| disease | Epidemic Typhus |
| alias | Louse-borne Typhus Fever, Typical Macule Cold-damage Disease, Louse-borne Typhus, Recurrent Maculopapular Cold-damage Disease, Epidemic Typhus, Brill-Zinsser Disease |
Epidemic macula and papule cold-damage disease (epidemic typhus), also known as louse-borne macula and papule cold-damage disease (louse-borne typhus) or "classic macula and papule cold-damage disease," is an acute pestilence transmitted by body lice carrying Rickettsia prowazekii. Its clinical features include persistent high fever, headache, petechial rash (or maculopapular rash), and central nervous system symptoms, with a natural course lasting about 2 to 3 weeks. Months to years after contracting epidemic macula and papule cold-damage disease, a relapse may occur, known as recurrent macula and papule cold-damage disease, also called Brill-Zinsser disease.
bubble_chart Epidemiology
This disease has a worldwide incidence. Between 1918 and 1922, 30 million people in the former Soviet Union and Eastern Europe contracted the disease, with approximately 3 million deaths. In China, from 1850 to 1934, due to famines, wars, and other reasons, there were 15 major outbreaks, affecting most regions of the country. In recent years, the incidence of epidemic macula and papule cold-damage disease has significantly decreased, primarily seen in Africa, especially in Ethiopia. After liberation, due to improvements in people's living conditions and strengthened epidemic prevention measures, the disease has been largely controlled domestically, with only sporadic or small outbreaks occurring in suburban and rural areas of colder regions.
(1) Source of Pestilence: The patient is the sole or primary source of pestilence for this disease. Patients are contagious from 1–2 days before the end of the incubation period until several days after the fever subsides, with the entire contagious period lasting about 3 weeks, though the first week is the most contagious. The pathogen can remain latent in the mononuclear-phagocyte system of some patients for extended periods, proliferating and causing relapse when the host's immunity is relatively weakened.
Recent studies have found that, in addition to humans, flying squirrels (flying squirrel) are also reservoirs for *Rickettsia prowazekii*. These squirrels are distributed in the eastern and central United States, and the vector for transmission among squirrels may be lice or fleas, though the route of human infection remains unclear.(2) Transmission Route: Body lice are the primary vector for transmitting this disease. While head lice and pubic lice can also serve as vectors, their role is minor. Ticks mainly transmit *Rickettsia prowazekii* among animals, but whether they can transmit it to humans requires further study.
Body lice feed exclusively on human blood and are highly active under suitable temperatures, facilitating their spread among populations. When a patient develops a high fever, the lice quickly flee to seek new hosts. The saliva of infected lice does not contain rickettsiae, but while feeding, they excrete feces containing the pathogen onto the skin, allowing the rickettsiae to enter the body through puncture wounds or scratches. Sometimes, scratching can crush lice, inoculating the pathogen from the lice's body into the skin. Dried louse feces can form aerosols that are inhaled through the respiratory tract or enter the body via the conjunctival membrane, posing a risk of aerosol infection, particularly for laboratory personnel. Individuals with the habit of crushing lice may become infected as rickettsiae penetrate the oral mucosa. Infection through autopsies or blood transfusions is extremely rare.
When lice ingest the blood of an infected patient, the pathogen enters their gastrointestinal tract, invading the epithelial cells of the louse's intestinal wall. After 4–5 days, the cells swell excessively and rupture, releasing large quantities of rickettsiae into the intestinal lumen, which are then excreted in louse feces. Typically, 7–10 days after infection (sometimes extending beyond 3 weeks), the lice die due to intestinal obstruction caused by the infection. The rickettsiae in lice are not transmitted transovarially. Lice leave Rebing infected or deceased individuals to seek healthy hosts, thereby facilitating the spread of the disease.
To date, the "human-louse-human" transmission cycle—with the patient as the source of pestilence and body lice as the vector—remains the fundamental concept in the epidemiology of this disease.(3) Susceptible Population: All age groups are highly susceptible to this disease, though children under 15 tend to experience milder seasonal symptoms. Reports from some regions in China indicate that mild or atypical cases are not uncommon. After one infection, immunity is relatively long-lasting, though reinfection can occasionally occur. Apart from relapsing macula and papule cold-damage disease, relapses (within a short period) are extremely rare.
