Approach

Diagnosis of various human Bartonella infections should be based on risk factors, clinical presentation, and laboratory findings. Although risk factors, such as a cat bite or exposure to lice, may be obvious in the majority of cases, initial presentation in many other cases can be enigmatic.

Although various laboratory methods are available for diagnosis of Bartonella species, including culture, direct staining, serology, histopathology, and molecular techniques such as polymerase chain reaction (PCR), none of these tests is fully reliable.​[5][31][42]​​ Bartonella cultures usually take several weeks and have variable growth. Although various serologic tests are available, most of them have low sensitivity and cross-reactivity with other antigens. Serology also cannot reliably differentiate among Bartonella species.[17]​ Molecular techniques including new PCR methods are being developed, but are still not widely available.[4][5][31]

Bartonella species are responsible for a broad spectrum of clinical syndromes, including prolonged fever of unknown origin, hematologic manifestation, encephalitis and encephalopathy, generalized lymphadenopathy, hepatosplenic disease, retinopathy, culture-negative endocarditis, osteomyelitis, arthritis, mediastinal mass, and pleurisy.[4][5] ​B henselae and B quintana are also known to cause bacillary angiomatosis in people who are immunocompromised.[4][5]

Three classic infections described in humans include:[4][5]

  • Cat-scratch disease (B henselae)

  • Carrion disease (B bacilliformis), which consists of a bacteremic phase (Oroya fever) and an eruptive phase (verruga peruana or Peruvian wart)

  • Trench fever (B quintana).

Therefore, the current approach should include a good history, looking for specific risk factors for individual species of Bartonella, and a thorough examination combined with specific laboratory tests.

Bartonella henselae

Cat-scratch disease (CSD)

  • The following factors should lead to further diagnostic workup.[4][5][31]

    • History of exposure to cats including bites, scratches, or any other contact.

    • Any scratch mark or suspicious skin lesions in the presence of cat exposure.

    • Presence of papular, pustular, or crusted lesion at the site of inoculation, which usually occur around 3 to 10 days after exposure.

    • Regional lymphadenopathy - ipsilateral regional lymphadenopathy affecting a single lymph node occurs in 85% of typical CSD patients. About 10% of the nodes suppurate.

  • Atypical CSD may present with various other systemic features:

    • Parinaud syndrome (fever, regional lymphadenopathy, and follicular conjunctivitis).

    • Unexplained encephalopathy with almost normal cerebrospinal fluid (CSF) - mental status change occurs as a result of encephalopathy, which is the most common neurologic manifestation of B henselae. Neurologic complications occur in only 2% of the infections.

    • Nuchal rigidity - CSF typically yields normal results, although pleocytosis and elevated protein may be present.

    • Painless visual loss, with unilateral, abrupt onset - this is a classic presentation of neuroretinitis, for which B henselae is the most commonly identified etiologic agent. Neuroretinitis is a form of optic neuropathy with optic disc swelling and macular stellate exudates. This is the most common posterior segment ocular complication of B henselae.

    • Mastoiditis, with breakdown of the osseous septa of the mastoid, may occur and requires mastoidectomy. Tissue diagnosis of CSD is made from granulation tissue and infected lymph nodes adjacent to the mastoid cortex.[43]

    • Bone pain - osteomyelitis secondary to B henselae infection may present with bone pain, tenderness, and fever.

    • Episodic abdominal pain - many patients with systemic symptoms present with right upper quadrant pain or periumbilical abdominal pain as a result of liver involvement.

    • Skin manifestations - maculopapular and urticaria eruptions, granuloma annulare, erythema nodosum, erythema marginatum, and leukocytoclastic vasculitis.

    • Bartonella endocarditis: Bartonella henselae may present as culture-negative endocarditis and is responsible for about 3% of endocarditis cases.[15]​ Usually involves aortic valves, and vegetations are found in 100% of cases. Typical symptoms of endocarditis such as prolonged fever of unknown origin, malaise, fatigue, night sweats, or heart palpitations may be present. Physical exam may be nonspecific, or may reveal classic findings such as Roth spots, Janeway lesions, Osler nodes, or splinter hemorrhages.

