Bartonella syndromes

OVERVIEW: What every practitioner needs to know

Are you sure your patient has bartonellosis? What should you expect to find?

Bartonella species are small gram-negative intracellular organisms. Three species cause the majority of human disease, and each causes a distinct clinical syndrome: Bartonella henselae, Bartonella quintana and Bartonella bacilliformis.

Bartonella henselae is the cause of cat scratch disease (CSD), which is associated with a history of exposure to cats, especially kittens, and their fleas.

The infection can take a classic cutaneous course, or become disseminated.

Patients may complain of an initial skin inoculation site that may appear as a vesicle or pustule. After 1-3 weeks, tender regional lymphadenopathy with overlying erythema develops as a classic manifestation of CSD. Patients with atypical presentations can have minimal lymphadenopathy. If the initial inoculation site is near the eye, conjunctivitis with preauricular lymphadenopathy may occur (Parinaud’s syndrome).

Disseminated infection is especially common in children but has also been reported in adults. Disseminated B. henselae infection has been associated with ocular findings, including neuroretinitis. Central nervous system (CNS) infections with B. henselae can result in cerebral vasculitis and encephalopathy, as well as transverse myelitis and radiculitis. Myalgias, arthralgias, arthritis, and osteomyelitis have been described. Less commonly, the organism is a cause of culture-negative endocarditis.

Bartonella quintana is the agent of trench fever. The vector is the human body louse (Peduculus humanus var. corporis). Patients often have a history of homelessness or alcoholism and present with fever, malaise, and bone pain (classically pretibial in location).

Bacillary angiomatosis is another clinical syndrome caused by B. quintana and B. henselae. This was first described in HIV-infected patients but also occurs in transplant recipients and other immunosuppressed patients. These patients have skin, mucous membrane, or subcutaneous lesions and bone pain. Less commonly, they have abdominal pain, nausea, and vomiting when there is significant hepatic or splenic disease.

Bartonella bacilliformis is the agent of bartonellosis, which has two phases: Oroya fever and verruga peruana. The vector is the sandfly. It is endemic to the Andes Mountains in South America.

Patients with the acute phase of bartonellosis (Oroya fever) may be asymptomatic (>50%) or may develop symptoms of fever, nausea, malaise, and headache 3 weeks after being bitten by an infected sandfly. This phase represents dissemination of the organism; it invades erythrocytes and endothelial cells, causing significant anemia.

Untreated, patients can become quite ill with a mortality rate of 40% because of anemia and complications, including anasarca, neurologic abnormalities, and superimposed infections with Staphylococcus, Salmonella, Shigella, or Enterobacter. Those that recover usually do so with minimal sequelae.

In the chronic phase of infection with B. bacilliformis (verruga peruana), the organisms that had invaded the capillary endothelial cells cause proliferation that results in exophytic, erythematous lesions of the skin, and mucus membranes.

Up to 60% of patients with verruga peruana do not recall an earlier, febrile illness consistent with oroya fever and likely had asymptomatic initial infection.

The lesions are divided into three successive categories. They start as miliary lesions that are small, pearly, and found in clusters on the dermis. These then progress to the nodular phase, which is more exophytic and can be subdermal with overlying red or purple discolored skin. The final phase is mular, which are more superficial, large, highly vascular lesions that can ulcerate and bleed.

Patients with verruga peruana may also complain of bone pain.

Physical exam findings in classic CSD include painful lymphadenopathy and possibly vesicular or pustular lesions at the initial site of skin inoculation. In disseminated disease, findings are specific to the organ system involved. Lesions can be found in the liver and spleen on CT or MRI.

In HIV-infected patients, B. henselae and B. quintana can cause bacillary angiomatosis with cutaneous or mucus membranes lesions. These lesions may start out pearly but often become red or purple due to vascular proliferation and may ulcerate and bleed. B. quintana tends to cause more tender, erythematous subcutaneous nodules, whereas B. henselae caused more lymphadenitis and hepatosplenic disease (a pattern expected from their disease manifestations in immunocompetent persons as well).

