Bartonella infections in people with HIV

INTRODUCTION — 

Bartonella infections can cause serious morbidity and mortality in people with human immunodeficiency virus (HIV), particularly those with advanced immunosuppression. This topic will address Bartonella infections in people with HIV.

Detailed information regarding the microbiologic tests for Bartonella is found elsewhere. (See "Microbiologic diagnosis of Bartonella infections".)

Other aspects of Bartonella infection are discussed separately:

●(See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

●(See "Treatment of cat scratch disease".)

●(See "Endocarditis caused by Bartonella".)

●(See "Bartonella quintana infections: Clinical features, diagnosis, and treatment".)

●(See "South American bartonellosis: Oroya fever and verruga peruana".)

●(See "Biology of Bartonella species".)

MICROBIOLOGY — 

Although more than 35 distinct species of Bartonella are officially recognized, only two Bartonella species cause a significant number of infections in individuals with HIV: Bartonella henselae and Bartonella quintana [1-3].

Among individuals with HIV and Bartonella-associated infections, B. henselae and B. quintana appear to have differing organ tropisms [4]. B. henselae predominantly causes cutaneous, lymph node, liver, and splenic lesions, whereas B. quintana most often causes cutaneous, subcutaneous, and bone infections. Either organism appears to be equally capable of causing cutaneous lesions. In addition, both organisms can cause endocarditis.

Detailed information on the biology of Bartonella can be found elsewhere. (See "Biology of Bartonella species".)

EPIDEMIOLOGY

Transmission — Primary routes of transmission for Bartonella vary by the species:

●People with HIV who have B. henselae infection usually have a history of cat exposure [4]. The transmission of B. henselae to humans is usually via a scratch from a cat whose claws are contaminated with feces from Bartonella-infected fleas. More details regarding the transmission of B. henselae are found elsewhere. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease" and "Biology of Bartonella species".)

●B. quintana infections predominantly occur in people who are unhoused and acquire the infection from infected body lice [4]. Details regarding the transmission of B. quintana are found elsewhere. (See "Bartonella quintana infections: Clinical features, diagnosis, and treatment" and "Biology of Bartonella species".)

Seroprevalence — Although clinically symptomatic bartonellosis is relatively uncommon, seroepidemiologic studies have reported a high seroprevalence of antibodies against Bartonella among individuals with HIV [5-8]. In general, with Bartonella serologic testing, cross reactivity between B. henselae and B. quintana is high, and these tests do not accurately differentiate between infection with B. henselae versus B. quintana. Although serologic testing may sometimes show positive test results for both B. henselae and B. quintana, in most cases, persons have been infected with only one of these organisms.

●A serologic study conducted during 1997 in Spain demonstrated elevated B. henselae titers (immunoglobulin [Ig] G ≥1:64) in a higher proportion of people with HIV than HIV-negative blood donors (9 of 52 [17 percent] versus 5 of 85 [5 percent], respectively) [5].

●A Bartonella seroprevalence study conducted in Catalonia, Spain (near Barcelona) from 2004 to 2005 surveyed 340 persons with HIV who were treated at a single hospital [7]. Antibody testing for B. henselae and B. quintana (using indirect immunofluorescence assay [IFA]) was performed, and 76 (22 percent) of the 340 patients had a reactive IgG antibody test (≥1:64) [7]. Among the positive samples, 57 percent showed reactivity to both B. henselae and B. quintana, 42 percent were reactive only to B. henselae, and 1 percent were reactive only to B. quintana [7].

●In a seroprevalence study in Warsaw, Poland, which was performed in 2016, investigators collected samples from blood donors and from 227 persons with HIV [8]. Analysis included IgM and IgG IFA testing for B. henselae antibodies [8]. Fourteen (6 percent) of 227 samples from people with HIV were positive, including 10 that were IgM positive and four that were IgG positive [8].

●A seroprevalence study performed in Greece during 2004 and 2005 found that among 253 persons with HIV who were tested for Bartonella antibodies, 41 percent had positive IgG antibodies (≥1:64) to B. henselae, and 15 percent had positive antibodies to both B. henselae and B. quintana [6].

●A serologic study conducted during 1990 through 1997 in San Diego, California performed B. henselae IFA IgG testing on 177 people with HIV who were enrolled in a longitudinal study of neurocognitive function; it found that 11 percent had a positive serology (≥1:128) for B. henselae [9].

Prevalence of disease — The prevalence of clinically evident Bartonella infections in people with HIV is relatively low. As an example, in one study from Germany, the prevalence of HIV-associated bacillary angiomatosis (BA) was 1.2 cases per 1000 patients [10].

GENERAL CLINICAL ISSUES

Clinical characteristics — In people with HIV, clinically evident Bartonella infections occur primarily among those with advanced HIV (eg, CD4 count <100 cells/microL). In one study of 42 patients with HIV with active B. henselae infection, the median CD4 count was 21 cells/microL [11].

