Bartonella

Bartonella is a genus of gram-negative bacteria in the family Bartonellaceae. As a facultative intracellular parasite, Bartonella can infect healthy people as well as act as an opportunistic pathogen. Bartonella species are transmitted by vectors such as ticks, fleas, sandflies, and mosquitoes. B. henselae is the most common of the 3 species known to cause human disease; it is a zoonosis that causes cat-scratch disease and bacillary angiomatosis (BA). The other 2 species are human-specific: B. bacilliformis causes trench fever and BA, and B. quintana causes Oroya fever, verruga peruana, and Carrion’s disease.

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General Characteristics

Basic features

  • Genus: Bartonella, closely related to the genera Brucella and Agrobacterium
  • Family: Bartonellaceae
  • Facultative intracellular parasitic bacteria
  • Stain very poorly using Gram stain:
    • Sometimes classified as gram-negative
    • Stain black with silver-impregnated stains (e.g., Warthin-Starry stain)
  • At least 22 named species; the 3 most relevant medically are: 
    •  B. henselae
    • B. quintana (formerly known as Rickettsiae quintana)
    • B. bacilliformis
Transmission electron micrographs showing morphology of B. bacilliformis

Transmission electron micrographs showing morphology of Bartonella bacilliformis:
Scale bars represent 100 nm in panel A and 500 nm in panel B.

Image: “Transmission electron micrographs showing morphology of B. bacilliformis” by Michael F. Minnick, Burt E. Anderson, Amorce Lima, James M. Battisti, Phillip G. Lawyer, and Richard J. Birtles. License: Public Domain

Epidemiology and Pathogenesis

Epidemiology

  • Bartonella spp. have a worldwide distribution.
  • No types of bartonellosis have a sex predilection
  • Cat-scratch disease (B. henselae):
    • Worldwide distribution
    • Affects approximately 1 in 10,000 persons
    • More common in children and adolescents than in adults (except for immunocompromised adults)
  • Carrion’s disease (B. bacilliformis)
    • Very rare infectious disease
    • Found only in Peru (endemic), Ecuador, and Colombia or associated with a history of recent travel to these regions
  • Trench fever (B. quintana) is most common in populations prone to infestations with lice, such as the homeless

Transmission

  • Mainly transmitted by vectors like fleas, lice, sandflies, or ticks
  • Zoonotic disease (transmitted from animals to people)
  • Reservoirs: 
    • Humans
    • Domestic animals, especially cats (asymptomatic carriers)
    • Wild animals, especially rodents, coyotes, or foxes

Host risk factors

  • Immunocompromised patients: 
    • Chemotherapy
    • Organ transplant
    • HIV/AIDS → bacillary angiomatosis is an AIDS-defining condition
  • Homelessness
  • Poor hygiene
  • Alcoholism

Pathogenesis

  • After exposure from a reservoir or vector, bacteria colonize the endothelial cells of the new host.
  • From the endothelial cells, the bacteria are released into the bloodstream, where they infect erythrocytes.
  • Bacteria invade and replicate in erythrocytes and in endothelial cells.
    • All Bartonella spp. induce host tissues to produce hypoxia-inducible factor-1α, which drives the production of vascular endothelial growth factor, causing vascular proliferation (angiogenesis).
    • Microscopic pathology of angiogenesis: capillary proliferation with prominent epithelioid endothelial cells showing nuclear atypia and mitosis, associated with neutrophils and bacteria
    • Facultative intracellular properties help in the evasion of a host immune response.
    • B. bacilliformis
      • Uses a polar flagellum for motility
      • Replicates in vacuoles
    • B. henselae and B. quintana:
      • Invade endothelial cells
      • Make a protein binder that adheres to feline RBC membranes
    • B. quintana:
      • Invades endothelial cells
      • Forms bacterial aggregates that are internally taken in by the invasome, a unique phagosomal structure
      • Invasomes proliferate and make intracellular blebs.
  • The intraerythrocytic life cycle causes hemolytic anemia.
  • Endothelial cell proliferation causes microvascular thrombosis and vessel occlusion, leading to tissue ischemia 
  • Erythrocytes are taken in by another vector (blood-sucking arthropod) to be transmitted to the next host.
Pathogenesis of Bartonella

Pathogenesis of Bartonella:
Following transmission by an arthropod vector (a), the Bartonella bacteria colonize the skin (b). The bacteria are then transported to the vascular endothelium (c) and are seeded into the bloodstream to invade erythrocytes (d). After replication inside the RBC (e), the bacteria persist in the intraerythrocytic niche (f), making them competent for transmission by another bloodsucking arthropod (g).