HIV-infected patients with bacillary angiomatosis may also present with point tenderness over the long bones, which may indicate osteomyelitis; usually, there are overlying skin lesions.

Physical exam findings of trench fever include fever that may range from an isolated episode to febrile periods of 4-5 days that recur several times with intercurrent afebrile episodes of 4-5 days duration. The fevers are thought to be due to B. quintana bacteremia. Patients may also have a macular or papular rash and splenomegaly. Bacillary angiomatosis is associated with physical exam findings of subcutaneous nodules, skin lesions, and bone lesions. The skin lesions can vary widely and can be cutaneous or subcutaneous. The red-purple appearance is associated with vascular proliferation. In contrast to B. henselae, B. quintana infections are not typically associated with marked lymphadenopathy or with hepatic or splenic lesions.

Physical findings of Oroya fever include pallor, weakness, painless hepatosplenomegaly, and generalized lymphadenopathy.

The lesions of verruga peruana are divided into three successive categories. They start as miliary lesions that are small, pearly, and found in clusters on the dermis. These then progress to the nodular phase, which is more exophytic and can be subdermal with overlying red or purple discolored skin. The final phase is mular, which are more superficial, large, highly vascular lesions that can ulcerate and bleed.

These lesions may also occur on mucous membranes or in viscera.

How did the patient develop bartonellosis? What was the primary source from which the infection spread?

Bartonella henselae is spread by exposure to cats, especially kittens, and their fleas. The human body louse is the vector for Bartonella quintana. B. quintana transmission is highest in crowded conditions in which persons have poor hygiene. B. quintana has rarely been associated with cats, in contrast to B. henselae.

B. Bacilliformis is transmitted by the bite of the sandfly, Lutzomyia verrucarum, and may be asymptomatic or cause two clinical phases of disease: Oroya fever in the acute phase and verruga peruana in the late phase.

Which individuals are of greater risk of developing bartonellosis?

• Homeless individuals, alcoholics, those living in crowded conditions, and those with poor hygiene are at greatest risk for B. quintara infections.

• Children or adults with exposure to kittens or adult cats are at risk for cat scratch disease.

• Travelers to the Andes region are more likely to develop symptomatic Oroya fever than local residents. However, the late phase of bartonellosis, verruga peruana, is more common in area residents than in travelers. Risk factors are young age and living in a household with others with the disease.

Beware: there are other diseases that can mimic bartonellosis:

• The appearance of CSD is similar to other causes of nodular lymphangitis, including infections with Streptococci, Staphylococci, Mycobacterium marinum, Nocardia species, Francisella tularensis, Yersinia pestis, Bacillus anthracis, Pseudallescheria boydii, and sporothrix shenckii. Malignancies, such as lymphoma, can also cause enlarged lymph nodes, although these are usually nontender. If the history is not classic for CSD or the patient does not respond to therapy, a lymph node biopsy should be performed with tissue sent for histology, gram stain, and culture.

• Trench fever can resemble tick-borne relapsing fever, malaria, typhoid fever, leptospirosis, tularemia, and babesiosis.

• Cutaneous bacillary angiomatosis can be indistinguishable from Kaposi’s sarcoma.

• Other febrile illnesses can mimic Oroya fever, including malaria, typhoid, leptospirosis, and dengue. In the chronic phase, verruga peruana lesions must be differentiated from Kaposi’s sarcoma, bacillary angiomatosis, and pyogenic granuloma.

• Bartonella endocarditis is indistinguishable clinically from other causes of culture negative endocarditis.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosisRoutine blood work is usually not helpful in diagnosing infections due to Bartonella species. One exception is that anemia will be seen in patients with Oroya fever.

For CSD, three of the following four criteria are needed for the diagnosis:

• Exposures to cats or their fleas

• Sterile pus from a lymph node, positive polymerase chain reaction (PCR) for Bartonella, hepatic or splenic lesions on CT

• Positive serology for B. henselae (enzyme immunoassay [EIA] or immunofluorescence assay [IFA]); The strongest association with true disease is with a titer greater than1:256, but anything greater than 1:64 on a single titer represents possible infection. This should be placed into the clinical context of the patient’s presenting history and symptoms and the results of other serological and histological testing.

