Are You Confident of the Diagnosis?

The diagnosis of bacillary angiomatosis (BA) can be made by finding the characteristic skin lesions confirmed by histopathologic examination (Figure 1). Biopsy shows angioproliferation and microorganisms stained with Warthin-Starry silver stain (Figure 2). Patients are usually immunocompromised. Although BA is a systemic disease, the cutaneous lesions lead to recognition of this entity.

Figure 1.

Bacillary angiomatosis. Angioproliferation and neutrophilic infiltrate (H&E).

Figure 2.

Bacillary angiomatosis. Positive staining with Wartin Starry stain.

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What you should be alert for in the history

BA occurs most commonly in patients with immunosuppression caused by HIV. CD4 count in affected patients is usually below 200cells/ul.

A German study of more than 17,500 HIV-infected patients performed between 1990 and 1998 showed the prevalence of 1.2 BA cases in 1000 HIV-infected patients. An American study estimated 1 case of BA for every 25 to 50 patients with HIV-associated Kaposi’s sarcoma.

With the introduction of HAART, the prevalence of BA decreased.

BA is caused by infection with Bartonella henselae (Bh) or Bartonella quintana (Bq). It has been reported that several HIV-infected patients have serologic evidence of exposure to Bh several years before developing clinical manifestations of BA. When serum samples from 340 patients with HIV were collected, antibodies to Bh and Bq were found in 76 (22.3%). Of several factors concerning the seroprevalence rate being studied (age, sex, intravenous drug use, CD4 count) only age was statistically significant.

BA has also been reported in patients with other causes of immunosuppression; in patients with leukemias and other neoplastic processes, and in recipients of solid organ transplants receiving immunosuppressive therapy. BA has also been reported in a few patients with intact immune systems.

BA seems to appear more often in men and the possibility that an unknown factor could be exerting a protective effect in women has been considered. BA in children is very rare but has been reported both in immunosuppressed and immunocompetent individuals.

The true incidence of Bartonella infections is difficult to establish because it is mostly not a reportable disease.

A cat scratch or bite is strongly associated with BA, as in cat scratch disease. Cats are the major reservoir for Bh, and up to 50% of cats in the United States have been found to have antibodies to Bh. Culture-positive cats are rarely sick and cannot be distinguished from those without Bh. Bh infection between cats depends on the cat flea (Ctenocephalides felix).

It was recently reported that 10% of healthy dogs and 27% of sick dogs in the southeastern United States were found to have antibodies to Bh, but whether it is of clinical significance is unclear. Contact with cats (traumatic or not) has been verified for 11 of the 21 patients with BA and HIV infection in a German study.

BA was demonstrated to remain viable in red blood cells stored for 35 days at 4 degrees C (red blood cells were inoculated with Bh in vitro). This raises the possibility of transmitting infection with Bh by transfusion of blood units collected from asymptomatic blood donors.

Characteristic findings on physical examination

Three types of skin lesions have been delineated in BA:

pyogenic granuloma-like lesions

subcutaneous nodules

hyperpigmented indurated plaques

The pyogenic granuloma-like lesions may vary in size from 1mm to several centimeters. They are red, often pedunculated nodules, firm but frail, often mildly tender and occasionally bleeding.

The subcutaneous nodules are located deeper and may be up to several centimeters in diameter. They usually show no epidermal changes but in some cases resemble abscesses and form ulcers (Figure 3).

Figure 3.

Bacillary angiomatosis, subcutaneous nodules.

The hyperpigmented plaques are more common in black patients and present as indurated oval plaques with indistinct borders (Figure 4, Figure 5). The surface of the plaque may be uneven and hyperkeratotic in the center. They are most often found on the extremities.

Figure 4.

Bacillary angiomatosis, hyperpigmentation.

Figure 5.

Bacillary angiomatosis, hyperpigmented plaques.

The skin lesions may be solitary or multiple, even as many as a few hundred. Patients with multiple lesions may display more than one type of morphology.

The lesions of BA also occur on respiratory and gastrointestinal mucosae (often in the oral cavity), in the heart, liver, spleen, lymph nodes, bone marrow, muscles and brain. The extracutaneous involvement of BA usually runs an indolent course but may have an acute presentation that can lead to death. Cutaneous lesions may or may not be present.

Patients with BA often have constitutional symptoms: fever, weight loss, and vomiting. This is particularly true in patients with extracutaneous involvement.

Expected results of diagnostic studies

Culture of Bh requires a 2-6 week incubation for primary isolation, and its isolation is often unsuccessful in patients without systemic disease. Bacteria can also be identified by electron microscopy.

