Scrub typhus is a serious public health problem in the Asia-Pacific area. It threatens one billion people globally, and causes illness in one million people each year. Caused by Orientia tsutsugamushi, scrub typhus can result in severe multiorgan failure with a case fatality rate up to 70% without appropriate treatment. The antigenic heterogeneity of O. tsutsugamushi precludes generic immunity and allows reinfection. As a neglected disease, there is still a large gap in our knowledge of the disease, as evidenced by the sporadic epidemiologic data and other related public health information regarding scrub typhus in its endemic areas. Our objective is to provide a systematic analysis of current epidemiology, prevention and control of scrub typhus in its long-standing endemic areas and recently recognized foci of infection.
The traditional endemic area of scrub typhus is known as the “tsutsugamushi triangle”. It is a region covering more than 8 million km2, from the Russian Far East in the north, to Pakistan in the west, Australia in the south, and the Japan in the east [23,48,49]. There are one billion people at risk of infection; the endemic area is highly populated [1]. The progress of globalization and associated travel contributes to the exportation of the infected persons to non-endemic areas [50]. The antigenic and genetic diversity of O. tsutsugamushi strains, and their unclear correlation with virulence for humans, confound the epidemiological study of scrub typhus [51]. Better understanding of the epidemiology of scrub typhus will help efforts to prevent and control the disease. This part of the article describes studies of the geographic distribution and risk factors of scrub typhus in both the endemic areas and in travelers from the rest of the world.
Even with its recent re-emergence in the traditionally endemic areas and worldwide, scrub typhus is still a neglected infectious disease [6,63,64]. The geographic distribution of scrub typhus is determined by the distribution of its vector and reservoir—mites, primarily of the genus Leptotrombidium. Humans are accidental hosts [1,51]. Outdoor workers, especially field workers in rural areas, have a higher risk of acquiring the disease [65]. It is reported that rice fields are an under-appreciated location where the biting of mites and transmission of O. tsutsugamushi occurs in the endemic areas [63]. Tropical weather provides stable and ideal conditions for transmission of the disease. High temperature and high humidity are optimal for mite activity. In more temperate climates, the transmission of scrub typhus is more seasonal due to the temporal activity of chiggers [45,63,66]. Scrub typhus has been a nationally notifiable disease in Bhutan, China, Japan, South Korea, Thailand, and Taiwan [67,68,69,70,71,72]. The reported seroprevalence of O. tsutsugamushi for each country is shown in Table 1 [73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106]. The reports of outbreaks of scrub typhus are summarized in Table 2 [43,94,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137]. The list of other countries with published cases of scrub typhus is found in S2 Table [80,136,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154]. All countries with reported cases are designated in Fig 1. The literature review confirmed that the majority of scrub typhus cases were reported in the “tsutsugamushi triangle” in the Asia-Pacific region (Table 3) [23,45,105,155,156,157,158]. There were a few cases reported in Central Asia and the Middle East, which are outside the traditional definition of the Asia Pacific region, but neighboring it [49,145,159]. The cases are primarily found in southwest China, and the southeast coastal and eastern regions of China. May is usually the start of the scrub typhus season, and June and July are the peak months. The pattern correlates with the weather and life cycle of mites [160]. Recent studies showed that the geographic distribution of the disease has expanded to northern China. It has existed in southern China for thousands of years [158,161]. Scrub typhus cases can be divided into 6 clusters in China. Cluster 1, the significant primary cluster, is located in southern and southeast China, which includes provinces of Guangdong, southern Fujian, Jiangxi, and Guangxi. The secondary cluster is mainly in southwest China, which includes Yunnan and Sichuan Provinces. Jiangsu, Anhui and Shandong provinces in East China are the third cluster for scrub typhus. Shaanxi province in the Northwest and Beijing Municipality were recognized as the fourth and fifth clusters in the analysis done by Zhang et al. The provinces of Zhejiang and northern Fujian were cluster 6 [158]. In other studies, there were reported cases in Hunan Province and Tibet [160]. Data collected between 2006 and 2012 show that the highest cumulative incidence was in the 60–69 year-old age group (0. 