oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.
Synonyms: Bang's disease (after a Danish vet), Mediterranean gastric remittent fever, Malta fever, Mediterranean fever, undulant fever, rock fever, Cyprus fever, Gibraltar fever.
The disease was first described in Hippocrates' time, although the organism was not isolated until 1887 when a British Army physician, David Bruce, isolated the organism from the spleens of 5 patients with fatal cases on Malta. The disease gets its names from both its course (undulant fever) and location (Malta fever, Crimean fever).
A Gram-negative, aerobic bacillus (facultative intracellular) which is endemic worldwide, causing disease mainly in domestic animals and subsequently transmitted to man.
Species affected include:
- Goats, sheep, camels, foxes, some deer species (Brucella melitensis).
- Pigs, reindeer, cattle, bison, hares, rodents, and various species of deer (B. suis).
- Cattle, bison, elk, buffalo, foxes, and various deer species (B. abortus).
- Dogs, coyote (B. canis).
There are many other strains and species, including B. ovis and the newly discovered B. maris, affecting cetaceans and seals - a possible source of a new occupational disease.
The majority of human infections result from B. melitensis the most pathogenic species in man, although B. suis is emerging as an agent in cattle and may become increasingly important.
- It is very common worldwide and believed to be greatly under-reported (in Nigeria 55% of the population were found to be seropositive). Frequency of brucellosis is higher in more agrarian societies. Central and Southwest Asia are seeing a large increase in cases. The reported frequency in the USA is 0.04 per 100,000 people. It is rare in UK residents but a high index of suspicion should be maintained for people travelling from endemic areas.
- The Middle East is also particularly high-risk.
- In countries where adequate animal control measures (surveillance and vaccination programmes) exist, it is largely an occupational disease.
- However, areas considered high-risk include:
- Southern France.
- North Africa (just considering the European area).
Mode of transmission
- Inhalation: the most common mode in endemic areas, affecting farmers, herdsmen (and particularly families where the animals share the same accommodation), laboratory technicians, and abattoir workers.
- Skin (intact or broken) or mucous membrane (conjunctival) contact: abattoir workers/meat packers, veterinarians (particularly accidental needle-stick injury or eye splashes with live vaccines), laboratory technicians and hunters.
- Consumption of infected/contaminated food: untreated milk/dairy products (particularly unpasteurised cheeses), raw meat or liver.
- Person-to-person (rare): by sexual transmission (has never been well documented), breast-feeding, blood transfusion, bone marrow transplant.
- Bioterrorism: although weaponised by the former Soviet Union, brucellosis is less likely to be used as an agent due to its low mortality, although the prolonged morbidity might hold attractions.
The organism can be freeze-dried enhancing its infectivity, and can survive in the environment for up to 2 years under conditions of darkness, coldness, and high CO2. Likely to be distributed by aerosol or contamination of food.
The key point is to think of the diagnosis and then take a travel and occupational history. Most cases involve exposure to an infected animal. The incubation period is typically 5-30 days but can be up to 6 months or possibly longer.
Brucellosis may be asymptomatic. Symptoms are generally nonspecific. Except for fever and malaise, most symptoms are only observed in half or fewer than half of patients. Symptoms may appear suddenly over 1-2 days or gradually over 7 days or more. Commonly:
- Fever is observed in 90-95% patients. It is a differential in pyrexia of unknown origin (PUO). Classically undulant but other patterns occur.
- Malaise (80-95% of patients).
- Sweating (in 40-90%).
- Myalgias( in 40-70%).
- Arthralgias (in 20-40%).
Also, back pain, headaches, loss of appetite, weight loss (in chronic infection), constipation, abdominal pain, sleep disturbances, cough, testicular pain, skin rash (less common).
May be apyrexial in the chronic form, with myalgia, fatigue, and depression (differential: chronic fatigue syndrome).
- In around half of patients: arthritis, spinal tenderness.
- In around a quarter of patients: looks ill, pallor, lymphadenopathy, splenomegaly, hepatomegaly, epididymo-orchitis, skin rash.