Outbreaks of this disease are more common in winter and spring, as cold weather and thicker, less frequently changed clothing favor the Chinese Taxillus Herb and reproduction of lice. Historically, the disease was more prevalent in colder regions, but in recent years, more cases have been reported in tropical areas such as Africa.
The pathogen is Rickettsia prowazekii, which shows no significant morphological differences from other rickettsiae and exhibits polymorphic changes during its developmental stages in the louse intestine. The basic form of the pathogen is tiny rod-shaped, arranged in chains along the long axis, and is Gram-negative. Typically, Chinese Taxillus Herb resides within the cytoplasm of human vascular endothelial cells and the epithelial cells of the louse intestinal wall. During rickettsemia, it may also attach to red blood cells and platelets. The chemical composition and metabolites of the pathogen include proteins, sugars, fats, phospholipids, DNA, RNA, internal toxin-like substances, and various enzymes. Its cell wall composition resembles that of Gram-negative bacilli.
The pathogen is highly sensitive to heat, ultraviolet light, and common chemical disinfectants, being killed within 30 minutes at 56°C or 5–7 hours at 37°C. However, it exhibits strong tolerance to low temperatures and desiccation, surviving for months to years below -30°C and remaining viable in dried louse feces for several months. The pathogen can grow in tissue cultures and thrives particularly well in the egg yolk sac of chicken embryos. Almost pure pathogens can be obtained by injecting infected tissue or secretions into the louse intestine. When inoculated into the abdominal cavity of male guinea pigs, it generally causes only fever and vascular lesions without significant scrotal reactions. The toxin-like substances can lyse the red blood cells of humans, monkeys, rabbits, and other warm-blooded animals in test tubes. Intravenous injection into large or small mice can cause dyspnea, convulsions, spastic limb paralysis, increased vascular permeability, reduced blood volume, and typically leads to death within 6–24 hours.The main pathogenesis of this disease involves vascular lesions caused by pathogens, toxemia induced by toxins, and some immune and allergic reactions, as mentioned in the overview.
bubble_chart Pathological Changes
In rickettsial diseases, the small vessel lesions in this disease and Rocky Mountain spotted fever are generally more pronounced, presenting as proliferative, thrombotic, or necrotic. The vascular endothelial cells proliferate extensively, forming thrombi, and the vessel walls exhibit segmental or circular necrosis. The outer membrane of the vessels is infiltrated with plasma cells, monocytes, and lymphocytes, resulting in the formation of characteristic "macula and papule cold-damage disease nodules" or granulomas resembling foxtail millet grains around the vessels. These lesions are widespread throughout the body, particularly in the dermis of the skin, myocardium, brain, cerebral membranes, testicular interstitium, kidneys, adrenal glands, liver, and alveolar walls, leading to various corresponding clinical symptoms such as rash, cardiovascular dysfunction, altered mental status, meningeal irritation signs, liver function impairment, pneumonia, and shock.
In the central nervous system, the damage to the gray matter of the cerebrum, cerebellum, medulla oblongata, basal ganglia, pons, and spinal cord plays a significant role. The severity and diffuseness of these lesions cause the patient's neuropsychiatric symptoms to persist for an extended period even after the body temperature has subsided.
Apart from the macula and papule cold-damage disease nodules, the early manifestations of this disease include systemic toxemia symptoms without characteristic pathological changes. Common findings include bronchopneumonia, meningoencephalitis, minor subarachnoid hemorrhages, and cloudy swelling of the liver and kidneys. The spleen is acutely enlarged, with hyperplasia of reticuloendothelial cells, lymphoblasts, lymphocytes, and plasma cells. The adrenal glands exhibit hemorrhage, edema, and degenerative changes in parenchymal cells.
bubble_chart Clinical Manifestations
It can generally be divided into typical and mild types, with an additional recurrent macula and papule cold-damage disease.
(1) Typical: The incubation period ranges from 5 to 21 days, averaging 10–12 days. A few patients may experience 2–3 days of prodromal symptoms, such as fatigue, headache, dizziness, fear of cold, and low-grade fever. Most cases have an acute onset, accompanied by shivering, severe and persistent headache, generalized muscle pain, conjunctival membrane congestion, and facial flushing.
