Study characteristics

A total of 276 articles were included in the taxonomic review, with a far 145 reviewed for data on a general discussion of scrub typhus ecology. only 6 articles were excluded, as the full text could not be obtained ( Fig. 1 ). taxonomic review articles were published between 1924 and 2018, and early articles reviewed dated back to 1878. taxonomic review papers included 198 in English, 39 in Standard Chinese ( Mandarin ), 19 in japanese, 9 in russian, 8 in Korean, 2 in Dutch and 1 in Thai ( Fig. 2 ) .Fig. 1figure 1 Study choice strategy flow chart Full size imageFig. 2figure 2 Number of included studies published in different languages over time

Full size picture The number of published articles has gradually increased over time. Some of the earliest shape was published in Dutch, reflecting the dutch presence in the East Indies ( now Indonesia ). From the mid-1960s to the mid-1970s there were a number of papers in russian. There has been fiddling publish probe in Russia since then. Articles in japanese were more frequent in the 1980s, followed by Korean in the 1990s to 2000s. Articles from these two countries are now by and large published in English. A rush in Mandarin Chinese articles is seen from the mid-1990s .

Geography

historically scrub typhus was thought to be present across a large swathe of South and East Asia, known as the “ tsutsugamushi triangle ”. In vectors and non-human hosts, the pathogen has been identified from as far north as the russian Kuril Islands, union of Japan and Inner Mongolia ( ~ 49°N ) [ 11, 12 ]. The most easterly record comes from the Eastern Solomon Islands ( ~ 167°E ) [ 13 ]. To the south there is evidence from North Queensland, Australia ( ~ 21°S ) and in the west from eastern Iran ( ~ 59°E ) [ 14, 15 ]. In 1946, Baker [ 16 ] published a study suggesting a rickettsial species consistent with scrub typhus that was detected in canadian voles trapped on Grosse Isle in the St. Lawrence River near Quebec City. More recently two studies using 16S rRNA sequence of blood samples from rodents in the Ardennes, France and in Senegal and from dogs near Kruger National Park, South Africa, identified organisms with close up sequence homology to O. tsutsugamushi [ 17, 18 ]. In 2006, serologic testify of human scrub typhus was reported from Chiloe Island in Chile [ 19 ]. In 2016, molecular screen confirmed further cases [ 20 ] and then in 2018, serologic tell of O. tsutsugamushi was demonstrated in dogs on Chiloe Island ( ~ 42°S ) [ 21 ]. In the like year, an organism with close homology to O. chuto was detected in pool Microtrombicula and Neotrombicula species chiggers in Baringo County, Kenya [ 22 ]. This follows the identification of a human event of O. chuto infection in the United Arab Emirates in 2010 [ 23 ] . Orientia tsutsugamushi has been identified from a high as 3200 megabyte above sea floor in the Kaghan Valley of Pakistan [ 24 ]. The disease, in sensu lato, has an expanding know geographic distribution and a lot remains to be understand of its distribution across tropical and subtropical regions, its bearing in vectors and hosts and character in causing human disease .

Studies sites per country

Articles included in this revue bridge publication across 94 years. Studies for which lab tests were performed on vectors and non-human hosts to identify O. tsutsugamushi took plaza at 793 sites in 30 countries ( Additional file 1 : postpone S3 ). South Korea and Japan had by far the most study sites recorded at 183 and 144, respectively ( accounting for 42.1 % of all analyze sites ). Thailand had 87 sites, China 66, Taiwan 63, Russia 53, India 44 and Malaysia 43. thirteen countries had 3 or less study sites ( Fig. 3 ) .Fig. 3figure 3 placement of study sites investigating O. tsutsugamushi in vectors and hosts. One report identifying O. tsutsugamushi -like organisms in small mammals in Quebec Province, Canada in 1946 is omitted here [ 16 ] Full size effigy It is worth noting that individual studies varied enormously in the number of collection sites, with some having just 1 and others 30 or more. additionally, more study sites than those reported hera exist in commit, but where data could not be separated by site some were amalgamated following the scheme described above. apart from an early on inconclusive investigation in canadian voles by Baker in 1946 [ 16 ], it is merely since 2015 that investigations into Orientia infection in vectors and hosts have taken set outside the Asia–Pacific region .

Negative study sites

In total, 53/793 ( 6.7 % ) study sites reported no cocksure vectors or hosts. These were located in 12 countries across the Asia–Pacific region and Brazil ( Fig. 3 ). Twenty-one of these sites were from a single sketch of ports and harbours in the Republic of China ( hereafter Taiwan ) [ 25 ] .

Geocoding accuracy

only 12 out of 793 ( 1.5 % ) sites were geocoded to administrative floor 0 ( corresponding to an nameless charge in the country ) and a further 12 sites to administrative flat 0.5. A sum of 100 out of 793 ( 13 % ) sites were geocoded at level 1, 124 ( 16 % ) sites at flat 2, 209 ( 26 % ) sites at level 3 and 336 ( 42 % ) were geocoded most accurately at level 4 ( either an claim site was provided or the greenwich village or equivalent given ). On the early hand, 456 out of 793 sites ( 58 % ) were geocoded at administrative level 3 or less, indicating that the majority of reported sites were no more accurate than the district or equivalent level .

Laboratory tests and sample types

Given the 94-year period from which included studies were drawn and the many countries in which studies were performed, it is unsurprising that a big range of lab tests and combinations of tests were used to test both vectors and hosts. More than 40 tests and combinations of tests were recorded ( Additional file 1 : table S2 ). These include some broad categories ( serology, antigen tests and molecular tests ) for which farther details were not provided. Four studies did not distinctly department of state the lab screen used. Two of these were review articles that contained data not published elsewhere [ 26, 27 ], one was a shortstop composition [ 28 ] and the one-fourth composition was on studies of transovarial transmission in chiggers collected from the angry [ 29 ]. To aid analysis, these tests were grouped into 8 categories ( Additional file 1 : mesa S2 ). serologic tests [ which include direct and indirect immunofluorescence ( DIF, IIF ), indirect immunoperoxidase ( IIP ), complement arrested development ( CF ), enzyme-linked immunosorbent assays ( ELISA ) and the Weil–Felix ( OXK ) test ] were performed in 121/276 ( 44 % ) articles. next most normally used was polish ( with or without microscopic ratification ) with 72/276 ( 26 % ) articles. All but one of these used the xenodiagnosis method acting of animal inoculation and passage. only 3 such studies were reported since the get down of the twenty-first hundred. molecular methods were used in 63 articles from 14 countries. The first of these was published in 1995. A range of O. tsutsugamushi PCR targets were used including 47 and 56 kDa, GroEL, OmpB, in-house targets and cuddle PCRs. Two of the studies used 16S rRNA sequencing [ 17, 18 ]. Microscopy alone ( “ harmonium impression smears ” ) was performed in 3 studies, 2 anterior to 1950 and 1 from India in 2012 [ 30, 31, 32 ]. Combinations of tests were used in 71/276 ( 26 % ) studies. fifty-three studies used a combination of culture ( xenodiagnosis ) and one of respective serologic tests. Less frequently, 11 ( 4 % ) studies ( all published since 2000 ) reported combinations of culture and molecular diagnosis. Four of these studies used L929 cell culture [ 33, 34, 35, 36 ]. Seven studies used a combination of molecular ( PCR ) and serologic ( ELISA or IIF ) tests to report O. tsutsugamushi testing of vectors and hosts. figure 4 shows the use of test groups over time .Fig. 4figure 4 Use of different categories of testing ground test over fourth dimension Full size prototype different sample types were used from host animals. Reflecting the frequency of serologic studies, 99/276 ( 36 % ) articles used serum specimens. wholly rake was analysed in 23/276 ( 8 % ) studies. Single organ types were tested in 69/276 ( 25 % ) studies, with spleen predominating in 62 studies, kidney in 2 and brain in 5 ( from the 1940s ). A high gear symmetry of studies 91/276 ( 33 % ) used a combination of tissues ( spleen, liver, kidney, lung, brain and hale blood ). In only 3 studies was the specimen not recorded, 2 of these were review articles [ 26, 27 ] and the other Audy ’ s War Office report [ 31 ] .

