Published online Apr 15, 2024.
https://doi.org/10.3947/ic.2023.0105
Tick-Borne Rickettsiosis and Tsutsugamushi Disease Recorded in 313
Abstract
Tsutsugamushi disease was first described in China by Hong Ge in 313. In his book Zhouhou Beiji Fang, three eschar-associated febrile diseases were described: Shashidu, Zhongxidu, and Shegongdu. Shashidu was identified as being identical to tsutsugamushi disease in Japan: it occurred in riverside areas, exhibited an eschar, and was transmitted by tiny red “sand lice”. The nature of Zhongxidu remains unknown, but we propose that it is another type of Orientia tsutsugamushi infection: it occurred in mountainous areas, an eschar was observed, and the causative vector was not identified. Moreover, Zhongxidu would have predated Shashidu by five centuries; thus, the first documentation of tsutsugamushi disease would date back 2.2 millennia. O. tsutsugamushi infection without eschar has not been identified in ancient Chinese literature and may be included in Shanghan. Several ancient Chinese books describe that Shegongdu occurs following a Shegong bite. Shegong is described as a bug resembling a cockroach or cicada with a crossbow-like structure, possibly the hypostome and unfolded palps of tick, in its mouth. Thus, Shegong refers to an engorged tick and Shegongdu is a tick-borne rickettsiosis. However, due to a lack of entomological knowledge, these findings have not been recognized for the past 1.7 millennia.
Introduction
Tsutsugamushi disease was first discovered by Japanese researchers from a Western medical perspective. While studying the clinical aspect, epidemiology, causative agent, and prevention of this disease, individual researchers had also searched ancient Chinese and Japanese literature. Keisuke Tanaka, an experienced clinician in Akita Prefecture, Japan, first mentioned in 1895 that Shashidu, described in Baopuzi, Zhouhou Beiji Fang, Zhubing Yuanhou Lun, and Bencao Gangmu, was identical to tsutsugamushi disease in Japan [1]. He also compiled previous Chinese and Japanese literature on tsutsugamushi disease and self-published it twice in 1908 and 1925 under the title Brief Summary of Research on Japanese Kedani Disease (in Japanese). Kedani disease is an older term for tsutsugamushi disease and was commonly used in Akita Prefecture. He also mentioned a poem written by Deyu Li [2]. Hatori (1919) described Bencao Gangmu and the treatise written by Kenkei Ohtomo, Treatment Experience of Kedai Disease (in Japanese) [3]. Kawamura (1926) mentioned Bencao Gangmu, Ohtomo’s treatise, and the paragraph in the monograph Dandoku Ron (Treatise on Eliminating Poisons) written by Hakuju Hashimoto (1810) [4].
At the time, tsutsugamushi disease occurred in riverside areas of Niigata, Akita, and Yamagata prefectures in Japan, was transmitted by the larvae of trombiculid mites, commonly called chiggers, and was associated with eschar formation. Meanwhile, Schüffner had described the occurrence of an enteric fever-like febrile disease in Sumatra, Indonesia, since 1910, which rarely showed eschar [5]. In Malaysia, Fletcher and Lesslar (1925) reported similar cases with no eschar but positive agglutination reactions to Proteus OXK and named the disease scrub typhus [6]. In the present article, we use the names tsutsugamushi disease and scrub typhus differently, as did Fletcher [6, 7].
According to the studies mentioned above, it is known that tsutsugamushi disease has been present since 313. However, most medical textbooks and articles only mention the occurrence of the disease in that year without fully discussing it. To understand the details of the records written by Hong Ge, we reviewed ancient and medieval Chinese literature, all of which is available in the public domain and on websites. Before proceeding further, it is noted that Ge often used metaphorical expressions, and thus it is difficult to capture his intent when the sentences are translated literally; therefore, we made liberal translations of many of his sentences, especially those related to medical matters. Additionally, there may be minor differences in content between the versions of the books, but these do not significantly affect our interpretations. To leave only objective descriptions in the following translations, sentences containing Oriental medical diagnoses or treatments were omitted.
1) Description by Hong Ge
Ge published two medical books, Yuhan Fang and Zhouhou Beiji Fang, and books on Taoism, including Baopuzi (completed writing in 317 or 318 and revised in 326–334). Zhouhou Beiji Fang (Zhouhou Fang), written in 313, is a concise three-volume work built on its 100-volume predecessor, Yuhan Fang. The latter book summarized the relevant books published up to that time and has now been lost. Literally, zhou means elbow; hou, behind or after; bei, prepared or for; ji, emergency; and fang, prescription or formula. When a man wears a traditional Chinese robe, his hands are usually positioned behind the contralateral elbows; therefore, zhouhou means handy. Thus, Zhouhou Beiji Fang is translated as the Handbook of Prescriptions for Emergency.
