Bartonellosis

  1. Overview
  2. Epidemiology
  3. Pathophysiology
  4. Bartonella henselae — Cat Scratch Disease
  5. Cat Scratch Disease — Atypical and Severe Forms
  6. Bartonella quintana — Trench Fever
  7. Bartonella bacilliformis — Oroya Fever and Verruga Peruana
  8. Diagnosis
  9. Treatment
  10. Prevention
  11. References
  12. Connections
  13. Featured Videos

1. Overview

Bartonellosis refers to infections caused by Bartonella species — facultative intracellular gram-negative bacteria belonging to the alpha-proteobacteria class. They are unique in their ability to survive and replicate both within erythrocytes and within endothelial cells, a dual tropism that drives the wide range of clinical syndromes seen across the genus.

Three species account for the majority of human disease:

Emerging species of clinical relevance include B. elizabethae (endocarditis) and B. grahamii (neuroretinitis), reflecting the expanding universe of human bartonelloses as molecular diagnostics improve. Trench fever was recognized as a significant epidemic illness during World War I; B. henselae was first identified and named in 1992 by Regnery and colleagues, catalyzed by the AIDS epidemic that brought bacillary angiomatosis to clinical attention.

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2. Epidemiology

Cat Scratch Disease (B. henselae): An estimated 12,000 to 22,000 cases occur annually in the United States, with children and adolescents disproportionately affected — approximately 70% of cases occur in individuals under 21 years of age. Roughly 40% of domestic cats carry B. henselae in their blood at some point; bacteremia rates are highest in kittens under one year. The cat flea Ctenocephalides felis transmits the bacterium between cats via infected flea feces (flea dirt), which cats then deposit under their claws during grooming. Transmission to humans occurs through a scratch or bite that inoculates flea feces into the skin — not directly from the flea bite itself.

Trench Fever (B. quintana): An estimated one million or more soldiers were infected during World War I, making it one of the most significant infectious diseases of that conflict. Today, trench fever re-emerges in communities with body louse (Pediculus humanus corporis) infestation: homeless individuals, refugees, and persons living in overcrowded, resource-poor settings globally.

Oroya Fever (B. bacilliformis): Geographically restricted to Andean valleys at altitudes of 500 to 3,200 meters in Peru, Ecuador, and Colombia — the range of its sandfly vector Lutzomyia verrucarum. Travelers to these endemic regions are at risk.

Bacillary Angiomatosis: Occurs almost exclusively in severely immunocompromised patients, particularly those with HIV/AIDS and CD4 counts below 100 cells/mm³. Both B. henselae and B. quintana cause this syndrome.

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3. Pathophysiology

B. henselae in immunocompetent hosts: Following inoculation via a cat scratch or bite, bacteria initially replicate in skin macrophages and are carried to the regional draining lymph node. There, a characteristic granulomatous response develops: stellate (star-shaped) areas of central suppurative necrosis surrounded by palisading histiocytes and lymphocytes. The Warthin-Starry silver stain identifies pleomorphic gram-negative bacilli within and around areas of necrosis. In immunocompetent individuals, this granulomatous response is self-limiting.

B. henselae in immunocompromised hosts: When cell-mediated immunity fails, the bacteria shift from driving a destructive granulomatous response to an angioproliferative one. Bartonella secretes effector proteins (via a type IV secretion system) that upregulate vascular endothelial growth factor (VEGF), driving abnormal proliferation of endothelial cells and small blood vessels — the histological basis of bacillary angiomatosis.

B. quintana: Body louse feces containing the bacterium are rubbed into skin abrasions (not injected by the bite itself). Bacteria invade erythrocytes and establish persistent bacteremia with intermittent episodes of high-level bloodstream release, producing the relapsing fever pattern. The mechanism of tibia pain (tibialgia) is not fully established but is thought to involve periosteal involvement.

B. bacilliformis: The Lutzomyia sandfly injects bacteria during a blood meal. In the acute (Oroya fever) phase, massive invasion of erythrocytes leads to hemolysis — up to 80% of red blood cells can be destroyed — producing severe hemolytic anemia. The resulting immunosuppression predisposes patients to secondary bacterial infections, classically Salmonella bacteremia. In survivors who mount an immune response, bacteria shift to invading vascular endothelial cells in the skin and mucous membranes, producing the chronic angioproliferative verruga peruana lesions.

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4. Bartonella henselae — Cat Scratch Disease

Cat scratch disease is the most common clinical presentation of bartonellosis in the United States. After a cat scratch or bite, an incubation period of 3 to 10 days passes before a small papule or pustule appears at the inoculation site — a subtle finding that patients often overlook or have already forgotten by the time they seek care.