1. Fever: Body temperature peaks by days 2–4 (above 39–40°C), remaining sustained during the first week and becoming remittent from the second week onward. The febrile course typically lasts 14–18 days, with the fever subsiding rapidly to normal within 2–4 days. In recent reports, the fever pattern is often remittent or irregular, possibly due to antibiotic use.
2. Rash: A key sign, appearing in over 80% of cases by days 4–6 of the illness. It initially appears on the chest, back, armpits, and both upper arms, spreading rapidly to the entire body within a day. The face is usually spared, and rashes on the lower limbs are less common. The rash is round or oval, about 2–4 mm in diameter, initially presenting as bright red maculopapules that fade under pressure, later turning dark red or petechial. The rash subsides in 5–7 days, while petechial lesions may persist for 1–2 weeks, leaving behind brownish-yellow patches or desquamation.
3. Neurological symptoms: Prominent and early-onset, manifesting as anxiety, agitation, severe headache, and possible mental dullness or delirium at onset. Occasionally, meningeal irritation signs, muscle and tongue tremors, unconsciousness, urinary incontinence, dysphagia, and hearing impairment may occur.
4. Cardiovascular symptoms: Heart rate increases proportionally with body temperature. Toxic myocarditis may present with gallop rhythm or arrhythmias. Shock or hypotension results from dehydration, microcirculatory disturbances, and cardiovascular and adrenal dysfunction.
Other symptoms include cough, chest pain, tachypnea, nausea, vomiting, reduced appetite, constipation, abdominal distension and fullness, and occasionally jaundice, cyanosis, or renal impairment. Splenomegaly is mostly grade I, while hepatomegaly occurs in some cases.
After fever subsides, symptoms generally improve except for severe neurological manifestations in critical patients. Headache lessens, and appetite returns.
(2) Mild: Mild cases have become more common domestically in recent years, possibly due to population immunity levels. Characteristics include: ① Shorter febrile course (8–9 days) and lower fever (around 39°C); ② Milder toxemia but still significant generalized pain; ③ Rash presents as congestive maculopapules on the chest and abdomen, with some cases being rash-free; ④ Mild and short-lived neurological symptoms, mainly headache and agitation; ⑤ Hepatosplenomegaly is rare.
(3) Recurrent macula and papule cold-damage disease: Also known as Brill-Zinsser disease, it is more common abroad, particularly among Eastern Europeans and their descendants in the U.S., with few domestic reports. Main clinical features include: ① Mild course with milder toxemia and central nervous system symptoms; ② Remittent fever lasting 7–11 days; ③ No rash or only sparse maculopapules; ④ Sporadic occurrence, no seasonal pattern, and higher incidence in older age groups.
bubble_chart Auxiliary Examination
(1) Hematuria Routine: White blood cell counts are mostly within the normal range, with about 1/4 exceeding 10,000/mm3, and a few below 5,000/mm3. Platelet counts generally decrease, and eosinophils are significantly reduced or absent. Proteinuria is common, and occasionally red blood cells, white blood cells, and casts are observed.
(2) Serological Immunological Tests: It is advisable to collect two or three serum samples (upon initial admission, during the second week of the illness, and during the convalescence stage). A fourfold or greater increase in antibody titer is diagnostic. Commonly used tests include the Weil-Felix test, complement fixation test, rickettsial agglutination test, and indirect hemagglutination test. Although the Weil-Felix test has relatively low specificity, it remains widely used due to the ease of obtaining and preserving the antigen. The principle is that certain rickettsiae share antigenic components with Proteus OX19, OXK, or OX2, so patient serum can produce agglutination reactions with the relevant Proteus strains. The agglutination titer of serum from patients with epidemic macula and papule cold-damage disease against OX19 strains generally exceeds 1:320, but it often reaches significant levels or peaks by the end of the second week or during convalescence. The titer then declines rapidly and becomes negative within 3–6 months. Non-rickettsial diseases such as Proteus urinary tract infections, leptospirosis, relapsing fever, malaria, and cold-damage disease may also yield positive reactions, though the titers are mostly lower and rarely show dynamic changes. Patients with other rickettsial diseases may also produce agglutination reactions with OX19 strains, but except for endemic macula and papule cold-damage disease, the titers are generally lower. Although recrudescent macula and papule cold-damage disease is also caused by Rickettsia prowazekii, the Weil-Felix test is often negative or shows a titer <1:160.