66 per 100,000), and the lowest one was in the 10–19 year-old age group (0. 11 per 100,000). The 50–60 year-old group accounted for the largest portion of all scrub typhus patients in China (21. 36%). There was no difference in incidence between genders [158]. A remarkable resurgence and a prominent outbreak occurred between 1976 and 1984 due to an increase of mite populations carrying O. tsutsugamushi. There was no explanation available for the increased number of mites during that period [162]. The disease has now been found in almost all areas of Japan except in Okinawa and Hokkaido prefectures. A retrospective study in 1998 demonstrated that Kyushu (51% of total cases), Tohoku-Hokuriku (27%) and Kanto (19%) had the largest numbers of cases [45]. In contrast to China, November accounted for the largest proportion of reported cases driven by the large number of cases in Kanto and Kyushu. May had the second highest monthly number of cases due to the cases in Tohoku-Hokuriku [45]. The age distribution differs between Japan and China. In Japan, 62% of cases were 51–75 years old, while in China this age group accounted for less than half of the total patients (~48. 2%) [45,158]. No significant gender differences were observed in Orientia infection in Japan. Not surprisingly, working in farming and forestry is an important risk factor for scrub typhus [45,162]. Scrub typhus was first reported in South Korea during the Korean War, but it was still unfamiliar to Korean civilians until 1986 [163]. The disease has subsequently been recognized as the most common rickettsial disease in South Korea [156,163,164]. Nation-wide seroepidemiologic and microbiologic surveys demonstrated that 27. 7% to 51% of acute febrile illness patients in South Korea were seropositive for O. tsutsugamushi between 1986 and 1993 [163]. The study confirmed that scrub typhus was widely spread in the country, and that it was frequently underdiagnosed [163]. Scrub typhus became a reportable disease in South Korea in 1994. Physicians must report all confirmed or suspected scrub typhus cases to both the local health bureau and the Korean Centers for Disease Control and Prevention (CDC). The gender inequality of scrub patients is unique in this country. Several studies confirmed that more female patients were reported than male patients (~65% vs 35%) [70,156]. One possible explanation is due to the conventional working behavior in farms in South Korea. Female workers typically work in a squatting position in dry fields, while male farmers tend to stand with tools in rice fields during work [70]. Other characteristics of the epidemiology of scrub typhus in South Korea are the increasing incidence in urban areas and expansion to northern regions [70,164,165]. The proportion of cases identified in urban areas increased from 20% (388 cases) in 2002 to 26. 9% (1,345 cases) in 2009, while that in farmers decreased from 43. 3% to 25%. However, further analysis revealed that outdoor activity in urban areas is the most common risk factor [70,164]. Similar to Japan, October and November are the peak months for scrub typhus cases. The age group 60–69 years old is the largest group for scrub typhus cases in South Korea (27. 48%), and 72. 2% patients were 50–79 years-old [70,156]. Scrub typhus was recognized as a typhus-like fever in India in 1917 [1,166]. It was a major cause of fever among military personnel along the Assam-India-Myanmar (formerly Burma) border during World War II, and the 1965 Indo-Pak war [1,43]. The disease resurged at the Pakistan border of India in 1990 [43]. The widespread use of insecticides and empiric treatment of febrile illness as well as changes in lifestyle all contributed to the subsequent decrease in incidence [43,167]. However, scrub typhus is still an under-diagnosed disease in India [43]. Field epidemiology studies indicate that the disease occurs all over India, from South India to Northeast India and Northwest India. There were cases reported from Maharashtra, Tamil Nadu, Karnataka, Kerala, Himachal Pradesh, Jammu and Kashmir, Uttaranchal, Rajasthan, West Bengal, Bihar, Meghalaya, and Nagaland [27,43,110,168,169]. The peak of the disease is between August and October. Leptotrombidium deliense is reported as the primary vector of O. tsutsugamushi [1,155]. Socioeconomic status and occupation are important risk factors for scrub typhus. Most scrub typhus patients in India are uneducated and live in rural areas [27,43]. The tropical climate of Thailand provides an ideal environment for the vectors of O. tsutsugamushi, L. deliense and L. chiangraiensis [1]. Nationwide sero-epidemiological studies revealed a high prevalence of scrub typhus in Thailand [157,170]. The rates of O. tsutsugamushi antibodies varied from 13% to 31% of residents