The hallmark of CSD develops 1 to 3 weeks after inoculation: regional lymphadenopathy in the lymph node territory draining the scratch site. The nodes are tender, warm, and enlarged, ranging from 1 to 5 cm. The most common locations reflect typical cat-contact anatomy:

In approximately 10 to 15% of cases, nodes suppurate and become fluctuant; needle aspiration may be required for diagnosis or symptomatic relief. Aspiration is preferable to incision and drainage, which risks fistula formation. Systemic symptoms — low-grade fever, malaise, headache, and fatigue — accompany the lymphadenopathy in most cases. The illness is self-limited in immunocompetent individuals, though lymph node enlargement can persist for 1 to 6 months, causing understandable concern for malignancy in families and clinicians who are not considering CSD.

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5. Cat Scratch Disease — Atypical and Severe Forms

In approximately 10% of CSD cases, atypical or extranodal manifestations occur. Several are clinically distinctive and warrant specific recognition:

Parinaud Oculoglandular Syndrome: A granulomatous conjunctival nodule develops on the palpebral or bulbar conjunctiva, accompanied by ipsilateral preauricular (in front of the ear) lymphadenopathy. This occurs when bacteria are inoculated directly into the conjunctiva — typically by rubbing the eye after handling a cat. It is the second most common form of CSD after classic lymphadenopathy.

Neuroretinitis: Unilateral painless vision loss with disc edema (swollen optic nerve head) and a macular star — a stellate pattern of lipid exudates radiating outward from the macula — is the hallmark finding on fundoscopy. The macular star is not always present acutely and may take weeks to fully develop. CSD is the most common identified cause of neuroretinitis and should be considered in any young person presenting with this picture.

Encephalitis: Occurring in 1 to 7% of CSD cases, CSD encephalitis presents with seizures, altered mental status, and fever, with CSF showing pleocytosis. It is alarming acutely but generally self-limited, with most patients recovering fully over weeks to months.

Hepatosplenic CSD: More common in children, this form presents as prolonged fever of unknown origin with abdominal pain. CT imaging reveals multiple hypodense lesions in the liver and/or spleen — granulomata that can mimic lymphoma or metastatic disease. Recognition prevents unnecessary biopsy and worry.

Bacillary Angiomatosis (immunocompromised hosts): In patients with advanced HIV infection (CD4 <100) or other causes of profound T-cell deficiency, B. henselae (and B. quintana) drive an angioproliferative syndrome rather than a granulomatous one. Skin lesions appear as red-to-purple vascular papules and nodules that can closely resemble Kaposi's sarcoma. Visceral involvement can include peliosis hepatis (blood-filled cystic spaces in the liver), splenomegaly, lymphadenopathy, and lytic bone lesions. Distinguishing bacillary angiomatosis from Kaposi's sarcoma requires tissue biopsy with Warthin-Starry silver stain and/or PCR, since the treatment differs fundamentally (antibiotics vs. antiretroviral therapy alone or chemotherapy).

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6. Bartonella quintana — Trench Fever

Trench fever takes its name from the trenches of World War I, where the combination of overcrowded conditions, poor hygiene, and ubiquitous body louse infestation created an ideal environment for epidemic spread. The disease's Latin species name quintana (meaning "fifth") refers to the characteristic relapsing fever, with episodes recurring approximately every five days.

Transmission: The body louse Pediculus humanus corporis transmits B. quintana through its feces. When an infected louse defecates on the skin during feeding, the host scratches and rubs the feces into skin abrasions — it is the feces, not the bite itself, that transmits bacteria (the same feces-in-abrasion mechanism as B. henselae via cat flea feces).

Clinical Features: After an incubation period of 15 to 25 days, the illness begins abruptly with fever, severe headache, and a distinctive shin pain (tibialgia) — a deep, aching bone pain in the tibia that is highly characteristic and helps distinguish trench fever from other febrile illnesses. Fever relapses occur every 4 to 5 days, and bacteremia may persist for months without treatment.

Modern Relevance — Endocarditis: B. quintana is among the most common causes of culture-negative endocarditis globally. When a homeless person, alcoholic, or refugee presents with subacute endocarditis and blood cultures remain negative after standard incubation, Bartonella serology and molecular testing of excised valve tissue must be pursued before concluding the endocarditis is truly culture-negative of unknown cause.

Bacillary Angiomatosis in HIV: Like B. henselae, B. quintana causes bacillary angiomatosis in severely immunocompromised patients. It tends to cause more subcutaneous and osseous (bone) lesions relative to B. henselae, though clinical distinction requires molecular species identification.

