Definition, etiology, pathogenesisTop
1. Etiologic agent: Gram-negative Brucella genus bacilli; 4 species are pathogenic for humans and animals: B melitensis (causes infections in the Mediterranean countries, Asia, and Africa), B suis (in North America and Central Europe; 5 biovariants), B abortus (in Europe and temperate climate countries of Africa, Asia, and South America; 7 biovariants), and B canis (causes infections in dogs, sporadically in humans in the United States, Europe, and Japan). Brucella spp are intracellular, non–spore forming bacteria, highly resistant to external environmental factors, and able to survive in water or soil for >3 months, but sensitive to heating (they die within <20 minutes at >65 degrees Celsius) and disinfectants such as Lysol, chloramine, or caustic soda.
2. Pathogenesis: Bacterial entry is followed by granulocyte activation and accumulation at the inoculation site. Then, the bacteria undergo opsonization and are phagocyted by granulocytes and monocytes. As facultative intracellular pathogens, they survive and proliferate inside granulocytes. Brucella bacilli likely initially proliferate inside the cells of lymph nodes located near the portal of entry. From there they are transported via blood to various organs, which they colonize. They have a particular affinity to tissues rich in reticuloendothelial cells, such as the liver, spleen, or bone marrow, as well as to musculoskeletal and genitourinary tissues. Abscesses and granulomas with or without necrosis are formed in tissues, and the tissues undergo caseation. The main antigen present in bacterial walls and a virulence factor is a smooth lipopolysaccharide (S-LPS) molecule. Some of its components are responsible for cross-reactions with Vibrio cholerae O1 and Yersinia enterocolitica O9 antigens.
3. Reservoir and transmission: The animal reservoir for B melitensis is sheep, goats, and rarely camels or cattle. The main animal reservoir for B abortus is cattle, but the pathogen has also been found in camels, bison, and yaks. B suis is found in domestic pigs and wild boars (biovariants 1-3), but it has also been reported in cattle (biovariant 1), reindeer (biovariant 4), and sporadically in hares and rodents. B canis occurs in dogs, especially ones bred in kennels. The bacteria have been isolated in foxes, minks, and predators fed with scraps contaminated (either deliberately or incidentally) with Brucella bacilli.
The source of infection in humans is sick animals, their secretions or excretions, or raw or undercooked food products derived from such animals (milk, cheese, meat). Infections during deliveries or miscarriages of infected farm animals following contact with biologic material (fetus, amniotic fluid, placenta) are particularly common. Transmission occurs through direct contact (injured skin, conjunctiva), respiratory system (inhalation), or oral route (consumption of contaminated products, eg, unpasteurized milk, cheese).
4. Risk factors: Contact with infected animals, their secretions and excretions, as well as consuming contaminated dairy products (in countries where brucellosis is not endemic, consumption of contaminated imported food).
Brucella bacilli may cause infection by inhalation (mainly laboratory infections). An infective dose is 10 to 100 bacteria. Considering the easiness of infection via this route, these bacteria are thought of as a potential biological weapon.
5. Incubation and contagious period: The incubation period is from several days (in cases of acute brucellosis [B melitensis]) to several months (in chronic brucellosis [B abortus]). Humans may be a source of infection, but transmission between humans is rare.
Clinical FEATURES AND NATURAL HISTORYTop
The disease has a very wide spectrum of symptoms, from asymptomatic to severe life-threatening infection. Due to the rich but rather nonspecific symptomatology, it is called a “great imitator.” The clinical picture and severity of the disease depend on bacterium species, infective dose, route of infection, and overall condition of the host, including their immune and nutrition status, diseases, and medications taken (especially antacids).
In acute brucellosis symptoms subside <8 weeks from infection onset; in subacute brucellosis, between 8 and 52 weeks; and in chronic brucellosis, >52 weeks. The disease may be acute, acute progressing to chronic, and primarily chronic.
Both in acute and in chronic disease, all tissues and organs may be involved, but symptoms typically occur in the osteoarticular, nervous, circulatory, and genitourinary systems and in the liver. Metastatic abscesses may develop. The disease onset may be sudden (acute brucellosis) or with symptoms progressing over weeks or months (chronic brucellosis). A recurrent course is typical of chronic disease (in 5%-15% of cases). Relapses usually occur within 6 months after treatment completion and have a milder course; they are not associated with drug resistance.
1) Acute brucellosis: Fever, severe weakness, myalgia, arthralgia, hyperhidrosis; sometimes gastrointestinal disorders; testicular pain in men.
