694818.
  51. Stover, C.K.; Marana, D.P.; Dasch, G.A.; Oaks, E.V. (1990). "Molecular cloning and sequence analysis of the Sta58 major antigen gene of Rickettsia tsutsugamushi: sequence homology and antigenic comparison of Sta58 to the 60-kilodalton family of stress proteins". Infection and Immunity. 58 (5): 1360–1368. PMC   258633 . PMID   2108930.
  52. Arai, S.; Tabara, K.; Yamamoto, N.; Fujita, H.; Itagaki, A.; Kon, M.; Satoh, H.; Araki, K.; Tanaka-Taya, K.; Takada, N.; Yoshikawa, Y.; Ishihara, C.; Okabe, N.; Oishi, K. (2013). "Molecular phylogenetic analysis of Orientia tsutsugamushi based on the groES and groEL genes". Vector Borne and Zoonotic Diseases. 13 (11): 825–829. doi:10.1089/vbz.2012.1155. PMC   3822374 . PMID   24107204.
  53. 1 2 3 Peter, J.V.; Sudarsan, T.I.; Prakash, J.A.J.; Varghese, G.M. (2015). "Severe scrub typhus infection: Clinical features, diagnostic challenges and management". World Journal of Critical Care Medicine. 4 (3): 244–250. doi:10.5492/wjccm.v4.i3.244. PMC   4524821 . PMID   26261776.
  54. Taylor, A.J.; Paris, D.H.; Newton, P.N.; Walker, D.H. (2015). "A systematic review of mortality from untreated scrub typhus (Orientia tsutsugamushi)". PLOS Neglected Tropical Diseases. 9 (8): e0003971. doi:10.1371/journal.pntd.0003971. PMC   4537241 . PMID   26274584.
  55. 1 2 3 Bonell, A.; Lubell, Y.; Newton, P.N.; Crump, J.A.; Paris, D.H. (2017). "Estimating the burden of scrub typhus: A systematic review". PLoS Neglected Tropical Diseases. 11 (9): e0005838. doi:10.1371/journal.pntd.0005838. PMC   5634655 . PMID   28945755.
  56. 1 2 Rajapakse, S.; Weeratunga, P.; Sivayoganathan, S.; Fernando, S.D. (2017). "Clinical manifestations of scrub typhus". Transactions of the Royal Society of Tropical Medicine and Hygiene. 111 (2): 43–54. doi:10.1093/trstmh/trx017. PMID   28449088.
  57. Mahajan, S.K.; Mahajan, S.K. (2017). "Neuropsychiatric manifestations of scrub typhus". Journal of Neurosciences in Rural Practice. 8 (3): 421–426. doi:10.4103/jnrp.jnrp_44_17. PMC   5488565 . PMID   28694624.
  58. Jain, P.; Prakash, S.; Tripathi, P.K.; Chauhan, A.; Gupta, S.; Sharma, U.; Jaiswal, A.K.; Sharma, D.; Jain, A. (2018). "Emergence of Orientia tsutsugamushi as an important cause of acute encephalitis syndrome in India". PLoS Neglected Tropical Diseases. 12 (3): e0006346. doi:10.1371/journal.pntd.0006346. PMC   5891077 . PMID   29590177.
  59. WHO (1999). "WHO Recommended Surveillance Standards (Second edition)". WHO/CDS/CSR/ISR/99.2. World Health Organization, Geneva. p. 124.
  60. Jiang, J.; Richards, A.L. (25 January 2018). "Scrub typhus: No longer restricted to the Tsutsugamushi Triangle". Tropical Medicine and Infectious Disease. 3 (1): 11. doi:10.3390/tropicalmed3010011. PMC   6136623 . PMID   30274409.
  61. Walker, D.H.; Paris, D.H.; Day, N.P.; Shelite, T.R. (2013). "Unresolved problems related to scrub typhus: A seriously neglected life-threatening disease". The American Journal of Tropical Medicine and Hygiene. 89 (2): 301–307. doi:10.4269/ajtmh.13-0064. PMC   3741252 . PMID   23926142.
