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Brucellosis
By
Steven Phillips, MD
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Brucellosis—Basics
•The Most Common Zoonosis in the World
•Cousin to Bartonella, Similar Antibiotic•Resistance, Generally More Severe Illness
•The Many Names of Brucellosis:•The Many Names of Brucellosis:
– Mediterranean Fever– Bang's Disease– Malta Fever– Undulant Fever (fevers worse in afternoon-eve)– Gibralta Fever– Rock Fever (as in rock of Gibralta)
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Brucellosis—Cause
Multiple Species of Brucella Genus
Six Initially Recognized SpeciesB. melitensisB. melitensisB. suisB. abortusB. neotomaeB. ovisB. canis
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Brucella—
Newly Discovered Species
New Species Continue to be Discovered
B. cetiB. ceti
B. pinnipedialisB. microti (not to be confused with babesia)B. inopinata
Zygmunt, Jacques, Bernardet, et al, 2012
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Brucellosis—Clinical Features
Metanalysis from 57 Studies
Fever 78% Weight Loss 26%Malaise 71% Splenomegaly 26%Sweats 54% Hepatomegaly 23%Sweats 54% Hepatomegaly 23%Arthralgia 65% Spondylitis 16%Myalgia 47% Sacroiliitis 16%Back Pain 45% Orchitis 10%Chills 45% Neurologic 4%Fatigue 39% Endocarditis 2%Headache 35%
Dean, Crump, Greter et al., 2012
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Brucellosis—Ocular Disease
132 Patients Evaluated
Ocular Disease in 21%
Of Those:Of Those:Anterior Uveitis 41%Choroiditis 32%Panuveitis 9%Papilledema 9%Retinal Hemorrhage 9%
Sungur, Hazirolan, Gurbuz , et al., 2012
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Brucellosis—
Laboratory Features
Review of 1028 Cases
Elevated CRP 58%Elevated ESR 51%Anemia 40%Anemia 40%Lymphomonocytosis 28%Elevated ALT/AST 25%Leukopenia 11%Thrombocytopenia 10%Leukocytosis 9%
Buzgan, Karahocagil, Irmak, et al., 2010
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Most Often Disabling
“debilitating and chronic”Dean, Crump, Greter et al., 2012
“significant morbidity and mortality” (2%)“significant morbidity and mortality” (2%)
Buzgan, Karahocagil, Irmak, et al, 2010
asymptomatic infection occurs mainlyfrom low virulence species, ie B. canis
Zhen Q1, Lu Y, Yuan X, et al, 2013
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Brucellosis—Microbiology
Aerobic coccobacillusIntracellularGram negativeGram negative
Intracellular Survival: Co-opts AutophagyVia Type IV Secretion System
– -Forms Brucella Containing Vacuole (BCV)– -Replicative Niche within BCV
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Brucellosis—Transmission
-Unpasteurized Dairy
-Animal Exposures—Multiple Body Fluids
-Laboratory Exposures—Aerosolization
-Humans Considered 'Dead End' Hosts
– But Uncommonly: Transplacental, Breast Milk, & Sexual Transmission Have Occurred
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Brucellosis—Seasonality
12.8% of Cases Present in the Winter
Hasanjani Roushan, Mohrez, Smailnejad Gangi, et al, 2004 Hasanjani Roushan, Mohrez, Smailnejad Gangi, et al, 2004
78% Present in the Spring/Summer
Lulu, Araj, Khateeb, 1988
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Brucellosis—Vector-born?
Isolated from ticks
Gudoshnik, 1958 Sidorov, 1960Sidorov, 1960Sidorov, Gubina, 1962 Taran, Pogorelov, Kulikova, et al, 1966Sidorov, Gubina, 1976
Isolated from fleas
Ozsan, 1962
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Brucellosis—Vector-born?
