| disease | Brucellosis |
| alias | Brucellosis, Undulant Fever, Brucellosis |
Brucellosis, also known as undulant fever, is an acute or chronic infectious disease caused by Brucella. It is a natural focal disease, and its clinical manifestations primarily include fever, profuse sweating, and arthralgia of varying severity.
bubble_chart Epidemiology
The disease is globally distributed, with over 500,000 cases reported to the WHO annually. The Mediterranean region, Asia, and Central and South America are high-incidence areas. In China, it is commonly found in Inner Mongolia, Northeast China, Northwest China, and other special regions. All 104 epidemic areas nationwide have met the basic control standards, but since the 1990s, sporadic cases have increased at a rate of 30-50%, with outbreaks occurring in some areas.
(1) Source of pestilence: Sheep are the primary source of pestilence in China, followed by cattle and pigs. When these livestock contract the disease, it often leads to late abortion or dead fetus in the early stages. Their vaginal secretions are particularly pestilent, and their skin and hair, various organs, placenta, amniotic fluid, fetus, milk, and urine are often contaminated. The milk of diseased animals contains a high number of bacteria, which can be excreted for several months to several years.
(2) Routes of pestilence: In China, herders assisting with lambing is the main route of pestilence, and veterinarians assisting with the birth of diseased animals are also highly susceptible to infection. Additionally, skinning cattle and sheep, shearing and beating wool, milking, cutting infected meat, slaughtering diseased animals, and children playing with sheep can all lead to infection, with bacteria entering the human body through broken skin at the contact site. Laboratory workers can often be infected through skin and mucous membranes. Consuming contaminated raw milk, dairy products, and undercooked meat from diseased animals can allow bacteria to enter the body through the digestive tract. Furthermore, bacteria can also infect through the mucous membranes of the respiratory tract, conjunctiva, and genital organs.
(3) Susceptible population: The population is generally susceptible to Brucella, with young and middle-aged males having a higher incidence rate than females due to occupational exposure. In China, herders in special regions have the highest infection rates, mostly occurring between late spring and early summer or between summer and autumn, which is related to the lambing season of sheep. After contracting the disease, there is a certain level of immunity, but reinfection is not uncommon.Internationally, Brucella is classified into six biotypes: Malta (sheep), late abortion (cow), pig, dog, forest rat, and sheep epididymis, totaling 19 biotypes. These include sheep type (3 biotypes), cow type (8 biotypes, with cow type 3 and cow type 6 having identical biological characteristics, which were merged into one biotype called 3/6 type by the International Society for Microbiology's Brucella Classification Committee in 1982), pig type (5 biotypes, originally 4 types, with the 5th type added at an international conference in 1982), forest rat type, sheep epididymis type, and dog type, each with one biotype. In China, the sheep type is absolutely dominant, followed by the cow type, with the pig type existing only in a few areas. Recent findings show that in 23 provinces, the infection rate of the dog type in dogs is 7.5%, and a sampling survey in five provinces revealed a human infection rate of 6.1%.
Brucella is a non-motile, tiny, polymorphic coccobacillus, Gram-negative, and does not form spores. The bacteria are very sensitive to light, heat, and common chemical disinfectants; it can be killed by sunlight exposure for 10-20 minutes, dampness-heat at 60℃ for 10-20 minutes, or a 3% bleach solution in a few minutes. Brucella has a strong survival ability in the external environment, surviving for several weeks to months in dry soil, skin and hair, and dairy products, and can survive in water for 5 days to 4 months.
Brucella only produces endotoxins and has a certain toxicity to experimental animals.After Brucella enters the human body through the skin or mucous membrane, neutrophils appear first. The phagocytosed bovine-type bacteria can be partially killed, but the ovine-type bacteria are not easily killed. The surviving Brucella travels with the lymph fluid to reach local lymph nodes. Depending on the body's disease resistance and the quantity and virulence of the invading bacteria, the bacteria may either be eliminated locally or grow and multiply in the lymph nodes to form an infection focus. When the bacterial proliferation reaches a considerable number, they break through the lymph node barrier and invade the bloodstream, at which point symptoms such as bacteremia and toxemia may appear.
After entering the bloodstream, the bacteria are prone to form new infection foci in the reticuloendothelial system such as the liver, spleen, bone marrow, and lymph nodes. Subsequently, the bacteria in these foci can re-enter the bloodstream multiple times, leading to relapses. The fever is of an undulant type (hence the disease is also known as undulant fever).
Brucella mainly resides within macrophages, and like other intracellular bacteria that cause chronic pestilence, its pathogenesis is primarily based on delayed-type hypersensitivity reactions.
The occurrence and development of brucellosis are quite complex, related to bacteremia, toxemia, and hypersensitivity reactions. Additionally, the bacteria invade multiple organs, and antimicrobial drugs and antibodies have difficulty entering the cells, resulting in complex and difficult-to-treat clinical manifestations.
