Brucellosis

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 bacilli (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.

• 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. Reported frequency in the USA is 0.04 per 100,000 people.¹
• Middle East is particularly high risk.²
• In countries where adequate animal control measures (surveillance and vaccination programmes) exist, it is largely an occupational disease.
• However areas considered high risk include:
  • Portugal
  • Spain
  • Southern France
  • Italy
  • Greece
  • Turkey
  • North Africa (just considering the European area)

Key point is to think of the diagnosis and then take a travel and occupational history. Most cases involve exposure to an infected animal. As brucella can take 1-8 weeks to incubate, include possible exposures in the preceding few months.

Symptoms

Brucellosis may be asymptomatic.³ Symptoms are generally non-specific. Except for fever and malaise, most symptoms are only observed in half or fewer than half of patients.¹Symptoms 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 PUO. Classically undulant but other patterns occur.
• Malaise (80-95% of patients)
• Chills
• Sweating (in 40-90%)
• Myalgias( in 40-70%)
• Tiredness
• 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 chronic form, with myalgia, fatigue, depression (differential: chronic fatigue syndrome).

Signs

• In around half of patients; arthritis, spinal tenderness.⁴
• In around a quarter of patients; looks ill, pallor, lymphadenopathy, splenomegaly, hepatomegaly, epididymo-orchitis, skin rash.
• Less than 5%; jaundice, 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 IgG antibodies indicate recent infection, raised IgM antibodies indicate active disease.
• Raised serum Brucella agglutinins.
• Blood cultures are positive in 10-90% of patients.
• CSF 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. Leucocytosis is rare, and a significant number of patients are neutropaenic.
• Plain X-ray of joints and spine are usually normal. Occasionally bone destruction at discovertebral junction with anterior osteophytes and reduced disc space. Bone scintigraphy more sensitive.
• CT or MRI gives more accurate picture of extension of infection into spine.

This is quite broad, given the symptoms of brucellosis are non-specific. Conditions to be considered include:

• Mechanical back pain
• Bronchitis
• Biological warfare agents
• Endocarditis
• Gastroenteritis
• Meningitis
• Osteomyelitis
• Pneumonia
• Subarachnoid haemorrhage
• Thrombocytopaenic purpura⁵
• Tuberculosis
• 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.^6,7 Doxycycline-rifampicin-aminoglycoside (triple drug regimen) and longer treatment regimes (>6 weeks) have the lowest rates of failure.⁸

Adults

• Doxycycline (100 mg PO bd for 6 wk) 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.
• Rifampin (600-900 mg/d) 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 wk) was found to be more effective than the doxycycline/rifampin combination.⁹
• Rifampicin 600 mg/day and ciprofloxacin 1 g/day for 30 days, has been used as an alternative.¹⁰
• Streptomycin currently is preferred over rifampin for combination therapy of any significant infection.¹¹

Children

• In paediatric patients older than 12 years, doxycycline (5 mg/kg/day for 3 wk) 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.

Pregnant women

• TMP-SMZ also was effective in treating pregnant women, either as a single agent or in combination with rifampin or gentamicin.

Potential problems

• 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 rifampin is high.
• No uniform recommendation exists for treatment of meningitis or endocarditis; however, TMP-SMZ plus rifampin 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. 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, sacro-iliitis and osteomyelitis.
• Genitourinary: especially epididymo-orchitis.
• Blood: immune thrombocytopaenic 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 & peripheral nerve dysfunction, cerebellar ataxia, spinal syndromes, etc.
• Abscess formation: most commonly hepatic, but also elsewhere.
• Chronic fatigue syndrome may be seen.

• Relies on control of the disease in animals, by 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 & disinfection of premises, and safe disposal of offal, for those exposed occupationally.
• There is no human vaccine available.