This manual has been revised twice. The first revision was made by Hongjing Tao in the early 500s, when he added twenty-two new prescriptions and deleted seven prescriptions from the original 86 prescriptions. In Tao’s manuscript, the revised chapters were marked in red. However, in later versions printed at various sites, these parts were indistinguishable. Both scholars traveled to many regions of China to find medicinal herbs; therefore, they may have seen or heard about these diseases and bugs first-hand. For example, the manual recommended the use of sweet wormwood (Artemisia annua) extracts to treat malaria; artemisinin was later found to be the active ingredient in the extracts. All but one of these versions have been lost. The second revision was made by Yongdao Yang in 1144, based on the version printed around 1105. It became an eight-volume book containing 73 prescriptions, and has been the source book for the current editions of the book.
The following three eschar-associated febrile diseases are described in this book: Zhongxidu, Shegongdu, and Shashidu. Yuan-Fang Chao described these three diseases as Shuiduhu (lit. water poisoning syndrome), Shegonghu (lit. shooting expert syndrome), and Shashihu (lit. sand louse syndrome) in his medical book Zhubing Yuanhou Lun (Treatise on the Causes and Manifestations of All Diseases) (610). The term Zhongxidu was changed to Shuiduhu, which has been more commonly used in the subsequent medical literature. Chao added the following sentences, which are underlined, to Ge’s descriptions of the three diseases.
(1) Shashidu
Ge described Shashidu (sha, sand; shi, louse; and du, poisoning; Shashidu literally means sand louse poisoning) as follows: “In the water of mountain valleys, there are numerous sand lice so small that they cannot be seen with the naked eye. When a person bathes in the water or passes through the meadows on cloudy and rainy days, these lice attach themselves to the skin of the person and burrow under the skin. The disease is diagnosed as follows: initially, the bite site becomes erythematous and resembles a grain of red beans or millet, which is painful to touch. Three days later, pain in all joints and chills develop, and a sore develops on the erythema. If the sand lice reach the bones, death occurs. After bathing in the water, rub the body several times with a hemp towel and once with a silk towel, then apply body powder immediately.” There is an additional sentence in Baopuzi: “The color of the lice is red.”
The above descriptions of Shashidu were appreciated by Tanaka, and it was accepted that tsutsugamushi disease occurred in 313 in China. Although Ge called the bug “sand louse”, it is not a louse nor does it live in water or sand. This misclassification reflects the limited level of entomological knowledge at the time. Additionally, the human body louse was well-known in ancient China. The red color of the sand lice is compatible with Leptotrombidium deliense chiggers, a chigger species prevalent in southern China.
Although chigger bites are usually asymptomatic, those caused by L. akamushi in Japan were described as often being associated with pricking pain when touched with clothes. Chiggers digest the host’s skin with saliva to form a feeding tube, a stylostome [8]. During this process, the destroyed host tissue may cause pain when touched; therefore, the pain does not appear to be specific to L. akamushi, and ancient Chinese patients may have complained of it as well. Alternatively, L. deliense is similar in morphology to L. akamushi; therefore, pain may also occur in China.
Ge clearly described the evolutionary change of the bite site from a papule to a “sore”. The term “sore” (the corresponding word is pronounced chuang in Chinese, chang in Korean, and kasa in Japanese) in Oriental medicine refers to an inflammatory skin lesion, most commonly an ulcer or occasionally a blister, usually covered with a dark crust or yellow exudate. Regarding the sequential changes of a chigger bite site, an erythematous macule around the bite site continues to enlarge beyond 2–3 days if the mite is infected, tender regional lymphadenopathy follows 3–4 days after the mite bite, and fever develops 3–4 days after the appearance of the lymphadenopathy. An erythematous papule develops in the center of the erythematous macule or patch on days 3–4 after the bite, and the papule enlarges and develops into a vesicle or bulla 5–20 mm in diameter on days 5–6 [9, 10, 11]. The rate of progression and the size of the papules or vesicles vary from patient to patient, possibly depending on pre-existing immunity [12]. A small papule (3–4 mm in diameter) with an ulcer at the top covered with a honey-colored crust has been frequently described in the past, but rarely in recent reports of tsutsugamushi disease [13]. The bulla usually appears as a flat white membrane with a dark-gray base. A small opening appears in the center of the bulla and enlarges, leaving ragged, fragmented, white membranes at the rim of the bulla [11]. On days 7–10, a central part of the dark-gray base soon becomes a clean ulcer without a covering crust. Fever develops around this time, and 2–3 days later the ulcer becomes covered with a black crust. The black crust is a dried exudate that has oozed from the ulcer; therefore, it is sometimes not observed if the ulcer is located in a moist area of the body, such as the axilla or groin, or if the patient is using a dermatologic ointment that prevents the exudate from drying out. Thus, when patients with tsutsugamushi disease seek medical attention for fever, clinicians usually observe a black-crusted lesion (eschar), or sometimes a clean ulcer. The eschar stops expanding after the second or third day of fever. Finally, a shallow ulcer or atrophic scar develops after the crust sloughs off at the end of the third week [14, 15].