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7. Bartonella bacilliformis — Oroya Fever and Verruga Peruana

Bartonella bacilliformis is the only Bartonella species known to cause disease through a single organism producing two completely distinct clinical phases in the same patient. Its geographic range is sharply limited by its vector: the night-biting sandfly Lutzomyia verrucarum, which thrives only in the narrow Andean inter-valley zone between 500 and 3,200 meters altitude in Peru, Ecuador, and Colombia.

Phase 1 — Oroya Fever (Acute/Bacteremic Phase): After an incubation period of approximately 3 weeks (range 2–14 weeks), the acute phase begins with high fever, rigors, and severe malaise. The defining feature is massive erythrocyte invasion by the bacteria, leading to profound hemolytic anemia — hemoglobin can fall to 3 to 4 g/dL. Patients develop pallor, jaundice, hepatosplenomegaly, and extreme weakness. Without treatment, mortality ranges from 40 to 88% — one of the highest fatality rates of any bacterial infection. Death commonly results from the anemia itself and from superinfection: the profound immune dysregulation during Oroya fever creates a window for opportunistic pathogens, most notably Salmonella bacteremia, which historically compounded the death toll.

Phase 2 — Verruga Peruana (Chronic Angioproliferative Phase): Patients who survive Oroya fever (and those with subclinical primary infection) may develop the chronic phase weeks to months later. As the immune system gains control of erythrocyte-phase infection, bacteria shift to invading vascular endothelial cells in the skin and mucous membranes, driving angioproliferation. Skin lesions called verrucomas appear — red-to-purple hemangioma-like nodules that range from tiny miliary papules (eruptive form) to large, pedunculated nodular tumors. The lesions bleed easily when traumatized. Though disfiguring and sometimes extensive, verruga peruana is not immediately life-threatening in most patients and may resolve spontaneously over months. The two phases represent opposite ends of host-pathogen equilibrium: Oroya fever reflects uncontrolled bacteremia overwhelming host defenses; verruga peruana reflects partial immune control that channels infection into an endothelial angioproliferative niche.

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8. Diagnosis

No single test is perfect for all forms of bartonellosis; diagnosis typically combines serology, PCR, and histopathology depending on the clinical syndrome.

Serology (IFA): Immunofluorescence antibody (IFA) testing for IgG against B. henselae and B. quintana is the mainstay of outpatient CSD and trench fever diagnosis. A single IgG titer of ≥1:64 is suggestive; a fourfold or greater rise between acute and convalescent samples is confirmatory. Significant cross-reactivity exists between B. henselae and B. quintana antigens, meaning species-level differentiation by serology alone is unreliable.

PCR: The most sensitive method for early diagnosis, particularly on lymph node pus, biopsy tissue, or blood (lysis-centrifugation specimens). PCR on excised cardiac valve tissue is the preferred method for confirming Bartonella endocarditis in culture-negative cases.

Culture: Bartonella grows slowly on enriched blood agar or in cell culture systems, requiring prolonged incubation of 2 to 6 weeks. Lysis-centrifugation blood cultures increase yield for bacteremia. Culture is insensitive for CSD in lymph nodes. Its main practical role is in confirmed B. quintana bacteremia settings.

Histopathology and Warthin-Starry Silver Stain: Lymph node biopsy in CSD shows the characteristic stellate necrosis with surrounding palisading histiocytes. The Warthin-Starry silver stain demonstrates pleomorphic gram-negative bacilli in the necrotic zones. Biopsy of bacillary angiomatosis lesions reveals lobular vascular proliferation with plump endothelial cells and interstitial granular material — the silver stain identifies clumps of bacilli in this material.

CBC and Routine Labs: Peripheral eosinophilia occurs in a subset of CSD patients. Elevated ESR and CRP reflect systemic inflammation. In Oroya fever, the CBC shows a severe hemolytic anemia with elevated reticulocyte count, indirect bilirubin, and LDH — the same picture as other hemolytic anemias. Bartonella-infected erythrocytes may be visible on a peripheral blood smear (Giemsa stain) in Oroya fever.

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9. Treatment

Treatment intensity and duration depend on the species, clinical syndrome, and immune status of the host.

Typical CSD (immunocompetent): Most cases are self-limited and resolve without antibiotics. When treatment is used to accelerate resolution of lymphadenopathy — particularly in children with cosmetically or functionally significant nodes — azithromycin 500 mg on day 1 followed by 250 mg on days 2 through 5 is supported by a randomized controlled trial (Bass et al., 1998) showing faster reduction in lymph node volume compared to placebo.

Severe or Systemic CSD (neuroretinitis, encephalitis, hepatosplenic CSD): Doxycycline 100 mg twice daily plus rifampin 300 mg twice daily for 4 to 6 weeks is the standard regimen for serious CSD manifestations. Rifampin provides intracellular penetration to reach bacteria within macrophages.