  62. Rahi, M.; Gupte, M.D.; Bhargava, A.; Varghese, G.Mm; Arora, R. (2015). "DHR-ICMR Guidelines for diagnosis & management of rickettsial diseases in India". Indian Journal of Medical Research. 141 (4): 417–22. doi:10.4103/0971-5916.159279. PMC   4510721 . PMID   26112842.
  63. Chanta, C.; Phloenchaiwanit, P. (2015). "Randomized Controlled trial of azithromycin versus doxycycline or chloramphenicol for treatment of uncomplicated pediatric scrub typhus". Journal of the Medical Association of Thailand. 98 (8): 756–760. PMID   26437532.
  64. Lee, S.C.; Cheng, Y.J.; Lin, C.H.; Lei, W.T.; Chang, H.Y.; Lee, M.D.; Liu, J.M.; Hsu, R.J.; et al. (2017). "Comparative effectiveness of azithromycin for treating scrub typhus". Medicine. 96 (36): e7992. doi:10.1097/MD.0000000000007992. PMID   28885357.
  65. Mørch, K.; Manoharan, A.; Chandy, S.; Chacko, N.; Alvarez-Uria, G.; Patil, S.; Henry, A.; Nesaraj, J.; et al. (2017). "Acute undifferentiated fever in India: a multicentre study of aetiology and diagnostic accuracy". BMC Infectious Diseases. 17 (1): 665. doi:10.1186/s12879-017-2764-3. PMC   5628453 . PMID   28978319.
  66. Wangrangsimakul, T.; Althaus, T.; Mukaka, M.; Kantipong, P.; Wuthiekanun, V.; Chierakul, W.; Blacksell, S.D.; Day, N.P.; Laongnualpanich, A.; Paris, D.H. (2018). "Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand". PLoS Neglected Tropical Diseases. 12 (5): e0006477. doi:10.1371/journal.pntd.0006477. PMC   5978881 . PMID   29852003.
  67. Kundavaram, A.P.; Jonathan, A.J.; Nathaniel, S.D.; Varghese, G.M. (2013). "Eschar in scrub typhus: a valuable clue to the diagnosis". Journal of Postgraduate Medicine. 59 (3): 177–178. doi:10.4103/0022-3859.118033. PMID   24029193.
  68. Varghese, G.M.; Janardhanan, J.; Trowbridge, P.; Peter, J.V.; Prakash, J.A.; Sathyendra, S.; Thomas, K.; David, T.S.; Kavitha, M.L.; Abraham, O.C.; Mathai, D. (2013). "Scrub typhus in South India: clinical and laboratory manifestations, genetic variability, and outcome". International Journal of Infectious Diseases. 17 (11): e981–987. doi:10.1016/j.ijid.2013.05.017. PMID   23891643.
  69. Kelman, P.; Thompson, C.W.; Hynes, W.; Bergman, C.; Lenahan, C.; Brenner, J.S.; Brenner, M.G.; Goodman, B.; Borges, D.; Filak, M.; Gaff, H. (2018). "Rickettsia parkeri infections diagnosed by eschar biopsy, Virginia, USA". Infection. 46 (4): 559–563. doi:10.1007/s15010-018-1120-x. PMID   29383651.
  70. Silva, N.; Eremeeva, M.E.; Rozental, T.; Ribeiro, G.S.; Paddock, C.D.; Ramos, E.A.; Favacho, A.R.; Reis, M.G.; Dasch, G.A.; de Lemos, E.R.; Ko, A.I. (2011). "Eschar-associated spotted fever rickettsiosis, Bahia, Brazil". Emerging Infectious Diseases. 17 (2): 275–278. doi:10.3201/eid1702.100859. PMC   3204763 . PMID   21291605.
