Instruct: Given a question, retrieve relevant passages that answer the question.
Query: Can you die from orientia tsutsugamushi?
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 World Health Organization in 1999 stated that:
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.
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.
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]
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]
Enormous antigenic variation in "Orientia tsutsugamushi" strains is now recognized, and immunity to one strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, to give an acceptable level of protection. A vaccine developed for one locality may not be protective in another, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine.
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]
In the past, rickettsioses were considered to be caused by species of Rickettsia. However, scrub typhus is still considered a rickettsiosis, even though the causative organism has been reclassified from "Rickettsia tsutsugamushi" to "Orientia tsutsugamushi".
Although the harvest mite chigger usually do not carry diseases in North American temperate climates, "Leptotrombidium deliense" is considered a dangerous pest in East Asia and the South Pacific because it often carries "Orientia tsutsugamushi", the tiny bacterium that causes scrub typhus, which is known alternatively as the Japanese river disease, scrub disease, or "tsutsugamushi". The mites are infected by the "Rickettsia" passed down from parent to offspring before eggs are laid in a process called transovarial transmission. Symptoms of scrub typhus in humans include fever, headache, muscle pain, cough, and gastrointestinal symptoms.
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.
Leptotrombidium () is a genus of mites in the family Trombiculidae, that are able to infect humans with scrub typhus ("Orientia tsutsugamushi" infection) through their bite. The larval form (called chiggers) feeds on rodents, but also occasionally humans and other large mammals. They are related to the harvest mites of the North America and Europe.
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]
Epidemic typhus is caused by the bacteria Rickettsia Prowazekii; it comes from lice. Murine Typhus is caused by the Rickettsia Typhi bacteria, from the fleas on rats. Scrub Typhus is caused by the Orientia Tsutsugamushi bacteria, from the harvest mites on humans and rodents. 
Queensland tick typhus is caused by the Rickettsia Australis bacteria, from ticks.
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]
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.
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]
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]
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]
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 0.8µm wide and 1.2 to 3.0µm 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]
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]
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.
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:
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]
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]