• Biopsy with a positive Warthin-Starry stain or granulomatous change consistent with cat scratch disease

Blood cultures can be done for Bartonella species, but the lab should be alerted since this fastidious organism requires special handling (ethylene diamine tetra-acetic acid [EDTA], blood tubes, chocolate agar plates incubated in 5% CO₂ at 37^oC for 3 weeks to optimize yield).

Cultures should be obtained prior to antibiotics, if possible, as even a single dose can render blood cultures negative.

In CSD, blood cultures are most often negative.

PCR of a lymph node biopsy can be useful for B. henselae, especially if the patient presents within 6 weeks of initial illness. PCR on blood is usually negative.

B. quintana is diagnosed as much as B. henselae. Given an appropriate clinical picture, the histopathological findings seen with bacillary angiomatosis or culture confirm the diagnosis. Serology for B. quintana is also EIA or IFA and interpreted as for B. henselae outlined above.

PCR that can distinguish B. quintana from other Bartonella species is commercially available.

For bartonellosis, Oroya fever can be diagnosed with blood culture or on Giemsa stained blood smear, given the large organism load. The cultures can still take 2-3 weeks to become positive. Verruga peruana is most often a clinical diagnosis in endemic areas, but histopathology can be helpful in atypical cases. Usually, organisms are not visible, but there is marked proliferation of blood vessels with neutrophils and endothelial cells prominent in the dermis.

What imaging studies will be helpful in making or excluding the diagnosis of bartonellosis?

• Imaging is generally not helpful. In CSD or disseminated bacillary angiomatosis in patients with HIV, abdominal CT may show lesions in the liver and spleen

• Plain radiographs or CT of the long bones of the lower extremity may show lytic lesions in patients with bacillary angiomatosis.

• Abdominal CT or extremity CT $$, plain radiographs $ ($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has bartonellosis, what therapies should you initiate immediately?

For patients with appropriate travel history, who present with a clinical picture consistent with Oroya fever, prompt antibiotic therapy should be started since mortality can reach 40% in untreated patients.

1. Anti-infective agents

(see Table I.)

Table I.n

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Because other conditions can mimic Bartonella infections, it is best to obtain a diagnosis, if possible, prior to treatment, especially for prolonged courses. For patients who have recently traveled to the Andes in S. America, prompt treatment to cover Oroya fever is warranted.

In other cases, if patients present in a very ill condition, it is appropriate to cover broadly for gram-negative and gram-positive organisms while undergoing a full work-up (please see the chapters on Fever and Fever of Unknown Origin and Sepsis for more on empiric therapy).

Bartonella can be a cause of culture negative endocarditis (please see the chapter on Endocarditis for recommended initial therapies).

What complications could arise as a consequence of bartonellosis?

What should you tell the family about the patient’s prognosis?

• Endocarditis can occur with Bartonella species. This is increasingly recognized as a contributor to culture-negative endocarditis. It may take up to 4 weeks for a blood culture to become positive with Bartonella species, and cultures may remain negative if drawn after initial doses of antibiotics are given.

• Consider endocarditis in patients with prolonged fever, a new murmur, and negative blood cultures. Proceed with the diagnostic work-up as outlined in the chapter on Culture negative endocarditis, but include tests for Bartonella as outlined previously in this chapter.

• In some cases, the diagnosis of Bartonella endocarditis has been made on histopathology of surgically removed valves in patients who underwent cardiac surgery secondary to culture negative endocarditis. For unknown reasons, the organism has a predilection for causing aortic valve endocarditis.

• In patients with Oroya fever, mortality can be as high as 40% if patients are not promptly treated.

• Most immunocompetent patients with CSD recover even without specific treatment.

How do you contract bartonellosis and how frequent is this disease?

Bartonella henselae is the cause of CSD, which is associated with a history of exposure to cats, especially kittens, and their fleas.