2) Chronic brucellosis: Most frequently locomotor system symptoms, myalgia; sometimes sensory deficits, radiculopathies. Patients report weakness, eating disorders, and/or excessive sweating. Psychiatric disorders, sleeping disorders, headache, and/or symmetric hearing disorders may develop. Symptoms of orchitis and/or potency disorders may be seen in men and menstruation disorders in women. Approximately 25% of patients report cough.
Some symptoms may occur in both acute and chronic brucellosis:
1) Fever: Most patients (80%-100% of cases) have high-grade fever, typically with a wavy or irregular pattern and often with shivers. Relative bradycardia is observed despite the fever; hypotension may occur. Due to the absence of pathognomonic symptoms, brucellosis is a frequent cause of fever of unknown origin (FUO) (see Fever of Unknown Origin) and neutropenic fever in endemic areas.
2) Lesions in the locomotor system are typically seen in chronic brucellosis. Arthritis involving single or multiple joints is observed, typically in the knee, hip, sacroiliac joint, shoulder, and sternoclavicular joint, and may be accompanied by osteomyelitis, most often in the thoracic and lumbar spine. The arthritis is degenerative and proliferative, with osteophyte formation.
3) Hepatitis occurs in 25% to 30% of patients, more often in acute brucellosis. Pathologic lesions may manifest as hepatitis, noncaseous granulomas, or minor abscesses. Cholecystitis develops rarely.
4) Abnormalities of the hematopoietic system: Enlargement of the spleen (20%-30% of cases) and lymph nodes (10%-20%); hypercellular bone marrow; sometimes granulomas. Abnormal complete blood count (see Complete Blood Count (CBC)).
5) Nervous system infection (neurobrucellosis) may manifest as lymphocytic meningitis and/or encephalitis, myelitis, brain and epidural abscesses, peripheral neuropathy, cranial nerve damage, symmetric damage of the cranial nerve VIII (with symptoms of hearing impairment at frequencies >1000 Hz).
6) Genitourinary system infection: Epididymo-orchitis in men (~20%); adnexitis, cervicitis, and abscesses in the lesser pelvis in women. Infected pregnant women are at risk of miscarriage. Interstitial nephritis, pyelonephritis, or glomerulonephritis may develop.
7) Skin lesions: Nonspecific fine macular or maculopapular rash, erythema nodosum, skin ulceration, or vasculitis occur in 2% to 6% of cases.
8) Cardiovascular brucellosis is rare and usually manifests as endocarditis (1% of all brucellosis cases) and rarely as myocarditis or pericarditis, arterial intima inflammation, and/or mycotic aneurysms.
9) Ocular lesions: Uveitis, iridocyclitis, keratitis, optic neuritis, endophthalmitis.
Clinical picture is not very characteristic, which is why establishing the diagnosis may be difficult, especially in nonendemic countries and in patients with a negative epidemiologic history. Brucella spp infection should always be considered in the differential diagnosis of FUO (see Fever of Unknown Origin).
1. Identification of the etiologic agent:
1) Biologic material culture (blood, bone marrow, tissues, cerebrospinal fluid [CSF], synovial fluid): Long incubation time (up to ≥30 days), low sensitivity (15%-70% for blood cultures).
2) Serologic studies are the basis for diagnosing brucellosis. IgM antibodies appear after 1 week of infection and IgG antibodies are produced starting week 2. Concentrations of both antibody classes decrease with time. Absence of the decrease indicates recurrence or transition into the chronic phase. Chronic brucellosis is associated with a high titer of IgG antibodies; low titer likely indicates a delayed phase of recovery. The following tests are used: enzyme-linked immunosorbent assay (ELISA) test, complement fixation test, Wright agglutination test, 2-mercaptoethanol (2-ME) agglutination tests, tube agglutination test (TAT), indirect immunofluorescence test, Coombs antiglobulin test, and colored passive hemagglutination test. Titers of ≥1:100 to 1:160 are considered significant diagnostic factors in regions where brucellosis is not endemic. Infection is confirmed by a ≥4-fold increase in titer during convalescence. If the antibody titer is very high, agglutination tests may yield false-negative results due to the prozone effect (inhibition of agglutination observed in samples at very high antibody level concentrations). ELISA tests, which are being used with increasing frequency, detect antibodies (IgA, IgM, and IgG) against cytoplasmic antigens. In doubtful cases (if relapse is suspected), the assays are easier for interpretation (antibodies against the S-LPS may persist long after recovery). ELISA tests are also helpful in the diagnostic work-up and monitoring of neurobrucellosis (CSF test).
3) Brucellin skin test (Burnet reaction): Injection of brucellin (killed bacteria extract) causes a delayed hypersensitivity reaction manifesting as an inflammatory infiltration at the injection site.