    • In addition, immunocompromised patients may also present with bacillary angiomatosis or peliosis hepatis.

    • Peliosis hepatis: immunocompromised patients may present with peliosis hepatis, characterized by dilated capillaries and blood-filled cavernous spaces in the liver, as seen on computed tomography (CT). Patients manifest with fever, chills, gastrointestinal symptoms, and hepatosplenomegaly.

    • Bacillary angiomatosis: B henselae and B quintana are both known to cause bacillary angiomatosis in people who are immunocompromised.[4][5] Reddish-brown papules similar to Kaposi sarcoma lesions are present.

  • Investigations

    • Definitive diagnostic workup may include one or more of the following tests based on presenting symptoms.[4][5][24][31][44]

    • Serology - indirect fluorescence assay (IFA) is preferred. Enzyme immunoassay (EIA) is also available.[31] A positive test includes 4-fold increase in titer between acute and convalescent phase; single IFA titer of ≥1:64 is considered positive. Serology can be negative early in the illness (<1 week); immunoglobulin (Ig)M turns negative by 3 months; IgG remains positive in 25% of patients beyond first year. IFA sensitivity: IgM 2% to 50%, IgG 14% to 100%; specificity: IgM 86% to 100%, IgG 34% to 100%. EIA sensitivity: IgM 60% to 85%, IgG 10% to 25%; specificity: IgM 98%, IgG 97%.

    • Culture of blood and other tissue samples: Bartonella species are hard to grow in culture. There is a poor yield on culture of nodal aspirates. Bacterial growth may take 2 to 6 weeks.

    • Aspiration of lymph node for stains (Warthin-Starry) and culture: histopathologic examination shows granuloma formation, microabscesses, follicular hyperplasia.

    • PCR: Lymph node, tissue sample such as heart valve, or blood sample can be sent for PCR analysis. Sensitivity is 43% to 76%; specificity is 100%. Helpful in rapid diagnosis when available.

    • Echocardiogram shows vegetations in 100% of cases with Bartonella endocarditis, usually involving aortic valves. Valves with vegetations can be sent for PCR analysis. It is helpful in rapid diagnosis when available.

    • Lumbar puncture with CSF analysis: in patients with nuchal rigidity, CSF typically yields normal results, although pleocytosis and elevated protein may be present.

    • Bone scan: increased uptake if osteomyelitis is present.

    • CT scan abdomen: immunocompetent children may present with hepatosplenic microabscesses secondary to B henselae infection. Immunocompromised patients may present with peliosis hepatis, characterized by dilated capillaries and blood-filled cavernous spaces in the liver.

  • Presence of any 3 of the following 4 criteria confirms diagnosis of B henselae infection (adapted from Margileth):[31][45]

    • Cat or flea contact regardless of presence of a scratch mark or a lesion at the inoculation site

    • Negative tuberculin skin test or interferon-gamma release assays, or negative serologies for other causes of adenopathy; sterile pus aspirated from node; positive PCR assay for B henselae; and/or liver/spleen lesions seen on CT scan

    • Positive EIA or IFA assay with a single titer of ≥1:64 or a 4-fold rise in titer between acute and convalescent phases

    • Biopsy showing granulomatous inflammation consistent with CSD or a positive Warthin-Starry silver stain.

Bartonella quintana

Trench fever (quintana fever)

  • Quintana or trench fever should be suspected in homeless patients and in patients with alcohol-use disorder with prolonged fever, especially if infested by Pediculus humanus humanus (the human body louse).[4][5]​​ Fever with chills, sweating, malaise, and anorexia occurs after an average incubation period of 8 days (range 5 to 20 days) of exposure to the body louse. Fever is classically maintained for 5 to 7 days, followed by recurrences every 3 to 5 days (hence the names "quintana" or "5-day fever"), but the pattern is variable and fever may occur only once.[17]

  • Generalized headaches with post-orbital pain may occur. Myalgia, arthralgia, and severe pain in the neck, back, and legs including tibia occurs; therefore, the disorder is sometimes known as shinbone fever.