Image by Lecturio. License: CC BY-NC-SA 4.0

Diseases Caused by Bartonella

Bartonellosis in humans is caused by 3 main species of Bartonella bacteria and produces a wide range of symptoms and diseases depending on the species and the immune state of the infected individual.

Table: Diseases caused by Bartonella species
SpeciesDisease
B. bacilliformis Carrion’s disease, also known as:
  • Oroya fever: initial bacteremic form
  • Verruga peruana: late-onset, eruptive form
B. quintana
  • Trench fever (“5-day fever”)
  • BA: if severely immunosuppressed; an AIDS-defining condition
  • Endocarditis (often culture-negative)
B. henselae
  • CSD
  • BA: if severely immunosuppressed; an AIDS-defining condition
  • Peliosis hepatis: BA in liver, spleen, lymph nodes
  • Endocarditis: with atypical CSD; often culture-negative
  • Neuroretinitis: with atypical CSD
  • Meningitis/encephalitis: with atypical CSD
BA: bacillary angiomatosis
CSD: cat-scatch disease

Carrion’s disease (South American bartonellosis)

Transmission:

  • Carried by night-biting sandflies of the genus Lutzomyia (formerly Phlebotomus)

Clinical presentation:

  • Biphasic clinical course that used to be considered 2 separate diseases
  • Acute phase:
    • Also known as Oroya fever
    • Develops 3–12 weeks after initial exposure
    • Sudden-onset high fever and chills
    • Profuse sweating
    • Severe headache
    • Weakness
    • Paleness of the skin
    • Abdominal, muscular, or joint pain
    • Meningoencephalitis and/or seizures
    • Severe hemolytic anemia may lead to:
      • Confusion, disorientation, or coma
      • Chest pain
      • Thrombocytopenia
      • Dyspnea
      • Organ dysfunction
  • Chronic phase:
    • Also known as verruga peruana
    • Usually develops within weeks or months in untreated individuals who may or may not have manifested the acute phase of the disease
    • Characteristic skin lesions
      • Reddish-purple in color
      • Develop in outbreaks over several regions of the body at once or in a migratory pattern
      • Usually located on exposed skin, such as the face, arms, and legs, but may also develop in mucous membranes and internal organs
      • Lesions are initially small and become nodular (0.2 to 4 cm in diameter)
      • Can potentially bleed, ulcerate, or become pustules

Trench fever

Transmission:

  • Mainly carried by the human body louse vector Pediculus humanus var. corporis (along with other species of lice, ticks, and fleas)
  • Transmission via inoculation of infected louse feces into abrasions of the skin or into conjunctivae 

Clinical presentation:

  • Incubation period: 5–20 days (average, 7.7)
  • Classic trench fever can range from mild flu-like illness to a debilitating illness 
  • Acute illness usually presents with malaise, fever, headache, dizziness, nausea and vomiting, bone pain, and sometimes a macular truncal rash 
  • The fever is usually episodic, presenting every 5 days (“5-day fever” or “quintan fever”).