4) Molecular tests: The polymerase chain reaction (PCR) method can be used, but it is not standardized.
2. Other tests:
1) Blood tests: White blood cell (WBC) count is usually normal or leukopenia with relative lymphocytosis is present; sometimes anemia and thrombocytopenia are observed; the serum C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) have low diagnostic value (can be normal or increased).
2) Synovial fluid examination: Features of effusion with low WBC count.
3) Histologic examination: Granulomas in biopsy specimens.
4) Imaging studies: Abdominal ultrasonography shows hepatosplenomegaly; multifocal lesions are visible on radiologic examination of bones and joints, primarily degenerative and proliferative in articular brucellosis; other studies may be performed depending on the location of lesions.
5) Neurologic, psychiatric, and ear, nose, and throat (ENT) examination (including an audiogram).
A probable case: Clinical picture epidemiologically associated with a confirmed case or high antibody titer in a single test.
A confirmed case: Clinical picture corresponding with brucellosis, confirmed in laboratory tests.
Differential diagnosis depends on clinical manifestations and dominant lesions and should include, among others, infectious osteitis, tuberculosis, sepsis, rickettsiosis, enteric (typhoid) fever, tularemia, malignancies, systemic connective tissue diseases. Diagnostic work-up of FUO: see Fever of Unknown Origin.
1. Generalized brucellosis.
1) First-line treatment (options):
a) Oral doxycycline 100 mg every 12 hours for 6 weeks; in the first 7 days administered together with an aminoglycoside, eg, IV gentamicin 5 mg/kg of body weight every 24 hours.
b) Oral doxycycline 100 mg every 12 hours with oral rifampicin 600 to 900 mg every 24 hours for 6 weeks.
c) Doxycycline with rifampicin and aminoglycoside (gentamicin or streptomycin).
2) Alternative treatment (if aminoglycosides are contraindicated): Doxycycline or rifampicin dosed as above in combination with oral ciprofloxacin 500 mg every 12 hours.
2. Arthritis, osteitis.
1) Oral doxycycline 100 mg every 12 hours with oral rifampicin 600 to 900 mg every 24 hours for 3 months; in the first week additionally use IV gentamicin 5 mg/kg of body weight every 24 hours for 7 days; or
2) Oral ciprofloxacin 750 mg every 12 hours with oral rifampicin 600 to 900 mg every 24 hours for ≥3 months.
3. Neurobrucellosis: Oral or IV doxycycline 100 mg every 12 hours with oral rifampicin 600 to 900 mg every 24 hours and IV ceftriaxone 2 g every 12 hours until normalization of CSF parameters.
4. Endocarditis: IV gentamicin 5 mg/kg of body weight every 24 hours for 2 to 4 weeks and rifampicin in combination with doxycycline and cotrimoxazole for 6 weeks to 6 months.
5. Brucellosis in pregnancy: Oral cotrimoxazole (5 mg of trimethoprim per kg) every 12 hours with oral rifampicin 600 to 900 mg every 24 hours for 4 weeks.
Depending on clinical features: Antipyretics and analgesics, physical therapy, glucocorticoid therapy in ocular disease (systemic and/or topical treatment; also to be considered in encephalitis).
Depending on the type of infection: Reactive postinfectious spondyloarthropathies, atrophy of seminiferous tubules leading to infertility, miscarriages, spinal cord injury, paraplegia, and other neurologic deficits, aneurysms in cardiovascular brucellosis.
Mortality is ~1% and usually refers to septic infections, with involvement of the heart or nervous system. Recurrences are possible if treatment is irregular. Therefore, patient follow-up is recommended for up to 2 years after the diagnosis to detect a potential recurrence.
Immunoprophylaxis: In some countries (Russia, China, France), a vaccine with attenuated bacteria is available, intended for occupational groups at risk of infection.
1. Elimination of prevalence among animals, avoiding consumption of food products that may be a source of bacteria (ie, unpasteurized milk, soft cheese, especially goat cheese, raw meat).
2. Patient isolation is not required. Brucella spp bacilli are sensitive to most disinfectants; standard cleaning and disinfection of the room where the patient stays is sufficient.
3. Personal protective equipment (PPE):
1) Health-care personnel taking care of a patient with brucellosis should use standard PPE.
2) Microbiologic laboratory personnel: Standard PPE should be used in laboratories with biosafety level (BSL) 2 or 3. Biologic material should be handled according to procedures for BSL-2 or BSL-3 laboratories (minimizing the risk of aerosol formation or splashing).
Laboratory employees who have contact with Brucella spp bacilli should undergo serologic examination after the contact and then after 6, 12, 18, and 24 weeks.