Ge’s recommendation to remove attached chiggers with a coarse towel is intriguing, but its preventive efficacy has not been evaluated. Insect repellents and doxycycline prophylaxis have been used primarily for soldiers [16, 17], but civilians living in rural areas differ from soldiers in several ways. They can bathe daily and seek medical attention when they become ill. More importantly, the risk of contracting the disease among civilians varies by area and season, making it difficult to determine whether the risk in a particular area is high enough to warrant the above prophylactic measures. Given the above differences between civilians and soldiers, rubbing with a coarse towel after bathing with soap and water may be a preventive method that civilians can use routinely. Since the location of eschars on the human body is well known, rubbing these areas could effectively remove or crush attached chiggers and may reduce the incidence of the disease.
(2) Shegongdu
Shegongdu (she, shooting; gong, expert; and du, poisoning; Shegongdu means shooting expert poisoning) is described as follows: “South of the Yangtze River, there are poisonous insects called Shegong, also known as short fox or yu (lit. water fox). They live in the water streams of mountain valleys. This bug has a crossbow-like transverse bone in its mouth. It looks like a large black cockroach and produces a bite-like lesion. Female and male bugs can be distinguished. The male bug has two horns around its mouth, and can fold the tips of the horns in and out. When a person wades, washes, or bathes in the stream, Shegong shoots to the shadow of the person, and then the person becomes ill. The diagnosis is made as follows: when a person is affected by the disease, this condition presents with the symptoms of Shanghan (see below), stroke-like neurological symptoms, an inability to speak, or fever and chills. The person may not be able to move all four limbs. Symptoms improve in the morning but worsen in the evening. In severe cases, the gums bleed within three days, and if left untreated, the person dies immediately. When the entire body is examined at presentation, four types of skin lesions can be observed in Shegongdu: a black (sore) surrounded by erythema that may be painful to touch, a sore that deepens as it lasts, an indurated papule, or a rapidly progressing sore that looks like flaming flesh and is the most urgent; however, all these types of lesions can lead to death.” Additionally, in Baopuzi, Ge described it as follows: “Shegong is like a cicada, has wings, and can fly. In winter, Shegong hides in the ground. Snow does not accumulate there and steam comes out of it.”
Epidemiologically, Shegongdu is similar to Shashidu, but the causative bug is large enough to be seen with the naked eye. Modern Chinese dictionaries describe yu as a turtle-like creature in fables and do not contain relevant scientific names for the terms Shegong, yu or shui hu (water fox), and Xi-gui-chong (see below). In Japan, the book Wakan Sansai Zue used the term Isagomushi for Shegong; however, current dictionaries refer to Isagomushi as Shatsu and caddis flies, which are completely different from cockroaches and cicadas. Korean dictionaries also refer to Xi-gui-chong as caddis flies (Fig. 1). Therefore, Shegong remains an unidentified bug.
Figure 1
Image of Shegong in Bencao Gangmu by Shi-Zhen Li [Attribution - CC0] (from the National Library of Korea), with some modifications to clarify the image. A crossbow-like structure in the head, three pairs of legs, and two wings can be seen. This image seems to resemble a caddis fly.
The reason why Ge used the word “fox” in the synonyms for the bug is a mystery. If Ge wanted to refer to a beaked animal, he would have used “dog”, a more friendly animal, instead of “fox”. Therefore, it seems that Ge intended to indicate the characteristics of the disease, not just the morphology of the bug. In the Orient, the tale of the nine-tailed fox has been famous since its documentation in Shanhaijing in 200 BC; however, its verbal versions are said to have been widely known for millennia prior to its publication. In this story, the fox is portrayed as a witchy animal that controls the minds of those who are affected. Therefore, it can be assumed that the neurological manifestations in Shegongdu cause the affected person to appear bewitched by the fox. If the above hypothesis is correct, Shegongdu would have had noticeable neurological manifestations, which is a well-known finding in severe rickettsial diseases. In this context, while the word “typhus” has been used in Western medicine since the 18th century to refer to the above neurological manifestation of rickettsial diseases, the word “fox” has been used in China with the same meaning as “typhus”.
The name of the vector, shooting expert, may have been derived from its resemblance to a crossbowman. However, it is another mystery how the presence of a transverse bone in its mouth is related to a shooting expert, how such a creature can survive with an obstacle in its mouth, and whether such a creature exists in nature. Underground hibernation during winter is not reasonable for arthropods and cannot be explained.
Various forms of eschar have been clearly described in Shegongdu, and they appear to be described in the order of frequency: the eschar form is the most common, followed by an ulcer and papule, and then a reddened sore. Although the evolution of eschar in rickettsial diseases has not been well studied as that in tsutsugamushi disease, it is expected that eschar in the former diseases will follow the same course as eschar in tsutsugamushi disease. Therefore, as in Shashidu, a hard nodule (third described lesion) may be the initial lesion, which then evolves into an ulcer (second described lesion) or an eschar (first described lesion). The eschars described above have an erythematous halo, which distinguishes the eschar caused by rickettsia from nonspecific ulcers covered with black crusts. Therefore, the above descriptions of Ge indicate that Shegongdu is an eschar-associated rickettsial disease, unless it is a rare disease with an eschar, such as tularemia or cutaneous anthrax.