Vectors

Orientia tsutsugamushi testing of individual and pooled vectors collected from hosts

A total of at least 74 “ vector ” species were tested for O. tsutsugamushi using a testing ground screen. Sixty of these were trombiculid mites and the rest were other members of the Acari : Ixodida, Laelapidae or Macronyssidae. Of the Trombiculidae, 46 species tested cocksure for O. tsutsugamushi at least once ( Additional file 1 : table S4 ). Vectors were tested either individually or as pools of individuals. Pool size varied enormously, from less than 10 to over 1000 chiggers. A total of over 123,000 individuals and 8000 pools ( accounting for over 1 million chiggers ) were tested. In some studies, the species were listed but details on the numbers tested ( denominator ) of each were not specified. In early studies, the overall number of different species tested were listed, but the data was not divided between two or more solicitation sites. In these cases, the species was reported as “ not identified ’ in prefer of the placement which was deemed a more useful data record. For pools of vectors, many were of mix species or unidentified, and in many studies vectors were identified only to genus rather than species. percentage infection rates among individual trombiculid mites range from 0.6 to 5 % depending on the lab tests employed ( table 1 ). The highest rates of infection were observed using immunofluorescence techniques that are sensitive but can suffer from false positives. polish is likely to be specific but may lack sensitivity. molecular methods gave an overall infection rate of 1.9 %. Pools of vectors gave expectedly higher incontrovertibility rates ranging from 9.6 to 56 % ( table 1 ). The highest rate was seen for unite molecular and serologic methods, although alone a small number of pools were tested in this manner. molecular techniques for pool vectors gave a positivity rate of 31 % and, surprisingly, using serologic tests, only 11 % were reported positive .Table 1 Summary of number of tested “vectors” and number of positives of all species combined. Data is divided into individual vectors or pooled (multiple) individuals and subdivided by laboratory test category Full size postpone

Orientia tsutsugamushi testing of key vector species by laboratory test category

A drumhead of O. tsutsugamushi test of individual and pool vectors collected from vertebrate hosts using different categories of lab test are shown in table 2 for the three most frequently reported species of chigoe. The median positive per web site varies importantly dependent on the number of studies and size of studies .Table 2 Summary of total and median tested and O. tsutsugamushi positive for the three most frequently reported Leptotrombidium chigger species, subdivided into laboratory test categories Full size postpone

Orientia tsutsugamushi testing of free-living vectors

A disjoined analysis of free-living trombiculid mites [ larva ( chiggers ), nymph and adults ] was carried out. In opinion of our current understanding of the life-cycle of trombiculid mites, O. tsutsugamushi -infected free-living larva should be considered likely vectors, although not necessarily to humans. In entire 40,995 individual and 266 pools of trombiculid mites were tested. infection rates for individuals were : 413/18,945 ( 2.2 % ) with culture alone, 380/15,852 ( 2.4 % ) with serologic tests, 304/6125 ( 5 % ) using unite culture and serology and 7/73 ( 9.6 % ) with molecular tests. thirty-one species of trombiculid mite were tested for O. tsutsugamushi and at least 23 species were positive ( table 3 ). All species were of the genus Leptotrombidium apart from Eutrombicula wichmanni, Odontacarus sp. and Microtrombicula chamlongi, all of which were reported positive from a single study in Thailand using immunofluorescence [ 37 ], Neotrombicula japonica from 1 study in Japan [ 38 ] and Helenicula miyagawai from Mt. Gwanak, outside Seoul, South Korea [ 39 ]. Of Leptotrombidium species tested in the greatest numbers, L. pallidum, L. deliense, L. scutellare and L. fletcheri were the most frequently positive .Table 3 Summary of free-living trombiculid mites (larvae, nymphs and adults) tested by different laboratory categories. All species testing positive for O. tsutsugamushi at least once are shown with total and median numbers tested and testing positive Full size table

Distribution of key vector species

There is very small published information summarising the distribution of chigoe species considered significant human vectors of scrub typhus. Kim et alabama. [ 40 ] recently reported the distribution of 9 congressman Leptotrombidium species. The locations of the 16 most frequently positive trombiculid species from articles included in this review are shown in Fig. 5 .Fig. 5figure 5 Distribution maps of the 16 most frequently reported O. tsutsugamushi -positive chigoe species from all studies included in this reappraisal Full size persona

Other positive trombiculid species

Orientia sp. cocksure tests have been reported from a far 17 genus of trombiculid mites, made up of at least 32 species ( Fig. 6 ). Figure 6 includes chiggers reported to genus merely ( including Leptotrombidium ) and nameless O. tsutsugamushi plus chiggers to provide a accomplished function of positives. It is probable that some of these will be among the 16 species shown above. These are distributed across the Asia–Pacific area, with the exception of the late reputation of an organism close to O. chuto in either Microtrombicula or Eutrombicula species of chiggers in Kenya [ 22 ]. The robustness of these data is variable, with many unlike testing ground tests, of variable specificity, used to identify the bearing of Orientia in vectors. furthermore, for a number of species, trombiculid mites were pooled and the possibility of mixed-species pools remains. A broad analysis of O. tsutsugamushi -positive species is given in Additional file 1 : table S5 .Fig. 6figure 6 localization of all other trombiculid mite species not listed in Fig. 5 testing incontrovertible for O. tsutsugamushi including those identified to genus flush only and nameless chiggers Full size picture

Hosts

Orientia tsutsugamushi testing of major host animal groups

A total of 234 species of “ host ” vertebrates ( excluding humans ) were tested for O. tsutsugamushi, with 122 species testing convinced ( Additional file 1 : table S6 ). In postpone 4 all different forms of testing ground tests are combined. A big number of hosts were reported here as either : ‘ species not identified ’ or ‘ multiple species listed ’ ( as for vectors above ) .Table 4 Summary of number of tested hosts and O. tsutsugamushi positives of all species, subdivided by laboratory test category Full size table serologic tests were performed most frequently, with 36,089/83,219 ( 43 % ) hosts being tested using these methods. These were besides most frequently O. tsutsugamushi positive at 10,868/35,960 ( 30 % ). culture with or without microscopy and culture with serologic confirmation were future most frequent with 16,486/83,219 ( 20 % ) and 14,195 ( 17 % ) tests performed, respectively, and alike rates of positivity at 2943/16,486 ( 18 % ) and 2761/14,195 ( 19 % ), respectively. Although rarely performed, microscopy alone expectedly had the lowest rates of positivity at 6/250 ( 2 % ). molecular methods were used to test 12,198 ( 15 % ) of hosts with 1170/12,198 ( 10 % ) plus ( table 4 ). To assist with summarising the results, the 234 species tested were classified into 21 groups ( table 5 ). The test of non-human hosts for O. tsutsugamushi has been performed chiefly on little mammals, long considered the major hosts for vector trombiculid mites. The Muridae ( rats and mouse ) included the major identify species tested at 52,670/62,726 ( 84 % ). The Cricetidae ( voles, hamsters, etc. ), Soricidae ( shrews ) and Sciuridae ( squirrels ) constituted just 4 %, 2 % and 2.7 %, respectively. Birds ( Aves ) constituted 0.5 % ( table 5 ) .Table 5 Summary of percentage of hosts testing O. tsutsugamushi positive, subdivided into taxonomic groups Full size table Of the major vertebrate groups tested, combining all test types, the Muridae had the highest symmetry of cocksure tests at 13,419/52,670 ( 25.5 % ). Of the other major groups of small mammal, the Cricetidae and Soricidae had exchangeable rates of favorableness at 12.2 and 13.2 %, respectively. Six percentage of the chiefly arboreal Sciuridae were plus. The Canidae tested 18 % positive, with the majority [ 307/319 ( 96 % ) ] tested using serologic methods. Among the Artiodactyla, cows, goats and pigs were tested by serologic methods only, testing 3.6 % cocksure overall. The group listed as “ multiple or nameless species ” had a similar incontrovertibility rate to the Muridae, most likely because the species composition was similar to that presented overall, with most being Muridae .

Orientia tsutsugamushi testing of key host species by laboratory test category

Additional file 1 : table S7 presents data for the 5 most frequently tested species subdivided by testing ground screen class. The major species tested and positivity rates are broadly coherent with the overall data presented above. Muridae report for most of the species listed. A large number of dogs were tested serologically in respective studies with a median convinced rate per locate of 5.5 %. Two chinese studies from Bole region of Xinjiang, China, explanation for the amazingly big number of sheep testing positive by PCR [ 41, 42 ]. wholly blood was collected and tested by 56 kDa PCR .

Orientia tsutsugamushi testing of other host species

Mus spp. have long been considered as unimportant host species for O. tsutsugamushi -carrying chigoe species [ 9 ]. however, in culture-based studies a median of 16 % incontrovertible ( median plus per study site/median tested at all sites ) was seen for wild M. caroli and ( 13.5/34.5 ) 40 % for M. musculus. many species of the Cricetidae have been tested. Using combination culture and serology, a median of 28 % ( 7.5/27 ) Microtus montebelli and 5 % ( 0.5/10 ) M. fortis were positive. By serology, 17 % ( 1/6 ) of Cricetulus triton and using molecular techniques 3 % ( 1/33 ) of Cricetulus migratorius tested positive. Suncus murinus was the most frequently tested of the Soricidae and a median of 6 % ( 1/15.5 ) was incontrovertible among all studies. Of the Sciuridae, Callosciurus notatus was positive with a median of 2 % ( 5/243.5 ) serologically and 13 % ( 1/8 ) using compound culture and serology. Chiroptera were tested alone by serologic methods and 12 % ( 38/308 ) of Eptesicus serotinus and 11 % ( 7/66 ) Rhinolophus ferrumequinum were convinced. For birds, using PCR, 17 % ( 2/12 ) of Motacilla cinerea ( grey wagtail ) and 10 % ( 1.5/15 ) of Passer domesticus ( house hedge sparrow ) were positive in China ( see below ) .