- Less than 5%: jaundice, central nervous system (CNS) abnormalities, cardiac murmur, pneumonia.
Presumptive diagnosis is supported by rose Bengal test (RBT) for screening; positive tests to be confirmed by one of the tests mentioned below:
- Antibody testing is the most reliable method for diagnosing brucellosis:
- The best test is the tube agglutination method, which tests for anti-O-polysaccharide antibody.
- Titres of 1:160 or higher are diagnostic.
- Raised immunoglobulin G (IgG) antibodies indicate recent infection, raised IgM antibodies indicate active disease.
- Raised serum brucella agglutinins.
- Blood cultures are positive in 10-90% of patients.
- Cerebrospinal fluid cultures are positive for brucellosis less than 50% of the time but antibody testing of the fluid yields a diagnosis.
- White cell count is usually normal. Leukocytosis is rare, and a significant number of patients are neutropenic.
- Plain X-ray of joints and spine are usually normal. Occasionally there is bone destruction at the discovertebral junction with anterior osteophytes and reduced disc space. Bone scintigraphy is more sensitive. Arthrocentesis may be necessary to exclude septic arthritis.
- CT or MRI scanning gives a more accurate picture of extension of infection into the spine.
- Liver or bone marrow biopsy may be appropriate in certain cases.
This is quite broad, given that symptoms of brucellosis are nonspecific. Conditions to be considered include:
- Mechanical back pain
- Biological warfare agents
- Subarachnoid haemorrhage
- Thrombocytopenic purpura
- Urinary tract infection
Of the currently existing alternative regimens, only the combination of doxycycline with gentamicin can be considered therapeutically adequate and cost- effective, the latter factor being a major obstacle in using quinolones for brucellosis. Doxycycline-rifampicin-aminoglycoside (triple drug regimen) and longer treatment regimes (>6 weeks) have the lowest rates of failure. One study of the treatment of brucellar spondylitis reported that six months of triple therapy were required to prevent recurrences.
- Doxycycline (100 mg PO bd for 6 weeks) is the most appropriate monotherapy in simple infection; however, relapse rates approach 40% for monotherapy treatment. NB: emphasise the need to complete the full 6-week course of antibiotics, as failure to do so increases the risk of relapse.
- Rifampicin (600-900 mg/day) usually is added to doxycycline for a full 6-week course. In patients with spondylitis or sacroiliitis, doxycycline plus streptomycin (1 g/day IM for 3 weeks) was found to be more effective than the doxycycline/rifampicin combination.
- Rifampicin 600 mg/day and ciprofloxacin 1 g/day for 30 days, have been used as an alternative.
- Streptomycin currently is preferred over rifampicin for combination therapy of any significant infection.
- In paediatric patients older than 12 years, doxycycline (5 mg/kg/day for 3 weeks) plus gentamicin (5 mg/kg/day IM for the first 5 days) is the recommended therapy.
- For children younger than 12 years, trimethoprim/sulfamethoxazole (TMP-SMZ) for 3 weeks and a 5-day course of gentamicin are most effective.
- TMP-SMZ was also effective in treating pregnant women, either as a single agent or in combination with rifampicin or gentamicin.
- Fluoroquinolones have a high relapse rate when used as monotherapy.
- Fluoroquinolones added to doxycycline have no advantage over the other regimens described but may be preferred in an area where resistance to rifampicin is high.
- No uniform recommendation exists for treatment of meningitis or endocarditis; however, TMP-SMZ plus rifampicin remains the preferred combination.
- In endocarditis, early replacement of the infected valve is recommended, along with medical therapy.
- Corticosteroids are recommended in CNS infection but evidence to support their efficacy is lacking.
- Most patients recover completely without complications, if they receive appropriate antibiotic treatment.
- The relapse rate is approximately 10%, even with treatment.
- Mortality is rare (approximately 2%). Death is usually associated with endocarditis.
- Relapse of infection may occur in 10% of patients.
Complications are rare in the patient who is treated appropriately:
- Cardiovascular: the primary complication is the need for valve replacement in the patient with endocarditis.