  71. Hulmani, M.; Alekya, P.; Kumar, V.J. (2017). "Indian tick typhus presenting as purpura fulminans with review on rickettsial infections". Indian Journal of Dermatology. 62 (1): 1–6. doi:10.4103/0019-5154.198030. PMC   5286740 . PMID   28216718.
  72. Walker, D.H. (1989). "Rickettsioses of the spotted fever group around the world". The Journal of Dermatology. 16 (3): 169–177. doi:10.1111/j.1346-8138.1989.tb01244.x. PMID   2677080.
  73. Denison, A.M.; Amin, B.D.; Nicholson, W.L.; Paddock, C.D. (2014). "Detection of Rickettsia rickettsii, Rickettsia parkeri, and Rickettsia akari in skin biopsy specimens using a multiplex real-time polymerase chain reaction assay". Clinical Infectious Diseases. 59 (5): 635–642. doi:10.1093/cid/ciu358. PMC   4568984 . PMID   24829214.
  74. Le Viet, N.; Laroche, M.; Thi Pham, H.L.; Viet, N.L.; Mediannikov, O.; Raoult, D.; Parola, P. (2017). "Use of eschar swabbing for the molecular diagnosis and genotyping of Orientia tsutsugamushi causing scrub typhus in Quang Nam province, Vietnam". PLoS Neglected Tropical Diseases. 11 (2): e0005397. doi:10.1371/journal.pntd.0005397. PMC   5344524 . PMID   28241043.
  75. Koraluru, M.; Bairy, I.; Varma, M.; Vidyasagar, S. (2015). "Diagnostic validation of selected serological tests for detecting scrub typhus". Microbiology and Immunology. 59 (7): 371–374. doi:10.1111/1348-0421.12268. PMID   26011315.
  76. Patricia, K.A.; Hoti, S.L.; Kanungo, R.; Jambulingam, P.; Shashikala, N.; Naik, A.C. (2017). "Improving the diagnosis of scrub typhus by combining groEL-based polymerase chain reaction and IgM ELISA". Journal of Clinical and Diagnostic Research. 11 (8): DC27–DC31. doi:10.7860/JCDR/2017/26523.10519. PMC   5620764 . PMID   28969124.
  77. Card, W.I.; Walker, J.M. (1947). "Scrub-typhus vaccine; field trial in South-east Asia". Lancet. 1 (6450): 481–483. doi:10.1016/S0140-6736(47)91989-2. PMID   20294827.
  78. Berge, T.O.; Gauld, R.L.; Kitaoka, M. (1949). "A field trial of a vaccine prepared from the Volner strain of Rickettsia tsutsugamushi". American Journal of Hygiene. 50 (3): 337–342. PMID   15391985.
  79. 1 2 Valbuena, G.; Walker, D. H. (2013). "Approaches to vaccines against Orientia tsutsugamushi". Frontiers in Cellular and Infection Microbiology. 2: 127. doi:10.3389/fcimb.2012.00170. PMC   3539663 . PMID   23316486.
  80. Choi, S.; Jeong, H.J.; Hwang, K.J.; Gill, B.; Ju, Y.R.; Lee, Y.S.; Lee, J. (2017). "A recombinant 47-kDa outer membrane protein induces an immune response against Orientia tsutsugamushi strain Boryong". The American Journal of Tropical Medicine and Hygiene. 97 (1): 30–37. doi:10.4269/ajtmh.15-0771. PMC   5508880 . PMID   28719308.
  81. Smadel, JE; Ley, H.L.Jr.; Diercks, F.H.; Traub, R. (1950). "Immunity in scrub typhus: resistance to induced reinfection". AMA Archives of Pathology. 50 (6): 847–861. PMID   14789327.
  82. MacMillan, J.G.; Rice, R.M.; Jerrells, T.R. (1985). "Development of antigen-specific cell-mediated immune responses after infection of cynomolgus monkeys (Macaca fascicularis) with Rickettsia tsutsugamushi". The Journal of Infectious Diseases. 152 (4): 739–749. doi:10.1093/infdis/152.4.739. PMID   2413138.