Bacillary Angiomatosis and Peliosis Hepatis: Prolonged therapy is essential — relapse is common with shorter courses. Doxycycline 100 mg twice daily or azithromycin 500 mg daily for a minimum of 3 to 4 months. In AIDS patients, maintenance therapy may be required until immune reconstitution with antiretroviral therapy raises the CD4 count above 200 cells/mm³.

Trench Fever and B. quintana Bacteremia: Doxycycline 200 mg/day for 4 weeks with gentamicin 3 mg/kg/day IV for the first 14 days is recommended for bacteremia to ensure bactericidal activity. For B. quintana endocarditis, gentamicin-based regimens for 6 weeks (as with other difficult endocarditis) are used.

Oroya Fever: Chloramphenicol 500 mg four times daily for 14 days is traditional and has the advantage of simultaneously covering concurrent Salmonella bacteremia — a life-threatening complication. Ciprofloxacin is an alternative. Ampicillin has also been used. Red blood cell transfusion may be necessary for severe anemia.

Verruga Peruana: Rifampin 10 mg/kg/day for 14 to 21 days is the treatment of choice for the chronic phase.

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10. Prevention

No licensed human vaccine exists for any form of bartonellosis. Prevention relies on vector control and behavioral measures.

Cat Scratch Disease: Avoiding rough play with kittens (who have higher B. henselae bacteremia rates) reduces the risk of scratches. Any cat scratch or bite should be washed immediately and thoroughly with soap and water. There is no medical justification for euthanizing a family pet following a CSD diagnosis — the disease is not transmitted between humans, and the cat's bacteremia is self-limiting. Effective flea control reduces cat-to-cat transmission and may lower cat bacteremia rates, decreasing household transmission risk.

Trench Fever and Bacillary Angiomatosis (B. quintana): Prevention targets louse infestation through delousing programs, provision of clean clothing and bathing facilities, and improved housing for homeless populations and refugees. Permethrin-treated clothing is effective against body lice in field settings.

Oroya Fever (B. bacilliformis): Travelers to endemic Andean valleys should use insect repellents and bed nets to reduce sandfly bites, particularly during night hours. Long clothing covering arms and legs in the evenings provides additional protection. Sandfly control measures in endemic communities include insecticide spraying.

Immunocompromised Patients: HIV-positive individuals with low CD4 counts should be counseled about the risk of bacillary angiomatosis from cat exposure. Avoiding rough handling of cats and rigorous wound care after any scratch are particularly important in this population.

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11. References

  1. Florin TA, Zaoutis TE, Zaoutis LB. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Lancet Infect Dis. 2008;8(7):466–476. PMID: 18550006
  2. Regnery RL, Anderson BE, Clarridge JE, Rodriguez-Barradas MC, Jones DC, Carr JH. Characterization of a novel Rochalimaea species, R. henselae sp. nov., isolated from blood of a febrile, human immunodeficiency virus-positive patient. J Clin Microbiol. 1992;30(2):265–274. PMID: 1537907
  3. Bass JW, Freitas BC, Freitas AD, et al. Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease. Pediatr Infect Dis J. 1998;17(6):447–452. PMID: 9655535
  4. Resto-Ruiz S, Burgess A, Anderson BE. The role of the host immune response in pathogenesis of Bartonella henselae. Microbes Infect. 2003;5(12):1069–1076. PMID: 14554253
  5. Maguina C, Gotuzzo E. Bartonellosis: new and old. Infect Dis Clin North Am. 2000;14(1):1–22. PMID: 10738670
  6. Koehler JE, Quinn FD, Berger TG, LeBoit PE, Tappero JW. Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis. N Engl J Med. 1997;337(23):1876–1883. PMID: 9407153
  7. Dehio C. Bartonella-host-cell interactions and vascular tumour formation. Annu Rev Microbiol. 2004;58:365–390. PMID: 15487941
  8. Lamps LW, Scott MA. Cat-scratch disease: historic, clinical, and pathologic perspectives. Am J Surg Pathol. 2004;28(4):553–558. PMID: 15024391
  9. Maurin M, Raoult D. Bartonella (Rochalimaea) quintana infections. Clin Microbiol Rev. 1996;9(4):525–542. PMID: 8894351
  10. Rolain JM, Brouqui P, Koehler JE, Maguina C, Dolan MJ, Raoult D. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother. 2004;48(6):1921–1933. PMID: 15155183
  11. Jacomo V, Kelly PJ, Raoult D. Natural history of Bartonella infections (an exception to Koch's postulate). Clin Diagn Lab Immunol. 2002;9(1):8–18. PMID: 11777823
  12. Breitschwerdt EB. Bartonellosis, one health and all creatures great and small. Vet Clin North Am Small Anim Pract. 2017;47(4):945–963. PMID: 28551115

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12. Connections

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