The reticuloendothelial system shows diffuse hyperplasia in the acute phase, while in the chronic phase, granulomas composed of epithelioid cells, giant cells, plasma cells, and lymphocytes may appear, which are tissue reactions to the bacteria's hypersensitivity. Similar lesions can be found in the liver, spleen, lymph nodes, and bone marrow. In ovine and porcine brucellosis, especially in the latter, suppurative granulomas often form.bubble_chart Pathological Changes
The proliferation and destruction of blood vessels caused by sexually transmitted diseases are also due to allergic reactions, mainly affecting the small blood vessels and capillaries of the liver, spleen, brain, kidneys, etc., leading to endovasculitis, thrombotic vasculitis, serous inflammation of organs, and micro-necrosis, among others.
Allergic inflammatory reactions in the bones, joints, and nervous system mainly manifest as arthritis, joint stiffness, spondylitis, osteomyelitis, neuritis, radiculitis, etc. The lungs may exhibit hemorrhagic catarrhal pneumonia, and cardiac lesions are less common than vascular lesions, including endocarditis, myocarditis, etc. The kidneys may show cloudy swelling, and occasionally diffuse nephritis and pyelonephritis. Additionally, there may be orchitis, epididymitis, endometritis, etc.
bubble_chart Clinical Manifestations
The clinical manifestations of this disease are highly variable. For individual patients, the clinical presentation can be very simple, manifesting only as a local abscess, or very complex, involving several organs and systems simultaneously. Sheep and swine brucellosis are generally more severe, while bovine brucellosis is milder, and some cases may not present with fever.
In China, sheep brucellosis is the most common, and the natural course of the disease in untreated individuals is 3 to 6 months (average 4 months), but it can be as short as 1 month or as long as several years.
The course of the disease can generally be divided into acute and chronic phases, with the acute phase often being less pronounced in bovine brucellosis.
The incubation period ranges from 7 to 60 days, typically 2 to 3 weeks, with a few patients developing symptoms several months or more than a year after infection. In laboratory settings, most infected individuals develop symptoms within 10 to 50 days.
Human brucellosis can be classified into subclinical infection, acute and subacute infection, chronic infection, localized infection, and recurrent infection. See Table 11-27.
Table 11-27 Clinical Classification of Brucellosis
| Duration of Symptoms Before Diagnosis | Main Symptoms and Duration | Laboratory Diagnosis | Others | |
| Subclinical | - | Asymptomatic | Serology (+), low titer | Common among slaughterhouse workers, herders, and veterinarians |
| Acute and Subacute | 2 to 3 months 3 months to 1 year | Sweating, arthralgia, fever, hepatosplenomegaly, lymphadenopathy, fatigue, loss of appetite, headache, etc. | Serology (+) Bone marrow culture (+) | Sheep type with severe complications |
| Chronic | >1 year | Mainly neuropsychiatric symptoms and low-grade fever | Serology negative or low titer, culture (-) | |
| Localized | Untreated subacute, chronic sexually transmitted disease cases | Bones, joints, urogenital organs, liver, spleen, etc., are commonly affected | Serology (+) special culture medium Culture (+) | |
| Recurrent | 2 to 3 months | Similar to acute phase, but fever is higher, with sweating, fatigue, and weakness | Serology (+) Culture (+) | Needs to be differentiated from reinfection |
(1) Subacute and Acute Infection The onset is usually gradual, with about 10-30% of cases having a sudden onset. A few patients may have prodromal symptoms lasting several days, such as weakness, insomnia, low-grade fever, loss of appetite, and upper respiratory tract inflammation. The main clinical manifestations during the acute phase include fever (45-100%), profuse sweating (40-95%), lack of strength (30-10%), arthritis (70-90%), and orchitis (20-40% of male sexually transmitted disease cases).
The most common fever type is the remittent type, while the undulant type, although accounting for only 5-20%, is the most characteristic. Its fever increases over 2-3 weeks, followed by a fever-free period of 3-5 days to 2 weeks before the fever rises again, creating a cyclical undulant pattern; most patients experience only 2-3 waves, though occasionally there can be more than 10. Other fever types include irregular and persistent low-grade fever.
Profuse sweating is a prominent symptom of this disease, often more pronounced than in other sexually transmitted diseases. It frequently occurs with a sudden drop in fever during the late night or early morning, accompanied by great dripping sweating. Most patients experience a lack of strength and feel weak.
Joint pain often causes patients to writhe and groan in unbearable agony. It can affect one or several joints, primarily the sacroiliac, hip, knee, shoulder, wrist, and elbow joints. During the acute phase, the pain may be migratory. The pain is described as stabbing and is generally unresponsive to common analgesics. Some patients may exhibit redness and swelling of the joints, with occasional suppuration. Local swelling, such as bursitis, tenosynovitis, and periarthritis, is also common. Muscle pain is frequently observed in the thighs and buttocks, with the latter sometimes experiencing spasmodic pain.