Ecological relationships of vectors and hosts

Bipartite network analysis is becoming increasingly used to understand host-parasite interactions [ 43 ]. These networks can help reveal the importance of certain species in the transmission ecology of a disease [ 44 ]. Bipartite network figures depicting the relationship between host animal species and vectors were constructed for selected country groups. A quantitative depicting was made for all host/vector species interactions ( shown by agate line thickness ). A sub-analysis is besides shown for interactions where either a vector or host tested positive for Orientia. Networks for Southeast Asia intelligibly show L. deliense and Ascoschoengastia indica as key chigoe species whether testing O. tsustugamushi positive or not ( Figs. 7, 8 ). Among those testing positive, the pattern of host species was different with fiddling overlap. In the China/Taiwan analysis, L. deliense is again the key species and associated with a wide master of ceremonies range ( Figs. 9, 10 ). Networks for Japan, Korea and far-eastern Russia reveal a unlike form of host-vector interactions. overall L. pallidum and G. saduski interact with Apodemus spp. and Microtus spp. hosts were by far the most frequent ( Figs. 11, 12 ). however, among O. tsutsugamushi- positive species, L. pallidum, L. orientale and Neotrombicula japonica appear to be key species .Fig. 7figure 7 Network analysis of small mammal and harvest mite species for studies from Southeast asian countries ( Thailand, Vietnam, Malaysia, Indonesia and Myanmar ) Full size tropeFig. 8figure 8 Network analysis of modest mammal and chigoe species testing positive for O. tsutsugamushi by any lab test for studies from Southeast asian countries Full size prototypeFig. 9figure 9 Network psychoanalysis of small mammal and harvest mite species for studies from the People ’ s Republic of China and Republic of China ( Taiwan ). The swiss albino mouse is included where it was used as a bait animal to collect chiggers Full size doubleFig. 10figure 10 Network analysis of small mammal and chigoe species testing positive for O. tsutsugamushi by any testing ground test for studies from the People ’ s Republic of China and Republic of China ( Taiwan ) Full size effigyFig. 11figure 11 Network analysis of small mammal and chigoe species for studies from Japan, South Korea and Russia Full size visualizeFig. 12figure 12 Network analysis of little mammal and chigoe species testing positive for O. tsutsugamushi by any testing ground test for studies from Japan, South Korea and Russia Full size picture

Non-chigger species

few non-trombiculid mites have been reported as testing positivist for O. tsutsugamushi ( Additional file 1 : table S5 ). In an unspecified web site in Japan, respective Haemaphysalis sp. ticks removed from scrub typhus-infected dogs tested positive by PCR [ 45 ]. A incision from Audy ’ s War Office report besides recorded O. tsutsugamushi in the lapp genus of ticks using xenodiagnosis [ 31 ]. Two of 12 pools of Ixodes sp. ticks removed from rodents tested positive for O. tsutsugamushi by PCR in Shandong Province, China [ 46 ]. Ornithonyssus bacoti ( Macronyssidae ) removed from rodents in Nagpur, India, tested incontrovertible by PCR ( 1 of 5 pools ) [ 47 ] and in the recapitulation of rickettsial disease in China by Fan et alabama. [ 26 ], Echinolaelaps echidninus and Laelaps turkestanicus besides tested incontrovertible, but farther details are not provided ( Fig. 13 ) .Fig. 13figure 13 location of O. tsutsugamushi -positive non-trombiculid touch species Full size picture

Chigger indices, percentage host infestation and Orientia positivity

lone 43/276 ( 16 % ) studies provided data on the harvest mite index ( mean number of chiggers per host species ) of collected animals. flush fewer studies, merely 34 ( 13 % ), reported the percentage infestation rates of collected animals ( share of host species with 1 or more chiggers found attached ). Chigger index was reported for 47 host species and percentage infestation for 52 species. consistent with overall data on hosts tested, the major genus and chigoe indices reported were : Apodemus spp. ( 66 ) ; Bandicota spp. ( 54 ) ; Mus spp. ( 4 ) ; Rattus spp. ( 50 ) ; and Suncus murinus ( 29 ) ( Additional file 1 : table S8 ). The median share infestation rates were : Apodemus spp. ( 38 % ) ; Bandicota spp. ( 95 % ) ; Mus spp. ( 27 % ) ; Rattus spp. ( 59 % ) ; and Suncus murinus ( 59 % ) ( Additional file 1 : board S9 ). Chigger exponent and minor mammal infestation rates were compared to O. tsutsugamushi positive and negative test results across all species and locations using the Mann–Whitney U-test. There was a significant affiliation of chigoe index with positive detection of the pathogen ( P < 0.005 ) ( Fig. 14 ). This relationship was not seen with percentage infestation. entirely a small numeral of O. tsutsugamushi positive samples were reported for which either the server chigoe index or percentage infestation rate was besides reported.

Fig. 14figure 14 Box plots showing little mammal host chigoe exponent ( count ) and share for O. tsutsugamushi positive and negative test results Full size double

Summary of ecological data

A total of 793 report sites were recorded from 276 included articles. For 610/793 ( 77 % ) study sites, no descriptive information on the habitat or other local ecological features was given. At 91 ( 12 % ) learn sites, only the identical briefest and most basic habitat categorization was given. frequently used terms included : cancel, fallow, fields, agrarian land, cragged, forest and forest edge, rice fields, grass, parks, riverbank, orchards and plantations, settlements, urban and rural. More detail description was provided for 57 ( 7 % ) study sites. In these cases, the above terms were normally used with extra, non-scientific habitat description. common examples included : crop names ( banana, tea, sugarcane and sweet potato ) ; forest types ( coniferous, deciduous, broadleaf, evergreen and bamboo ) ; and general plant types ( Miscanthus, lalang, palm, Pandanus and Lantana ). A small minority of just 31 ( 4 % ) survey sites provided detail scientific habitat and or ecological description, including dirt type. To be classified as such, at least one plant must have been identified to the species level. Of the 31 sites, 20 were sites where O. tsutsugamushi was identified in vectors or non-human hosts. Ten sites were in Japan where normally reported plants included Phragmites communis, Quercus serrata, Cryptomeria japonica, Phyllostachys pubescens, Artemisia sp. and others. Of 4 sites in Malaysia, Imperata cylindrical, Paspalum and Melastoma were reported. extra reports from 2 sites in Tajikistan ( Populus pruinosa, Tamarix sp. and Salix sp. ), 2 sites in Taiwan ( Bidens pilosa, Miscanthus sp. and Leucaena sp. ), and individual sites from Russia and the Philippines were found. No clearly dominant establish species were reported among the sites, even in the like nation. Soil type ( loam, red clay, hummus, etc. ) was recorded at lone 5 sites. No analysis of soil was performed in any of the include studies. A very small issue of studies reported rain either as an annual trope or total precipitation during the cogitation period. Of the 13 studies, 10 were in China, 2 in India and 1 in Russia. Twelve studies reported average, minimal and maximum temperatures at the study sites. The modal temperatures reported ranged from 12 to 26 °C and maximum of 42 °C and minimum of − 2 °C .

General ecology themes

Trombiculid mite life-cycle

many aspects of the life-cycle of chiggers are well understand from lab colony studies, although how this may vary in nature is not. Neal & Barnett [ 48 ] provided a detailed account of the life-cycle of Trombicula akamushi in lab conditions. Males produce stalk spermatophores that are deposited in the environment and taken up by females to fertilise their eggs. Egg deposit begins between 6 and 21 days post-insemination. egg laying continues for equally much as 253 days in one casing, with mean daily egg production ranging from 2.4 to 21.7 and a maximum of 41 recorded. After 7–11 days the ovum ruptures to produce a quiescent deutovum. A far 5–7 days former the 6-legged larva emerges. These larva stay within a few centimetres of their birthplace and after 2 days may start to display host-seeking behavior by forming clusters on leaves, grasses and twigs above the dirty surface. Larvae can survive for many months awaiting the opportunity to feed. The larva feed on digest tissue fluent from a vertebrate host, becoming engorged and increasing in size by several fold. Larvae will feed from anything between 2 to 12 days or longer, depending on the chigoe species. They then detach and return to a suitable habitat on the land coat. Over about 3 days they develop into another quiescent phase : the nymphophane or protonymph. After a further 7–10 days the 8-legged deutonymph emerges. This, and the pornographic stage, feed on arthropod eggs ( e.g. Culex mosquito eggs ), or recently deceased or quiescent soft-bodied insects such as Collembola [ 49, 50 ]. Two weeks late the nymph develops into the tritonymph ( teleiophane ), lasting about 2 weeks from which the adult ultimately emerges [ 9, 48, 51, 52, 53, 54, 55, 56 ] ( Fig. 15 ). Adults may survive for 15 months or more. Their food preferences in the wild for different species remain obscure. In some tropical species of Leptotrombidium, the entire cycle may take just 2 or 3 months, allowing at least 2 generations per year. only a unmarried coevals is potential in more temperate zones [ 9 ]. It can frequently be seen that groups of attach chiggers are of similar size, suggesting that opportunities may arise for batches of chiggers, possibly from the same brood, to latch onto a master of ceremonies [ 9 ] .Fig. 15figure 15 ( adapted from Audy [ 55 ] ) Chigger and scrub typhus life-cycle Full size image This detail understand of the trombiculid mite life-cycle is about wholly derived from studies on mites kept in lab colonies, due to the challenges involved in observing mites in their natural habitat. It is frankincense unknown how these stages may vary in nature. Comparisons in the life-cycle between O. tsutsugmaushi infected and uninfected chigoe lines of L. imphalum and L. changraiensis have suggested developmental stages are delayed in infect lines, but host-feeding prison term is reduced. A short feeding meter may confer a survival advantage [ 57 ]. From testing ground studies, typical female to male ratios of offspring compass from 5:1 to 2:1. however, in infect chiggers, 95–100 % are female [ 29, 57, 58, 59, 60, 61, 62 ]. several maternally inherited bacterial species including Rickettsia are known to manipulate arouse ratios towards female offspring [ 63, 64, 65, 66 ]. The exact reasons and mechanisms by which O. tsutsugamushi manipulates sex ratios in mites remain unknown. The occurrence of infect males is rare but has been reported in L. pallidum [ 67 ], L. imphalum [ 68 ], L. arenicola [ 62 ] and L. fletcheri [ 62 ]. however, O. tsutsugamushi is not found in spermatophores [ 69 ]. parthenogenesis has been demonstrated in L. arenicola, but to what extent this occurs in nature and in early species is not known [ 70 ] .