in suburban Bangkok, to 59% to 77% of residents in the northern and northeastern regions [157]. A human case was first reported from the central region of Thailand in 1952 [157,171]. The pathogen was first isolated from rodents in the same part of the country two years later [172]. There was a substantial increase in the number of confirmed cases in Thailand from the 1980s to the 2000s [157]. Growing awareness of the disease and development of new diagnostic tools may at least partially contribute to this trend [157,173,174]. Different from China and Japan, the male to female gender ratio of scrub typhus patients in Thailand is 2: 1 [157]. The age distribution of the disease in Thailand is that the 50–59 year old group is the largest group (22. 3%), but both the 30–39 year old and 40–49 year old groups are similar, ~20%. Outdoor activity, especially occupational exposure, is a critical risk factor [157]. The earliest reports of scrub typhus cases in Vietnam can be dated back to the 1960s during the Vietnam War [175,176,177,178]. Most of the patients in the 1960s and 1970s were military personnel, especially American servicemen in South Vietnam [46,178]. The disease had been neglected in Vietnam since then until the end of the last century and the beginning of 21st century, resulting in a gap in publications during that time [179]. Differing from past studies, current studies and case reports of scrub typhus in Vietnam have been focused on the northern part of the country. There was only one study in the central part of Vietnam, Quang Nam province, which identified that the main genotype in the area was the Karp group [180]. Recent studies of scrub typhus in North Vietnam demonstrated that the cumulative incidence of scrub typhus was about 1. 1% among the general population, and ~3. 5% among patients admitted to hospitals [103,105]. The peak season in North Vietnam is summer though cases occur throughout the year. The transmission pattern of scrub typhus in tropical South Vietnam may be different because a seasonal pattern is more obvious in a temperate climate [66,105]. There was no significant difference between urban and rural areas [103]. In addition to the countries described above, there are quite a few other countries with reported scrub typhus cases in the tsutsugamushi triangle. Scrub typhus has been recognized on the islands of the southwest Pacific including Indonesia and the Philippines, and the continent of Australia for almost a century [149,181,182,183,184]. It was recognized as “coastal fever” in 1913 and scrub typhus after the 1920s in Australia. The endemic areas in Australia are the tropical coastal periphery of northeastern Queensland, the tropical region of the Northern Territory, and the adjacent Kimberly region of Western Australia [1,181,182]. A new strain, Litchfield, different from those from other Asia-Pacific area countries was isolated in Australia in 1998 [185]. The Philippines did not confirm the occurrence of scrub typhus until World War II. The first but failed US scrub typhus vaccine was prepared from the lungs and spleens of white rats infected with Volner strain of O. tsutsugamushi. The Volner strain was originally isolated from the blood of a soldier in the Philippines [149,186]. The history of scrub typhus in Malaysia could be traced back to 1915 [187,188,189]. World War II made the disease known in the Solomon Islands, Republic of Vanuatu, and Papua New Guinea [128,146,190,191,192]. Our literature search found isolated Orientia infection in human patients in Far East Russia and Pakistan, and further studies may be necessary to confirm the distribution and other epidemiological features of scrub typhus in these countries [48,153,154,193,194,195,196]. The distribution of scrub typhus covers a large and diverse area. In the Asia-Pacific region alone, different countries in the endemic area have different climates, environment, and culture, which all contribute to the different characteristics of epidemiology of the disease [1,64]. Our study has the limitation that we only analyzed literature in English within the databases of PubMed and Google Scholar. There were quite a few publications in Chinese, Japanese, Korean, Russian, and other languages not included in the analysis. Our literature review determined that there are a few sporadic scrub typhus cases from countries and regions outside the traditional “tsutsugamushi triangle” in the Asia-Pacific area (Fig 1). UAE is outside the traditional endemic triangle. However, the case reported in 2010 demonstrated a scrub typhus case confirmed to be caused by a new Orientia species, O. chuto [49]. The Australian patient concerned had traveled to Dubai, UAE and the United Kingdom before the onset of her febrile illness. She noticed an eschar on her abdomen after the Dubai visit. An IFA, polymerase chain