Orchitis is another characteristic symptom of brucellosis, resulting from the involvement of the testis and epididymis. It is mostly unilateral and can swell to the size of a goose egg, accompanied by significant tenderness.
Secondary symptoms include headache (30-84%), neuralgia, hepatosplenomegaly (about 50%), lymphadenopathy, and less commonly, skin rashes.
(2) Chronic Infection: The characteristics include: ① Multiple complaints, especially night sweats, headache, myalgia, and arthralgia. Other symptoms may include fatigue, prolonged low-grade fever, shivering or chills, gastrointestinal symptoms such as poor appetite, diarrhea, constipation, as well as insomnia, depression, and irritability, which can easily be misdiagnosed as neurasthenia. ② Symptoms lingering from the acute phase, such as back pain, arthralgia, sciatica, significant lack of strength, night sweats, and prolonged low-grade fever. Fixed and stubborn arthralgia is more common in the ovine type, while suppurative complications are more frequent in the porcine type.
If the course of medication is insufficient, the recurrence rate can reach 10-40%, which is higher than in patients who have not received specific treatment (6-10%). A recurrence after three years of thorough treatment is referred to as reinfection.
bubble_chart Auxiliary Examination
(1) Peripheral Blood Picture: White blood cell count is normal or slightly low, with a relative or absolute increase in lymphocytes. The erythrocyte sedimentation rate increases during the acute phase and remains high during the chronic phase. Anemia is not clear and is only seen in severe cases or those with prolonged sexually transmitted disease foci.
(2) Various Cultures: These take a long time, and cultures can only be abandoned if no growth is observed after 4 weeks. The positive rate of bone marrow culture is higher than that of blood, especially during the chronic phase. The positive rate of blood culture in acute phase patients with sheep-type can reach 60-80%. Brucella bovis requires 10% carbon dioxide for initial isolation. The bacteria can also be isolated from urine, cerebrospinal fluid of patients with meningitis, pus, etc., and specimens can be inoculated into guinea pigs or mice.
(3) Various Immunological Tests
1. Serum Agglutination Test: The tube method directly detects antibodies to lipopolysaccharide antigens, with a titer ≥1:160 considered positive. However, it can also be positive after vaccination, so paired sera should be tested. A fourfold or greater increase in titer suggests recent Brucella infection.
2. Enzyme-Linked Immunosorbent Assay (ELISA): This method has a higher positive rate than the agglutination test, and the sensitivity for detecting IgM and IgG is similar. Since antibodies in chronic patients are of the IgG type, this method can be used for the diagnosis of both acute and chronic sexually transmitted disease patients. Recently, the avidin-enzyme-linked test has been used, which is more sensitive than ELISA.
3. 2-Mercaptoethanol (2-ME) Test: This method detects IgG and is used to distinguish natural infection from vaccine-induced immunity. One month after natural infection, the agglutination in the body is mainly of the IgG type (initially IgM type), and this IgG is resistant to 2-ME; whereas the agglutinins within 3 months after vaccine-induced immunity are mainly IgM, which can be destroyed by 2-ME.
4. Complement Fixation Test: Complement-fixing antibodies are also of the IgG type, with titers exceeding 1:16 by the third week of the disease course. This test has a higher positive rate and specificity than the agglutination test, but it appears later than the agglutination test.
5. Anti-Human Globulin Test: Patients may also produce an incomplete antibody, which can bind to antigens but is not visible to the naked eye. When anti-human globulin immune serum is added to the antigen-incomplete antibody complex, a directly visible reaction occurs. Incomplete antibodies appear early and disappear late, so they can be used for the diagnosis of patients in both acute and chronic phases. Due to the complexity of this method, it is only suitable for suspected patients with negative agglutination tests, with a titer >1:80 considered positive.
6. Intradermal Test: The Brucellin skin test is a delayed hypersensitivity reaction, with results observed after 24-48 hours. Only local redness without swelling is considered negative, while local redness and induration with a diameter of 2-6 cm is considered positive. The positive rate of the skin test is very low within 6 months of the disease course, and almost 100% of chronic phase patients show positive or strongly positive reactions.
7. Other Immunological Tests: These include reverse passive hemagglutination test, radioimmunoassay, indirect immunofluorescence test, etc. Due to their complexity, they are not suitable for widespread use.
(4) Other Examinations: Cerebrospinal fluid examination is suitable for patients with meningitis, showing increased cerebrospinal fluid cells (mainly lymphocytes), increased protein, and otherwise normal. Electrocardiography may show prolonged P-R interval, myocardial damage, low voltage, etc. X-ray examination of bones and joints may show soft tissue calcification, strong bone repair response with little destruction, narrowing of intervertebral discs and spaces, etc. Changes in liver function and electroencephalogram are non-specific.