The overall clinical features of Shegongdu appear to be more severe than those of Shashidu and Zhongxidu because of the early development of neurological and hemorrhagic manifestations. Words indicating death were used twice in Shegongdu compared to once in Shashidu and Zhongxidu. Bencao Gangmu quoted Xuanzhong Ji, written by Pu Guo (276–324), which stated that “When individuals are shot by the spirit of Shegong, six or seven of ten of them will die.” It is difficult to compare the severity of spotted fever rickettsiosis and tsutsugamushi disease, mainly because such studies have rarely been conducted in Asian countries. An analysis of cases notified through national surveillance during 2007–2016 in Japan showed mortality rates of 0.48% for tsutsugamushi disease and 0.91% for Japanese spotted fever [18]. In an Australian study, Queensland spotted fever showed a higher incidence of delayed defervescence than scrub typhus, and those with delayed defervescence had more severe disease [19]. Thus, the records of Ge and our interpretations are supported by these studies. Additionally, from the above data, it can be estimated that the mortality rate of Zhongxidu (tsutsugamushi disease) was 30–35%, which is not so different from that of Japanese patients with tsutsugamushi disease before 1950 (20–46%) [20], although the characteristics of patients and the quality of supportive care differed significantly between ancient China and Japan.
(3) Zhongxidu
Zhongxidu (zhong, middle, amid, or in; xi, stream in the valley; du, poisoning; Zhongxidu indicates poisoning in the stream) is described as follows: “ Shuidu-bing (lit. water poison disease) occurs in all mountainous villages and prefectures east and south of Suzhou, Changzhou, and Huzhou, and its sources are present in the water streams of mountain valleys. It occurs during the transition period from spring to autumn. Zhongxidu is caused by shuidu (lit. water poison), and is also called zhong-shui (lit. in the water), zhong-xi (lit. in the stream), zhong-sa (lit. in the splashing water), shui-zhong-bing (lit. disease in the water), or xi-wen (lit. warm stream). The disease is similar to Shegongdu, but there is no such bug in this disease. The disease is diagnosed as follows: it begins with fever, chills, mild headache, eye pain, chest discomfort, tremors in all four extremities, stiff joints, and tendon pain. Sleepiness increases, such that even if the patient is awake in the morning, the patient becomes very sleepy in the evening. The hands are paradoxically cold. Three days after the onset of the disease, a sore resembling an insect bite appears on the lower body, which can be found only by purposeful searching because it is not accompanied by pain, itching, or cold. It is not necessary to treat the sore immediately. After 6–7 days, the bite-like sore ruptures into an ulcer covered with a black crust and surrounded by erythema, resembling a hen’s eye; the internal organs are involved and the fever peaks. Diarrhea does not cease. Eight to nine days after the onset of the disease, even an experienced doctor cannot cure the disease, and feels that the patient’s condition is serious. When the doctor examines a sore on the lower body, if it is present and red like cut beef, it signals a serious condition, while if it resembles the teeth of a snakehead fish, it indicates a slowly progressing condition. However, regardless of the sore’s appearance, the disease can progress, potentially leading to death within 20 days of the onset of the disease.”
The clinical features of this disease are similar to those of Shegongdu, with fever and eschar. However, the vector responsible for the transmission has not yet been identified or characterized. Therefore, this disease is essentially identical to Shashidu rather than Shegongdu in terms of the difficulty in identifying the vector. However, the exact nature of this disease remains unknown.
There are several synonyms for this disease, all of which suggest that the putative bug is related to water but not as closely as Shashi and Shegong. Compared to Shashidu, this disease was more prevalent in larger areas, especially hilly or mountainous areas, south of the Yangtze River. This indicates that its epidemiology is similar to that of scrub typhus in terms of warm climates and exposure to shrub areas. Because chiggers require moist topsoil, individuals are more likely to become infected with O. tsutsugamushi in shrub or grass areas near streams in mountain valleys than in shrub areas with dry topsoil. The symptoms of Zhongxidu are initially mild, but become severe in the second week, and death occurs at the end of the second or beginning of the third week after onset, which is a typical course of tsutsugamushi disease or rickettsial infection. A painless ulcer that is not associated with itching and is surrounded by erythema can exclude most nonspecific ulcers from the ulcer of tsutsugamushi disease. The appearance of a vesicle at the bite site on day 3 after a chigger bite and its progression to an ulcer or eschar on days 6–7 is a well-known finding in tsutsugamushi disease, as previously described in Shashidu.
2) Other Chinese literature
After the publication of the above books, other medical books, including Beiji Qian Jinyao Fang (first published in 652 and supplemented in 682) and Wai Dai Mi Yao Fang (752), described the above diseases. However, these books did not add any new content on the diseases.
