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Tuesday, January 20, 2009

BARTONELLA INFECTIONS

BARTONELLA INFECTIONS - Mary H. Hohenhaus, MD
BASICS
DESCRIPTION
• Fastidious intracellular Gram-negative bacilli
- At least 20 distinct species, 8 known to cause disease in humans
- Bartonella henselae and B. quintana most common in North America
• Infections manifest in 2 broad categories
- Localized skin lesions and prominent regional lymphadenitis (cat scratch disease [CSD])
- Bacteremia with localized vascular lesions in various organs and potential for persistent disseminated infection
• System(s) Affected: Cardiovascular; Gastrointestinal; Hemic/Lymphatic/Immunologic; Musculoskeletal; Nervous; Pulmonary; Skin/exocrine
• Synonym(s): Bartonellosis
GENERAL PREVENTION
Vector avoidance
EPIDEMIOLOGY
• CSD: Predominantly children
• Others: Predominantly adults
Incidence
• Carri'on disease: 12.7/100 person-years in endemic areas
• CSD: Estimated 9.3/100,000 in US (~25,000 cases annually)
• Endocarditis: Estimated 3-4% of cases, up to 1/3 of "culture negative" cases
• Others: Unknown
Prevalence
• Seroprevalence studies of B. henselae suggests many childhood infections are asymptomatic.
• Studies of B. quintana in homeless populations suggest seroprevalence of 10%.
RISK FACTORS
• Vector exposure with cutaneous inoculation
- B. bacilliformis: Lutzomyia sandflies, limited to Andean South America
- B. quintana: Human body louse, typically in alcoholic, homeless men
- B. henselae: Domestic cat (especially scratch/bite from kitten)
- Others: Unknown
• Cell-mediated immune dysfunction (particularly in bacillary angiomatosis/bacillary peliosis)
- HIV infection, especially with CD4+ lymphocyte count 100/mcL
- Chronic steroid, immunosuppressant, or alcohol use
PATHOPHYSIOLOGY
• Erythrocyte and endothelial cell invasion
• Stimulation of angiogenesis
ETIOLOGY
• B. bacilliformis: Carri'on disease
• B. quintana: Trench fever, bacillary angiomatosis (subcutaneous and osseous lesions), bacillary peliosis, endocarditis
• B. henselae: CSD, acute and persistent bacteremia, bacillary angiomatosis (hepatosplenic lesions), bacillary peliosis, endocarditis (preexisting valvular disease), neurologic manifestations
• B. clarridgeiae, B. elizabethae, B. grahamii, B. vinsonii, B. washoensis: Case reports of CSD, bacteremia, endocarditis, myocarditis, others

DIAGNOSIS
• Diagnosis of typical CSD traditionally requires at least 3 of the following
- Animal contact (usually cat) resulting in a scratch, abrasion, or ocular lesion
- Positive serologic test
- Characteristic lymph node pathology
- No evidence of other cause
• Diagnosis of other syndromes requires high clinical suspicion and identification of compatible syndrome; if test results are not helpful, response to appropriate antibiotics may be suggestive.
SIGNS AND SYMPTOMS
• Carri'on disease (aka Bartonellosis; usually has 2 distinctive stages: An acute, life-threatening illness associated with high fever, hemolytic anemia, and a chronic, benign cutaneous eruption consisting of raised, reddish-purple nodules.
- Oroya fever (acute bacteremia): In severe cases, abrupt onset 3 weeks after inoculation. Profound anemia, many complications, may be fatal.