Epidemiological data and occupational history are of significant value in assisting the diagnosis of this disease. If there are also some specific clinical manifestations of the disease, such as undulant fever, orchitis, etc., the diagnosis can be basically established. Positive results from cultures of blood, bone marrow, pus, etc., are the basis for a definitive diagnosis.
Agglutination tests (or ELISA, complement fixation tests, etc.) should be measured weekly, and a high titer or a doubling of the titer has diagnostic value. When the agglutination test is negative in chronic patients, ELISA or anti-human globulin test should be performed. To differentiate between natural infection and artificial immunization, or to determine whether the disease is active, a 2-ME test can be performed.
bubble_chart Treatment Measures
(1) Acute Infection
1. General and Symptomatic Treatment Patients should rest in bed, pay attention to the supplementation of water, electrolytes, and nutrition, and be given sufficient amounts of vitamin B and C, as well as easily digestible food. Antipyretic analgesics can be used simultaneously for those with high fever. Adrenocortical hormones (steroids) can help improve blood symptoms, but must be used in conjunction with antibiotics, with a treatment course of 3 to 4 days. It is believed that steroids are indicated for those with infections involving the central nervous system and those with long-term testicular swelling and pain.
2. Antibacterial Treatment Rifampin is effective against this disease. The treatment regimen recommended by the World Health Organization is rifampin 600-900mg/day plus doxycycline 200mg/day, with a treatment course of 6 weeks. For infections caused by sheep and pig types, it is advisable to use tetracycline in combination with streptomycin, generally adopting two treatment courses, with an interval of 5-7 days each time, and each course lasting 3 weeks. The daily dose of tetracycline is 2g, divided into 4 doses. Fever generally subsides within 3-5 days after medication, at which time the dose can be reduced to 1.5g. The daily adult dose of streptomycin is 1g, divided into 2 intramuscular injections. The recurrence rate of using tetracycline alone is 30%, which can be reduced to 10% when used in combination. The combination of SMZ and TMP also has some effect on this disease and can be used for those allergic to tetracycline, pregnant women, etc. The treatment course should be 4-6 weeks, as a shorter course is prone to recurrence (recurrence rate 4-50%). Streptomycin also needs to be used in combination, with an adult dose of 1g per day, divided into 2 intramuscular injections, with a treatment course of 3 weeks.
(2) Chronic Infection It is generally believed that the combination of tetracycline and streptomycin has a certain treatment course, but the course of tetracycline should be extended to more than 6 weeks, and streptomycin is suitable for 4 weeks. Surgical drainage can be performed for purulent sexually transmitted disease foci.
Brucella osteomyelitis should be thoroughly debrided, supplemented with long-term antibacterial treatment. In addition to tetracycline and streptomycin, a combination of chloramphenicol and gentamicin can also be tried. Spondylitis or intervertebral disc infection generally does not require surgical drainage. Arthritis patients occasionally need synovectomy.
Brucella endocarditis should be treated with tetracycline, with a treatment course of 2-3 months. Streptomycin for 6 weeks. Tetracycline can also be combined with gentamicin compound formula SMZ to cure this disease. Rifampin can also be added on the basis of the above. However, successful treatment often requires valve replacement.
The bacterial treatment course has been used for more than 20 years, administered intravenously, with the initial dose being 250,000 bacterial bodies, followed by 500,000, 1.25 million, 2.5 million, 5 million, 10 million, 20 million, 50 million, 75 million, 100 million, and 150 million. Each injection causes a brief fever effect. Contraindications include active pulmonary subcutaneous nodules, wind-dampness heat, malignant tumors, liver and kidney dysfunction, and pregnancy.
The prognosis is favorable, with most patients recovering within 3 to 6 months, and only 10-15% of cases having a disease course exceeding 6 months. The mortality rate without antibiotic treatment is 2-3%, with the main causes of death being myocarditis, severe central nervous system complications, pancytopenia, etc. Chronic patients may inherit joint lesions, tendon contractures, etc., leading to restricted limb movement.
Endocarditis, pericarditis, meningitis, encephalitis, myelitis, bronchopneumonia, pleurisy, endometritis, etc. Individual patients may experience aphasia, paralysis, hearing loss, deafness, keratitis, optic neuritis, retinitis, nephritis, pyelonephritis, etc. About 1% of pregnant patients experience late abortion.
The acute phase of this disease is easily confused with cold-damage disease, sub-cold-damage disease, Bi disease, wind-dampness-like arthritis, epidemic common cold, other viral respiratory infections, viral hepatitis, malaria, lymphoma, systemic lupus erythematosus, etc. The chronic phase of brucellosis should be differentiated from various bone and joint diseases, neurological Guanneng disorders, etc.