Cat-scratch disease (CSD)

Transmission:

  • Cats are the most important carriers, though there are cases of transmission from dogs.
  • Routes of transmission:
    • Scratch or bite from an infected cat
    • Bite from cat fleas
    • Contact with cat saliva through broken skin or mucosal surfaces

Clinical presentation:

  • May not manifest until several days or weeks after the initial exposure
  • Characteristic papular lesions
    • Begin as a macule at the site of infection that can become a painless papule after 3–10 days
    • The papule may become a vesicle, crust, and heal with a scar after 1–3 weeks.
  • Gradual enlargement of regional lymph nodes
    • Usually located in the axilla, neck, or groin regions
    • Swollen nodes are tender and can last 2–3 months or longer
    • May appear red and warm to the touch
    • Suppuration may occur
  • General or flu-like symptoms:
    • Malaise, back and body aches
    • Fatigue
    • Headache
    • Low-grade fever
    • Loss of appetite and weight loss
    • Sore throat
  • Complications (“atypical CSD”), which usually present in immunocompromised individuals:
    • Granulomatous hepatitis and/or splenitis
    • Osteomyelitis
    • Bacillary angiomatosis
    • Meningitis and/or encephalitis 
    • Neuroretinitis
    • Parinaud’s oculoglandular syndrome (similar to conjunctivitis plus lymphadenopathy)
    • Parotitis
    • Endocarditis
Clinical presentation of a patient with bacillary angiomatosis

Clinical presentation of a patient with bacillary angiomatosis:
A: Multiple red papules on the chest and abdomen
B: 2 nodules on the back
C: Papules on the face with a subcutaneous mass lesion over the left zygomatic arch

Image: “Bacillary angiomatosis presenting with facial tumor and multiple abscesses” by Markowicz M, Käser S, Müller A, Lang G, Lang S, Mayerhöfer M, Stanek G, Rieger A. License: CC BY 4.0

Bacillary angiomatosis

  • Occurs primarily in immunocompromised individuals
    • Especially in patients with AIDS and a CD4 count < 100 cells/μL
    • Constitutes an AIDS-defining condition
  • Vascular proliferative disease that mainly affects the skin, but can develop in other organs (e.g., bone marrow, liver, spleen, or lymph nodes)
  • Characteristic erythematous skin lesions
    • Usually elevated
    • May be surrounded by a scaly ring 
    • Very friable and bleed easily

Peliosis hepatis

  • Occurs primarily in immunocompromised individuals, especially in patients with AIDS
  • Vascular proliferation of sinusoid hepatic capillaries that result in blood-filled sacs within the liver parenchyma
  • Commonly associated with peliosis of the spleen and lymph nodes

Diagnosis

Most cases of bartonellosis can be diagnosed through the detection of characteristic symptoms and physical findings and a complete medical history. Specialized laboratory tests are used to confirm the diagnosis. 

  • Bartonella infection can be difficult to detect, confirm, and diagnose. 
  • Serologic testing is the most cost-effective diagnostic tool, but false negatives can occur even during active infection.
  • Detection of IgG and IgM antibodies in blood serum by indirect immunofluorescence assays are used to detect B. henselae in suspected cases of cat-scratch disease. 
  • Microscopic examination of Giemsa-stained blood smears is used to detect B. bacilliformis in suspected cases of Carrion’s disease. 
  • PCR analysis of tissue and body fluid is the most specific diagnostic test to detect Bartonella spp.
  • Other Bartonella spp. are visible only with silver stains.
  • Abdominal imaging tests are used to confirm suspected cases of liver and spleen complications.

Management

Aside from supportive care, management is dependent on the specific species of Bartonella contracted and the severity of each case.  

  • CSD:
    • In mild cases: Antibiotics may not be necessary, but azithromycin can shorten the duration of symptoms.
    • In moderate cases: azithromycin, erythromycin, or doxycycline (may add steroids for refractory lymphadenopathy)
    • In severe cases: rifampin and either erythromycin or doxycycline
  • Carrion’s disease:
    • Acute phase: chloramphenicol or ciprofloxacin (in pediatric cases, ciprofloxacin is not used and beta-lactams are added)
    • Chronic phase: rifampin or macrolides
  • Trench fever: doxycycline and gentamicin
  • Bartonellosis in immunocompromised patients: prolonged course of erythromycin or doxycycline