PCR-enzyme immunoassay is a quick identification method. Amplification of the Bh gene has been applied with 100% specificity in some studies, Sensitivity, however, ranged only between 43% and 73%. Variable sensitivity and the need for highly specialized equipment and personnel make PCR somewhat impractical.

Serology for Bh is more practical than PCR. The two major diagnostic methods are indirect fluorescence assay (IFA) and enzyme immunoassay (EIA). Positive IgM EIA indicates acute disease. As IgM antibodies do not last long (3 months), they are discovered infrequently and the negative results do not exclude acute disease.

IgG antibodies also decrease with time, with only 25% of patients remaining positive after 1 year. Disadvantages of serology include variable sensitivity and specificity, inability to differentiate between active and previous infection, and occasional cross-sensitivity with other Bartonella species. In immunosuppressed patients, there are often no detectable antibodies.

The diagnosis of BA is thus mainly based on clinical assessment and histopathologic findings; laboratory evaluation is used to confirm initial suspicion.

Diagnosis confirmation

The differential diagnosis of BA includes Kaposi’s sarcoma, pyogenic granuloma, verruga peruana and various angiomas, particularly epithelioid hemangioma.

Differentiation from Kaposi’s sarcoma is of greatest significance as both conditions usually occur in HIV-infected patients and in other states of immunoincompetence. As BA is potentially lethal and is treatable, if overlooked, the outcome can be tragic. Rarely Kaposi’s sarcoma and BA may coexist in the same patient; macules, patches and superficial plaques characteristic for Kaposi’s sarcoma are usually not seen in BA. If BA appears as plaques, the lesions are poorly defined and often resemble cellulitis.

The histopathologic features also usually allow differentiation between BA and Kaposi’s sarcoma. Detection of the granular clumps of bacteria is a distinctive marker of BA. Their nature can be confirmed by Warthin-Starry stain or electron microscopy. Both conditions are angioproliferative, but the vascular spaces of Kaposi’s sarcoma are slit-like whereas in BA they are round.

Endothelial cells in BA are polygonal, but in Kaposi’s sarcoma they are spindle-shaped. Neutrophils are numerous with debris, and stroma is markedly edematous in BA. Hyaline globules often seen in Kaposi’s sarcoma are absent in BA, whereas Kaposi’s sarcoma usually shows positive staining with HHV8.

Pyogenic granulomas may be clinically indistinguishable from BA, as pyogenic granuloma-like lesions are one of the main clinical presentations of BA and may also resemble BA histopathologically. Pyogenic granuloma is most often solitary, but grouped lesions as well as widely disseminated lesions have been reported.

In BA, the lesions are more often multiple and have variable morphology, though single lesions of BA can occur.

The histopathology differs. Neutrophils in pyogenic granuloma are present only in eroded or ulcerated lesions, granular material is absent, and staining with silver stain is negative. The clinical and histopathologic similarities between BA and pyogenic granuloma prompted investigations as to a possible similar cause. A large series of pyogenic granuloma specimens were tested for Bartonella species; none were found positive.

Verruga peruana caused by Bartonella bacilliformis may resemble BA as the lesions are papules or nodules, some pedunculated, often hemangiomatous or hemorrhagic. The lesions in verruga peruana, usually multiple, involve the face, limbs and mucous membranes.

Only a few patients with verruga peruana recall having an acute febrile illness (Oroya fever) in the previous few months. The biopsy of verruga peruana, though showing the features of angioproliferation, lacks dense neutrophilic infiltrate. Bartonella bacilliformis can be seen in the cytoplasm of endothelial cells. Verruga peruana is endemic in parts of Peru and of the neighboring Andean countries, and the diagnosis should be considered only if the patient visited the endemic areas.

Vascular tumors, particularly epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) may cause diagnostic difficulties in the clinical diagnosis. Solitary or multiple dermal or subcutaneous nodules are localized mainly on the scalp and face. There is usually peripheral blood eosinophilia in epitheliod hemangioma.

In the biopsy, there is proliferation of small- to medium-sized blood vessels, which often show a lobular architecture. The vascular channels are lined by enlarged (epithelioid) endothelial cells. A perivascular infiltrate is composed mainly of lymphocytes and eosinophils, not of neutrophils.

Who is at Risk for Developing this Disease?

The response to infection with Bh depends on immune status of the infected individual. In those with an intact immune system, the response is granulomatous. Bartonella infection induces a tumor necrosis factor (TNF) gamma-mediated TH1 cell response, producing a granulomatous disease (cat scratch disease).