The most common form of bartonellosis in people with HIV is bacillary angiomatosis (BA), which typically presents as cutaneous violaceous lesions. Bartonella infections can also involve internal organs in people with HIV and can produce a broad array of additional manifestations including bacillary peliosis hepatis (infection of the liver), splenitis, osteomyelitis, and bacteremia. Details regarding specific bartonellosis syndromes in people with HIV are found below. (See 'Specific syndromes' below.)

Clinical onset can be gradual with nonspecific symptoms, so the diagnosis is often delayed until several months into the course of illness [12]. With all forms of bartonellosis, patients may or may not have constitutional symptoms such as fever, chills, night sweats, malaise, headache, anorexia, and weight loss.

Diagnostic challenges — Bartonellosis in individuals with HIV is often not suspected during the initial presentation. Reasons for missed diagnoses include the substantial variability in presentation between Bartonella syndromes, the nonspecific findings for each syndrome, and the rarity of HIV-related bartonellosis in general (especially in the era of antiretroviral therapy [ART]).

Definitive diagnosis of bartonellosis in people with HIV requires detection of the organism by polymerase chain reaction (PCR) or culture or visualization of the organism on tissue biopsy. Diagnostic approaches for each specific syndrome in people with HIV are discussed elsewhere. (See 'Specific syndromes' below.)

Serologic testing can be helpful but cannot definitively diagnose or exclude bartonellosis in the absence of other more definitive tests. Furthermore, the coexistence of HIV can complicate the interpretation of Bartonella serologic results:

●A positive serologic result does not always imply active infection, especially in people with HIV who, as described above, have relatively high rates of seropositivity at baseline (see 'Seroprevalence' above). Furthermore, data on the serologic response to Bartonella infection in people with HIV are scarce and mostly are derived from studies involving individuals with cat scratch disease [13,14].

●A negative serologic test does not necessarily rule out the diagnosis, especially in people with HIV with who have a CD4 count less than 200 cells/microL because they may not be able to generate antibody responses at detectable levels (or increased titers over baseline) [15]. One observational study found that nearly 25 percent of people with advanced HIV who had culture-confirmed Bartonella infection never developed a positive Bartonella antibody titer [16].

Details on the use and interpretation of PCR, culture, histopathology, and serologic tests for Bartonella are found elsewhere. (See "Microbiologic diagnosis of Bartonella infections".)

Rationale for treatment recommendations — All people with HIV who are diagnosed with Bartonella infection should receive antibiotic therapy [12,17,18]. No randomized trials have evaluated the optimal treatment regimen for bartonellosis in people with HIV. Data to inform antibiotic selection and duration are limited primarily to case series and small observational studies, and our approach is based on these as well as clinical experience. It is also largely consistent with other expert guidelines [12,17].

●Doxycycline and macrolides as primary treatment options – Reviews of published case series and case reports have described successful use of erythromycin or doxycycline, primarily in populations without HIV [17-19]. Other macrolide antibiotics (eg, azithromycin or clarithromycin) have been used successfully as an alternative to erythromycin and may be better tolerated, but there is less published clinical experience with those options [20].

Trimethoprim-sulfamethoxazole, fluoroquinolones, penicillins, and first-generation cephalosporins have less reliable activity against Bartonella and thus are not recommended [21].

●Duration of therapy – Generally, treatment is continued for three months, with the option to extend therapy if complete clinical resolution has not occurred. The optimal duration of treatment for people with HIV has not been established, but relatively long durations are suggested due to the intracellular nature of the organism and the advanced level of immunosuppression among most individuals with HIV who are diagnosed with Bartonella infection.

Detailed treatment recommendations for specific Bartonella syndromes are described below. (See 'Specific syndromes' below.)

When to initiate antiretroviral therapy — In general, ART should be administered to people with HIV who are not receiving ART at the time of Bartonella diagnosis. When selecting a regimen, it is important to assess for drug interactions, particularly if rifampin is used. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

However, the exact timing for when to initiate ART depends on the clinical presentation of Bartonella infection. In persons with HIV who have central nervous system (CNS) or ophthalmic bartonellosis, we agree with guidelines that suggest deferring ART two to four weeks after starting antimicrobial treatment for Bartonella [12]. For patients with other manifestations of Bartonella (eg, skin lesions, endocarditis), we administer ART as soon as possible since restoration of the immune system may augment the response to antimicrobial therapy. (See "Overview of immune reconstitution inflammatory syndromes".)