Transovarial and transstadial transmission

infection of O. tsutsugamushi via the ovum is known as transovarial transmittance and through the diverse stages of the life-cycle as transstadial transmission. Nagayo & Kawamura first gear recognized this in the 1920s [ 71, 72 ]. In adults, the ovaries appear to most frequently harbour O. tsutsugamushi compared with early organs [ 73 ]. In larva, a higher incidence of O. tsutsugamushi in the salivary organs was seen in unengorged larva than in gorge [ 74, 75 ]. Transovarial infection of Orientia has shown to be effective in chiggers kept in the lab. Rapmund et alabama. [ 29 ] reported airless to 100 % efficiency over 4 generations in L. akamushi. In L. deliense and L. arenicola, infection to the F2 generation was approximately 95 % and 92.6 %, respectively. however, a commemorate decline in transmission was seen after 17 generations with fewer eggs produced [ 76, 77 ]. similarly, rates of 93–100 % were reported from Malaysia and Thailand in L. chiangraiensis, L. fletcheri and L. arenicola [ 58, 78 ]. Transstadial transmission must clearly be portray if transovarial transmission rates are high ; however, testify of O. tsutsugamushi in different life stages has been difficult to demonstrate. several studies showed lower rates of O. tsutsugamushi isolation in stages other than engorged larva, particularly in eggs, deutova and adults [ 29, 59, 73, 79 ]. This was besides noted when free-living adults and nymphs were collected from a hyperendemic area in Malaya and all tested negative [ 80 ]. These findings led investigators to postulate whether O. tsutsugamushi are in some way reactivated during the feeding stagecoach and become occult in other stages [ 9, 73 ]. Whether minor mammals or other hosts can act as a reservoir of O. tsutsugamushi infection is of crucial importance in understanding the ecology and population genetics of this pathogen. To date there has been relatively little probe of this, all performed in the lab setting. In one study, 3 different species of harvest mite were allowed to feed on experimentally infected wild-caught rodents. After 10 days, 9.1 % of L. fuji, 5 % of L. pallidum and 0 % of L. deliense were infected and at 20 days all were negative [ 81 ]. In a promote analyze, Takahashi et aluminum. [ 82 ] were able to demonstrate transstadial transmission but no transovarial transmission. Walker et aluminum. [ 60 ] carried out a similar sketch with L. deliense and L. arenicola. No L. arenicola acquired O. tsutsugamushi ; however, 7.5 % of L. deliense did, with attest of transstadial transmission to the adult stage, but transovarial infection could not be demonstrated. Toyokawa [ 83 ] was able to demonstrate that respective typical vector species including L. akamushi and L. scutellare were able to acquire O. tsutsugamushi during feeding. Traub et alabama. [ 84 ] besides investigated this question and showed 60–100 % of engorged larva ( tested in pools ) were O. tsutsugamushi -positive 1–4 days after detaching. This human body fell to 10–27 % after 5–15 days. A single case ( 1/43 ) of transovarial transmittance was reported. In 2009, Frances [ 85 ] re-examine this subject and again demonstrated that L. deliense feeding on an infected host will acquire O. tsutsugamushi and impart it transstadially. indeed, infection could be demonstrated in all life sentence stages, but no vertical transmission occurred. A individual event of transovarial infection in Blankaartia acuscutellaris occurred, despite the fact that the gorge larva tested veto. This case was intemperate to explain, but could reflect very depleted levels of O. tsutsugamushi post-feeding. The possibility remains for O. tsutsugamushi to be boosted in the chigoe population from crazy small mammals. The existing evidence suggests that chiggers credibly act as both master of ceremonies and reservoir of the disease. There is a lot doubt about the interaction between Orientia and transovarial and transstadial transmission. The lack of testify of upright transmission of O. tsutsugamushi following acquisition from an infect host in the lab, led to meditation that this consequence may be sol rare as to be probably irrelevant in nature. however, tell is growing that for many vector-borne pathogens, the prevalence in vectors is very low and transmission is ineffective. For exemplar, tick-borne encephalitis virus prevalence was 0.5–2 % in Ixodes ricinus in endemic areas [ 86 ] and 1.7 % of the lapp species of check were infected with Anaplasma phagocytophilum in Switzerland [ 87 ]. even if infection is infrequent in nature, this may be sufficient to maintain and spread the pathogen in the population .

Chigger behaviour

larval chiggers are present in a huge rate of habitats, depending on species, where they await the opportunity to attach to a suitable host to feed. During this time, chiggers remain identical inactive, probably moving less than 45 centimeter [ 88 ]. Chiggers are primarily stimulated by carbon paper dioxide, exhaled from an approaching host. They display damaging geotaxis and phototaxis, and neither sound, heat, vibration, human perspiration nor saliva, nor versatile other chemicals could induce a clear bay response [ 89, 90, 91, 92 ]. Chiggers tend to be inactive until the temperature rises above 10 °C and begin to crawl above 12 °C. Chiggers can crawl at approximately 10 cm per moment at 28 °C [ 93 ]. They are amazingly audacious, surviving for 60 days at 1–2 °C and even − 20 °C for a calendar month [ 93 ]. Chigger survival submerged in body of water for 2 weeks ( with subsequent normal lengthiness of the life-cycle ) has been recorded, with authoritative implications in its ecology [ 52, 84 ] .

Chigger feeding

once aboard a host, chiggers may move around for some prison term, before attaching at a suitable site to feed [ 9 ]. The larva attaches by means of its astute talk parts ( chelicera ) and develops a characteristic eating tube ( stylostome ) over several hours. The stylostome is formed by the chigoe ’ south salivary enzymes, which contain homologues of click cement proteins and credibly form the structure of the tube on contact with host tissues [ 94 ]. The stylostome may extend for 120 μm or more. Below the distal end of the stylostome a pool of digested epithelioid and lymphoid tissues is created and this is “ sucked ” up by the chigoe [ 95, 96, 97 ]. There is little attest that chiggers routinely ingest blood, particularly as the stylostome probably only extends a little beyond the epidermis. Traub et alabama. [ 84 ] and Traub & Wisseman [ 98 ], however, reported visualising loss blood cells within the stylostome. presumably, O. tsutsugamushi is normally acquired from lymphoid weave, although no known animal studies have demonstrated this. It is wide reported in the literature that chiggers feed only once during their life-cycle, attaching from anywhere between 2 days and respective weeks depending on the species [ 52, 53, 99, 100, 101, 102, 103, 104 ]. In temperate climates, some species of chigoe appear to overwinter on the host and detach once conditions are suitable for development into the next instar [ 105 ]. If this is the case, then axiomatically chiggers must be able to act as both vector and host. Traub et aluminum. [ 84 ] reported that when a host was killed once chiggers had begun to engorge, 250/1000 individuals detached and reattached to a new host. infection of O. tsutsugamushi to the moment horde could not be demonstrated. They went on to claim that 5 % of chiggers feeding on a host will voluntarily detach and after regressing in size, one third reattached to a new host [ 9 ]. however, Kohls et alabama. [ 106 ] could not elicit any reattachment of chiggers to a second horde. The lack of studies in this area reflects the challenges involved. Traub & Wisseman [ 98 ] postulated that reattachment might be a more authoritative phenomenon in nature, with frequent small mammal deaths. Live-trapped animals examined immediately after death frequently have a big proportion of free-swimming chiggers present on the animal ’ second body, together with clusters remaining attached ( personal observation ). To what extent these typify detached chiggers, or chiggers in the process of finding a site for attachment is strange. The phenomenon of co-feeding chiggers and the character this plays in exchanging O. tsutsugamushi between individual vertebrates is a much-overlooked topic. Chiggers tend to aggregate into tight clusters to feed, identical frequently consisting of the same species and lapp senesce. Frances et alabama. [ 107 ] were able to show transmittance of O. tsutsugamushi to uninfected L. deliense ( 1.6 % ) and B. acuscutellaris ( 2.5 % ) co-feeding with infect chiggers. This may not only act as an crucial method of horizontal transfer of O. tsutsugamushi between individuals of the like and other species, but besides account for some of the enormous song diverseness and universe of multiple strains in the same individual vertebrates [ 108, 109 ]. The mechanism and processes driving the development of song diversity and the interaction of the pathogen between chiggers and mammal hosts ( including humans ) is an authoritative area for future inquiry .