Granuloma formation and macrophage function are both defective in patients with HIV infection.

In immunoincompetent patients, the response is predominantly vasoproliferative. Bartonella is thought to modulate host or target cell cytokines and growth factors, which leads to angiogenesis. In reponse to Bh infection, monocytes, endothelial cells and hepatocytes produce interleukin-8 (IL-8).

In in vitro angiogenesis assays, Bh-induced cell proliferation and capillary transformation were found to be IL-8 dependent.

The host immune state determines the number and distribution of the lesions in BA.

What is the Cause of the Disease?

BA is caused by infection with Bartonella henselae (Bh), a fastidious, Gram-negative, aerobic and oxidase-negative bacillus, or by Bartonella quintana (Bq). Bh is also a cause of cat scratch disease and has been associated with a bacteremic syndrome and peliosis hepatitis. Bq causes trench fever.

Positive silver stain of bacteria in the histopathologic specimens, ultramicroscopy, culture and serology have confirmed the role of these Bartonella species in BA.

Systemic Implications and Complications

Extracutaneous BA spares no organ. The liver is often involved and may be affected without skin lesions.

Bacillary peliosis caused by Bh, but not Bq, is a peculiar form of hepatosplenic Bartonella disease seen in immunocompromised hosts. It is characterized by formation of blood-filled cystic spaces, usually without the degree of vasoproliferation seen in skin lesions. It presents with gastrointestinal symptoms, abdominal distention, hepatosplenomegaly, fever, chills and severe anemia.

The most common cardiac manifestation is endocarditis. Pulmonary involvement is rare and may take the form of pneumonia or pleural effusion.

Neurologic complications of Bh infection are rare, and the most common presentation is encephalopathy. Ocular manifestations are not rare, with neuroretinitis being the most common.

Clinical manifestations of bone involvement are deep painful nodules, osteolytic on radiographs. Osteomyelitis has been described.

Bartonella bacteremic syndrome is a complex symptom syndrome of malaise, fatigue, anorexia, weight loss and fever. Symptoms often remain unrecognized for weeks or months.

Treatment Options

Erythromycin orally or intravenously








Treatment of BA depends on the extent of clinical involvement and the immune state of the patient.

There is a significant divide in the literature between susceptibility of Bh to antibiotics in vitro and their clinical efficacy. Bartonella species have been found sensitive to a number of antimicrobial agents. The following agents have shown bacteriostatic activity in vitro: macrolides, tetracyclines, beta-lactams, cephalosporins, rifampin, ciprofloxacin and trimethoprim-sulfamethoxazole.

Only aminoglycosides demonstrated bactericidal activity against Bartonella in vitro.

The present knowledge of the treatment of BA is based on the observational case studies rather than controlled studies.

Immunocompromised patients usually respond much better and quicker than the immunocompetent. As BA predominantly affects individuals with impaired immunity, the response to treatment is fast and the cutaneous lesions begin to resolve within the first week of therapy and resolve completely within 4 weeks.

It is recommended to treat patients for 8 to 12 weeks. Relapses are common and maintenance therapy is often required. Usually antibacterial agents in the same dose are used for the initial treatment and maintenance.

Optimal Therapeutic Approach for this Disease

The most frequently used agents are macrolides. In spite of only bacteriostatic properties, erythromycin has shown a dramatic effect in BA. The effect of erythromycin on Bq-induced endothelial cell proliferation was studied using a wild-type strain and an erythromycin-resistant Bq mutant. It was shown that erythromycin significantly inhibited the proliferation of dermal microvascular cells induced by both Bq strains (Figure 6, Figure 7).

Figure 6.

Bacillary angiomatosis before treatment.

Figure 7.

Bacillary angiomatosis after 3 weeks of oral erythromycin 2g daily.

Doxycycline and gentamycin failed to exert such an effect. These data indicate that erythromycin irrespective of its only bacteriostatic effects, markedly inhibited endothelial cell proliferation; this may be a clue to its efficacy in BA. Erythromycin is given in a dose of 2.0g daily orally (most often 500mg 4 times daily). Erythromycin is used intravenously in cases of gastrointestinal intolerance or when absorption is expected to be poor.

Some recommend clarithromycin (250mg twice daily orally) or azithromycin (1.0g a single daily dose). Clarithromycin has less gastrointestinal side effects. Drug concentrations of clarithromycin and azithromycin in the skin after oral administration are higher than that of erythromycin. Doxycycline 100mg orally twice daily has also been found effective. Doxycycline can also be given intravenously.