The rationale for this approach is based upon concern that an immune reconstitution inflammatory syndrome (IRIS) may lead to serious complications related to certain Bartonella infections. Although there are only rare reports describing IRIS with Bartonella infection in persons with HIV [19,22], poor clinical outcomes related to IRIS have been demonstrated in patients with other opportunistic infections that affect the CNS and the eye such as cryptococcosis, cytomegalovirus, and toxoplasmosis. (See "Overview of immune reconstitution inflammatory syndromes" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'When to initiate antiretroviral therapy (ART)' and "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes' and "Toxoplasmosis in patients with HIV", section on 'Toxoplasmosis and immune reconstitution syndrome (IRIS)'.)

SPECIFIC SYNDROMES — 

Bartonellosis in people with HIV manifests as several distinct syndromes that sometimes overlap.

Bacillary angiomatosis — Bacillary angiomatosis (BA) is characterized by unique vascular lesions that most frequently involve the skin but can affect other organs such as bone, lymph nodes, respiratory tract, and gastrointestinal tract.

Clinical manifestations — Like other bartonellosis syndromes in persons with HIV, BA typically occurs in people with a CD4 count less than 100 cells/microL, and systemic symptoms may or may not occur. (See 'Clinical characteristics' above.)

In addition, BA has unique clinical features that vary depending on the affected organ(s), as detailed in the sections that follow.

Dermatologic manifestations — Dermatologic lesions are the most common manifestation of BA.

●Cutaneous lesions – Cutaneous BA may appear as angiomatous vascular lesions that are difficult to diagnose because of variations in appearance [18,23]. The lesions most frequently consist of papular, nodular, pedunculated, or verrucous forms. They typically first develop as small, smooth red-to-purple papules that may subsequently erode, with or without crusting. They can gradually expand into large pedunculated lesions or nodules that can be friable. Lesions may bleed profusely with trauma (picture 1A-C).

Infrequently, cutaneous BA lesions have no superficial evidence of vascularity and instead appear as hyperpigmented hyperkeratotic plaques with scaling. Cellulitic plaques sometimes overlie an osteomyelitic bone infection [1,18,24]. (See 'Osteomyelitis' below.)

Most often, cutaneous lesions in BA are solitary or several in number but rarely may appear in a disseminated version manifested by more than 100 small lesions [24].

●Subcutaneous lesions – Subcutaneous lesions may develop as deeper tender nodules that have erythematous or normal-appearing overlying skin [18]. These lesions can erode through the cutaneous surface and become superinfected. Less frequently, the lesions develop as an enlarging, deep suppurative ulcer (picture 2) [25].

●Mucosal lesions – Oral lesions can occur with or without cutaneous manifestations. Several reports have described lesions on the gingival region, buccal mucosa, oral labial mucosa, hard palate, and posterior pharynx [26]. The mucosal lesions appear as smooth purple papules or plaques that may resemble pyogenic granuloma or Kaposi sarcoma. Rarely, patients may develop a nodular mass of the conjunctiva [27].

Lymphadenopathy — BA can involve single or multiple lymph nodes in people with HIV [18]. Involved lymph nodes may be those that drain either a cutaneous BA lesion or the liver and spleen in cases of liver or spleen involvement. Suppuration and drainage of involved lymph nodes does not typically occur.

Osteomyelitis — Bone infection in patients with BA is not uncommon. Although osteomyelitis most often presents in individuals with cutaneous disease, rarely it can develop prior to any other manifestations of BA [28]. Typically, it presents as painful bone lesions, most often involving long bones such as the tibia, fibula, and radius. An overlying erythematous cutaneous plaque is often present. Bone radiographs show lytic lesions, and technetium scans show increased uptake at these same sites. Bone lesions can range from focal, well-circumscribed lytic areas to ill-defined areas that show aggressive cortical destruction with notable periosteal reaction.

Other syndromes — BA lesions have also been described in the gastrointestinal and respiratory tracts. In gastrointestinal disease, endoscopy reveals raised ulcerated nodules in the stomach and intestines. Respiratory disease manifests as BA lesions in the larynx, trachea, or bronchi [18].

Diagnostic approach — BA should be considered in people with advanced HIV (ie, CD4 <100 cells/microL) who present with angiomatous vascular cutaneous lesions. When dermatologic findings are not present, suspicion for BA may be blunted due to the lack of visible findings, but BA should be considered in persons with HIV and a CD4 count less than 100 cells/microL who have lymphadenopathy, osteomyelitis, or other consistent syndromes without a clear etiology. (See 'Diagnostic challenges' above.)

Definitive diagnosis of BA requires a tissue biopsy of an affected organ, usually the skin. Biopsy samples should be sent for histopathology, polymerase chain reaction (PCR) testing, culture, and, if available, Warthin-Starry silver staining. In addition to tissue biopsy, if clinical suspicion is high, we typically send blood samples for culture and PCR. Although sensitivity is lower for blood tests than for tissue samples, a positive blood PCR or culture can help to confirm the diagnosis. We also send Bartonella serologic testing, which can help support or diminish a diagnosis of BA but should not be used to make a definitive diagnosis. More details regarding collection and interpretation of these microbiologic tests for Bartonella are found elsewhere. (See 'Diagnostic challenges' above and "Microbiologic diagnosis of Bartonella infections".)