Criteria for vectorship

To definitively establish vectorship, several criteria should be met. The vector must be naturally infected with the pathogen and it must be able to transmit it to a master of ceremonies. The vector should be prevalent in the place where infection occurs and naturally infect hosts should be confirmed. ultimately, evidence should be found of the vector feeding on a host, including humans [ 9 ]. Due to the size of chiggers, the latter can be challenging, although has been reported [ 88, 110 ]. It is possible that unlike species of chigoe have unlike propensities for biting certain vertebrates. Traub & Wisseman [ 9 ] suggested that intrazootic harvest mite species may exist that sustain O. tsutsugamushi among, for model rodents, but are not predisposed to bite humans. In a human volunteer study, L. fletcheri, a well-established vector species in Malaysia, promptly attached to humans, whereas L. arenicola did not, even when keep on the skin in a encapsulate for 24 hours [ 111 ] .

Habitats and microhabitats

The Oxford English Dictionary defines scrub as : “ [ ME, volt-ampere. of shrub ], ( a ) vegetation consisting chiefly of brush or stunted forest growth, ( b ) land covered with this ”. attest suggests that scrub typhus is present in a far greater range of habitats than that described by the word “ scrub ”. Orientia tsutsugamushi in vectors and hosts has been found on flaxen beaches in Malaya [ 112 ], in abstruse jungle [ 113 ], in semi-urban or peri-urban environments [ 39, 114 ], in localize areas within semi-desert, alpine meadows and subarctic frigid moraine at 3200 m above sea flat in West Pakistan [ 24 ]. Chiggers appear to be relatively habitat specific, although some key vector species, such as L. deliense, seem to be able to colonise a greater compass of habitats. Leptotrombidium deliense is frequently found in scrub and forest, while L. fletcheri may be collected from certain grassy areas and L. arenicola from vegetation alongside beaches [ 115, 116 ]. At the larger scale, certain general types of habitats seem to favour the bearing of scrub typhus. however, it must be remembered that the bearing of sufficient numbers of a conserve host animal is inextricably linked to the bearing of the vector and consequently the disease. Neither chiggers nor vertebrates they feed on are uniformly distributed in any environment. During WW2, Audy et alabama. [ 31 ] conducted detail investigations into the association of both human cases and vector chigoe species with different habitats. This is chronicled in the 403-page report of the Scrub Typhus Research Laboratory, South East Asia Command published in 1947 [ 31 ]. Three key risk habitats were identified : ( iodine ) artificial barren as a result of ( a ) rural abandoned clearings due to shifting polish practices, ( bel ) domestic or suburban neglected areas or ( hundred ) neglected gardens and plantations ; ( two ) water meadows including the grassy edges of urine bodies and seepages in dry areas ; and ( three ) hedgerows or outskirt habitats, typically where two types of habitat touch such as forest edges ( ecotones ) [ 54, 117 ]. It might be expected that areas with chiggers would become gradually feeder, except for unsuitable lacuna of terrain, frankincense forming an endemic area or region [ 116 ]. In a holocene across-the-board survey in Northwest Yunnan, China, chigoe diverseness was lower in the flatlands, but base abundance and intensity was higher than in the mountains. Leptotrombidium deliense predominated in flatlands, and L. scutellare in mountains [ 118 ]. Ecotones may provide the conditions to allow both rodents and chiggers to thrive. One study of forest and open scrubland transects found the highest numbers of chiggers attached to rodents trapped in ecotones ( three times more L. deliense than away from the ecotone ) [ 102, 116 ]. Goff [ 119 ] in Papua New Guinea reported an abundance of L. deliense in interrupt habitat but not in undisturbed areas. A more detail appraisal collecting free-living chiggers using black plates placed on the ground, found chiggers to be more normally associated with clear areas in scrub habitat, along paths, fringes of scrub habitat and under trees and bushes [ 120 ]. Using a similar method acting on Hachijo Island, Japan, chiggers were located in damp areas in the passage between hills and flat areas and in forests near flatcar areas [ 93 ]. In Taiwan, a detail assessment of plowed and fallow habitats found three times more chiggers in the fallow fields. There was no affiliation with rodent density or species, suggesting that the microhabitats of the fallow field, with more shade, flick litter and shrub provided more suitable habitat for harvest mite survival [ 121 ]. holey, well drained, damp soil appears to be most suitable, but no detail studies have been performed [ 56 ]. certain plant species have often been cited as associated with scrub typhus, such as grasses including Imperata cylindrica ( kunai grass in New Guinea, kogan grass in the Philippines, lalang grass in Malaya ), Saccharum spontaneum, Eleusine indica, Cyperus iria and Paspalum conjugatum [ 53, 99, 100, 101, 122 ]. In the “ yudokuchi ” or noxious areas of northwest Honshu along riverbanks, Miscanthus sinensis and Phragmites communis are park [ 123 ]. however, Audy [ 116 ] concluded that detail botanic surveys did not prove useful as no clear correlation coefficient between plant species and the disease emerged. He proposed a more synecological word picture using the broader habitat groups described above and it is from here that the term “ scrub ” became synonymous with the disease. Whether scrub typhus occurs in primary forest and has a sylvatic cycle that can “ escape ” to infect bordering chigger-mammal-chigger cycles and humans has been much debated [ 54 ]. Almost no studies of vectors and hosts have been carried out in what can be described as true elementary forest. Traub et alabama. [ 113 ] reported positive isolation of O. tsutsugamushi from three rodents ( Rattus mulleri, R. edwardsi and R. rajah group ) ampere well as a pond of Ascoschoengastia audyi chiggers collected from a Callosciurus squirrel in primary Malayan jungle. Although Muul & Liat [ 124, 125, 126 ] besides reported O. tsutsugamushi by isolation and serologically in forest rodents ( Rattus sabanus ) and a unmarried squirrel C. notatus, the forest at Bukit Lanjan near Kuala Lumpur was not strictly elementary. even within rainforests, habitat can vary with little clearings due to fallen trees, paths and along the banks of rivers and streams [ 98 ]. These may provide the opportunity for increased densities of rodents and chiggers [ 116 ]. Forests tend to have greater humble mammal diversity, but lower density, with each mammal associated with finical harvest mite species [ 55 ]. There is no definite tell of humans acquiring scrub typhus in primary forest, given that very few humans live wholly in undisturbed afforest without altering it. A survey of antibodies to scrub typhus in the Orang Asli tribes of Malaysia, found higher levels in those be in deep afforest clearings compared to those on the forest edge or in villages [ 127 ]. however, it was impossible to say where the disease was acquired and whether the periphery habitats within the forest were crucial .

