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Bartonella-Associated Infections in HIV-Infected Patients

Bacteria of the genus Bartonella are very small, gram-negative bacilli that were classified as Rochalimaea until being moved recently to Bartonella because the two were closely related genetically. Of the ten known Bartonella species, five cause human infection and two, B. henselae and B. quintana, cause disease in HIV-infected patients. The first bartonella infection identified in the U.S. (1983) was in an HIV-infected individual who developed multiple subcutaneous nodules that were shown on electron microscopy to contain numerous bacilli. Many cases of this infection in HIV-infected patients have been reported since, but bartonella was not identified as the causative organism until 1990 (B. henselae) and 1992 (B. quintana).

In the 12 years since the first description in HIV-infected individuals, the spectrum of bartonella-related diseases has greatly expanded. We have evaluated more than 50 patients with bartonella infection at San Francisco General Hospital/University of California, San Francisco, but, unfortunately, these infections remain difficult to diagnose. Because bartonella infections can be fatal in HIV-infected patients, yet are readily treatable with inexpensive antibiotics, it is extremely important for the AIDS caregiver to consider bartonella in the differential diagnosis of vascular cutaneous lesions, osteomyelitis, hepatosplenomegaly, thrombocytopenia, and fever of unknown origin. Patients who have pet cats, are homeless, or have a CD4 cell count less than 50/mm³ are at special risk.

Bartonella Infections in HIV-Infected Patients (Table 1)

Manifestations of B. quintana or B. henselae in HIV-infected individuals (usually severely immunocompromised patients with late-stage HIV infection and CD4 cell counts below 100) include bacillary angiomatosis (BA), bacillary peliosis hepatis (BP), bacteremia, or a combination of these. BA and BP are manifest as lesions formed by blood vessels proliferating in response to bartonella infection.

Cat scratch disease (CSD) usually presents as granulomatous lymphadenitis following a cat scratch. Although more common in immunocompetent patients, CSD is also seen in patients with concomitant HIV infection, often before profound immunosuppression has developed. It is unknown why more severely immunocompromised individuals develop vascular proliferative lesions in response to this organism, while immunocompetent patients' pathology is usually granulomatous.

Both immunocompetent and immunocompromised individuals develop isolated bartonella bacteremia. This is often subacute, persisting for months before diagnosis; in one case at least eight months elapsed before BA was diagnosed. Untreated bartonella infection can be fatal in HIV-infected patients.

Bacillary Angiomatosis: The clinical appearance of cutaneous BA lesions in HIV-infected patients can vary widely. There may be a single lesion or thousands, covering the entire body. They are usually vascular and friable and bleed profusely when traumatized. It is often impossible to distinguish clinically between lesions of BA and Kaposi sarcoma (KS), but BA lesions often have a collarette of scale at the base, and KS lesions seldom do. In addition to angiomatous papules or dry scaling lesions, BA can appear as subcutaneous nodules, a cellulitic plaque or a deep, highly vascularized, soft tissue mass.

In addition to KS, pyogenic granuloma, lymphoma and various subcutaneous tumors and infections can produce vascularity similar to BA lesions, so it is essential to biopsy subcutaneous and vascular cutaneous lesions. Furthermore, bacillary angiomatosis can occur concomitantly with KS, so biopsy should be performed on any new, different-looking cutaneous lesion in a patient with previously biopsied KS.

Radiographically, osseous BA appears as a lytic lesion or lesions that show focal uptake with technetium bone scanning. These lesions are very painful and most commonly involve the long bones, especially the tibia, fibula, and radius; rib and vertebrae involvement have been reported and the bone marrow can also become infiltrated. A cellulitic plaque often overlies the osseous BA lesions.

Almost any organ can be affected by BA, including brain parenchyma and lymph nodes. Bartonella infection may also be related to some neurologic syndromes and both intraluminal and extraluminal gastrointestinal BA have been identified. On endoscopic visualization, intraluminal BA has been described as raised, nodular, ulcerated mucosal abnormalities of the stomach and large and small intestine. Extraluminal gastrointestinal BA has been diagnosed when a large intra-abdominal mass developed and eroded through the intestinal lumen, causing massive upper GI hemorrhage.

Bacillary Peliosis Hepatis and Splenitis: Bartonella bacilli infection in the liver and spleen of HIV-infected individuals also causes vascular proliferative lesions, although the histopathologic features differ from those of BA. Vascular lakes that form in the liver parenchyma can enlarge to form cystic, blood-filled spaces visible on CT as multiple hypoechoic lesions scattered through an enlarged liver. However, conditions such as KS, lymphoma, pyogenic bacterial infection, and extrapulmonary pneumocystosis can produce similar multiple, hypodense lesions. Rapid diagnosis is essential since different etiologies require different treatments.

Biopsy of a liver with BP lesions carries a theoretical risk of hemorrhage, so any lesions more amenable to biopsy, such as lymph nodes or concomitant cutaneous BA, should be sought; if liver biopsy is necessary, patients should be carefully monitored afterward. The most prominent laboratory abnormality identified in patients with BP is an elevated serum alkaline phosphatase. Patients with concomitant bacillary splenitis can develop splenomegaly and severe thrombocytopenia or pancytopenia.