In BA, characteristic histologic findings with detection of the organism in biopsied tissue can confirm the diagnosis. Standard hematoxylin and eosin (H&E) staining characteristically shows lobular vascular proliferations composed of rounded vessels lined by variably protuberant plump endothelial cells (picture 3) [29,30]. In addition, clusters of neutrophils, neutrophilic debris, and lymphocytes are scattered throughout the lesions, especially around eosinophilic granular aggregates. Warthin-Starry staining may reveal large numbers of small dark-staining bacilli consistent with Bartonella. Further detail regarding histopathology and Warthin-Starry staining for Bartonella syndromes is found elsewhere. (See "Microbiologic diagnosis of Bartonella infections", section on 'Histopathology'.)

Differential diagnosis — BA lesions have variable appearances, and tissue biopsy not only helps to confirm the diagnosis but also rules out alternative diagnoses that have a similar appearance.

Cutaneous BA lesions may resemble Kaposi sarcoma, pyogenic granuloma, cherry angioma, dermatofibroma, or hemangioma. The nodular and plaque forms of BA may resemble lesions caused by atypical mycobacteria, tuberculosis, coccidioidomycosis, cryptococcosis, histoplasmosis, or sporotrichosis. Verruga peruana, the cutaneous lesion associated with South American bartonellosis, can resemble cutaneous BA. (See "South American bartonellosis: Oroya fever and verruga peruana".)

Concomitant disease has been reported in at least one patient who had both cutaneous BA and Kaposi sarcoma that were only differentiated by biopsies of multiple dermatologic lesions [18].

Treatment — Treatment of BA depends on the presence of bacteremia and severity of illness.

●BA without bacteremia

•Clinically stable patients – Based on numerous case reports, we suggest treatment with oral doxycycline (100 mg orally twice daily) for individuals with BA who are clinically stable [18]. Oral erythromycin (500 mg orally four times daily) is also considered a first-line agent, but we prefer doxycycline due to fewer side effects and drug interactions and a more favorable dosing schedule. For patients who are unable to take doxycycline or erythromycin, azithromycin (500 mg orally once daily) can be used as an alternative. Clarithromycin (500 mg twice daily) is also considered an alternative agent, but we prefer azithromycin if an alternative medication is needed because when compared with clarithromycin, it has fewer side effects, fewer drug interactions, better tolerance, and intravenous and oral formulations are available.

•Critical infection – For patients with severe infection (eg, multifocal disease or clinical decompensation [hypotension or requiring care in the intensive care unit]), we agree with guidelines that suggest using parenteral doxycycline (100 mg intravenously [IV] every 12 hours) plus rifampin (300 mg orally or IV every 12 hours) [12]. For patients who are unable to receive doxycycline, we suggest rifampin plus either erythromycin (500 mg IV every six hours) or azithromycin (500 mg IV once daily). The patient can transition from intravenous to oral therapy after becoming clinically stable.

Regardless of the severity of illness, the duration of therapy in persons with HIV is a minimum of three months, with the option to extend to longer courses if complete clinical resolution has not occurred or there is an indication for long-term suppressive therapy, such as a relapse of Bartonella infection after at least three months of treatment, and the CD4 cell count is less than 200 cells/microL.

●BA with bacteremia – For patients with bacteremia, we suggest a more aggressive treatment regimen. Details are discussed below. (See 'Bacteremia' below.)

Additional rationale for treatment choices in HIV-associated Bartonella is discussed elsewhere. (See 'Rationale for treatment recommendations' above.)

Bacillary peliosis hepatis and splenitis — Peliosis hepatis is a spectrum of liver illnesses with similar pathology that can have infectious or noninfectious etiologies. When peliosis hepatis is caused by Bartonella infection, it is termed "bacillary peliosis hepatis." More information regarding peliosis hepatis syndromes can be found elsewhere. (See "Peliosis hepatis".)

Clinical manifestations — The clinical presentation of bacillary peliosis hepatis is variable [31]. Splenitis sometimes occurs with bacillary peliosis hepatis, but splenitis in the absence of bacillary peliosis hepatis is rare [18].

In general, reports suggest that patients often present with abdominal pain with or without systemic symptoms (eg, fever). Physical examination may reveal cutaneous BA lesions, although this is not universal (see 'Dermatologic manifestations' above). Hepatomegaly and splenomegaly may be detected on examination. Although rare, patients may present with hypovolemic shock due to hepatic hemorrhage and hemoperitoneum [32].