Seasonality: temperature, rainfall and humidity

The seasonality of human scrub typhus has been well described in several countries across Asia. In Japan, South Korea, Taiwan and northern parts of China the infection presents about entirely from leap until early winter. In Thailand, Burma and India disease has been described as most coarse from June until November, but present throughout the year. In Malaysia, the island of New Guinea and the Pacific Islands seasonality has been less clearly defined. To what extent this model is dependent on temperature, rain, humidity and vector sum numbers of vector chiggers remains ill-defined. Traub & Wisseman [ 9 ] noted that all cases have occurred in either tropical or subtropical conditions and that no significant outbreaks have been reported during the dry season in India or central/southern Burma. In more northern latitudes, some seasonality is to be expected, with winter temperatures dropping besides depleted for chiggers to feed or chiggers overwintering on their hosts and hence not available to attach to humans [ 105 ]. respective studies have linked the disease to the presence of different species of chiggers at different times of the year, in different parts of a particular country. In South Korea, for model, L. scutellare numbers peak in fall corresponding to the highest rates of human cases [ 128, 129, 130, 131, 132, 133 ], although this was not seen in all investigations [ 134 ]. Leptotrombidium pallidum is more park in northerly and eastern areas, where fewer cases are seen and frankincense L. scutellare is believed to be the key vector [ 135 ]. A like design is reported from Japan, with L. scutellare and L. pallidum causing autumn-winter cases and L. akamushi summer cases [ 136, 137, 138, 139, 140 ]. Outbreaks in soldiers training on Mt. Fuji ’ south foothills were seasonal, despite the soldiers ’ presence year cycle [ 114 ]. A late drumhead of homo scrub typhus in Japan over a 59-year period demonstrated major outbreaks in October to December, with smaller case numbers in May to June in southern prefectures, whereas northern and northeastern areas had highest rates in May-June and moderate numbers in October to December [ 141 ]. similarly, in Shandong, China peak human cases corresponded to peak L. scutellare numbers [ 142 ]. In the Primorye region of russian Siberia, L. pavlovskyi peaked in summer and is implicated in human cases [ 143 ]. In lower Burma and Manipur ( India ) the seasonal pas seul in numbers of L. deliense was reportedly alike to that of homo cases [ 53, 54, 144 ] and in Thailand L. deliense was most abundant during the showery season from April to December [ 145 ]. In tropical North Queensland cases peaked from March to July, coinciding with the showery season and the menstruation immediately after the rains [ 146 ]. In Tamil Nadu, India, the highest incidence occurred from October to December, coinciding with acme chigoe numbers, although chigoe numbers did not fall greatly at early times of the class [ 147 ]. In Maharashtra, only minor seasonal magnetic declination was seen in Suncus murinus and Rattus blandfordi chigoe indices, whereas Rattus rattus rufescens had lower rates overall and dear absence of chiggers from April to June [ 148 ]. In Malaysia, however, no mark seasonality in either human or rodent infections was seen, with only a small decrease during the dry season [ 30, 125 ]. In the Pescadores Islands, Taiwan, many cases presented in military personnel from April until November. hera, L. deliense is the vector and harvest mite numbers fall to closely zero in winter and a close up correlation of harvest mite abundance with homo infection was reported [ 149, 150 ]. Olson et alabama. [ 149 ] estimated a minimum necessity of 0.69 chiggers per shrew as the critical abundance needed to result in 1 homo sheath per month. The importance of temperature was investigated on the Pescadores Islands. Chiggers were recorded on rodents 12 days after the beginning 30 °C day temperature of the year and the first homo shell occurred 10 days subsequently, although this varied year-to-year dependent on cold spells [ 151 ]. Others besides reported a close correlation on the Pescadores between beggarly monthly temperature, chigger abundance and human cases, but not sol with rain [ 152, 153 ]. In a more widespread cogitation across Taiwan, homo case incidence correlated well with overall chigoe abundance, although surprisingly not with O. tsutsugamushi infected chigger abundance [ 154 ]. In Guangzhou, China, each 1 °C temperature emanation corresponded to a 14.98 % increase in the monthly total of homo cases [ 155 ] or an odds ratio of 3.8 [ 156 ]. however a clear correlation of cases with temperature was not seen in two studies from South Korea and India [ 157, 158 ]. In both Japan and South Korea it has been intelligibly demonstrated that the monthly distribution of cases become more evenly distributed at more southerly latitudes [ 131, 159 ]. Audy ’ s [ 144 ] extensive investigations in India and Burma revealed that chigoe abundance falls during the dry season. The proportion of rodents carrying L. deliense rose after rains began, but the mean total per rodent ( chigoe index ) lagged behind by a few weeks [ 55 ]. In Malaya, using bait animals in a hyperendemic area, 10 times fewer chiggers attached to rodents during dry periods than wet [ 80 ]. In the same study, but using human volunteers, 70 % became infect during wet periods compared to 5–29 % in dry spells. however the picture was slightly confuse as more harvest mite pools tested positivist during the time period with the lower harvest mite index ( of 12 ) compared to a high exponent of 304 [ 80 ]. In Thailand, chigoe species diverseness was higher in the dry season and human scrub typhus incidence correlated strongly with chigger diverseness [ 160 ]. In more tropical climates, annual temperature variation is less mark and here rainfall may be more critical to chigger abundance and homo disease [ 89, 150 ]. Where and how these two factors converge and interact in unlike regions is not amply sympathize. In tropical North Queensland all but 1 homo case was reported east of the 60 edge isohyet ( where 1500 millimeter or more rain falls per annum ) [ 146, 161 ] and in Thailand chigoe abundance and human cases are highest during the showery temper [ 59 ]. In a study transect in Malaya, harvest mite abundance could be maintained by sprinkling the ground with water after the rains had ceased [ 162 ]. temperature and humidity are surely authoritative factors in chigoe exploitation. A minimal temperature is required for eggs to hatch and in hot climates ; chiggers are more active in cooler dampen good morning conditions and seek recourse from very high temperatures by entering dirty angstrom deeply as 18 curium below the surface [ 55, 89, 163, 164, 165 ]. Scrub typhus risk has besides been associated with hours of cheerfulness, lower atmospheric pressure ( associated with rain ) and in some studies humidity [ 142, 155, 166 ]. The importance of a meter slowdown between upwind events ( such as exceptionally heavy monsoonal rains ) and human cases should not be underestimated and may reflect both rodent engender success and the chigger life-cycle. In Guangzhou, after 4 months lag, every 10 % increase in relative humidity was associated with 8.5 % ( 95 % CI : 2.7–14.5 % ) increased odds for infection, and a 1-unit increase in multivariate El Niño Southern Oscillation ( ENSO ) exponent between 2006 and 2014 was associated with a 23.6 % increased odds of cancel typhus cases after a 5-month slowdown [ 156 ] .

Vectors

trombiculid mites are considered to be the major vector of scrub typhus. The term chigoe credibly derives from the spanish chico meaning modest, and initially referred to the scrub-itch trombiculid mites of North America. Later the terminus became synonymous with all trombiculid mite larva [ 167 ]. Chiggers belong to the family Trombiculidae, subclass Acari, class Arachnida and phylum Arthropoda [ 51 ]. There are over 3000 species of Trombiculidae present across about the integral universe. The designation of chiggers to the species level is technically challenging given their small size and the miss of accessible and update taxonomic keys. indeed, there has been much confusion over designation, with many genus and species names changing over clock time. late advances in recognition using autofluorescence techniques and genetic barcoding of conserve 18S rDNA or mitochondrial cytochrome c oxidase subunit 1 genes may pave the way to greater taxonomic clarity [ 39, 168 ]. Over 50 species of chiggers are known to bite humans and of these, 10 species have good evidence of transmitting O. tsutsugamushi to humans and a further 5 are potential vectors [ 51 ]. lone members of the genus Leptotrombidium are confirmed vectors to humans ; among these L. deliense, L. akamushi, L. arenicola, L. imphalum, L. scutellare, L. pallidum and L. pavlovskyi are the most important [ 51 ]. Chiggers may be collected from hosts, using total darkness plates or other objects placed on the ground, from the open of boots of a standing person and from dirty airfoil matter using Berlese or Tullgren funnels [ 56, 93, 163 ]. The prevalence of O. tsutsugamushi in chiggers is depleted, with a median per site reaching 18 % in L. pallidum, but less than 10 % in other cardinal species using molecular diagnostic tools ( table 3 ). free-living chiggers by and large have lower share infection rates compared to engorged chiggers ( board 3 ). In one report, for case, 2.6 % of gorge L. deliense collected from hazardous rodents were positive by DIF while barely 1.1 % of offspring from the same collection were positive ( i.e. naturally infected ) [ 59 ]. Santibáñez et alabama. [ 51 ] provides a holocene detail update on the role of chiggers as vectors of human pathogens and Stekolnikov [ 169 ] published an update key to the genus Leptotrombidium in 2013. It is likely that Trombiculidae are divided into the follow groups : those that do not bite humans or carry Orientia ; those that sting humans but do not carry Orientia ( scrub-itch mites ) ; those that carry Orientia but do not bite humans ( possibly intrazootic ) ; and those that both carry Orientia and bite humans [ 159 ]. Of the latter, there are few common species, possibly ascribable to their habitat preferences and likelihood of encountering humans. Nadchatram [ 170 ] attempted to classify chiggers into 7 ecological groups, of which group 1 are the red-orange coloured territory surface dwellers with a broad crop of hosts including humans. The hypothesis of other vectors of scrub typhus should not be ignored, particularly in areas distant to the classical music scrub typhus “ triangle ”, including the United Arab Emirates and Chile. several reports of ticks testing positive for O. tsutsugamushi have been published [ 45, 46 ] and recently for a non-chigger touch, Ornithonyssus bacoti [ 47 ]. Orientia tsutsugamushi has been shown to multiply in inoculate hard tick ticks [ 171 ]. Traub & Wisseman [ 9 ] cited russian research that suggested O. tsutsugamushi survived in fleas for 11 days and could be transmitted by the flea bite, but details were lacking. The history of leech bites at the locate of eschars in scrub typhus cases in Chile has prompted far probe but no stream evidence of leeches being vectors exists [ 19, 172 ]. Chiggers have been found to carry fresh Rickettsia, Anaplasm a and Borrelia species, but to what extent these are pathogens or transmitted to humans is strange [ 173, 174 ]. evidence from China implicates trombiculid mites in the infection of Hanataan virus [ 175 ]. It seems probable that arthropods that feed on rickettsiaemic hosts may be able to acquire Orientia, but the bacteria credibly can not cross the gut wall and forth infection has not been documented .