Bartonella quintana is the agent of trench fever. The vector is the human body louse (Peduculus humanus var. corporis). Patients often have a history of homelessness or alcoholism.

Bartonella bacilliformis is the agent of bartonellosis, which has two phases: Oroya fever and verruga peruana. The vector is the sandfly. It is endemic to the Andes Mountains in South America.

How do these pathogens cause bartonellosis?

Bartonella species evade mechanisms of the human immune system using complex pathogen-host interactions.

In general, Bartonella infects erythrocytes and stimulates replication endothelial cells, leading to bacteremia and vascular proliferation as some clinical manifestations.

B. bacilliformis have several virulence factors that facilitate binding to and invasion of erythrocytes, including flagella and fimbriae, as well as deformin protein.

Angiopeptin-2 and vascular endothelial growth factor are increased in B. bacilliformis infection, which contributes to vascular proliferation.

B. henselae and B. quintana both express bepA, a translocated protein that inhibits endothelial cell apoptosis by raising intracellular levels of cAMP.

Intracellular survival of Bartonella species may be enhanced by the organism’s production of superoxide dismutases.

What other clinical manifestations may help me to diagnose and manage bartonellosis?

• Cat Scratch Disease: The infection can take a classic cutaneous course, or become disseminated.

• Patients may complain of an initial skin inoculation site that may appear as a vesicle or pustule. After 1-3 weeks, tender regional lymphadenopathy with overlying erythema develops as a classic manifestation of CSD. Patients with atypical presentations can have minimal lymphadenopathy. If the initial inoculation site is near the eye, conjunctivitis with preauricular lymphadenopathy may occur (Parinaud’s syndrome).

• Disseminated infection is especially common in children, but has also been reported in adults. Disseminated B. henselae infection has been associated with ocular findings, including neuroretinitis. CNS infections with B. henselae can result in cerebral vasculitis and encephalopathy, as well as transverse myelitis and radiculitis. Myalgias, arthralgias, arthritis, and ostemyelitis have been described. Less commonly, the organism is a cause of culture-negative endocarditis.

• Physical exam findings in classic CSD include painful lymphadenopathy and possibly vesicular or pustular lesions at the initial site of skin inoculation. In disseminated disease, findings are specific to the organ system involved. Lesions can be found in the liver and spleen on CT or MRI.

• Bartonella quintana is the agent of trench fever. The vector is the human body louse (Peduculus humanus var. corporis). Patients often have a history of homelessness or alcoholism and present with fever, malaise, and bone pain (classically pretibial in location).

• Physical exam findings of trench fever include fever that may range from an isolated episode to febrile periods of 4-5 days that recur several times with intercurrent afebrile episodes of 4-5 days duration. The fevers are thought to be due to B. quintana bacteremia. Patients may also have a macular or papular rash and splenomegaly.

• Bacillary angiomatosis is another clinical syndrome caused by B. quintana and B. henselae. This was first described in HIV-infected patients but also occurs in transplant recipients and other immunosuppressed patients. These patients have skin, mucous membrane, or subcutaneous lesions and bone pain. Less commonly, they have abdominal pain, nausea, and vomiting when there is significant hepatic or splenic disease.

• Bacillary angiomatosis is associated with physical exam findings of subcutaneous nodules, skin lesions, and bone lesions. The skin lesions can vary widely and can be cutaneous or subcutaneous. The red-purple appearance is associated with vascular proliferation. In contrast to B. henselae, B. quintana infections are not typically associated with marked lymphadenopathy or with hepatic or splenic lesions.

• Bartonella bacilliformis is the agent of bartonellosis, which has two phases: Oroya fever and verruga peruana. The vector is the sandfly. It is endemic to the Andes Mountains in South America.

• Patients with the acute phase of bartonellosis (Oroya fever) may be asymptomatic (>50%) or may develop symptoms of fever, nausea, malaise, and headache 3 weeks after being bitten by an infected sandfly. This phase represents dissemination of the organism; it invades erythrocytes and endothelial cells, causing significant anemia.