Combination therapy with addition of rifampin (300mg orally twice daily) to either erythromycin or doxycycline was recommended for immunocompromised patients with severe life-threatening disease.

Treatment failures have been observed when fluoroquinolones, trimethoprim-sulfamethoxazole and narrow-spectrum cephalosporins were used.

For extracutaneous involvement of BA, similar antibacterial regimens are used. The details are beyond the scope of this article, as the treatment depends on the organ affected and there is a significant lack of knowledge of effective therapy for more complicated sequelae of infection.

Patient Management

Regular follow-up of patients with BA is mandatory as relapses are common. In HIV-infected patients, relapses reflect the actual immune state of the patient. Detection of relapses of the cutaneous lesions is based on the clinical findings. Relapses occur when antibiotics are given for less than 3 months, especially in immunocompromised HIV-infected patients.

When there are symptoms and signs pointing toward extracutaneous involvement, appropriate imaging and radiographic studies have to be performed.

Patients with HIV infection have to be on retroviral therapy, and their CD4 count and viral load must be regularly monitored.

Unusual Clinical Scenarios to Consider in Patient Management

As BA may literally involve any organ system, the potential for unusual clinical presentations is virtually limitless. In any immunocompromised patient, especially those with HIV, BA should be added to the differential diagnosis in the presence or absence of cutaneous lesions.

What is the Evidence?

Cockerell , CJ, Whitlow , MA, Webster , GF, Friedman-Kien, AE. “Epithelioid angiomatosis: A distinct vascular disorder in patients with the acquired immunodefciency syndrome or AIDS-related complex”. Lancet. vol. 2. 1987. pp. 654-5. (First series of patients with BA [then termed epithelioid angiomatosis] is reported and the disease is characterized as a separate entity.)

Wong , R, Tappero , J, Cockerell, CJ. “Bacillary angiomatosis and other Bartonella species infections”. Sem Cut Med Surg. vol. 16. 1997. pp. 188-9. (A comprehensive review of BA and diseases caused by other species of Bartonella.)

Fiorin , TA, Zautis , TE, Zautis, LB. “Beyond scratch disease: widening spectrum of Bartonella henselae infection”. Pediatrics. vol. 121. 2008. pp. e1413-25. (State-of-the-art review article summarizing the current knowledge regarding the microbiology, clinical manifestations, diagnostic techniques and treatment of Bartonella infection.)

Plettenberg , A, Lorenzen , T, Burtsche , BT, Rasokat , H, Kaliebe , T, Albrecht , H. “Bacillary angiomatosis in HIV-infected patients- an epidemiological and clinical study”. Dermatology. vol. 201. 2000. pp. 326-31. (A review of 21 patients with HIV-associated BA observed among over 17,500 HIV-infected patients. Clinical details of cutaneous and extracutaneous involvement, treatment and follow-up.)

LeBoit , PE, Berger , TG, Egbert , BM, Beckstead , JH, Yen , TS, Stoler, MH. “Bacillary angiomatosis. The histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease”. Am J Dermopathol. vol. 13. 1989. pp. 909-20. (A detailed study of 21 biopsy specimens from 13 patients with BA. Histopathologic criteria for the diagnosis of BA and discussion on histopathologic differential diagnosis.)

Levy , I, Rolain J-, M, Lepidi , H, Raoult , D, Feinmesser , M, Lapidoth , M. “Is pyogenic granuloma associated with Bartonella infection?”. J Am Acad Dermatol. vol. 53. 2005. pp. 1065-6. (Not one of the 45 pyogenic granuloma specimens tested positive for Bartonella species.)

Magalhaes , RF, Pitassi , LH, Salvadego , M, de Moras , AM, Barjas-Castro , ML, Velho, PE. “Bartonella henselae survives after the storage period of red blood cells units: is it transmissable by transfusion?”. Transfus Med. vol. 18. 2008. pp. 287-91. (Bartonella henselae remained viable in red blood cells units at 4 degrees C for 35 days. The authors consider that these data reinforce the possibility of infection by transfusion of blood collected from asymptomatic donors.)

Meghari , S, Rolan , JM, Grau , GE, Platt , E, Barrasi , L, Mege , JL. “Antiangiogenic effect of erythromycin: in vitro model of Bartonella quintana infection”. J Infect Dis. vol. 193. 2006. pp. 380-6. (In vitro study demonstrated that erythromycin markedly inhibits the proliferation of dermal microvascular endothelial cells induced by infection with Bartonella quintana.)