In 849, Deyu Li, a poet and former prime minister of the Tang Dynasty, wrote a poem entitled Writing While Going into Exile in Yazhou (in Chinese). In this poem there are the following sentences: “I avoid the sand on the swallow’s legs because I am afraid of Shatsu falling from the sand. Fire rice is harvested in a slash-and-burn field in May.” Yazhou is a district in Hainan Island. He first used the term Shatsu or Shachu to refer to “sand bug”. Shift cultivation was practiced in these regions, and this agricultural technique is associated with the occurrence of scrub typhus on abandoned land after farmers move to another area. Unharvested crops are left in the rice field, and field rodents move into the field, creating mite islands. Subsequently, when newcomers enter this field, they become infected with O. tsutsugamushi.
Taiping Shenghui Fang (Formulas of Great Peace and Sagely Benevolence), compiled by Huaiyin Wang in 992, provided more detailed descriptions of the diseases, but essentially the same content. In Bencao Gangmu (Compendium of Materia Medica), written by Shi-Zhen Li in 1596, there were additional descriptions based on several other books as follows: “Shashi is about the size of a body louse, and its color is red. Shatsu exists in Tanzhou, Yuanzhou, Chuzhou, and Jian. Shatsu lives in snake scales and is a kind of Shashi (Taiping Guangji, 978).” “Individuals living south of the Yangtze River remove Shashi with bamboo leaves and then apply lettuce juice to the bite site. If the bug has already penetrated deeply, it is plucked with a needle. Its morphology is similar to that of a scabies mite (Zhouhou Fang).”; this description is not present in the current version of Zhouhou Fang and may have been quoted from another version of Zhouhou Fang that is not currently available. Although Shatsu was described as a kind of Shashi in Bencao Gangmu, the description was different from that of Deyu Li. Li’s description can be explained as chiggers falling from birds, but the description in Bencao Gangmu appears to be snake mites, which are not human ectoparasites. Therefore, the identity of Shatsu cannot be confirmed.
Shi-Zhen Li described Shegong as Xi-gui-chong (lit. ghost bug in the stream) as follows: “Shegong is a cicada-like bug, one cùn (※approximately 3 cm at present, but shorter in earlier years) wide and 2–3 cùns long. The front of the bug is wide and the rear is narrow and flat in shape.” He also quoted several books as follows: “The abdomen of the bug is soft and its back is hard like a turtle shell. It is black in color (Baopuzi).” “It resembles a softshell turtle. In June and July, it grows wings under the shell, and can fly and make the sound ‘bhi bhi’. The wide legs resemble those of a crab, while two (legs) are like a crossbow on an arrow (Lu ji).” (Fig. 2), and “it resembles a dung beetle (Yuyang zazu).” The author of the book Lu ji lived from 261 to 303, indicating that Shegong was already described before Zhouhou Fang.
Figure 2
Image of Shegong in Wakan Sansai Zue by Ryoan Terajima [Attribution - CC BY] (from the National Diet Library, Japan). It is depicted as an ovoid bug with a beak, a shell on the back, two wings under the shell, and two pairs of middle and hind legs like the legs of a crab.
Despite the aforementioned publications, the natures of Shashidu, Shegongdu, and Zhongxidu remained unclear until Tanaka’s report in 1895. Thus, Chinese scholars appeared to lose interest in these diseases. Yixue Rumen (Introduction to Medicine), written by Chan Li around 1580, briefly described all three of the above diseases in one paragraph under the title of Shuidu (Soodok in Korean). Bencao Gangmu also described Zhongxidu as a type of Shegongdu. Yangyi Daquan (1760) briefly described only the formulas for the treatment of Shegongdu and Shashidu.
In contrast to waning interest in China, the first discovery of tsutsugamushi disease in Japan in 1878 stimulated renewed interest in the disease from the perspective of Western medicine. Tanaka first recognized Shashidu as being identical to tsutsugamushi disease in Japan; however, he may not have recognized Zhongxidu as tsutsugamushi disease because it occurred in scrub areas and its vector was not identified. He also could not recognize Shegongdu as a tick-borne rickettsial disease because tick-borne spotted fever rickettsiosis was not reported in Western medicine until 1896 [21].
3) Nature of Shegong and Shegongdu
Ge and other scholars described Shegong as a small, ovoid, flat to fat, green to brown or black bug with horns on its head that bites humans and causes a febrile illness and characteristic skin lesions. However, based on current entomological knowledge, it is difficult to identify such a bug. One possible explanation is that Shegong is an engorged tick.