Complement-fixing antibodies can reach significant titers (1:40) within the first week of illness, with a positivity rate of 50–70% in the first week and over 90% by the second week. Low titers may persist for 10–30 years, making this test useful for epidemiological surveys. The complement fixation test using purified particulate antigens of R. prowazekii not only has group specificity but also species specificity, allowing differentiation between epidemic and endemic macula and papule cold-damage disease. Complement-fixing antibodies in recrudescent macula and papule cold-damage disease patients appear earlier, peaking mostly between days 8–10 of illness, with IgG predominating, whereas IgM predominates in epidemic macula and papule cold-damage disease.
The rickettsial agglutination test using soluble antigens is highly specific and simple to perform, with the microagglutination method further conserving antigen. Positive reactions appear earlier than with the Weil-Felix test, with over 80% of cases positive by the fifth day of illness. A tube test titer >1:40 or a microagglutination titer >1:4 is considered positive. The positivity rate reaches nearly 100% within 2–3 days, with titers peaking around one month into the illness and then declining rapidly, disappearing within months, making it unsuitable for retrospective studies. This test has group specificity and can differentiate between other rickettsial diseases such as scrub typhus, various spotted fevers, and Q fever. Patients with endemic macula and papule cold-damage disease may show lower positive titers. The agglutinating antibodies in active epidemic macula and papule cold-damage disease patients are primarily IgM, whereas those in recrudescent cases are mainly IgG.
The indirect hemagglutination test shares some characteristics with the microagglutination method and also has group specificity. Hemagglutinating antibodies appear between days 5–7 of illness, rise rapidly, and maintain high levels for 2–10 weeks, declining faster than complement-fixing antibodies. A titer >1:100 is generally considered positive.
Other serological immunological tests include indirect immunofluorescence, rocket immunoelectrophoresis, and the staphylococcal protein A (SPA) slide co-agglutination method.
(3) Pathogen Isolation Not applicable to general laboratories. Rickettsemia usually occurs within the first week of illness, and blood samples should be collected before the administration of antibiotics for inoculation into the peritoneal cavity of guinea pigs or the egg yolk sac of chicken embryos. Alternatively, body lice collected from patients can be reared and observed in the laboratory. After the lice become ill and die, smears can be stained to examine for Rickettsia. Guinea pigs are sensitive to Rickettsia prowazekii. Blood (3–5 ml) from patients in the early stage of the disease can be injected into the peritoneal cavity of male guinea pigs. After 7–10 days, the animals develop a fever reaction. Scrapings of the tunica vaginalis or peritoneum can be examined, or smears of tissues such as the brain, adrenal glands, or spleen can be prepared, stained, and examined under a microscope to identify large quantities of Rickettsia within the cytoplasm. The guinea pig scrotal reaction is negative or shows only grade I redness without significant swelling, which can serve as a reference for differentiation from endemic macula and papule cold-damage disease.
(4) Molecular biological examination: Detection of specific DNA of Rickettsia prowazekii using DNA probes or PCR methods offers advantages such as speed, specificity, and sensitivity.
(5) Others: For patients with meningeal irritation signs, cerebrospinal fluid examination should be performed. The fluid is mostly clear, with slight increases in white blood cells and protein, while sugar levels are generally normal. Electrocardiograms may indicate myocardial damage, such as low voltage, changes in T waves and S-T segments, etc. A few patients may show changes in liver or kidney function.