Differential Diagnosis

  • Cervical lymphadenitis: cervical lymph nodes may become enlarged, inflamed, and tender owing to viral infections (e.g., adenovirus) or bacterial infections (e.g., Staphylococcus aureus). Management of cervical lymphadenitis is by diagnosing the underlying cause. Biopsies are rarely needed.
  • Hodgkin lymphoma: malignancy of B lymphocytes within lymph nodes. The histologic finding for Hodgkin lymphoma is a Reed-Sternberg cell (giant B cell with eosinophilic inclusions). Presentation of the disease is with lymphadenopathy and constitutional “B symptoms.” Hodgkin lymphoma is managed with chemotherapy and radiotherapy. 
  • Non-Hodgkin lymphomas (NHL): diverse group of malignancies of B-cell, T-cell, and natural killer (NK)–cell origin. Lymph nodes are involved in ⅔ of NHLs; the remainder of NHLs are extranodal. In the United States, NHLs are 10ⅹ more common than Hodgkin lymphoma and represent a common cause of cancer-related death.
  • Cellulitis: common and painful bacterial skin infection that affects the deeper layers of the dermis and subcutaneous tissue. Cellulitis presents as an erythematous, edematous area that feels warm and tender to the touch. The condition is caused most commonly by Staphylococcus aureus and Streptococcus pyogenes. Diagnosis is usually clinical, and management is with antibiotics based on suspected organisms.
  • Kaposi’s sarcoma: aggressive, malignant vascular tumor that is an AIDS-defining condition and usually presents in patients with a CD4 count < 500 cells/μL. Kaposi’s sarcoma is caused by HHV-8 and is transmitted via saliva and sexual contact. The condition presents as a pink, red, purple, or brown papular or plaque-like lesions that are not painful or pruritic.
  • Hemangioma: benign tumor made up of blood vessels and capillaries. Hemangioma usually presents as a purple or red, well-demarcated papule.
  • Pyogenic granuloma: benign, vascular lesion of unknown cause or origin. Pyogenic granuloma sometimes develops after minor trauma or injury. The granuloma appears as a red or purple papule that is friable and bleeds easily. 
  • Brucellosis: zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations of brucellosis include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Clinical manifestations, exposure history, serology, and culture data are used in the diagnosis. Treatment involves a combination of antibiotics, including doxycycline, rifampin, and aminoglycosides.

References

  1. Hammoud, K. (2019). Bartonellosis (Bartonella Infection). Emedicine. Retrieved February 18, 2021, from https://emedicine.medscape.com/article/213169-overview#a6.
  2. Spach, D. (2020). Clinical features, diagnosis, and treatment of Bartonella quintana. UpToDate. Retrieved February 18, 2021, from https://www.uptodate.com/contents/clinical-features-diagnosis-and-treatment-of-bartonella-quintana-infections
  3. Nelson VA, Saha S, Mead PS. (2016). Cat-scratch disease in the United States, 2005-2013. Emerg Infect Dis 22:1741–1746. https://pubmed.ncbi.nlm.nih.gov/27648778/
  4. Versalovic J, Carroll KC, Funke G, Jorgensen JH, Landry ML, Warnock DW. (2011). Manual of Clinical Microbiology, 10th ed. Washington, DC: ASM Press.
  5. Angelakis E, Raoult D. (2014). Pathogenicity and treatment of Bartonella infections. Int J Antimicrob Agents 44:16–25. https://pubmed.ncbi.nlm.nih.gov/24933445/
  6. Eicher SC, Dehio C. (2012). Bartonella entry mechanisms into mammalian host cells. Cell Microbiol 14:1166–1173. https://doi.org/https://doi.org/10.1111/j.1462-5822.2012.01806.x
  7. Corey C. (2018). Herpes simplex virus infections. In Jameson JL, et al. (Eds.), Harrison’s Principles of Internal Medicine, 20th ed. Vol. 1, pp. 1345–1354. 
  8. Giladi M, Ephros M. (2018). Bartonella infections, including cat-scratch disease. In Jameson JL, et al. (Ed.s), Harrison’s Principles of Internal Medicine, 20th ed. Vol. 1, pp. 1209–1214. 

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