Typical laboratory abnormalities include an elevated alkaline phosphatase with or without mild aminotransferase elevation. Some patients have pancytopenia or thrombocytopenia.

Abdominal computed tomography (CT) typically shows hepatosplenomegaly with hypodense lesions scattered throughout the parenchyma of the liver and spleen [33]. However, other conditions can produce similar CT findings such as lymphoma, disseminated Mycobacterium avium complex, and extrapulmonary Pneumocystis pneumonia. Ultrasound typically shows abnormal lesions that may be hypoechoic, hyperechoic, or heterogenous depending on the stage of illness.

Diagnostic approach — In general, bacillary peliosis hepatis and/or splenitis should be considered in people with advanced HIV (eg, CD4 less than 100 cells/microL) and compatible features including abdominal pain, hepatomegaly, elevated alkaline phosphatase, and characteristic findings (ie, hypodense lesions) on abdominal CT or liver lesions on ultrasound.

To make a definitive diagnosis of bacillary peliosis hepatis and/or splenitis, specific microbiologic testing is necessary. We suggest sending a combination of microbiologic tests including blood samples for PCR testing, culture, and serology. More details regarding these tests and their interpretation are found elsewhere. (See 'Diagnostic challenges' above and "Microbiologic diagnosis of Bartonella infections".)

Tissue biopsy is the most definitive method of diagnosis, but liver or spleen biopsy carries an attendant risk of hemorrhage in individuals with peliosis hepatis and splenitis. Thus, a definitive diagnosis of peliosis hepatis or splenitis is often not obtained, and presumptive therapy is initiated based on available supportive data such as serologic tests and radiographic findings. Biopsy should only be considered when the diagnosis remains unclear and the patient is clinically worsening on presumptive therapy. In lieu of liver or spleen biopsy, skin biopsy may provide a definitive diagnosis in individuals with cutaneous lesions consistent with BA.

If liver biopsy is performed, histopathologic findings typically consist of cystic blood-filled spaces and fibromyxoid stroma that contains a mixture of inflammatory cells, dilated capillaries, and granular purple material. Warthin-Starry staining of these lesions demonstrates findings similar to BA.

More detailed information on the diagnostic approach and testing for Bartonella and for peliosis hepatis is described elsewhere. (See "Microbiologic diagnosis of Bartonella infections" and "Peliosis hepatis", section on 'Diagnosis'.)

Treatment — If bacillary peliosis hepatis or splenitis is suspected, we suggest parenteral therapy for initial treatment because these infections can have a rapidly progressive course with devastating hemorrhagic complications. Treatment suggestions for this syndrome are based on case reports, clinical experience, and expert opinion [31,34,35]. (See 'Rationale for treatment recommendations' above.)

For stable individuals with bacillary peliosis hepatis and/or splenitis, we prefer to start with parenteral doxycycline (100 mg IV twice daily) or erythromycin (500 mg IV four times daily). For patients who are unable to take doxycycline or erythromycin, azithromycin (500 mg IV once daily) is an acceptable alternative. If patients have life-threatening bacillary peliosis hepatis or splenitis (eg, hypotension or requiring care in the intensive care unit), we add rifampin (300 mg IV every 12 hours) to the regimen as a second agent.

After clinical improvement, patients can transition to the oral formulation of their parenteral regimen. The total duration of therapy is typically three months, with the option to extend therapy if complete clinical resolution has not occurred or there is an indication for long-term suppressive therapy, such as a relapse of Bartonella infection after at least three months of treatment, and the CD4 cell count is less than 200 cells/microL.

For bacteremic patients, treatment recommendations are discussed below. (See 'Bacteremia' below.)

Central nervous system infection — Central nervous system (CNS) infection is relatively uncommon in patients with HIV.

Clinical manifestations — Case reports have described various CNS syndromes in people with HIV.

One report described a patient with a 2 cm brain mass that preceded the development of a cutaneous BA lesion [36]. Brain biopsy studies, including Warthin-Starry staining and electron microscopy, showed evidence of typical-appearing Bartonella bacilli. The patient had gradual, but dramatic, clinical and radiographic improvement during a prolonged course of erythromycin.

Another report involved a patient with trigeminal neuralgia, low back pain, and spine MRI findings suggestive of vascular defects in L3 and L4 [37]. The patient's lesions resolved with antibiotic therapy.

Other reports have described aseptic meningitis due to B. henselae in patients with HIV [38,39].

Early reports suggested dementia and psychiatric symptoms possibly related to Bartonella infection, but a large study using the San Diego HIV Neurobehavioral Research Study database failed to show any correlation between B. henselae serostatus and neurocognitive decline in people with HIV [9,38,40].

Treatment — Management of CNS infections depends on the presence or absence of bacteremia. Treatment recommendations are based on case reports, guidelines, and experience with other bartonellosis syndromes. (See 'Rationale for treatment recommendations' above.)

