| disease | Scrub Typhus |
| alias | Jungle Spotted Fever, Tsutsugamushi Disease, Scrub Typhus, Scrub Typhus |
Scrub typhus (tsutsugamushi disease), also known as jungle macula and papule cold-damage disease (scrub typhus), is an acute pestilence caused by Orientia tsutsugamushi (Rickettsia tsutsugamushi). It is a natural focal disease, with rodents serving as the primary pestilence source and chigger mite larvae as the transmission vector. Clinical features include high fever, toxemia, rash, eschar, and lymphadenopathy. Jin Ge Hong described the prevalence of this disease in southern China over 1,600 years ago, referring to it as "sand flea fever."
bubble_chart Epidemiology
In China, the disease primarily occurs in the southeastern coastal provinces and southwestern regions such as Guangdong, Guangxi, Fujian, Taiwan, Zhejiang, Yunnan, Sichuan, Hainan, and the Xisha Islands. Cases or reports of seropositive immune reactions in populations have also been documented in Hunan, Guizhou, Shandong, Jiangxi, Inner Mongolia, Tibet, and Xinjiang. However, overall, the incidence of the disease in China has shown a declining trend. The disease is also prevalent in Japan, Southeast Asia, islands in the western Pacific and Indian Oceans, and the southeastern regions of the former Soviet Union.
Due to the influence of rodent and mite breeding, the epidemic exhibits distinct seasonality and regionality. Cases generally begin to appear in May, peaking from June to September, though some areas report cases year-round or even predominantly in winter.
(1) Source of Pestilence The disease is primarily endemic among rodents. Wild and domestic rats often show no symptoms after infection but carry the pathogen long-term, making them the main source of pestilence. Although the pathogen is present in the blood of infected humans, human-to-human transmission via mite bites is rare, so humans are not a significant source of pestilence.
(2) Transmission Route The mites responsible for transmitting the disease include *Leptotrombidium deliense* and *Leptotrombidium akamushi*. In Taiwan, *Leptotrombidium akamushi* is the primary vector, while in other provinces and regions such as Guangdong, Guangxi, Fujian, Zhejiang, Yunnan, and Sichuan, *Leptotrombidium deliense* is the main vector. Mites are extremely small, with adults measuring no more than 1 mm in length and appearing red-orange, red, or pale yellow. They often cluster in grassy, forested areas. Larvae attach to rodents passing by, feeding on their tissue fluids. After a single blood meal, they drop to the ground and develop into nymphs and adults. Larvae acquire *Rickettsia* from infected animals and retain it through adulthood, even passing it transovarially to the next generation. When infected second-generation larvae bite rodents, they transmit the pathogen to healthy rodents, perpetuating the cycle. Humans can become infected when working or resting in fields or grasslands in endemic areas, especially during farming seasons or floods. Mite nymphs and adults are free-living and can overwinter in soil.(3) Susceptible Population Humans are generally susceptible to *Orientia tsutsugamushi*. Farmers, adolescents frequently exposed to grasslands, and outdoor laborers are particularly vulnerable. The disease is more common in males than females. After infection, immunity to the same strain is long-lasting, while cross-immunity to other strains lasts only a few months.
The pathogen appears as diplococci or short rods, arranged in pairs or clusters near the nucleus in the cytoplasm, measuring 0.3–0.5μm × 0.8–2.0μm. It is highly sensitive to heat and chemical disinfectants, losing viability after 10 minutes at 55°C, and can be rapidly killed by 0.5% phenol; however, it exhibits relatively stronger resistance to low temperatures.
bubble_chart Pathological Changes
After being bitten by chigger mite larvae, local papules, ulcers, or eschars may develop. The pathogen first proliferates locally, then enters the bloodstream via the lymphatic system, leading to rickettsemia. The toxins released after the death of the pathogen are the main pathogenic factors, causing inflammatory changes and some degenerative changes in various organs, as well as clinical symptoms of toxemia.