Ticks have a capitulum and a body. Additionally, hard ticks are distinguished from soft ticks by the presence of a scutum on the body. The scutum is a hexagonal, shell-like plate that covers the upper back of the body and is usually darker than the rest of the body. When an adult female tick feeds and engorges, the body swells immensely and the tick becomes ovoid and plump in shape. As the capitulum and scutum are displaced by the swollen body, the scutum looks like a wide-open mouth, and the capitulum appears to protrude from the mouth. Engorged ticks vary in color from green to brown or black depending on the tick species, which can explain the colors of Shegong, and range in length from 6–10 mm. Adult male and female ticks differ in size and morphology; in particular, engorged adult female ticks are much larger than their male counterparts. The mouthparts of the capitulum are attached onto the base of the capitulum and consist of a hypostome, a pair of chelicerae, and a pair of palps, arranged from the inside out. These structures are 0.5–1.5 mm long, depending on the tick species, and can be easily observed with the naked eye. In contrast, chiggers are approximately 0.2–0.3 mm in diameter, 0.4–0.5 mm when fully engorged, which is not easily visible to the untrained eye, but experienced individuals can detect their presence. Tanaka described a chigger attached to the skin as looking like a red dot.
During feeding, the palps of ticks unfold and become firmly attached to the skin of the host, resembling a transverse bone. Because the hypostome and chelicerae are already vertically present in the center of the transverse bone, it gives the appearance of a crossbow. This figure was clearly described in Bencao Gangmu as “two (legs) are like a crossbow on an arrow.” This led Ge to believe that the Shegong’s mouth contains a crossbow-like transverse bone, and that Shegong holds a toxin in its mouth, thereby injecting it into an individual using this crossbow-like structure. Several scholars have described this bug as resembling a softshell turtle, rather than a turtle. Softshell turtles cannot completely retract their head and legs under their shell, whereas turtles can. Therefore, the term “softshell turtle” would be used to indicate that the capitulum is partially embedded in an ovoid dark-brown body. The term “dung beetle” also refers to a black, ovoid, dome-shaped bug with a horn on its head. Overall, the above descriptions of Shegong are compatible with the characteristics of engorged adult female ticks, especially hard ticks, such as Ixodes sp., Dermacentor sp., and Haemaphysalis sp., all of which are currently found in China [22, 23, 24].
However, there are descriptions that are incompatible with engorged ticks: the bug has wings, is somewhat larger than engorged adult female ticks, and is a warm-blooded creature. Perhaps Ge and other Chinese scholars believed that Shegong was a small water-dwelling mammal (“water fox”) that bites humans and injects a toxin to induce Shegongdu, which is characterized by the state of being “bewitched by a fox”. Shortly thereafter, the bug may return to the water, maintain a cicada- or turtle-like morphology, and grow to the size of cicadas (2–8 cm). In summer, the bug may have wings like cicadas. The bug may live underground through the winter like cicadas, but hibernates like bears, as this bug is believed to be a kind of fox. The following year, the bug may return to the water and continue its life cycle. This misconception may have arisen because ancient Chinese scholars observed engorged adult ticks only on the skin of patients with Shegongdu and were unable to observe the subsequent changes of these ticks. Thus, they were unaware that the cicada-like morphology of the engorged adult ticks was temporary. They may have assumed that Shegong is a cicada-like mammal with a life cycle comparable to that of cicadas. Conversely, this misconception provides evidence that ancient Chinese scholars attempted to explain the persistence of Shegong in nature. For the same reason, the gender of Shegong was reversely described in the Chao’s book, as males are generally larger than females in mammals. Thus, the adult male Shegong described above is an engorged female tick. All these misunderstandings seem to be caused by the different natures of Baopuzi and Zhouhou Fang. Baopuzi is a book about Taoism, not medicine. While in Zhouhou Fang Ge only describes what he had observed in patients with Shegongdu, in Baopuzi he may have expressed his thoughts about the disease more freely. However, because later scholars combined these descriptions without sufficient consideration, his hypothesis came to be regarded as a medical fact that could not be explained by entomological knowledge.
Regarding the past and present situation of tick-borne rickettsial diseases in China, although there are too few studies on these diseases, some rickettsioses showing eschar, such as Rickettsia conorii, R. sibirica, R. slovaca, and R. japonica infections, have been reported in humans and ticks [24, 25, 26]. Therefore, it can be said that tick-borne rickettsioses have been present in China since ancient times. Additionally, the occurrence of Shegongdu in the valleys is reminiscent of the first documentation of Rocky Mountain spotted fever in the Bitterroot Valley, Montana. Thus, all these descriptions suggest that Shegongdu is a tick-borne rickettsial disease.
4) Nature of Zhongxidu
The development of a bite-like sore in Zhongxidu suggests that a biting vector is responsible for the disease; however, the inability to identify the vector means that the vector is very small and does not cause itching or pain. Therefore, mosquitoes, fleas, body lice, bed bugs, schistosome cercariae, and sand flies were excluded. Mites and ticks are possible; however, ticks can be excluded based on their visibility. Thus, Zhongxidu is certainly a mite-borne febrile disease associated with eschar, more specifically tsutsugamushi disease with epidemiologic characteristics of scrub typhus, unlike tsutsugamushi disease in Japan at that time.