●CNS infection without bacteremia – Patients with HIV and CNS disease should receive doxycycline (100 mg orally or IV twice daily) for at least three months. Intravenous doxycycline therapy is preferable for initial therapy in hospitalized patients and should be switched to oral therapy once an appropriate clinical response occurs.

For severe CNS disease, we add rifampin (300 mg orally or IV twice daily) as a second agent [12]. Several case reports in persons without HIV have described combination therapy with rifampin to treat patients with neurologic involvement, including retinitis [41-43]. However, we typically do not add rifampin for nonsevere CNS disease because data to support rifampin in people with HIV are lacking, and rifampin may cause problematic drug interactions that limit the choice of antiretroviral regimens.

The macrolides are likely inferior to doxycycline for the treatment of CNS disease due to lower cerebrospinal fluid penetration. However, they could be considered as an alternative for individuals unable to take doxycycline [17,44,45].

●CNS infection with bacteremia – For all patients with bacteremia and CNS infection, we suggest doxycycline (100 mg IV twice daily) plus rifampin (300 mg orally or IV twice daily) for at least three months.

Unexplained fever — Bartonella should be considered in the differential diagnosis of unexplained fever in individuals with CD4 counts below 100 cells/microL [12].

●In a study of 382 patients from San Francisco with unexplained fever (95 percent of whom were infected with HIV), 12 (3 percent) had confirmed Bartonella infection by culture or PCR of blood or tissue [16]. An additional 56 (15 percent) had only positive serology, 21 of whom had serologic titers ≥1:512. Most of the patients with evidence of Bartonella infection had advanced HIV disease and a CD4 count less than 100 cells/microL. It is not clear that Bartonella, when isolated, was the cause of unexplained fever in these patients since no information on therapy and follow-up was provided.

●In another report, extended-incubation blood cultures identified two cases of Bartonella infection among 45 AIDS patients who had unexplained fever [46].

When bartonellosis is suspected for unexplained fever in people with HIV, microbiologic testing should include blood samples for serology, PCR testing, and culture. Details regarding these tests and their interpretation are found elsewhere. (See 'Diagnostic challenges' above and "Microbiologic diagnosis of Bartonella infections".)

Abnormalities on physical examination or laboratory work should prompt further evaluation for one of the organ-specific bartonellosis syndromes. Details regarding specific syndromes are found elsewhere. (See 'Specific syndromes' above.)

For treatment of unexplained fever due to bartonellosis with no evidence of organ-specific disease, we suggest management similar to treatment for BA, preferably with oral doxycycline 100 mg twice daily for at least three months.

Bacteremia — Bacteremia is sometimes detected in individuals with BA, bacillary peliosis hepatis, or splenitis. It can also be discovered during workup for unexplained fever or other systemic symptoms.

The diagnosis of bacteremia is established by positive blood culture or blood PCR results. However, bacteremia is probably significantly underdiagnosed because isolation of the Bartonella organisms in culture remains difficult, and PCR testing of blood is not routinely ordered and has suboptimal sensitivity. More information on diagnostic testing for Bartonella is found elsewhere. (See "Microbiologic diagnosis of Bartonella infections".)

●Whenever Bartonella bacteremia is detected, careful physical examination and basic laboratory work, including liver function tests, should be performed, which may prompt further evaluation of one of the organ-specific bartonellosis syndromes. (See 'Specific syndromes' above.)

●All individuals with bacteremia should have workup for endocarditis, including echocardiogram. Detailed information can be found elsewhere. (See "Endocarditis caused by Bartonella".)

For patients with bacteremia (without endocarditis), we suggest treatment with doxycycline (100 mg orally or IV twice daily) for at least three months. We typically add rifampin (300 mg orally or IV twice daily for the first 14 days of treatment), although some experts would not add a second agent [47]. Intravenous gentamicin (3 mg/kg/day given once daily for the first 14 days) is an alternative to rifampin, but gentamicin should not be used in persons with baseline renal insufficiency and should be discontinued if renal insufficiency develops. If gentamicin is used, the dose should be adjusted, if needed, to maintain trough serum concentrations of <1 mcg/mL. (See "Dosing and administration of parenteral aminoglycosides".)

There are no data regarding treatment regimens for Bartonella bacteremia in individuals with HIV. Case series and trials in patients without HIV suggest that combination therapy that includes a 14-day course of gentamicin is effective for the treatment of bacteremia or endocarditis [47,48]. The potential benefit of using rifampin or gentamicin as a second drug in the treatment of bacteremia (without endocarditis) should be weighed against the potential nephrotoxicity with gentamicin and the potential problematic drug interactions between rifampin and other medications, particularly HIV antiretroviral medications. (See 'Rationale for treatment recommendations' above.)

Endocarditis — Bartonella is a known cause of culture-negative endocarditis, and Bartonella-associated endocarditis has been reported among individuals with HIV [49].