• Untreated, patients can become quite ill with a mortality rate of 40% due to anemia and complications, including anasarca, neurologic abnormalities, and superimposed infections with Staphylococcus, Salmonella, Shigella, or Enterobacter. Those that recover usually do so with minimal sequelae.

• In the chronic phase of infection with B. bacilliformis (verruga peruana), the organisms that had invaded the capillary endothelial cells cause proliferation that results in exophytic, erythematous lesions of the skin, and mucus membranes.

• Up to 60% of patients with verruga peruana do not recall an earlier, febrile illness consistent with oroya fever and likely had asymptomatic initial infection. The lesions are divided into three successive categories. They start as miliary lesions that are small, pearly, and found in clusters on the dermis. These then progress to the nodular phase, which is more exophytic and can be subdermal with overlying red or purple discolored skin. The final phase is mular, which are more superficial, large, highly vascular lesions that can ulcerate and bleed. These lesions may also occur on mucous membranes or in viscera.

• Patients with verruga peruana may also complain of bone pain.

• Physical findings of Oroya fever include pallor, weakness, painless hepatosplenomegaly, and generalized lymphadenopathy.

How can bartonellosis be prevented?

There currently are no vaccines that confer protection against infections with Bartonella species.

Avoidance of cats, kittens, and their fleas decreases risk of developing infection with B. henselae.

Good hygiene helps avoid the vector of B. quintana, the human body louse.

B. bacilliformis only occurs if a person is exposed to sandflies in the South American Andes regions, so avoiding areas in which this insect is common decreases the risk.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Agan, BK, Dolan, MJ. “Laboratory diagnosis of Bartonella infections”. Clin Lab Med. vol. 22. 2002 Dec. pp. 937-62. (This is a review of current recommended diagnostic algorithms.)

Biswas, S, Rolain, JM. ” infection: treatment and drug resistance”. Future Microbiol. vol. 5. 2010 Nov. pp. 1719-31. (A review of important issues in treatment of Bartonella.)

Dehio, C. “Molecular and cellular basis of pathogenesis”. Annu Rev Microbiol. vol. 58. 2004. pp. 365-90. (Overview of the organism’s virulence and pathogenic features.)

Eicher, SC, Dehio, C. ” entry mechanisms into mammalian host cells”. Cell Microbiol 2012 Apr 23. (Another overview of the organism’s virulence and pathogenic features, focused on cell entry.)

Kaiser, PO, Riess, T, O’Rourke, F, Linke, D, Kempf, VA. ” spp.: throwing light on uncommon human infections”. Int J Med Microbiol. vol. 301. 2011 Jan. pp. 7-15. (This source outlines the ranges of human disease that can occur with Bartonella species.)

Piérard-Franchimont, C, Quatresooz, P, Piérard, G. “Skin diseases associated with Bartonella infection: facts and controversies”. Clin Dermatol. vol. 28. 2010 Sep-Oct. pp. 483-8. (This source reviews skin manifestations of Bartonella infections.)

Nelson, CA, Saha, S, Mead, PS. “Cat-Scratch Disease in the United States, 2005-2013”. Emerg Infect Dis. vol. 22. 2016 Oct. pp. 1741-6.

Raybould, JE, Raybould, AL, Morales, MK, Zaheer, M, Lipkowitz, MS, Timpone, JG, Kumar, PN. “Bartonella Endocarditis and Pauci-Immune Glomerulonephritis: A Case Report and Review of the Literature”. Infect Dis Clin Pract (Baltim Md). vol. 24. 2016 Sep. pp. 254-260.

Markowicz, M, Käser, S, Müller, A, Lang, G, Lang, S, Mayerhöfer, M, Stanek, G, Rieger, A. “Bacillary angiomatosis presenting with facial tumor and multiple abscesses: A case report”. Medicine (Baltimore). vol. 95. 2016 Jul. pp. e4155

Parra, E, Segura, F, Tijero, J, Pons, I, Nogueras, MM. “Development of a real-time PCR for Bartonella spp. detection, a current emerging microorganism”. Mol Cell Probes.. 2016 Oct 13. pp. S0890-8508(16)30082-2

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