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BRUCELLOSIS
Hail M. Al-Abdely, M.D.
Associate Consultant
Infectious Diseases
Historical Background
• Malta Fever
– Major health problem to British troops in Malta in the 19th and early
20th centuries.
Cases(1901-07)
Deaths
Navy
1705
30
Army
1947
55
Civil services
4627
489
Historical Background
• 1860 J.A. Maraston; assistant surgeon in
the British Army in Malta -- first accurate
description “Mediterranian Gastric Remittent
Fever”
• David Bruce (1855-1931)
-1883 sent to Malta to provide medical care
to the troops.
- 1887 isolated “micrococcus” from spleens
of 4 soldiers died of the disease.
Historical Background
• 1897 A.E. Wright ; pathologist in British army developed agglutination test.
What is the source?
“Mediterranean Fever Commission”
1904
Historical Background
• 1905 Zammit; Maltese physician
- Goats were the source of infection.
• 1897 E. Bang; Danish veterinarian
-described intracelular pathogen causing abortion in cattle named
“Bacillus abortus”.
• 1918 A. Evans; American microbiologist
-made the connection between Bacillus abortus and micrococcus
melitensis & named it Bacteriaceae.
Historical Background
• 1920 Meyer and Shaw suggested BRUCELLA
• 1914 Mohler isolated organism from liver & spleen of
Pigs--B.suis.
• 1957 B. neotome, 1963 B. ovis, 1966 B. canis
Epidemiology
• Worldwide zoonosis
• Only 17 countries declared brucellosis
free1986
• Six species
1. B.abortus - mainly cattle
2. B.melitensis - sheeps & goats
3. B.suis - pigs
4. B. canis - dogs
5. B. ovis - sheep (not human pathogen)
6. B. neotomae - desert wood rat
(not human pathogen)
• B. melitensis -- most common worldwide
Epidemiology in Saudi Arabia
• Endemic disease
• Mostly B. melitensis & b. abortus.
• No clear figures about incidence &
prevalence.
• Incidence : 5.4 per 1000 per year.
• Prevalence : 8.6 - 38 % - some regions.
Bacteriology
•
•
•
•
Gm - ve cocci, coccobacilli, bacilli.
Strict aerobic, nonmotile, nonspore forming.
B. ovis, B. abortus --CO2 supplementation.
Grow in regular media -- prolonged
incubation > 4 weeks.
Bacteriology
• Surface lipopolysccharide cell wall
– smooth vs non-smooth.
– determine virulence.
» smooth LPS : B. melitensis,suis,abortus
» Non-smooth LPS B.canis, ovis.
– the basis for agglutination test.
Transmission
• Zoonosis affecting domestic animals.
• Concentrated in milk, urine, genital organs.
ROUTES OF TRANSMISSION
• Oral : unpasteurised milk & products
raw milk or meet.
• Respiratory: lab workers.
• Skin: accidental penetration or abrasion
– - at risk farmers & veterinarians.
• Other routes:
Conjunctival, Blood transfusion,
Transplacental, ? person to person.
Pathogenesis
Entry to the body
Macrophage activation
Intracelluar multiplication
Lymphatics
RES organs
Blood
Any organ
Polymorph migration &
Phagocytosis
Pathogenesis
• Cell mediated immunity also activated with granuloma
formation (mainly with B. abortus)
• Humoral antibody response of little importance
• Main way of body control of the infection is through
committed T-lymphocytes producing lymphokines (Interferon) which activate macrophage killing
• Pyogenic infection more with B. melitensis and B. suis
Clinical Manifestations
•
•
•
•
•
Incubation period: variable 2- 8 wks.
Presentation: acute 50% & insidious 50%
Sx & signs not specific.
Can affect any organ.
Common nonspecific Sx:
- fever with rigors.
- sweats, malaise, anorexia.
- headache, back pain.
