Epidemiology and Pathogenesis

Organisms belonging to the genus Bartonella cause numerous infections in humans; most of these infections are thought to be zoonoses. Interest in these organisms has increased because of their recognition as causes of an expanding array of clinical syndromes in immunocompromised and immunocompetent patients. For example, Bartonella species have been recognized with increasing frequency since the early 2000s as a cause of culture-negative endocarditis. Humans acquire infection either naturally (infections caused by Bartonella quintana or Bartonella bacilliformis) or incidentally (other Bartonella species) via arthropod-borne transmission. Nevertheless, questions remain regarding the epidemiology of these infections; some epidemiologic information is summarized in Table 33-1.

Bartonella is a facultative intracellular bacterium that closely interacts with the host cells and has unique abilities to cause either acute or chronic infection as well as the proliferation of microvascular endothelial cells and angiogenesis (forming new capillaries from preexisting ones) or suppurative manifestations. Three Bartonella species (B. quintana, B. bacilliformis, and B. henselae) are capable of causing angiogenic lesions. Research has demonstrated that some species are capable of interacting with host red blood cells, endothelial cells, and possibly bone marrow progenitor cells. Colonization of vascular endothelium is considered a crucial step in the establishment and maintenance of Bartonella-triggered angioproliferative lesions. Within several hours following infection of cultured human umbilical vein endothelial cells, Bartonella species adhere to and enter these cells by an actin-dependent process resembling other bacterial-directed phagocytosis or uptake into host cells. Recent studies have also shown that B. henselae possess nine outer membrane proteins (OMP), one of which is able to bind to endothelial cells.

Typically, Bartonella species multiply and persist in the red blood cells in the reservoir host and share common persistence and dissemination strategies. In addition to angioproliferation, recent data indicate bartonellae can inhibit endothelial cell apoptosis (programmed cell death); these organisms also activate monocyte and macrophage cells capable of producing potent angiogenic factors. Although more research is needed regarding the pathogenesis of infections caused by Bartonella, it is evident these organisms possess unique pathogenic strategies to expand their bacterial niche in order to sustain survival within the human host. It is evident that the pathologic response to these infections varies substantially with the status of the host immune system. For example, infection with the same Bartonella species, such as B. henselae, can cause a focal suppurative reaction (i.e., CSD) in immunocompetent patients or a multifocal angioproliferative lesion (i.e., bacillary angiomatosis) in immunocompromised patients. B. quintana, the etiologic agent for trench fever, also causes bacillary angiomatosis in immunocompromised patients.

Spectrum of Disease

The diseases caused by Bartonella species are listed in Table 33-1. Because B. quintana and B. henselae are more common causes of infections in humans, these agents are addressed in greater depth.

Trench fever, caused by B. quintana, was largely considered a disease of the past. Clinical manifestations of trench fever range from a mild influenza-like headache and bone pain to splenomegaly (enlarged spleen) and a short-lived maculopapular rash. During the febrile stages of trench fever, infection may persist long after the disappearance of all clinical signs; some patients may have six or more recurrences. B. quintana has reemerged and has been reported in cases of bacteremia, endocarditis, chronic lymphadenopathy, and bacillary angiomatosis primarily in low socioeconomic groups in Europe and the United States, as well as in patients infected with the human immunodeficiency virus (HIV). Bacillary angiomatosis is a vascular proliferative disease involving the skin (other organs such as the liver, spleen, and lymph nodes may also be involved) and occurs in immunocompromised individuals such as organ transplant recipients and HIV-positive individuals. Prolonged bacteremia with B. quintana infections may be associated with the development of endocarditis and bacillary angiomatosis.

B. henselae is associated with bacteremia, endocarditis, and bacillary angiomatosis. Of note, recent observations indicate that B. henselae infections appear to be subclinical and are markedly underreported, as problems with current diagnostic approaches are recognized (see Laboratory Diagnosis). In addition, B. henselae causes CSD and peliosis hepatitis. About 24,000 cases of CSD occur annually in the United States; about 80% of these occur in children. The infection begins as a papule or pustule at the primary inoculation site; regional tender lymphadenopathy develops in 1 to 7 weeks. The spectrum of disease ranges from chronic, self-limited adenopathy to a severe systemic illness affecting multiple body organs. Although complications such as a suppurative (draining) lymph node or encephalitis are reported, fatalities are rare. Diagnosis of CSD requires three of the four following criteria:

Bartonella clarridgeiae is a newly described species capable of causing CSD and bacteremia.

Peliosis hepatitis caused by B. henselae may occur independently or in conjunction with cutaneous bacillary angiomatosis or bacteremia. Patients with peliosis hepatitis demonstrate gastrointestinal symptoms. Symptoms include fever, chills, and an enlarged liver and spleen that contain blood filled cavities. This systemic disease develops in patients infected with HIV and other immunocompromised individuals.

Clinical specimens submitted to the laboratory for direct examination and culture include blood, which has been collected in a lysis-centrifugation blood culture tube (Isolator; Wampole Laboratories, Cranbury, New Jersey), as well as aspirates and tissue specimens (e.g., lymph node, spleen, or cutaneous biopsies). There are no special requirements for specimen collection, transport, or processing that enhances organism recovery. Refer to Table 5-1 for general information on specimen collection, transport, and processing.

Approach to Identification

Bartonella spp. should be suspected when colonies of small, gram-negative bacilli are recovered after prolonged incubation (Figure 33-1). Organisms are all oxidase, urease, nitrate reductase, and catalase negative. Various methods may be used for confirmation and identification of Bartonella spp. Species identification is possible by adding 100 μg/mL of hemin to the test medium, as well as biochemical profiling using the MicroScan rapid or Rapid ANAII system (Innovative Diagnostic Systems, Norcross, Georgia) anaerobe panels, polyvalent antisera, or a variety of molecular methods.

Antimicrobial Susceptibility Testing and Therapy

Treatment recommendations for Bartonella diseases, including CSD, depend on the specific disease presentation. The efficacy of various antibiotics for CSD is difficult to assess as a result of the self-limiting nature of the disease and the decrease in symptoms in the absence of therapy. In addition to the clinical presentation, the treatment must be specifically adapted to the correct Bartonella sp. Antimicrobial susceptibilities have been determined in the presence of eucaryotic cells or without cells (i.e., axenic media). However, these conditions have not been standardized and interpretive criteria have not been determined, according to Clinical and Laboratory Standards Institute (CLSI). Moreover, results of in vitro testing may not correlate with clinical efficacy; for example, the administration of penicillin is not effective therapy despite susceptibility in vitro. Recent treatments with azithromycin indicate successful, more rapid resolution of adenopathy of CSD; however, it is presently unclear if antibiotic therapy is effective in immunocompetent patients. For patients with severe CSD (about 5% to 14% of cases), other successful antibiotic regimens have included rifampin, doxycycline, erythromycin, and azithromycin or doxycycline in combination with rifampin. For bacillary angiomatosis and peliosis, doxycycline and erythromycin are considered the drugs of choice. Suggested therapy for endocarditis, suspected or documented, is gentamicin with or without doxycycline, respectively.

Prevention

There are no vaccines available to prevent infections caused by Bartonella spp. Exposure to cats or cat fleas has been implicated in the transmission of B. henselae to humans. Therefore, it is recommended that immunocompromised individuals avoid contact with cats, especially kittens, and control flea infestation.