The treatment of Bartonella endocarditis in people with HIV is the same as for patients without HIV. (See "Endocarditis caused by Bartonella", section on 'Antimicrobial therapy'.)

A detailed discussion of Bartonella endocarditis is found elsewhere. (See "Endocarditis caused by Bartonella".)

PREGNANT INDIVIDUALS — 

Based on a limited number of individual case reports, the clinical features of bacillary angiomatosis (BA) in pregnant individuals appear to be similar to those in nonpregnant individuals [50,51]. Data regarding bartonellosis syndromes other than BA in pregnant people with HIV are scarce. However, cases of maternal death have been reported in pregnant individuals without HIV who develop idiopathic peliosis hepatitis not due to Bartonella [52-54].

For treatment of bartonellosis in pregnant individuals, we agree with guidelines that recommend erythromycin or an alternative macrolide [12]. For syndromes for which combination therapy is indicated, we suggest a macrolide plus either rifampin or gentamicin depending on the syndrome. The duration of therapy in pregnancy is identical to the duration recommended based on each syndrome. (See 'Specific syndromes' above.)

In general, doxycycline is not recommended for pregnant individuals due to increased risk of hepatotoxicity and the accumulation of tetracycline in fetal teeth and bones, which can cause permanent staining of fetal teeth. In certain circumstances, however, such as with a very serious Bartonella infection, use of doxycycline may outweigh the risk. Third-generation cephalosporins, such as ceftriaxone, may be effective, but data are limited. First- and second-generation cephalosporins are not recommended due to lack of efficacy against Bartonella [12].

FOLLOW-UP AFTER TREATMENT

Monitoring response to therapy — Patients should be monitored closely during therapy for resolution of signs and symptoms including fever and cutaneous or other bacillary angiomatosis (BA) lesions.

For patients with bacillary peliosis hepatis, laboratory abnormalities (eg, alkaline phosphatase, thrombocytopenia) should improve during therapy. We recommend repeating abdominal imaging after four to six weeks of treatment.

We typically do not monitor IgG levels to follow treatment response because changes in levels (or lack thereof) may be difficult to interpret, and there is a lack of data to support this approach. However, some experts recommend following IgG levels based on a case report of a patient with aortitis whose IgG levels decreased on therapy, but it was unclear whether treatment led to the falling titer versus immune reconstitution from the initiation of antiretroviral therapy (ART) during treatment [12,55].

Refractory infection — There are no studies that have addressed the optimal approach for patients who fail to respond to therapy. In such patients, we add rifampin if it was not used in the original treatment regimen. For patients with peliosis hepatis, we also consider adding gentamicin for 14 days. In addition to revising antimicrobial therapy, ART should be optimized to promote immune reconstitution.

Recurrent infection — For patients who have a relapse of disease after receiving at least three months of therapy, we agree with guideline recommendations for an additional full course of treatment followed by long-term suppression with doxycycline or a macrolide at the same doses used for treatment [12]. ART should be optimized to promote immune reconstitution. Long-term suppressive therapy can be discontinued after at least three months of therapy once the CD4 count has been >200 cells/microL for at least six months.

COMPLICATIONS

Hemophagocytic lymphohistiocytosis — B. henselae has been associated with hemophagocytic lymphohistiocytosis (HLH). There are case reports of Bartonella-related HLH in people with HIV [56,57]. In one report, a 31-year-old man with HIV who was a renal transplant recipient developed Bartonella-related HLH and had an excellent outcome with a combination of doxycycline, increased corticosteroid dosing, and reduced mycophenolate dosing [57]. In another case report, a 69-year-old man with HIV and B. henselae-associated HLH was successfully treated with azithromycin, doxycycline, and corticosteroids [56]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Immune reconstitution inflammatory syndrome — On rare occasion, people with HIV and Bartonella infection can develop significant worsening of Bartonella infection after initiating antiretroviral therapy (ART) [19,22]. This immune reconstitution inflammatory syndrome (IRIS) occurs as a consequence of rapid up-regulation in the immune system and, if severe, may require corticosteroid therapy. (See "Overview of immune reconstitution inflammatory syndromes".)

The timing of when to initiate ART in people with HIV and bartonellosis is described above. (See 'When to initiate antiretroviral therapy' above.)

PREVENTION — 

Prevention of bartonellosis in people with HIV primarily focuses on behavioral modifications; the role for antimicrobial prophylaxis is limited.