Generalized lymph nodes show grade I enlargement, with more pronounced swelling in lymph nodes near ulcers or eschars, and central necrosis may occur. Viscera are generally congested, the spleen is enlarged several times, the liver shows grade I enlargement with focal necrosis. The heart exhibits focal or diffuse myocarditis, possibly accompanied by hemorrhage and small degenerative changes. The lungs are congested, with bronchopneumonia and pleural effusion. The brain shows lymphocytic meningitis, and small hemorrhagic spots may be seen in the brainstem. The kidneys sometimes exhibit widespread acute inflammatory changes. The gastrointestinal tract, especially the lower ileum, is often extensively congested.
"Macula and papule cold-damage disease nodules" are also observed in this condition, with infiltration of mononuclear cells, plasma cells, lymphocytes, etc., around small blood vessels. However, the endothelial cell swelling of the vascular membrane is less pronounced than in epidemic macula and papule cold-damage disease, and thrombosis is also less common.
The incubation period ranges from 5 to 20 days, usually 10 to 14 days. The onset is often sudden, with a rapid rise in body temperature to 39–40°C or higher, accompanied by shivering, severe headache, limb pain, nausea, vomiting, constipation, facial flushing, conjunctival congestion, cough, and chest pain. Some patients report retro-orbital pain or pain upon eye movement. Severe cases may present with neurological symptoms such as delirium, hearing impairment, and altered consciousness, as well as cardiovascular symptoms like tachycardia or bradycardia and microcirculatory disturbances.
(1) Eschar and ulcer: One of the characteristic features of the disease, seen in 65–98% of patients. At the site of larval bite, a red papule appears first, which then forms a blister and ruptures, with central necrosis forming a brown or black scab, known as an eschar. The eschar is round or oval, surrounded by a red halo, and after the scab falls off, a small ulcer forms. The size varies, with a diameter of 1–15 mm (average about 5 mm), slightly raised edges, and a base of light red granulation tissue. It is generally painless and non-itchy, though occasionally it may become secondarily infected. Most patients have only one eschar, but some may have 2–3 or even more than 10. Larvae tend to invade moist and odor-prone areas of the body, so eschars are commonly found in the armpits, groin, perineum, external genitalia, and anus, but they may also appear on the head, neck, chest, breasts, limbs, abdomen, buttocks, back, eyelids, and toes.
(2) Lymphadenopathy: Present in the vast majority of cases. Local lymph nodes near the eschar enlarge to the size of a walnut or broad bean, are tender and movable, do not suppurate, and resolve slowly. Superficial lymph nodes throughout the body may show grade I enlargement.
(3) Rash: Macular or maculopapular, dark red, fading on pressure, with a few being hemorrhagic; size varies, generally about 3–5 mm, more common on the chest, back, and abdomen, spreading to the limbs. The face is rarely affected, and the palms and soles are free of rash. A small number of patients develop small red enanthem on the palate and cheeks around days 7–8 of illness. The incidence of rash varies significantly across outbreaks, ranging from 30% to 100%, possibly due to differences in strains, disease severity, and timing of medical consultation. The rash typically appears between days 2–8 (average days 5–6) and gradually fades after 3–7 days.
(4) Others: Myocarditis is relatively common, manifested as weak heart sounds and diastolic gallop rhythm. Hepatosplenomegaly is generally grade I, with splenomegaly (30–50%) being slightly more frequent than hepatomegaly. Other symptoms include generalized hyperesthesia, diffuse skin flushing, and dry or moist rales in the lungs.
The natural course of the disease lasts 17–21 days, with fever gradually subsiding. The duration is significantly shortened with specific drug treatment.
bubble_chart Auxiliary Examination
(1) Hematuria Routine
Leukocyte count is decreased or normal, but increases when complications occur. Proteinuria is present in half of the patients, and red blood cells, white blood cells, and casts may occasionally be seen.
(2) Serological Immunological Tests
1. Weil-Felix Test: The patient's serum can agglutinate with Proteus OXk strains. Only 30% of cases are positive in the first week, rising to about 60% by the end of the second week, and reaching 80–90% in the third and fourth weeks. Titers range from 1:80 to 1:1280 or higher, gradually increasing with the course of the disease. Titers begin to decline after the fourth week, and by the 8th–9th week, most become negative. A single serum sample has limited diagnostic significance.
2. Complement Fixation Test: This test has higher specificity and sensitivity than the Weil-Felix test. However, due to significant antigenic differences among strains, polyvalent antigens or local representative strain antigens should be used. The complement-fixing antibody titer rises rapidly during the course of the disease and can persist for about five years.