- Asymptomatic persistent bacteremia: 15% of untreated Oroya fever survivors
- Verruga peruana: Crops of nodular angiomatous skin lesions months after Oroya fever; mucosal and internal lesions also; involute in months to years
• Typical CSD (up to 90% of cases)
- Days after inoculation 2-3-mm nontender papules develop at the trauma site; progress to reddened then crusted vesicles
- Tender regional adenopathy 1-8 weeks postinoculation; fever, malaise, headache
- Usually involves nodes of upper extremities, neck, head
- Suppuration of nodes common, but only 10% require drainage
- Resolution in 2-4 months for majority
• Atypical CSD
- Parinaud oculoglandular syndrome: Unilateral granulomatous conjunctivitis and preauricular lymphadenitis
- Neuroretinitis: Abrupt, painless unilateral vision loss; macular star exudate, papilledema; self-limited, with return of visual acuity
- Encephalopathy: Rapid progression from headache to lethargy, coma, and seizure; sequelae rare
- Other manifestations self-limited, sequelae rare: Granulomatous hepatitis/splenitis, osteolysis, atypical pneumonitis, fever of unknown origin, mononucleosis-type syndrome, others
• Bacteremia (short-term mortality uncommon)
- B. quintana (urban trench fever, Wolhynia fever, shin-bone fever, quintan fever): Incubation days-weeks; sudden onset of fever, headache, leg pain; self-limited illness may be brief (4-5 days), prolonged (2-6 weeks), most commonly paroxysmal (3-5 episodes of 5 days' duration). Insidious course in HIV.
- B. henselae: If HIV-infected, insidious onset of fatigue, malaise, aches, weight loss, recurring fevers, headache; localizing findings uncommon. If HIV-uninfected, abrupt onset of fever (may persist or relapse), myalgias, arthralgias, headache; localizing findings unusual; may persist without symptoms.
• Endocarditis: Fever, dyspnea, murmur, embolic phenomena; aortic valve involvement most common
• Bacillary angiomatosis: Mostly immunocompromised hosts (e.g., HIV-infected); involves skin (crops of subcutaneous or dermal nodules and/or skin-colored to purple papules; may ulcerate with serous or bloody drainage and crusting), regional lymph nodes, internal organs
• Bacillary peliosis: Involves liver and spleen in immunosuppressed persons; can involve lymph nodes; nonspecific clinical manifestations
• Neurologic syndromes in HIV: Cognitive dysfunction, behavioral disturbances; may be mistaken for dementia, psychiatric disease
TESTS
Lab
• Skin testing reagents: Not recommended
• Giemsa-stained blood smear may show B. bacilliformis adherent to erythrocytes
• Non-bacilliformis species
- Indirect fluorescent antibody and enzyme immunoassay tests are available
 Interpretation complicated by variable correlation between titers and disease stage, lack of uniformity among serologic tests, and cross-reactivity among Bartonella species and other bacteria.
ALERT
Advise lab if Bartonella infection is suspected so that blood, tissue, and cerebrospinal fluid cultures are prepared with appropriate media under optimal conditions; prolonged incubation required.
• Polymerase chain reaction (PCR) and immunohistochemical labeling primarily research tools, although PCR of valve tissue can aid diagnosis of endocarditis
• Drugs that may alter lab results: Antibiotics (cultures falsely negative)
Imaging
Ultrasonography, CT, or ECG as indicated
Diagnostic Procedures/Surgery
• Biopsies for histology/culture of nodules, lymph nodes, or internal organs
• Lumbar puncture if CNS involvement
Pathological Findings
• Verruga peruana: Neovascular proliferation; bacteria uncommonly are identified.
• CSD: Granulomas, stellate necrosis, mixed inflammatory infiltrates; bacilli in tissue may be demonstrable by silver impregnation stains (e.g., Warthin-Starry).
• Endocarditis: Warthin-Starry-stained bacilli may be seen in vegetations.
• Bacillary angiomatosis
- Lobular proliferations of small blood vessels are seen, containing cuboidal endothelial cells interspersed with inflammatory cells, mostly neutrophils.
- Warthin-Starry stain or electron microscopy may show clusters of bacilli
• Bacillary peliosis: Blood-filled cystic structures. Warthin-Starry stain may show surrounding clumps of bacilli.