Table 11-18 Differences between epidemic macula and papule cold-damage disease, endemic macula and papule cold-damage disease, and relapsing macula and papule cold-damage disease
| Main distinguishing points | Epidemic macula and papule cold-damage disease | Endemic macula and papule cold-damage disease | Relapsing macula and papule cold-damage disease |
| Pathogen | Rickettsia prowazekii | Rickettsia mooseri | Rickettsia prowazekii |
| History of epidemic macula and papule cold-damage disease | No | Generally no | Yes |
| Epidemiological pattern | Epidemic | Endemic or sporadic | Sporadic |
| Epidemic season | Winter and spring | Summer and autumn | Variable |
| Transmission vector | Body louse | Rat flea | None |
| Severity of illness | Severe, with prominent neurological symptoms | Mild | Mild |
| Duration of fever | 12–18 days | 9–14 days | 7–11 days |
| Rash | Numerous, widespread, petechial | Sparse, rarely hemorrhagic | Mostly absent |
| Fatality rate (without specific treatment) | Higher | Very low | Very low |
| Weil-Felix test (OX19) | Strongly positive, 1:320–1:5210 | 1:160–1:640 | Negative or below 1:160 |
| Complement fixation test (corresponding granular antigen) | Positive, peak at 12–16 days of illness, mainly IgM antibodies | Positive, mainly IgM antibodies | Negative, peak at 8–10 days of illness, mainly IgG antibodies |
| Guinea pig scrotal reaction (intraperitoneal inoculation) | Grade I scrotal redness | The scrotum is significantly red and swollen, and the testicles are also enlarged. | grade I scrotal redness |
Epidemiological data such as local prevalence, season of onset, travel history to endemic areas, and history of tick bites provide important reference value. Clinical symptoms like the duration of fever, the timing and characteristics of rash, and prominent central nervous system symptoms aid in diagnosis. A high titer in the Weil-Felix test (1:320 or higher) and/or dynamic changes (a fourfold or greater increase in paired serum samples) can confirm the diagnosis. If available, additional tests such as complement fixation, microagglutination, and indirect hemagglutination may be performed.
bubble_chart Treatment Measures
The principles are fundamentally the same as those for other acute pestilential diseases.
(1) General treatment: Oral care and regular repositioning are extremely important to prevent oral infections, pulmonary infections, bedsores, etc. Provide a high-calorie semi-liquid diet and ensure adequate fluid intake, with a daily adult intake of around 3000ml (adjusted for the elderly and those with cardiac insufficiency) to maintain a daily urine output of 1000–1500ml.
(2) Symptomatic treatment: For severe headaches and significant neurological symptoms, administer analgesics and sedatives. In cases of cardiac insufficiency, use cardiotonic agents. For severe toxemia symptoms accompanied by hypovolemia, consider replenishing plasma, dextran, etc., and short-term use of adrenal corticosteroids, supplemented with vasoactive drugs or heparin if necessary (refer to "Septic Shock"). Use antipyretics cautiously to avoid profuse sweating and collapse. For secondary bacterial infections, administer appropriate antibiotics based on the infection site and bacterial sensitivity.
(3) Etiological treatment: Chloramphenicol, tetracycline, and doxycycline are highly effective against this disease and relapsing macula and papule cold-damage disease. The addition of other antibiotics, such as trimethoprim, is generally unnecessary. Significant improvement in symptoms (including headaches) occurs within 12–24 hours after medication, with toxemia symptoms rapidly alleviating or disappearing. Body temperature normalizes within 24–96 hours, most commonly within 48 hours. The rash subsides several days after the fever resolves.
The adult dose of chloramphenicol and tetracycline hydrochloride is 1.5–2.0g daily, divided into 3–4 oral doses. Treatment can be discontinued 1–2 days after the fever subsides, with a total course of 3–6 days. Some international protocols recommend a 10-day course, but relapses are rare under domestic conditions, making prolonged treatment unnecessary. For patients unable to take oral medication, switch to intravenous infusion, with the daily dose of tetracycline hydrochloride not exceeding 1.5g for adults, transitioning to oral administration once tolerated. Doxycycline can also replace chloramphenicol or tetracycline, with an adult daily dose of 200mg, divided into two doses, for a course of 2–3 days. Domestic reports indicate good efficacy with a single 200mg dose, achieving faster fever reduction than the tetracycline group. After treatment with chloramphenicol, rickettsiae may remain latent in the body for some time, even after the patient's temperature has fully normalized. The treatment for relapsing macula and papule cold-damage disease is the same as for epidemic macula and papule cold-damage disease.
The prognosis depends on factors such as age, the patient's general condition, the presence of complications, and the timing of treatment. Poor prognosis is associated with severe toxemia, bronchopneumonia, or significant central nervous system symptoms. Concurrent relapsing fever also worsens the prognosis.