Hosts

There are two major groups of vertebrates that host chiggers ; the “ assert hosts ” which comprise small mammals ( rodents and shrews ), ground-dwelling birds and “ incidental hosts ” ( early birds and larger mammals including humans ). several reports provide detailed lists of animal hosts that reveal the enormous range of species that can be parasitized [ 9, 55, 176, 177 ]. Harrison & Audy [ 176 ] reported L. deliense from 87 species of master of ceremonies. entirely monkeys, gerbils, hamsters and humans are thought to suffer clinically with scrub typhus [ 55, 178 ]. The patchy distribution of chiggers in the environment has already been alluded to, and will be discussed further. Maintaining hosts are able to acquire chiggers and either re-deposit them at the same site or a nearby web site, whereby the saturation of this interaction ( i.e. total of hosts ) contributes to the abundance of mites and where O. tsutsugamushi is portray, the hazard of disease [ 55, 144 ]. incidental expense hosts, such as birds and monkeys, may play a function in transporting chiggers to more distant sites and setting up new focus of infection. It has been estimated that in ideal conditions, a single small mammal server could support four generations of chiggers per class, with a total of 10,000 feeding on that individual [ 55 ]. In peninsular Malaysia, one Rattus argentiventer was estimated to support 4000 chiggers/month [ 179 ]. individual rodents can host over 1000 chiggers at one time, tree shrew 5000 and ground-dwelling birds american samoa many as 11,000 [ 55 ]. The rate of turnover of chiggers is an crucial factor for vector competence [ 102 ]. The traffic pattern and degree of infestation of hosts is dependent on several factors. Host demeanor and habitat exploitation is of great importance. Terrestrial and scansorial mammals are more heavily infested and frequently infected with O. tsutsugamushi than arborical mammals [ 9, 126, 180, 181 ]. More renaissance man rodents that exploit unlike types of habitats, such as Rattus species are much implicated in scrub typhus. indeed, Traub & Wisseman [ 98 ] postulated that scrub typhus distribution closely mirrors the distribution of Rattus and Leptotrombidium species, with the plaza of Rattus taken by voles in Korea and Japan. Vertebrate home range size may be important, with greater exposure to chiggers and the ability to host bombastic numbers of ectoparasites with more extensive ranging [ 54, 59, 179 ]. however, data on home range sizes for rodents are relatively few. In Taiwan, studies of larger species ( Bandicota indica and Rattus losea ) reported not more than 500 m ranges [ 121 ]. At Changi Camp, Singapore, vitamin a much as 640 thousand was recorded for Rattus species [ 182 ]. On Shichito Island, Japan, re-trapping of Rattus norvegicus took place up to 50 m away, 50–60 m for mouse and 25–30 thousand for voles [ 183 ]. In Malaysia, one Rattus tiomanicus was re-trapped 560 megabyte away [ 184 ]. Vertebrate body size may besides be important but data are inconsistent. Traub & Wisseman [ 52 ] report less than 20 chiggers attached to individual tigers, leopards, civets and deer, whereas little rodents and shrews may have thousands. Small terrestrial mammals may be good suited to acquiring chiggers, as they forage on and in the grind where their backs and ears are at the height of many species of questing chiggers. Small mammal burrows and nests may besides be suitable locations for chiggers to attach. The site of harvest mite attachment varies in different hosts. In rodents the ear pit are typically parasitized, in the Tupaidae the midplane and inguinal region, in shrews the perianal sphere and in macaques the eyelids and eyebrows [ 52 ]. Traub & Wisseman [ 52 ] suggested that host grooming efficiency may explain why mouse frequently have few chiggers, whereas shrews have many. however, there appear to be few studies on grooming efficiency between different little mammal species. other possible factors affecting attachment locate include skin thickness, hair type, skin immune reception and microclimatic conditions [ 170, 185, 186 ]. Some harvest mite species attach to specific areas of a horde ’ randomness body, for case Schoengastia schuffneri has a preference for rat groins [ 119, 122 ]. In humans, the attachment web site is often associated with areas of atmospheric pressure, for case the armpit or around the girdle [ 9 ]. There is some degree of horde specificity among chiggers, although to what extent this is dependent on host contact with habitat-specific harvest mite species is indecipherable [ 187 ]. Some chigoe species when presented with a human finger refuse to attach, but when presented with a dame readily attach and gorge [ 89 ]. Rodents, like humans in endemic areas, probably become infect repeatedly with O. tsutsugamushi during their life. In the wilderness, capture R. tiomanicus were rickettsaemic for a intend of 97 days [ 184 ]. In the lab, rickettsaemia was recorded in R. rattus after a Leptotrombidium bite from sidereal day 7 until 8 weeks subsequently [ 188 ]. In another analyze, viable O. tsutsugamushi were recovered from the kidney of a Rattus annandalei 4 months after being infected [ 181 ]. In an endemic set, at least a 50 % life infection rate in rodents has been estimated [ 184 ]. Orientia tsutsugamushi yields from weave are greatest from spleen, followed by liver and kidney. Lung tissue is besides frequently positive, but results are inconsistent [ 78, 181, 189, 190 ]. The role of birds in the ecology and distribution of scrub typhus has been about wholly ignored. several bird species have been reported as efficient hosts of vector harvest mite species. Ground-living birds such as quail are frequently heavily colonised, with 18,500 T. akamushi removed from 9 birds in Malaysia [ 54 ]. Others reported L. deliense and T. pseudoakamushi on chinese quail ( Coturnix chinensis), Greater coucal ( Centropus javanicus or C. sinensis ), Raffles ’ malkoha ( Rhinortha chlorophaea ) and oriental reed warbler ( Acrocephalus orientalis ) [ 191, 192 ]. In Japan the green pheasant ( Phasianus colchicus tohkaidi or P. versicolor ) harboured L. pallidum [ 193 ]. japanese scientists reported 72 species of birds carrying trombiculid mites, including L. pallidum and L. scutellare, but all attempts at isolating O. tsutsugamushi from these failed [ 194 ]. Kitaoka et aluminum. [ 194 ] showed that chickens and pigeons could both be experimentally infected and remain rickettsaemic for arsenic long as 42 days. The domestic chicken was reported to harbour both L. scutellare and L. pallidum. Kitaoka et aluminum. [ 195 ] besides exposed chickens to areas of high disease endemicity and was able to recover O. tsutsugamushi from a liver and spleen pool of 1 chicken and from L. pallidum attached to the chickens. The entirely records of violent birds carrying O. tsutsugamushi come from Khasansky District, Primorye, Russia and Xinjiang Province, China. In the Russian Far East, these were black-faced butt ( Emberiza spodocephala ) and long-tailed rosefinch ( Carpodacus sibiricus ) tested using xenodiagnosis [ 196 ]. In China, 5/91 house sparrows ( Passer domesticus ) and 3/16 grey wagtails ( Motacilla cinerea ) tested positive from irascibility tissue by PCR [ 41, 42 ]. These species ( except the nonmigratory Passer domesticus ) breed in Russia and northern China and migrate to South Korea, southerly Japan, southerly China, South and East Asia depending on the species [ 197 ]. long-distance migrants arriving in Europe from Africa have been found to be carrying non-European mites [ 198 ]. Chiggers may be transported by birds in both local areas ( ground-living birds ) and over long distances ( migrants ). These could potentially set up new focus of disease and explain the reference of scrub typhus along island chains, for example East to the Solomon Islands and southwest to the Chagos Islands. This besides raises the challenging potential for far extension towards Madagascar and the african continent. however, holocene reports of humans and dogs infected with O. tsutsugamushi in Chile would suggest a unlike mechanism of spread, as there are no known dame migration routes between Asia/Australia and Chile [ 199 ]. Human department of transportation of rodents through international trade and shipping has been implicated in the ranch of many infectious diseases .

Immunity and strain diversity

There has been identical fiddling inquiry into the dynamics of antibodies to scrub typhus in either animal or human hosts. One study of rodents in Thailand demonstrated that IgG persisted for 10 months in animals removed from the godforsaken and keep in captivity [ 59 ]. IgM was detected until week 6 in naturally infected R. rattus [ 188 ]. Studies in humans in the early 1950s clearly showed that tied in those with late natural scrub typhus infection, there was no meaning protective effect to re-exposure by a unlike tenor [ 200 ]. homologous immunity was stronger, providing dispatch protection for at least 3 years [ 201 ]. similarly, in cynomolgus macaques ( Macaca fascicularis ), homologous unsusceptibility was discernible for at least 8 months, but not after 5–6 years [ 202 ]. multiple strains may be present in a one colony of chiggers ( L. pallidum ) established from one individual [ 203 ]. additionally, multiple strains can be maintained in an L. imphalum colony by transovarial infection [ 57 ]. In humans, blend infections identified by multi-locus sequence type ( MLST ) comprised arsenic much as 25 % of cases in Thailand and 8.6 % in Laos [ 204, 205 ] lab studies showed that infection of strains from chiggers to rodents was varying, in that alone the Karp try was found in rodents fed upon by Karp and Gilliam-infected chiggers [ 206 ]. In Shandong Province, China, sequence of the 56 kDa gene from rodents, chiggers and humans in one area suggested some consistency in key genotypes [ 207 ] ; whereas in a study from 6 Thai provinces, a boastfully diversity of genotypes was seen in humans with only 2 genotypes normally distributed throughout the nation [ 208 ] .