As for the descriptions of “red beef-like ulcer” and “snakehead’s teeth-like ulcer” in Zhongxidu, it is difficult to explain them with the current knowledge of tsutsugamushi disease. One possibility is that the former is an eschar that is secondarily infected with pyogenic bacteria, such as Staphylococcus aureus, which causes cellulitis; thus, the skin turns deep red and looks like red beef. Subsequently, cellulitis and deep soft tissue infections can progress to fatal sepsis. This complication was also described in Shegongdu. Of the four types of eschars in Shegongdu, the fourth, which is the most dangerous and resembles a flamed-red ulcer, appears to be identical to the red beef-like ulcer in Zhongxidu. Since secondary bacterial infections of eschars are rarely described in modern medical literature, it is curious why this complication was so common in ancient China. It is possible that this complication was iatrogenic. At the time, it was believed that Shashidu was caused by a small bug that had entered the human body; therefore, indigenous individuals may have tried to remove the bug by inserting a needle, possibly several times and deeply, as described in Bencao Gangmu. Without proper antisepsis of the overlying skin, this practice can introduce normal skin flora into the sterile deep soft tissues, causing cellulitis and deep soft tissue infections.
Regarding the description of the “snakehead’s teeth-like ulcer”, it may be an eschar showing a ruptured bulla, as shown in our previous report [11]. A small (5–20 mm in diameter) oval ulcer with an indurated and slightly raised rim resembles the mouth of a fish, and the jagged remnants of the white membrane attached to the rim may resemble its teeth. This form of eschar is observed in individuals with pre-existing immunity to O. tsutsugamushi, and is therefore predicted to have a benign clinical course [11]. Additionally, the description of a papule resembling a grain of millet in Shashidu indicates that the papule is small and develops in individuals with pre-existing immunity [12]. All these findings suggest that O. tsutsugamushi infection was prevalent in these areas at the time.
Comparing the above descriptions of Zhongxidu with the present status of tsutsugamushi disease in China, several findings are in good agreement. Before 1986, O. tsutsugamushi infection was restricted to the south of the Yangtze River. At present, this infection occurs in all provinces except Qinghai, and is more common in areas south of the Yangtze River during the summer and autumn seasons, while in northern regions it occurs mainly during the autumn. The main vector in southern China is L. deliense, which is orange-red in color [27].
5) When the diseases were first described
There are three synonyms for Zhongxidu in Zhouhou Fang and five in Zhubing Yuanhou Lun, whereas Shashidu has no synonyms and Shegongdu has two. This means that Zhongxidu had been described by at least three other authors before the year 313, and that this disease was more common and widespread than Shashidu and Shegongdu. It is possible that Zhongxidu was the first rickettsial disease described in China, after which Shegongdu was added. Finally, Ge distinguished Shashidu from Zhongxidu after understanding the relationship between “sand lice” and Shashidu. This sequence of discoveries is represented by the following prescription numbers in Zhouhou Fang: 64th, Zhongxidu; 65th, Shegongdu; and 66th, Shashidu.
Ge intentionally omitted footnotes and references from this manual for conciseness; therefore, we cannot say when and by whom the diseases were first described in China. Considering that Chao added two synonyms to Zhongxidu 297 years after Ge, it is estimated that the addition of one synonym would take approximately 149 years. Thus, the three synonyms for Zhongxidu in Zhouhou Fang mean that 447 years would have elapsed prior to the publication of this manual; therefore, this entity would have been first described around 134 BC. As for Shegongdu, it is difficult to estimate the time of its first publication in this way because no synonym was added in the Chao’s book. It is possible that ancient Chinese scholars began to pay attention to the characteristic skin lesion, eschar, after the publication of Zhongxidu around 134 BC, and may have discovered another eschar-associated febrile disease, Shegongdu, after identifying cockroach-like bugs on the skin of these patients. Huangdi Neijing (Yellow Emperor’s Canon of Internal Medicine), one of the oldest medical books published in 475–221 BC, did not contain any words relevant to Shashi, Shegong, and Zhongxidu or Shuidu; therefore, it is believed that the above three diseases were identified and described after 221 BC. Several non-medical books describe “water fox” or “short fox”, although they are not as detailed as the medical books mentioned above. Shuowen Jiezi (121), one of the oldest Chinese dictionaries, describes that “Water fox is short fox, and is like a softshell turtle. It has three legs, hurts individuals by shooting the spirit, and chases bugs or sounds (of individuals).” (Fig. 3). Given that dictionaries generally lag behind medical literature in including newly recognized diseases, it is plausible that Shegongdu was recognized and established far before 121, but after 134 BC.
Figure 3
Image of a “water fox” (Shegong) in Gujin Tushu Jicheng by Menglei Chen [Attribution - CC0] (from Wikimedia Commons). The creature resembles a softshell turtle with a transverse bone across its mouth, has three legs, and is shooting something. Note that both ends of the transverse bone resemble the partially unfolded palps of a tick.