DIFFERENTIAL DIAGNOSIS
• Typical CSD: Sporotrichosis, histoplasmosis, plague, tularemia, brucellosis, mycobacteria, staphylococci, streptococci, other agents associated with injection drug use; lymphoma; metastatic malignancy
• Atypical CSD: Other agents causing similar syndromes
• Non-bacilliformis bacteremia syndromes
- Immunocompromised: Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, Mycobacterium avium-complex
- Arthropod exposure: Rickettsial infections, tularemia, plague, babesiosis, borreliosis
- Cat/dog scratch/bite: Pasteurella
- Influenza, infectious mononucleosis, hepatitis
• Endocarditis: Other slow-growing bacteria (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella, Coxiella)
• Bacillary angiomatosis/bacillary peliosis: Kaposi sarcoma; pyogenic granuloma, hemangioma
• Neurologic syndrome in HIV: Tertiary syphilis, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, alcohol or drug abuse
TREATMENT
STABILIZATION
• Outpatient for uncomplicated infection
• Initial hospitalization may be necessary for IV antibiotics or complications.
GENERAL MEASURES
• CSD: Supportive therapy (e.g., aspiration suppurative nodes)
• Systemic syndromes (including CSD-associated neuroretinitis and encephalopathy): Antibiotics
Activity
Fully active if uncomplicated
MEDICATION (DRUGS)
First Line
• Oroya fever: Chloramphenicol 500 mg (pediatric dose 50-75 mg/dg/d) PO/IV q.i.d. + -lactam for 14 days (not available in US) (1) [B]; ciprofloxacin 500 mg (250 mg for children 7-12 years) PO b.i.d. for 10 days
• Verruga peruana: Rifampin 10/mg/kg/d (not to exceed 600 mg/d in children) for 10 days (1) [B])
• Typical CSD: No clear benefit, although oral azithromycin may speed resolution of extensive lymphadenopathy: Adults and children >45.5 kg: 500 mg on day 1; 250 mg daily on days 2-5; children 45.5 kg: 10 mg/kg on day 1; 5 mg/kg daily on days 2-5 (1) [A]
• Retinitis: Doxycycline 100 mg PO b.i.d. + rifampin 300 mg PO b.i.d. for 4-6 weeks (1) [B]
• Trench fever or chronic B. quintana bacteremia: Doxycycline 200 mg PO daily for 4 weeks + gentamicin 3 mg/kg IV daily for 2 weeks (1) [A]
• Bacillary angiomatosis: Erythromycin 500 mg (pediatric dose 40 mg/kg/d to maximum daily dose of 2 g/d) PO q.i.d. or doxycycline 100 mg PO b.i.d. for 3 months; consider longer course if immunocompromised (1) [B]
• Bacillary peliosis: Erythromycin 500 mg (pediatric dose 40 mg/kg/d to maximum daily dose of 2 g/d) PO q.i.d. or doxycycline 100 mg PO b.i.d. for 4 months; consider longer course if immunocompromised (1) [B]
• Endocarditis (culture positive): Gentamicin 3 mg/kg IV daily for 2 weeks + doxycycline 100 mg PO b.i.d. for 6 weeks (1) [B]
• Endocarditis (culture negative): Gentamicin 3 mg/kg IV daily for 2 weeks + ceftriaxone 2 g IV/IM daily for 6 weeks +/- doxycycline 100 mg PO/IV b.i.d. for 6 weeks (1) [B]
SURGERY
Valve replacement if indicated in endocarditis
FOLLOW-UP
PROGNOSIS
• CSD: Spontaneous resolution usually in 2-4 months without specific therapy
• Other syndromes: With proper treatment, full resolution; if relapse, consider long-term suppressive antibiotics after retreatment
COMPLICATIONS
Relapse, especially in HIV infection
PATIENT MONITORING
Close follow-up after completion of antibiotics to monitor for relapse
REFERENCES
1. Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother 2004;48(6):1921-1933.
ADDITIONAL READING
• Agan BK, Dolan MJ. Laboratory diagnosis of Bartonella infections. Clin Lab Med. 2002;22:937-962.
• Dehio C. Molecular and cellular basis of Bartonella pathogenesis. Ann Rev Microbiol. 2004;58:365-390.
• Slater LN, Welch DF. Bartonella, including cat-scratch disease. In: Mandell, Bennett, Dolin, eds. Principles and Practice of Infectious Diseases, 6th ed. Philadelphia: Churchill Livingstone, 2005.


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