Relapsing Bacteremia: Bacteremia can occur with BA or BP or in their absence. Relapsing bacteremia has been reported in both immunocompetent and immunocompromised individuals; it can recur after many months and in spite of treatment with appropriate antibiotics. Before treatment, these patients often have fever, chills, and weight loss.

Endocarditis: Endocarditis due to B. quintana has been reported in both immunocompromised and immunocompetent people. The presenting symptoms are usually those of subacute bacterial endocarditis, with malaise, weight loss, and fever. Valvular vegetations can often be demonstrated on echocardiography, as was reported for one HIV-infected patient with B. quintana endocarditis who developed both aortic and mitral valvular vegetations. Because bartonella organisms are not isolated from routine blood cultures, bartonella appears to be a cause of culture-negative endocarditis.

Cat Scratch Disease: Lesions of CSD include a primary cutaneous lesion at the site of the cat scratch, followed by lymphadenopathy involving the node or nodes draining the scratch site. In immunocompetent individuals, CSD is usually self-limited, all manifestations resolving within two to four months. Although this form of B. henselae infection occurs almost exclusively in patients with an intact immune system or with early HIV infection, fine-needle aspiration of the inflamed lymph node should always be performed to rule out other causes of lymphadenopathy, such as lymphoma or mycobacterial disease.

Diagnostic Approaches (Table 2)

Histopathology: The most difficult aspect of diagnosis remains the recognition of bartonella infections by the clinician. When focal bartonella infection is suspected, the best method for diagnosis is tissue biopsy followed by histopathologic examination. The hematoxylin and eosin staining of biopsied cutaneous tissue reveals characteristic changes, including a lobular proliferation of small, capillary-sized blood vessels lined with enlarged endothelial cells. There is usually a mixed inflammatory infiltrate of lymphocytes and neutrophils.

The most distinctive changes of BA are noted after Warthin-Starry silver staining of tissue: numerous small, darkly staining organisms can be seen scattered throughout the connective tissue, especially in association with adjacent endothelial cells. BA lesions in brain, bone, and lymph node contain similar Warthin-Starry staining bacilli.

The bartonella bacillus can be visualized on electron microscopy of BA lesions. Although the histopathologic appearance of vascular proliferative lesions in the liver caused by bartonella infection differs from that of BA, Warthin-Starry staining of biopsy tissue reveals similar bacilli in the liver parenchyma, near the blood-filled peliotic spaces.

Serology: An indirect immunofluorescence antibody test (IFA) that detects bartonella-specific IgG antibodies has been developed at the CDC; preliminary data suggest it may be useful for diagnosing bartonella infection in HIV-infected patients. According to the CDC's IFA test findings, the background prevalence of antibodies to bartonella in the normal human population ranges from 4% to 6%; for patients with CSD, the sensitivity is approximately 84%. Preliminary studies of HIV-infected patients with culture-proved BA reveal a percentage of seropositivity similar to that of patients with CSD, despite HIV patients' very low CD4 cell counts. Titers usually decrease at least fourfold with treatment; a rising titer was predictive of relapse in one patient, indicating that serologic monitoring may provide information about treatment efficacy.

Bartonella IFA reagents from the CDC are available to regional and state health laboratories. Serologic testing is also available from commercial labs, but sensitivity and specificity have not been verified against standardized sera from patients with culture-proved bartonella infection.

Culture: Bartonella bacilli are very fastidious and thus difficult to isolate. They grow best on chocolate or heart-infusion agar supplemented with 5% rabbit blood. Plates must be fresh (fewer than seven days old), and kept moist. Inoculated plates should be incubated in 5% CO₂ at 35°C for at least three weeks. Sterilized candle jars are useful for keeping plates moist and isolating them from airborne contaminants.

Bartonella species are more easily isolated from blood than from tissue. The best system for isolation from blood is the lysis-centrifugation tube (Wampole, Cranbury, NJ). Detection of bartonella growth in Bactec blood culture bottles usually requires removal of an aliquot from the bottle and staining with acridine orange. B. henselae and B. quintana have each been isolated directly from BA tissue samples that were homogenized and spread onto agar. Cultivation of the tissue homogenate with endothelial cells is more efficient, but available only on an experimental basis.

Treatment

Choice of Antibiotics: All HIV-infected patients with bartonella infection should be treated with antibiotics. The drug of first choice is erythromycin; if this is not well tolerated, treatment should be changed to doxycycline. Although treatment of BA has not been studied systematically, we have observed an excellent response to each of these antibiotics, and case reports also support their use. Rifampin and gentamicin may have clinical efficacy, but data are insufficient to support recommendation of either one as a single agent for the treatment of bartonella infection in the immunocompromised individual.