The severity of outbreaks often varies significantly, with pediatric cases generally being milder. Before the availability of specific treatments, the case fatality rate ranged from 5% to 17%, and could reach 40–50% in patients over 50 years old. With the use of tetracyclines, chloramphenicol, and other treatments, the prognosis has greatly improved, reducing the fatality rate to about 1.5%. Cases occurring after vaccination tend to have a shorter course and milder symptoms.
This disease has caused multiple pandemics in history, resulting in significant harm. Currently, epidemic macula and papule cold-damage disease remains one of the epidemiological surveillance projects of the World Health Organization. The key to prevention lies in louse prevention, louse eradication, and widespread public health campaigns.
(1) Management of pestilence sources: Patients should undergo louse eradication treatment. After delousing, isolation can be lifted, but it is still advisable to concentrate them in specialized wards or designated rooms. Patients should bathe and change clothes, with hairy areas requiring multiple washes. Killing worms agents such as 1-3% malathion should be sprayed onto clothing and hair.
(2) Cutting off transmission routes: Strengthen health education and encourage the public to bathe and change clothes frequently. Clothing, bedding, etc., can be deloused using physical methods such as dry heat, dampness-heat, or boiling, maintaining a temperature above 85°C for 30 minutes. Alternatively, chemical delousing with ethylene oxide fumigation can be used, fumigating for 6-24 hours at an optimal temperature of 20-30°C.
(3) Protecting susceptible individuals: Inactivated vaccines include louse intestine vaccine, chicken or duck embryo vaccine, and mouse lung vaccine. The commonly used inactivated mouse lung vaccine in the country is suitable for residents in epidemic areas, newcomers to affected areas, military personnel, epidemic prevention medical staff, and laboratory workers. In the first year, three subcutaneous injections are administered at intervals of 5-10 days. For those aged 15 and above, the first dose is 0.5 ml, followed by 1 ml for the second and third doses. For those under 14, the doses are 0.3-0.4 ml, 0.6 ml (second dose), and 0.8 ml (third dose). Subsequently, an annual booster injection is given, with the same dose as the third injection. After six or more vaccinations, long-lasting immunity can be achieved, which is also effective against Rickettsia mooseri infection. Post-vaccination reactions are mild, with only grade I redness and swelling at the injection site. The attenuated E-strain live vaccine has been widely used in some countries, requiring only one subcutaneous injection, with immunity lasting up to five years.
Taking tetracycline or chloramphenicol can also provide temporary preventive effects, but most scholars do not advocate this approach, as satisfactory therapeutic effects can be achieved with early administration after the onset of the disease.
Bronchopneumonia is a common complication of epidemic macula and papule cold-damage disease. Other complications include otitis media, parotitis, endocarditis, meningoencephalitis, and occasionally necrosis or gangrene of the toes, fingers, scrotum, earlobes, or nasal tip, as well as noma, gastrointestinal bleeding, pleuritis, late abortion, acute nephritis, etc. Mild cases and recurrent macula and papule cold-damage disease rarely present with complications.
In addition to differentiating this disease from endemic macula and papule cold-damage disease and recurrent macula and papule cold-damage disease (Table 11-18), it is also necessary to distinguish it from external cold, scrub typhus, measles, epidemic cerebrospinal meningitis (meningococcal meningitis), relapsing fever, leptospirosis, and epidemic hemorrhagic fever. Special complications of cold-damage disease, blood and stool cultures; local eschars and lymphadenopathy in scrub typhus, serological immunological tests; typical rashes and mucosal spots in measles; cerebrospinal fluid findings and skin smear tests in meningococcal meningitis; fever patterns, calf muscle tenderness, and peripheral blood smears in relapsing fever; systemic bleeding tendency, specific sequelae, and serum agglutination-lysis tests in leptospirosis; conjunctival hemorrhage, disproportionate proteinuria relative to fever, and serological immunological tests in epidemic hemorrhagic fever—combined with epidemiological data—are all helpful for differentiation. Relapsing fever and this disease may occur in the same patient. In the United States, this disease must also be distinguished from Rocky Mountain spotted fever, the rash of which is centrifugal in distribution, rarely appears on the abdomen, and first emerges on the ankles and wrists.