  • Bartonella endocarditis: it may also present as culture-negative endocarditis, especially in urban homeless people. Typical symptoms of endocarditis such as fever, malaise, fatigue, night sweats, or heart palpitations may be present. Physical exam may be nonspecific or may reveal classic findings such as Janeway lesions, Osler nodes, or splinter hemorrhages.

  • Bacillary angiomatosis: B henselae and B quintana are both known to cause bacillary angiomatosis in people who are immunocompromised.[4][5] Reddish-brown papules similar to Kaposi sarcoma lesions are present.

Investigations

  • Various serology assays are available:[5][46]

    • Indirect immunofluorescence (IIF)

    • EIA

    • Complement fixation

    • Hemagglutination

    • Western Blot Assay (highly specific).

  • The preferred serologic method is IIF assay; a titer of >50 is considered positive; titers >800 are associated with bacteremia and endocarditis.[44][46] Because this test has cross-reactivity with Coxiella burnetii and Chlamydia pneumoniae, a Western Blot assay should be ordered for confirmation.

  • Blood culture requires special media such as chocolate agar or sheep blood agar.[4][5] Bacterial growth may take 9 to 36 days.

  • Echocardiogram shows vegetations in 100% of cases with Bartonella endocarditis, usually involving aortic valves. Valves with vegetations can be sent for PCR analysis. It is helpful in rapid diagnosis when available.

  • Biopsy of skin or other suspected tissue followed by histopathologic exam, immunohistochemistry, and PCR should be done, when available.[4][5][46] ​PCR can also be performed on blood for suspected bacteremia.[17]

Bartonella bacilliformis

  • Patients with an appropriate history of exposure, such as living in or travel to endemic regions in South America (Peru, Ecuador, and Colombia) within the Andes mountains, with exposure to sand fly, should be suspected of having Carrion disease.

  • Those who present with prolonged fever, constitutional symptoms (anorexia, malaise, chills), hepatosplenomegaly, lymphadenopathy, mental state changes, pericardial effusion, and severe anemia should be suspected of having Oroya fever, whereas those with subsequent development of nodular skin lesions should be suspected of having verruga peruana (Peruvian wart).

  • After weeks to months of a prolonged bacteremic prodromal phase, patients develop nodular lesions on the face and trunk. Initially these are in the miliary form: red papules <3 mm in size. The second stage of lesions is the mular form, characterized by sessile, red, nodular tumors of about 5 mm diameter. The third-stage lesions are larger, painless, subcutaneous nodules, located mostly on the extensor surfaces of the extremities, and prone to bleeding, ulceration, and infection.

  • Case reports suggest B bacilliformis can cause endocarditis, but this is rare.[47][17]

In the acute phase, a blood smear shows intraerythrocytic bacilli. This is best visualized with Romanowsky, Giemsa, or Wright stains. Blood cultures and serologic tests are useful for diagnosis. Positive growth on culture may take 5 to 30 days. Culture requires a semisolid agar with rabbit serum and hemoglobin, incubated at a lower temperature (77°F to 82°F; 25°C to 28°C).

Various assays for serologic diagnosis are available.[5][48] Cutoff values for a positive titer vary by type of assay used:

  • IIF

  • EIA

  • Complement fixation

  • Hemagglutination

  • Western Blot Assay (highly sensitive and specific).

In the eruptive phase, a skin biopsy should be done.[4][5][48] Biopsy specimen can also be sent for immunohistochemistry and culture of the organism.[5] Histopathology shows proliferation of endothelium, monocytes and macrophages; Warthin-Starry stain reveals the organisms.

Bartonella vinsonii

B vinsonii has been isolated from immunocompetent patients, in whom it can be an intravascular bacterial pathogen that causes endocarditis, vasoproliferative neoplasia, arthritis, and neurologic disease (e.g., headaches, insomnia, progressive weight loss, muscle weakness, and lack of coordination).[12]

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