In severely ill patients, such as those with osteomyelitis, endocarditis, or severe peliosis hepatis, erythromycin or doxycycline should be administered IV, at least initially, and patients may benefit from the addition of either gentamicin or rifampin. Treatment failures with ciprofloxacin and TMP-SMX have been reported in patients concomitantly infected with HIV and bartonella; treatment with these drugs is thus not recommended. In addition, from our experience and numerous case reports, the first-generation cephalosporins and penicillin derivatives have no activity against bartonella bacilli in vivo and should not be used. Patients should be cautioned that they may develop a Jarisch-Herxheimer reaction after the first several doses of antibiotics.

Immunocompetent patients with uncomplicated CSD usually do not require antibiotic therapy; indeed, the efficacy of antibiotic treatment in these individuals has not been demonstrated. However, because of the potential for severe sequelae in patients with CSD and concomitant HIV infection, these latter patients should be treated with antibiotics even when the CD4 cell count is normal.

Duration of Therapy: Within the past five years we have increased the recommended duration of treatment for BA and BP because a substantial number of patients relapsed after short (several weeks to two months) courses of therapy and because of increasing evidence that most cases of cutaneous BA and other apparently localized bartonella infections in fact are disseminated, often chronic, disease. Every patient with cutaneous BA should be evaluated for additional sites of infection, such as bone, liver, and heart. For patients with only isolated cutaneous BA, we currently recommend a minimum of three months of antibiotic therapy. Patients with more severe disease -- such as osteomyelitis, endocarditis, or BP -- should be treated initially with one or two antibiotics IV and receive a minimum total of four months of antibiotic treatment. Patients in whom treatment is stopped after three to four months should be followed closely for relapse in the same or a different organ; some patients may require lifelong suppressive therapy.

Prevention

Reservoirs and Vectors: In early BA case reports, cat exposure was anecdotally linked with BA in HIV-infected patients. Systematic evaluation of patients with BA and the multiple environmental risk factors to which they were exposed revealed that only traumatic cat contact (cat scratches or bites) was associated with development of BA. Similarly, kittens or young cats, especially kittens with fleas, proved to be a risk factor associated with the development of CSD in immunocompetent hosts. In one report, all seven cats belonging to four HIV-infected patients who developed BA were found to be bacteremic with B. henselae, the species that had infected the patients. Some of the cats had very high levels of bacteremia, even greater than 1,000 colony-forming-units per milliliter of blood, yet they were all apparently healthy and asymptomatic.

A survey of pet and pound cats in the San Francisco Bay area revealed that 41% (25 of 61) were bacteremic with B. henselae, some for months and some indefinitely. Seroprevalence studies in other areas of the country and world indicate that B. henselae infection is widespread in cats. The U.S. has 57 million pet cats (a third of American households have them), so there is a large reservoir from which B. henselae can be acquired by humans.

It is assumed that the human is infected when scratched or bitten by a cat whose saliva or claws are contaminated with its own, B. henselae-containing blood. The increased risk flea-infested cats pose for humans may be accounted for by cats scratching their flea bites and drawing blood, contaminating their claws. B. henselae bacilli have been isolated from fleas combed from a bacteremic cat, implicating the cat flea as a potential arthropod vector. The flea may serve as a vector of B. henselae from cat to cat, increasing the size of the feline reservoir, or as a vector from cat to human. The tick is an additional possible arthropod vector; several cases of B. henselae bacteremia have developed in temporal proximity to tick exposure.

Recommendations for HIV-infected cat-owners include practical measures such as avoiding rough play, which can result in cat scratches or bites, and not allowing cats to lick any open wounds the patient may have. Scratches and bites should be washed immediately with soap and water. Control of flea infestation is important. Older cats are less likely to scratch or bite or to be bacteremic. If serologic testing becomes widely available, older cats without antibodies (who are almost never bacteremic) could be selected preferentially and kept indoors and flea-free to minimize their owners' exposure to B. henselae.

We do not recommend that HIV-infected patients give away their pets, but these patients should inform their caregivers that they have a pet cat and they should watch for scratches that don't heal and development of any vascular cutaneous lesions, new lymphadenopathy, or fevers.

The source of the B. quintana infection which causes BA remains unknown, but in World War I, the body louse transmitted B. quintana from human to human in the trenches. An outbreak of urban trench fever was reported in Seattle among HIV-negative, homeless alcoholics and, although lice were not directly implicated in this outbreak, the homeless population is at increased risk for lice infestation. Recommendations are currently limited to treating and reducing exposure to the body louse. Improvements in sensitivity, specificity, and availability of diagnostic tests and the identification of all vectors and reservoirs are important goals which, if reached, will facilitate treatment and prevention of bartonella infections in HIV-infected individuals.

— Jane E. Koehler, MD

Dr. Koehler is Assistant Professor of Medicine, Division of Infectious Diseases, University of California-San Francisco. She is also a Pew Scholar in the Biomedical Sciences and receives support from the University-wide AIDS Research Program and NIH grant AI36075.

Published in Journal Watch HIV/AIDS Clinical Care December 1, 1995

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