●Behavioral modifications – We counsel patients, especially those with a CD4 count <200 cells/microL, on how to decrease the risk of developing Bartonella. Since the development of B. henselae infection is related to cat exposure, we advise the following for our patients:

•Avoid cat scratches

•Control flea infestations

•Avoid acquisition of an unhealthy cat or a cat that is younger than one year old

People who are homeless or intermittently housed should receive the following to reduce the risk of B. quintana exposure:

•Education regarding prevention of lice infestation

•Treatment of lice infestation to minimize their risk of developing systemic B. quintana infection

●No role for primary prophylaxis – We agree with guidelines that primary prophylactic antimicrobials are not recommended to prevent Bartonella infection in people with HIV [12]. A single retrospective, case-control study reported a protective effect against Bartonella infection in patients receiving a macrolide or a rifamycin for prophylaxis against disseminated M. avium complex [4]. Despite this finding, prophylactic therapy specific for Bartonella infection is not recommended given the low incidence of Bartonella infection in people with HIV and the lack of prospective data [12].

●Limited role for secondary prophylaxis – Secondary prophylaxis is only recommended in people with HIV who have experienced a recurrence of bartonellosis. Detailed recommendations are found above. (See 'Recurrent infection' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in individuals with HIV".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Among people with HIV, symptomatic Bartonella infections occur primarily in those whose CD4 count is <100 cells/microL. (See 'Clinical characteristics' above.)

Bartonella henselae and Bartonella quintana are the two primary causes. Patients with B. henselae infection usually have a link to cats, whereas B. quintana predominantly infects people who are homeless and have head or body lice exposure. (See 'Microbiology' above and 'Transmission' above.)

●Diagnosis – Definitive diagnosis in people with HIV requires detection of the organism by polymerase chain reaction (PCR) or culture or visualization of the organism on tissue biopsy. Serologic testing can be helpful but cannot definitively diagnose or exclude bartonellosis. The specific clinical syndrome determines the most appropriate tests to order. (See 'Diagnostic challenges' above and 'Specific syndromes' above and "Microbiologic diagnosis of Bartonella infections".)

●Clinical syndromes – Bartonellosis in people with HIV manifests as several distinct syndromes that sometimes overlap. Constitutional symptoms may occur including fever, chills, malaise, headache, anorexia, and weight loss. (See 'Clinical characteristics' above.)

•Bacillary angiomatosis (BA) – This syndrome is characterized by unique vascular lesions that most frequently involve the skin but can affect other organs. (See 'Bacillary angiomatosis' above.)

-Clinical manifestations – Cutaneous lesions usually appear as angiomatous vascular lesions that are papular, nodular, pedunculated, or verrucous. They may resemble Kaposi sarcoma, pyogenic granuloma, cherry angioma, dermatofibroma, hemangioma, or other cutaneous lesions. If other organs are involved, manifestations may include lymphadenopathy, bone pain from osteomyelitis, or respiratory or gastrointestinal symptoms. (See 'Clinical manifestations' above.)

-Diagnosis – Definitive diagnosis of BA requires a tissue biopsy of an affected organ, usually the skin. (See 'Diagnostic approach' above.)

-Treatment – For clinically stable patients without bacteremia, we suggest doxycycline (100 mg orally twice daily) rather than a macrolide (Grade 2C). For critically ill patients, we suggest doxycycline (100 mg intravenously [IV] every 12 hours) plus rifampin (300 mg IV every 12 hours) rather than monotherapy with doxycycline (Grade 2C). The typical duration of therapy is three months, with the option to extend therapy if complete clinical resolution has not occurred or if there is an indication for long-term suppressive therapy. (See 'Treatment' above.)

•Bacillary peliosis hepatis and splenitis – This syndrome is characterized by vascular lesions in the liver and/or spleen. Patients often present with fever, weight loss, hepatosplenomegaly, elevated alkaline phosphatase, and hypodense lesions on abdominal CT. (See 'Clinical manifestations' above.)

Diagnosis is usually made based on clinical features and imaging, coupled with blood samples for PCR testing, culture, and serology. Tissue biopsy is usually not performed due to risk of hemorrhage. (See 'Diagnostic approach' above.)

For treatment, we suggest parenteral doxycycline (100 mg IV twice daily) or erythromycin (500 mg IV four times daily) as opposed to oral therapy (Grade 2C). Transition to oral therapy is appropriate once clinical improvement has occurred. For severely ill patients, we add rifampin (300 mg IV every 12 hours) as a second agent. The duration of therapy is typically three months. (See 'Treatment' above.)

•Other syndromes – Other clinical syndromes and suggested treatment regimens in people with HIV are discussed in the text (eg, central nervous system [CNS] infection, bacteremia, endocarditis).

●Prevention – People with HIV and a CD4 count <200 cells/microL should avoid cat scratches, unhealthy cats, and cats younger than one year old. Lice infestations should be prevented and rapidly treated, especially in individuals who are homeless. There is generally no role for primary prophylaxis with antibiotics. (See 'Prevention' above.)

ACKNOWLEDGMENT — 

UpToDate gratefully acknowledges John G Bartlett, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.