3. Immunofluorescence Assay: Indirect immunofluorescence is used to detect serum antibodies, with a higher positive rate than the Weil-Felix test. Fluorescent antibodies typically appear by the end of the first week, rise significantly by the end of the second week, peak in the 3rd–4th week, and remain at a certain level after six months. They can persist for several years to a decade, aiding epidemiological investigations.
4. Animal Inoculation: Whole blood (0.3–0.5 ml) from febrile patients can be inoculated intraperitoneally into mice. The animals generally develop symptoms by the 10th day and die within 11–16 days. Smears or imprints of the spleen, liver, or peritoneal membrane can be stained (preferably with fluorescent antibodies) to detect pathogens located in the cytoplasm of mononuclear cells.
(3) Molecular Biological Testing: A PCR method has been established to detect the Sta58 major antigen gene fragment of scrub typhus rickettsiae. This method offers high sensitivity and specificity, but it is difficult to perform in most laboratories.
Residence history in epidemic areas, epidemic season, occupation, eschar, regional lymphadenopathy, rash, and Weil-Felix test are of significant reference value. Complement fixation test, indirect immunofluorescence assay, or solid-phase radioimmunoassay can assist in diagnosis, with a fourfold or greater increase in paired sera being particularly significant. Animal inoculation tests may be performed when necessary.
bubble_chart Treatment Measures
Essentially similar to epidemic maculopapular cold-damage disease, chloramphenicol or tetracycline was commonly used domestically in the past, at a dosage of 1–2 g per day for a course of 3–6 days. Currently, doxycycline is also employed, believed to be more effective than the aforementioned drugs, with the treatment duration potentially shortened (200 mg administered at once, or 200 mg on the first day followed by 100 mg on days 2–3). Ciprofloxacin has also shown good efficacy in treating this disease, with a dose of 0.2 g twice daily. Recurrence is rare after treatment, though higher recurrence rates have been reported abroad, possibly due to different strains. Re-treatment with the same medication remains effective in cases of recurrence.
The case fatality rate of scrub typhus varies by region, ranging from 9% to 40% without antibiotic treatment, which is related to factors such as different strains of the pathogen and the patient's health. Deaths are rare with timely use of chloramphenicol, tetracycline, and other antibiotics. The prognosis is worse for the elderly, pregnant women, and those with chronic comorbidities such as cardiovascular diseases. Most deaths occur in the second or third week, primarily due to pneumonia, heart failure, septic shock, DIC, and other complications.
(1) Eliminating the source of pestilence: Mainly involves eradicating wild and domestic rats through comprehensive measures combining various rodent traps and chemical rodenticides.
(2) Cutting off transmission routes: Improving environmental hygiene and eliminating vectors by clearing weeds around houses to prevent Chinese Taxillus Herb (chigger mites), cultivating wasteland to drive away rodents, and spraying killing worms agents indoors, outdoors, and surrounding areas to exterminate various arthropods.
(3) Protecting susceptible individuals: When working or camping in epidemic areas, personal protection is essential to avoid bites from chigger mite larvae. Remove and burn weeds on the ground and surrounding areas, then apply insecticidal chemicals. Tighten cuffs and trouser legs or wear long cloth socks, and apply insect repellent to exposed skin or clothing to prevent chigger mite larvae from approaching. Inactivated vaccines and attenuated live vaccines are still under development. Preliminary studies indicate that the 56KDa membrane protein antigen of scrub typhus rickettsia exhibits strong immunogenicity. The gene encoding this protein has been successfully expressed in large intestine bacteria, but further research is needed to determine its suitability as a vaccine.
Complications include bronchopneumonia, encephalitis, pleuritis, otitis media, parotitis, late abortion, thrombophlebitis, DIC, and septic shock. Occasionally, bleeding at various sites and intravascular hemolysis may occur. The complications observed domestically are relatively fewer, with bronchopneumonia and cardiovascular insufficiency being more common.
Scrub typhus should be differentiated from other rickettsial diseases, cold-damage disease, leptospirosis, etc. Attention should also be paid to cases of mixed infections, such as scrub typhus combined with cold-damage disease or scrub typhus combined with leptospirosis.