In lice, replication & transovarialtransmission demonstrated
Neglia, Veneziano, De Carlo E, et al, 2013Neglia, Veneziano, De Carlo E, et al, 2013
“suggests possible Brucella transmissionby blood sucking insects in nature”
Vitry, Hanot, Deghelt et al, 2014
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Brucellosis—Diagnosis
Clinical Diagnosis
Laboratory Diagnosis
-Culture—Fastidious, Slow Growing, False Negatives-Culture—Fastidious, Slow Growing, False Negatives
-PCR—Strain Limitations, Multiple Sampling
-Serologies—Subject to False Seronegativity
– ELISA & Agglutination Antibody (Most Common)
– Complement Fixation, Brucellacapt (Neither in US)
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Brucellosis—Treatment
Antibiotics Most Commonly Used
Streptomcyin or GentamicinDoxycyclineStreptomcyin or GentamicinDoxycyclineRifampinBactrimQuinolones
Resistant to Ceftriaxone
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Brucellosis—Treatment
Agreed Upon Facts:
-Earlier Treatment = Better Outcomes-Earlier Treatment = Better Outcomes
-Single Agent Antibiotics Don't Work
-Treatment < 6 Wks = Very High Failure Rates
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Brucellosis—
Minimum Treatment
Aminoglycoside x 3 wks + Doxy x 6 wks or
Doxy + Rifampin x 6 wksDoxy + Rifampin x 6 wks
-Aminoglycoside + Doxy is More Effective
-Streptomycin = Gentamicin in Efficacy
10% Failure in Early Uncomplicated Disease
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Brucellosis—Treatment
•Even with Longer Treatments—•High Failure Rate in Complicated Disease
•Brucella Spondylitis
•40% Failure/Relapse Despite 120 Days of•Combination Antibiotics
Solera, Lozano, Martinez-Alfaro, 1999
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Brucellosis—Long Term
Combination Antibiotics
18 Brucellar Spondylitis Patients—– Triple Antibiotics for 18 Months– Result: All Patients No Longer Disabled
Aminoglycoside, doxy, rifampin—3 wks
Then, doxy/rifampin/tmp-smx or doxy/rifampin/cipro for 18 months
Ioannu, Karadima, Pneumaticos, et al. 2011
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Chronic Brucellosis
Been Formally Studied for Over 100 Years First Pubmed Article for Undulant Fever Dated 1912
Still No Agreed Upon Curative TreatmentStill No Agreed Upon Curative Treatment
Chronically Symptomatic & Repeatedly Relapsing Brucellosis Occurs Despite Every Antibiotic Treatment Known
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Chronic Brucellosis
2-33 years after diagnosis & treatment
– 3 Groups– Chronic Focal Symptoms– Chronic Focal Symptoms– Chronic Subjective Symptoms– Asymptomatic
“B. melitensis DNA after therapy in 80% of patients”Required up to 28 PCR samples from each patient
Castaño, Solera, 2009
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Brucellosis—Mechanisms of
Virulence & Persistence
BlebsGamazo C, Winter AJ, Moriyón, et al, 1989
L-formsSchmitt-Slomska, Caravano, Anoal, et al, 1981
BiofilmsAlmirón, Roset, Sanjuan, 2013
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Brucella Induced Anergy
'Cured' seronegative patients have continued T-cell anergy as if they 'Cured' seronegative patients have continued T-cell anergy as if they were still infected
Skendros, Sarantopoulos, Tselios, et al., 2008
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Reversing Brucella
Induced Anergy
Levamisole: Dual Activity:– Antiparasitic– Immunopotentiator– Immunopotentiator
Taki, Schwartz, 1994
Antibiotics + Levamisole Superior toOnly Antibiotics
Irmak, Buzgan, Karahocagil et al, 2003
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Levamisole Toxicity
Can Cause Severe Auto-Immune Disease
– Neutropenia– Vasculitis– Vasculitis
Arora, 2013
Withdrawn from the US Market in 1999
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Other Possible
Immunopotentiation Options
Ivermectin—Antiparasitic
Immunopotentiation DemonstratedImmunopotentiation Demonstrated
Njoo, Hack, Oosting, 1994Blakley, Rousseaux, 1991
-Does Not Cause Auto-Immune Side Effects
-Has Not Been Studied for Brucellosis
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Other Possible
Immunopotentiation Options
14 patients with relapsing chronic brucellosis, anergic to brucella antigensbrucellosis, anergic to brucella antigens
-Vitamin C—1 gm per day orally for 15 Days -Significant Reversal of Brucella-Induced Anergy
Boura, Tsapas, Papadopoulou, et al., 1989
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Other Possible
Immunopotentiation Options
Polyporus Umbellatus—Edible Mushroom
Reversal of Brucella-Induced Anergy
Zhang, Gao, Cun, et al., 1993
Activates Macrophages Via TLR-4 (Brucella Not Evaluated in this Study)
Li, Xu, 2011
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Immunology:
Gamma Interferon
Animal Inoculation
– Attenuated Brucella=– Strong Gamma Interferon Response– Strong Gamma Interferon Response
– Virulent Brucella=– Aborted Gamma Interferon Response
Pérez-Sancho, Durán-Ferrer, García-Seco, et al., 2014
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Immunology:
Gamma Interferon
“interferon-gamma is the principal cytokine active against Brucellainfection”infection”
Skendros , Boura, 2013
Immunotherapy Studies with GammaInterferon Have Not Been Done
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Immuno-Therapy
32 Anergic Chronic Brucellosis Patients
Group 1: Interferon AlphaGroup 2: LevamisoleGroup 3: Conventional AntibioticsGroup 3: Conventional Antibiotics
Groups 1 & 2: Clinical Improvement andGroups 1 & 2: Clinical Improvement andAugmented Immune Response to Augmented Immune Response to BrucellaBrucella
Group 1 > Group 2; Group 3 Was No Change
Printzis, Raptopoulou-Gigi, Orphanou-Koumerkeridou, et al., 1994
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Ever Get the Feeling that
Nobody’s Listening?