If our assumption is correct, Ge described two types of O. tsutsugamushi infections, one as Shashidu and the other as Zhongxidu, according to their differences in epidemiology and identifiability of the causative vector, just as Fletcher described scrub typhus and tsutsugamushi disease based on their clinical variations [6, 7]. Since Zhongxidu would have predated Shashidu by five centuries, the first description of Zhongxidu (tsutsugamushi disease) would date back much earlier, to 2.2 millennia ago.
Since epidemic typhus is an unlikely cause of the Plague of Athens (430–426 BC) and the Antonine Plague (165–180) based on available evidence [28], and the cases recorded by Hippocrates did not have typical features of epidemic typhus [29, 30, 31], the Ge’s record in 313 represents the first documentation of tick-borne rickettsiosis and that of rickettsial diseases as a whole.
6) Scrub typhus and Shanghan
Descriptions of scrub typhus and murine typhus cannot be found in the aforementioned books. These diseases may be included under Shanghan because they do not have distinctive clinical features, particularly eschar. Shanghan (lit. cold damage) is a well-known but poorly defined febrile condition that is believed to be caused by cold damage. This syndrome was established by Zhongjing Zhang around 220 with the publication of his famous book Shanghan Lun (Treatise on Cold Damage Diseases), and subsequently studied intensively by many scholars. They divided the syndrome into several subgroups and attempted to treat each subgroup using various combinations of herbal medicines. Although the cause of Shanghan is difficult to investigate retrospectively, it is currently considered one of several infectious diseases, such as typhus (spotted Shanghan), typhoid fever, malaria, and other undifferentiated fevers.
As described above, Ge stated that Shegongdu can manifest as Shanghan. In Bencao Gangmu, “water Shanghan” was described as a synonym for Shashidu, because the initial symptoms of Shashidu are headache and high fever, which are similar to Shanghan. Therefore, if an eschar was observed, it was diagnosed as Shashidu or Zhongxidu; if it was not, it may have been diagnosed as Shanghan. It was also described that Shashidu, Shegongdu, and Zhongxidu shared similar clinical features, leading to the belief that they could be treated with the same method. In Japan, Ohtomo (1819), who had studied Oriental medicine and Rangaku, described that kedani disease was a colloquial name for Shashidu and that both diseases were similar to Shanghan. Taken together, it can be said that Oriental medicine had recognized the clinical similarity between tick-borne rickettsiosis (Shegongdu), tsutsugamushi disease (Zhongxidu and Shashidu), and Shanghan (scrub typhus, typhoid fever, and other causes of undifferentiated fever).
Western medicine had encountered similar difficulties. In Europe, the distinction between typhus, typhoid fever, and relapsing fever was not made until 1804–1843, when Prost (1804) and Pierre Louis (1829) showed that typhoid fever was associated with ileal ulcers, whereas typhus was not. Gerhard (1837) confirmed this finding in the United States. Thanks to Louis Pasteur and Robert Koch, typhoid fever can be diagnosed by bacteriological culture before patients die of the disease. The development of agglutination tests, such as the Widal test (1896) and the Weil-Felix test (1916), facilitated this distinction. Craigie (1843) distinguished relapsing fever from typhus on clinical grounds. However, as these diagnostic methods were not available in ancient China, the above diseases could not be distinguished. Schüffner experienced the same difficulty in distinguishing scrub typhus from enteric fever in Sumatra, Indonesia; thus, in 1910, he reported scrub typhus as “pseudotyphoid in Deli” [5]. In Laos, scrub typhus is listed as a cause of “malaria syndrome”, which is clinically similar to malaria but smear-negative [32]. For the same reason, recent articles usually refer to scrub typhus at presentation as “undifferentiated fever”; however, this term is too simplistic to characterize the clinical features of scrub typhus.
Conclusion
Arthropod-borne diseases can only be fully realized when both diseases and arthropods are recognized. The former was possible even in ancient China, but the latter began only after the development of modern entomology with the aid of microscopes or magnifying glasses since the 17th century. Laboratory rearing of arthropods makes it possible to understand their entire life cycle. For example, successful rearing of mites began between 1909 and 1946 [33, 34, 35].
Shashidu and Zhongxidu are characterized by fever and eschar, but differ in vector visibility and epidemiology. However, the ability to observe chiggers is a matter of experience for the observer, and epidemiological differences can be explained by our current knowledge of O. tsutsugamushi infections. Therefore, these two diseases are essentially the same entity: O. tsutsugamushi infection.
Shegong has been an unidentified bug because of inconsistent descriptions by different scholars. In ancient China, facts about Shegong were intermingled with myths, fables, and imaginations, all of which contributed to the ambiguous descriptions of this bug. However, the characteristic crossbow-like structure in the mouth of Shegong and the evolutionary changes of the eschar indicate that Shegongdu is an eschar-associated rickettsial disease transmitted by ticks.
Funding:None.
Conflict of Interest:No conflict of interest.
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