Clinical Manifestations
Acute
(8wks)
Undulant
(<52 wks)
Chronic
(>52wks)
Young adults
> 40 yrs
Arthralgia
Children,
young adults
++
+++
+++
High fever
95%
50-70%
No
Hepatomegaly
66%
50%
Occasional
Splenomegaly
50-70%
< 40%
Rare
Psychiatric
No
Occasional
Frequent
Ocular
(uveitis)
No
1-2%
5-10%
Age
Clinical Manifestations
• GIT 70% : anorexia, abd. pain, vomiting,
diarrhea,contipation, hepatosplenomegaly.
• LIVER : Involved in most cases but LFTs normal
or mildly abnormal.
– granulomas (B. abortus).
– hepatitis (B.melitensis).
– abscesses (B.suis).
Clinical Manifestations
•
•
•
•
Skeletal 20-60% :
arthritis, spondylitis, osteomyelitis.
sacroiliitis - most common.
athritis - oligoarticular : hip, knee & ankles.
Joint asp. - monocytosis, culture +ve in 50 %
Clinical Manifestations
• Neurologic
– Meningitis, encephalitis, radiculopathy &
peripheral neuropathy, intracerebral
abscesses
– Meningitis
» acute or chronic
» neck rigidity < 50%
» CSF
• lymphocytic pleocytosis
• (N) or low sugar
• increase protein
• culture +ve < 50%
• agglutination +ve in >95%
Clinical Manifestations
• Cardiovascular
– Edocarditis 2% (major cause of mortality)
– Rx: valve replacement and antibiotics
– Pericarditis & myocarditis
• Pulmonary
– Inhalation or hematogenous
– Cause any chest syndrome
– Rarely Brucella isolated from sputum
Clinical Manifestations
• Genitourinary
– Epidydemoorchitis
– Pyonephrosis (rare)
• Cutaneous
– Nonspecific
• Hematologic
– Anemia
– Leukopenia
– Thrombocytopenia
Diagnosis
• History of animal contact is pivotal
• In endemic area, it should be in the
DDx of any nonspecific febrile
illness
Diagnosis
• Laboratory
– WBC (N) or
. monocytosis
– ESR of little help
– Blood cultures
» slow growth = 4 weeks
» new automated system BATEC identifies he organism 4-8
days
» more recent (BACT/ALERT) - 2.8 days
• PCR
Diagnosis
• Serology
– Main laboratory method of diagnosis
– Serum agglutination test - most widely used
» measures agglutination for IgG, IgM, IgA
» 2ME - break sulf-hydrile bonds in IgM polymer no agglutination
» which level is diagnostic ??
1 : 160 - non endemic area
1 : 320 - endemic area
» SAT - false negative
• Prozone
• Blocking antibodies
– Other tests: coombs, ELISA, CFT, FTA
S
IgM
Brucella Antibodies
• AGG = IgG + IgM
• 2ME = IgG
Prognosis
• Preantibiotic era
– Mortality 2% mainly endocarditis
• Morbidity
– High with B. melitensis
– Nerve deafness
– Spinal cord damage
Prevention
– Control of disease in domestic animals
» immunization using B. abortus strain 19 and B. melitensis
strain Rev 1
– Routine pasteurization of milk
– In labs strict biosafety precautions
Treatment
Drugs against Brucella
• Tetracyclines
• Aminoglycosides
– Streptomycin since 1947
– Gentamicin
– Netilmicin
• Rifampicin
• Quinolones - ciprofloxacin
• ?3rd generation cephalosporins
Treatment
Drugs against Brucella
• Treatment for uncomplicated Brucellosis
– Stremptomycin + Doxycycline for 6 weeks
» ? TMP/SMX + Doxycycline for 6 weeks
– WHO recommendation 1986
» Rifampicin + Doxycycline for 6 weeks
• Treatment of complicated Brucellosis
– Endocarditis, meningitis
– No uniform agreement
– Usually 3 antibrucella drugs for 3 months
Untreated Brucellosis
10000
Titer
1000
IgG
IgM
100
10
1
2
3
4
Weeks
5
6
Treated Brucellosis
10000
Treatment
Titer
1000
IgG
IgM
100
10
1
2
3
4
Months
5
6
7
Relapse
Predictors of Relapse
Male sex
Inadequate antibiotic therapy.
Positive culture on initial disease
Thrombocytopenia
Ariza, et al: CID 20:1241, 1995