reaction (PCR), and sequencing were employed to determine the etiologic pathogen. The molecular variance of the 47-kDa gene, 56-kDa gene and other nucleotide sequences, and geographical difference led the researchers to propose the new Orientia species. There was only one known Orientia species, i. e. , O. tsutsugamushi, before this case [23,49]. Before the two scrub typhus reports in Chile, there was no reported autochthonous scrub typhus case in the Western Hemisphere. A patient was bitten by terrestrial leeches on Chiloé Island in southern Chile in 2006 [139]. Both PCR, a molecular biological test, and, IFA, a serological test, showed diagnostic confirmation of O. tsutsugamushi infection. The molecular analysis further indicated that the pathogen is closely related but not identical to other O. tsutsugamushi and O. chuto species. It was significantly closer to Orientia sp. than to other rickettsiae. The results suggested that the pathogen from the Chilean sample was not a simple import from an endemic area. In addition, the case also reminds us that there might be other vectors, such as leeches, for Orientia [139]. The latest study reported three native cases on the same island in 2016 [151]. The researchers used both serological testing and molecular analysis to diagnose the patients. At least one patient received diagnosis by two serological tests from both the local hospital and the Mahidol-Oxford Tropical Medicine Research Unit in Thailand, and molecular analysis at the Lao-Oxford-Mahosot-Hospital-Wellcome Trust Research Unit. They used paired antibody titer comparison for diagnosis, which is more reliable than a single titer diagnosis [197]. The second patient was documented by molecular analysis of the agent but half of the IFA serologic tests were negative. The third patient had two high single-titer IFA results but negative PCR results. No leech bite was observed in these cases [151]. More follow-up studies could fill these gaps. There are case reports from Cameroon, Kenya, Congo, Djibouti and Tanzania in Africa [102,143,144,147]. The only case report from Cameroon was an American who visited Cameroon before developing a febrile illness [143]. The patient’s IFA titer to O. tsutsugamushi increased from 1: 256 to >1: 1,024 two weeks after admission, but PCR analysis of formalin-fixed, paraffin-embedded skin samples was negative. Several clinical features were not typical [143]. The researchers in Kenya screened samples of reactive sera from patients with febrile illness in Kenya. Western blot was performed to confirm the specificity. About 5% of the serum samples contained antibodies reactive with O. tsutsugamushi [102]. The clinical features and serological test, IIP, confirmed the diagnosis of O. tsutsugamushi Kato strain in the only case in Congo. However, the patient resided and was diagnosed in Japan. The patient visited Congo for 23 days, and noticed symptoms 8 days after he left Congo. The researchers contacted local centers for disease control in Japan where the patient lived and worked. They did not find similar reports in Japan so they concluded that the patient contracted the disease in Congo. No other case in Congo has been reported [147]. Therefore, it is reasonable to suspect the possibility of domestic infection in Japan instead of acquisition in Congo. More epidemiologic studies of scrub typhus are necessary to confirm the existence of scrub typhus in Congo. A new study of 49 abattoir workers in Djibouti demonstrated that three workers were seropositive against Orientia, and one worker seroconverted during the study [80]. The titers observed in the study were 100–400 for ELISAs, and 1: 128 for IFA. The cut-off titer and methods used in this study may be controversial, and require further validation [197]. In addition, the study did not provide the participants’ travel history even though the authors played down this confounder due to the subjects’ socioeconomic status [80]. A Dutch traveler to Tanzania contracted O. tsutsugamushi there. Researchers in the Netherlands confirmed the case with clinical features (fever, eschar, etc.) and serological tests, i. e. , IFA [144]. No other case has been reported in Tanzania.
Scrub typhus is a serious public health problem in the Asia-Pacific area. There is an estimated one million new scrub typhus infections each year, and over one billion people around the world are at risk. Without appropriate treatment, the case fatality rate of scrub typhus can reach 30% or even higher. Scrub typhus has long been a neglected infectious disease so many aspects of the disease, including its diagnosis to prevention, are unknown. We here provide a comprehensive review of the epidemiology, prevention and control of scrub typhus.
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A review of the global epidemiology of scrub typhus