Mite islands

The concept of “ mite islands ” was first base put forward by Audy [ 167 ] in the 1940s. The mind was based on the patchy distribution of homo cases and of chiggers in the environment. The size of touch islands should be considered on two scales. At the largest scale, islands consist of endemic areas, ranging from a few square miles, to thousands of square miles, frequently bounded by major ecological barriers. At the small scale, an “ island ” of mites may be less than 30×30 curium and patchy over an area of hundreds of metres. The Japanese were well aware of this, describing localised bad areas as yudokuchi ( “ noxious area ” ). The patchiness may be more marked in dry climates, where mites are associated with damper areas. The islands may expand and contract over time, dependant on a countless of factors [ 55, 116, 117, 159, 209 ]. Mite islands have been recorded in an enormous compass of habitats from man-made barren, neglected cultivation and plantations to urine meadows and forest edge [ 55, 117 ]. More strange habitats include parks [ 210 ], walled vegetable gardens [ 211 ] and alpestrine meadows [ 24 ]. There have not been reports from very arid habitats or deeply forest. The presence of a mite island is credibly subject on factors such as desirable climatic conditions, species composition and stability of the vertebrate population, saturation of the vertebrate–chigger–host interactions, food issue ( for larva and adults ), dirty, microclimate and chigoe predators [ 54, 55 ]. The role of humble mammals in the minor dynamics of touch islands is of importance. Rodents probably forage on similar routes and therefore chiggers can be picked up and returned to desirable habitats on a even basis. even within the lapp areas, two rodents of the same species can have markedly different numbers of chiggers attached. additionally, a rodent removed from its home range for three days and then replaced will very quickly acquire the chiggers that would have attached in the intervene fourth dimension [ 212 ]. rodent burrows have been reported to yield large numbers of free-living chiggers [ 56 ]. several studies demonstrate the patchy distribution of chiggers in nature. In a transect through Imperata cylindrica grass in Malaysia using rabbits or rats as bait animals or black plates to collect free exist chiggers, numbers varied at different points along the transects. Variation besides occurred over prison term and the highest numbers were seen at the depart of the showery temper [ 80, 88, 213 ]. In these studies, no well-defined connect to habitat type was identified, although in another discipline negative areas were more frequently on cadaver soil [ 214 ]. Another analyze collecting wild rodents in similar habitat in an area of 1300 m2 could find no cluster of O. tsutsugamushi infected rodents [ 215 ]. In Japan, studies using lookout voles ( Microtus montebelli ) besides reported the patchy distribution of O. tsutsugamushi infected voles and a changing pattern over time [ 210, 216, 217 ]. Most cocksure sites were positive on more than one affair over the course of 3 years [ 218 ]. In chemoprophylaxis studies with humans, individuals seated on pot 45 curium apart had significantly differing numbers of chiggers attached, which was consistent to the localization if two people changed position [ 88 ]. The differences between endemic and non-endemic areas have besides been examined in a few cases. In Japan, 50 % L. pallidum tested positive for O. tsutsugamushi in an endemic area ( of homo disease ) and alone 3.8 % in a non-endemic area [ 219 ]. At the locate of an intense outbreak of disease in plantation workers on the Goodyear Estate, Deli, Sumatra, 50.5 % of rats were infested with mites with a harvest mite index of 104, whereas on two nearby estates without outbreaks, 6.3 % and 2.3 % of rats were infested with indices of 7 [ 192 ]. The study by Ishikura et aluminum. [ 219 ] surely suggests that even areas thought to be non-endemic for scrub typhus, but occurring within an endemic region, may not be wholly free of risk. Our understanding of this remains poor. The dynamics of touch island size and distribution over time are besides not well understand. Some hyperendemic sites have become low to no-risk sites over the course of several years [ 54, 220 ]. It is probable that the factors mentioned above as important for the establishment of a mite island may change as, for example, a plantation matures resulting in less rodent food handiness and unlike microclimatic conditions less desirable for vector harvest mite species [ 9 ] .

Land use, climate change and disease risk

The importance of changing climate, habitats and environment on the gamble of infectious diseases is becoming increasingly recognised [ 221, 222, 223, 224 ]. There has been little inquiry into these impacts for scrub typhus. The multiple impacts of humans on habitat, such as through shifting cultivation and gain of forests, has been linked to the creation of periphery and scrub type habitats that are thought to favour more intense host–chigger–host cycles. Some countries with the infrastructure to record scrub typhus incidence have reported declines in homo cases ( Japan [ 225 ] and Taiwan [ 226 ] ), whereas others have seen increases ( South Korea [ 227 ] and China [ 228 ] ). The reasons behind these changes are not well understand. Saito et alabama. [ 229 ] suggested that the fall in incidence in Japan could be partially due to less river flood as a resultant role of far-flung decameter build. Kuo et aluminum. [ 121 ] in Taiwan reported that the abandonment of rice growing fields following Taiwan ’ s join of the World Trade Organisation in 2001, led to an increase in desirable harvest mite habitat which had been controlled by regular plowing. amazingly, however, the rates of O. tsutsugamushi infection in small mammals in fallow and ploughed fields were not statistically different despite much higher numbers of chiggers in fallow areas. In South Korea, a late study suggested that climate exchange might be partially responsible for the northern expansion of the key vector L. scutellare [ 39 ] .

Humans

Focalization of human cases

The concept of touch islands as described above first came about as a leave of many observations of focal outbreaks among soldiers in WW2. classic examples include an outbreak of 756 cases in Ceylon after 4 days ’ exposure [ 114 ] and in Sansopor, Dutch New Guinea, in which 931 cases with 34 deaths occurred over 1 calendar month, with about all cases linked to abandoned greenwich village gardens and plantations [ 122, 230 ]. In Finschhafen, New Guinea, reoccupation of a camp abandoned fair 6 weeks previously resulted in 16 cases and 6 deaths, all of who were involved in clearing grass to make an outdoor film [ 100 ]. grove workers were besides affected in well-described focal outbreaks. Cases often occurred in groups of workers detailed with clearing specific areas of the plantation [ 191, 231, 232 ]. The importance of shifting cultivation and the vector sum exposure to potentially high risk habitats was besides noted [ 116 ]. There has been a steep raise in reports published of scrub typhus outbreaks in the final decade, particularly in India and China [ 1 ]. This is most likely due to a combination of increasing awareness, kingdom practice changes from expanding human populations and climate deepen with more extreme weather events. A strike expression of many of the reports on outbreaks is that those exposed ( e.g. military personnel, plantation workers ) were immunologically naïve to scrub typhus [ 232, 233, 234, 235 ].

Human behaviour and disease risk

In scrub typhus endemic areas, disease risk varies over the course of the year, with fewer human cases during winter periods in northern latitudes and dry periods in tropical latitudes. To acquire a chigoe morsel, photograph to suitable habitat is required. occupational gamble is important, with the main charge of disease in farmers, plantation workers and the military [ 53, 55, 146, 231 ]. There have been increasing cases due to recreational exposure in suburban parks and gardens [ 39, 236 ]. certain activities, such as lying or sitting immediately on the ground are particularly hazardous [ 117 ]. A late detailed analysis of farming practice between a high incidence area in South Korea and a low incidence area of Japan with alike environmental and climatic features and the like vector ( L. scutellare ) identified certain gamble factors. Working longer hours in the sphere, more flex ahead or squat at oeuvre, resting on the land, miss of protective clothes and less wash of clothes and skin were all statistically significantly associated with scrub typhus infection [ 237, 238 ]. A separate study of farmers in South Korea identified water system around the home, dry field farming and working with livestock as meaning gamble factors [ 238 ]. ecological niche modelling using utmost information algorithm has recently been used to predict scrub typhus happening across China, based on data from Jiangsu Province [ 239 ] .

Interventions to reduce risk

No vaccine presently exists to prevent scrub typhus. Vaccine growth was first attempted and trialled at the end of WW2, with some auspices provided to naturally acquired scrub typhus in a little number of test cases [ 240, 241 ]. however, amply vaccinated military personnel were not prevented from acquiring austere disease [ 242 ]. farther attempts in Japan in the 1940s besides failed to provide lasting exemption [ 243 ]. The Japanese successfully used the balmy Pescadores tense of O. tsutsugamushi to demonstrate protection from a deadly strain [ 244 ]. Valbuena et alabama. [ 245 ] provide a more detailed account of the history of vaccine growth. however, a number of other contraceptive measures can be taken and these have been summarised recently by Xu et aluminum. [ 1 ]. Avoiding bad areas and reducing the find of a touch bite by avoiding sitting or lying immediately on the ground are important. The use of insecticides on clamber and clothe has been shown to be effective in several studies during WW2 [ 56, 93, 99, 101, 117 ]. physical removal of impound mites is airy due to their modest size, although Malay mothers were reported to remove chiggers from their children with a needle [ 178 ]. Thorough wash of clamber and clothes with a detergent after outdoor activities is recommended. Clearing desirable habitat for chiggers may reduce gamble in the long term. similarly, rodent manipulate, although challenging to accomplish in drill, can reduce disease risk, although conversely the contiguous disease gamble may increase, with a big population of chiggers abruptly without their usual food informant. For short-run, bad activities such as soldiers on mathematical process or field workers, there is some testify that weekly doxycycline may be effective prophylaxis [ 246 ]. public betrothal with attentiveness to the measures described above is probable to be very utilitarian. The lotion of numerical model to strategies to reduce scrub typhus gamble in humans by Min et aluminum. [ 247 ] suggested that reducing contact between humans and chiggers is more effective than attempting to either manipulate rodents or chiggers .

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