- Bone: residual musculoskeletal complaints may be present in the patient with long-term infection, sacroiliitis and osteomyelitis.
- Genitourinary: especially epididymo-orchitis.
- Blood: immune thrombocytopenic purpura has been described as a consequence of brucellosis infection.
- Neurological: mental state, visual, hearing changes (may be the most common cause of acquired hearing loss in endemic areas), cranial and peripheral nerve dysfunction, cerebellar ataxia, spinal syndromes, etc.
- Abscess formation: most commonly hepatic but also elsewhere.
- Chronic fatigue syndrome may be seen.
- Infection in pregnancy may result in abortion, congenital and neonatal infections and infection of the delivery team.
- This relies on control of the disease in animals, by a combination of surveillance, slaughtering and vaccination.
- Pasteurisation of milk and avoidance of consumption of unpasteurised milk products, raw or undercooked meat.
- Education, protective clothing, adequate ventilation and disinfection of premises and safe disposal of offal, for those exposed occupationally.
- There is no human vaccine available.
Further reading & references
- Pappas G; Treatment of brucellosis. BMJ. 2008 Mar 29;336(7646):678-9. Epub 2008 Mar 5.
- Brucellosis, World Health Organization
- Maloney GE; Brucellosis, eMedicine, Apr 2009
- Brucellosis deliberate release guidelines, Health Protection Agency (2007)
- Reddy S, Manuel R, Sheridan E, et al; Brucellosis in the UK: a risk to laboratory workers? Recommendations for J Clin Pathol. 2010 Jan;63(1):90-2. Epub 2008 May 21.
- Pappas G, Papadimitriou P, Akritidis N, et al; The new global map of human brucellosis. Lancet Infect Dis. 2006 Feb;6(2):91-9.
- Celebi G, Kulah C, Kilic S, et al; Asymptomatic Brucella bacteraemia and isolation of Brucella melitensis biovar 3 from human breast milk. Scand J Infect Dis. 2007;39(3):205-8.
- Priest JR, Low D, Wang C, et al; Brucellosis and sacroiliitis: a common presentation of an uncommon pathogen. J Am Board Fam Med. 2008 Mar-Apr;21(2):158-61.
- Kiki I, Gundogdu M, Albayrak B, et al; Thrombotic thrombocytopenic purpura associated with Brucella infection. Am J Med Sci. 2008 Mar;335(3):230-2.
- Brouillard JE, Terriff CM, Tofan A, et al; Antibiotic selection and resistance issues with fluoroquinolones and doxycycline against bioterrorism agents. Pharmacotherapy. 2006 Jan;26(1):3-14.
- Hasanjani Roushan MR, Mohraz M, Hajiahmadi M, et al; Efficacy of gentamicin plus doxycycline versus streptomycin plus doxycycline in the treatment of brucellosis in humans. Clin Infect Dis. 2006 Apr 15;42(8):1075-80. Epub 2006 Mar 13.
- Skalsky K, Yahav D, Bishara J, et al; Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008 Mar 29;336(7646):701-4. Epub 2008 Mar 5.
- Ioannou S, Karadima D, Pneumaticos S, et al; Efficacy of prolonged antimicrobial chemotherapy for brucellar spondylodiscitis. Clin Microbiol Infect. 2010 Sep 15. doi: 10.1111/j.1469-0691.2010.03272.x.
- Solera J, Martinez-Alfaro E, Espinosa A; Recognition and optimum treatment of brucellosis. Drugs. 1997 Feb;53(2):245-56.
- Agalar C, Usubutun S, Turkyilmaz R; Ciprofloxacin and rifampicin versus doxycycline and rifampicin in the treatment of brucellosis. Eur J Clin Microbiol Infect Dis. 1999 Aug;18(8):535-8.
- European Commission - Guidelines for Treatment
- Karcaaltincaba D, Sencan I, Kandemir O, et al; Does brucellosis in human pregnancy increase abortion risk? Presentation of two J Obstet Gynaecol Res. 2010 Apr;36(2):418-23.
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Dr Hayley Willacy
Dr Laurence Knott