Bacillary Angiomatosis

Practice Essentials

Bacillary angiomatosis is a vascular, proliferative form of Bartonella infection that occurs primarily in immunocompromised persons. While the disorder is treatable and curable, it may be life threatening if untreated. Bacillary angiomatosis is the second-most-common cause of angiomatous skin lesions in persons infected with the human immunodeficiency virus (HIV). Multiple lesions often demonstrate more than 1 morphologic appearance. Black patients, in particular, may bear the plaque form (see the image below).

View Image

A 40-year-old HIV-positive homosexual man with lichenoid cutaneous plaques on his upper extremities.

Signs and symptoms

Patients with bacillary angiomatosis commonly have a history of HIV infection, organ transplantation, leukemia, or chemotherapy.^[1] Inoculation bartonellosis may be evident in immunocompetent individuals as a pyogenic granuloma–like nodule at the site of a cat scratch or at a burn site.^{[2, 3]}

Cutaneous lesions due to bacillary angiomatosis may take one of the following forms:

• Solitary or multiple red, purple, flesh-colored, or colorless papules (hemangiomalike lesions) varying in size from 1 mm to several centimeters
• Nodules, often covered with a fine, tightly adherent scale
• Large, friable, pedunculated, or polypoid exophytic masses
• Hyperpigmented, hyperkeratotic, indurated plaques, typically on the extremities and often overlying osseous defects

Lesions can also occur in the oral mucosa, tongue, oropharynx, nose, penis, and anus. Bone pain, frequently in the forearms or legs, can also occur.

Visceral involvement associated with bacillary angiomatosis may be asymptomatic or may cause the following symptoms:

• Fever, chills, malaise, night sweats, anorexia, and weight loss
• Symptoms of peliosis hepatis: Abdominal pain, nausea, and vomiting
• Jaundice secondary to biliary obstruction caused by external compression of periportal lymph nodes
• Intra-abdominal mass and gastrointestinal bleeding
• Symptoms of colonic bacillary angiomatosis: Abdominal cramps, tenesmus, and bloody diarrhea
• Symptoms of CNS bacillary angiomatosis: Psychiatric symptoms, such as exacerbation of depression or new-onset psychosis; personality changes, including anxiety and irritability; headache; trigeminal neuralgia; seizures; and back pain
• Difficulty breathing secondary to laryngeal obstruction

Diagnosis

Lab studies

The diagnosis of cutaneous bacillary angiomatosis and extracutaneous disease is most often based on clinical features coupled with biopsies of lesions. Histology reveals vascular proliferation with the presence of neutrophils adjacent to the blood vessels and masses of bacteria, which can be demonstrated by modified silver staining (Warthin-Starry silver stain). Detection of Bartonella DNA in tissue specimens by polymerase chain reaction (PCR) assay or of Bartonella antigens by immunohistochemical methods is diagnostic.^[4]

Imaging studies

Radiography can be used to find bone lesions; chest radiography can reveal pulmonary parenchymal nodules.

Computed tomography (CT) scanning of the brain can detect intracerebral bacillary angiomatosis. CT scanning and magnetic resonance imaging (MRI) can be used in the diagnosis of peliosis hepatis, while chest and abdominal CT scans may reveal mediastinal, retroperitoneal, or mesenteric lymph node enlargement.

Procedures

• Biopsy: Specimens of skin, subcutaneous or mucosal lesions, or, in cases of peliosis hepatis, the liver are diagnostic
• Endoscopy: With gastrointestinal involvement, may reveal ulcerated nodules of the mucosa of the stomach, small intestine, or large intestine
• Bronchoscopy: With lung involvement, may reveal polypoid lesions

Management

Bacillary angiomatosis can be cured in most patients with antibiotics. Clinical experience strongly favors the use of erythromycin or a tetracycline derivative in this disorder.

Cryotherapy, electrodesiccation and curettage, and surgical excision of solitary cutaneous lesions can be useful as adjunctive therapy.

The reader is referred to the 2014 guidelines published by the Infectious Diseases Society of America (IDSA) for the treatment of bacillary angiomatosis (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).^[5]

• References

Background

Bacillary angiomatosis is a vascular, proliferative form of Bartonella infection that occurs primarily in immunocompromised persons. It was first described in 1983 in a patient infected with the human immunodeficiency virus (HIV).^[6] The disease has since been described in patients following organ transplantation and in other individuals with a weakened immune system, although it is occasionally reported in immunocompetent patients.^[1] Initially, bacillary angiomatosis was called epithelioid angiomatosis, because of its histologic appearance (see the image below). (See Pathophysiology and Etiology.)

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A 35-year-old retrovirus-negative Mexican immigrant who had undergone recent splenectomy for idiopathic thrombocytopenic purpura, with multiple violac....

In 1990, Relman et al identified a visible but uncultivable bacillus from affected tissues of patients with bacillary angiomatosis.^[7] The gram-negative organism was later named Bartonella (formerly Rochalimaea) henselae. A similar bacterium, B quintana, has also been detected in and cultured from lesions caused by bacillary angiomatosis.

The systemic nature of the disease became evident when postmortem examinations showed nodules in the larynx, gastrointestinal tract, peritoneum, and diaphragm.

Bacillary angiomatosis often responds to therapy with oral erythromycin, although other oral antibiotics and antituberculosis medications, including tetracycline, other macrolides, trimethoprim-sulfamethoxazole, ciprofloxacin, and rifampin, may also be effective. While the disorder is treatable and curable, it may be life threatening if untreated. The disease is the second-most-common cause of angiomatous skin lesions in persons infected with HIV. (See Treatment and Medication.)

Patient education

Immunocompromised patients and their caregivers should be advised to avoid cat contact and to control flea infestations in cats.

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Pathophysiology

B henselae and B quintana are small gram-negative rods in the family Bartonellaceae. Bartonella, Rickettsia, Ehrlichia, and Afipia species all are part of the alpha-2 subgroup of the Alphaproteobacteria.

Bacillary angiomatosis can affect almost any organ system, although it most commonly affects skin and subcutaneous tissue. Subcutaneous lesions may erode into underlying bones (ie, osseous bacillary angiomatosis), especially the tibia, fibula, and radius. Involvement of ribs and vertebrae has been described. Rarely, skeletal muscles may be involved, resulting in pyomyositis. Mucous membranes of the conjunctiva, upper airway, and perineum (anus and penis) may also be affected. Bacillary angiomatosis may be accompanied by disseminated visceral disease (peliosis), mainly in the liver (peliosis hepatis), spleen, and lymph nodes.

Other internal organs that may be involved include the following:

• Brain
• Bone marrow
• Heart
• Lungs
• Pleura
• Larynx
• Oropharynx
• Tongue
• Esophagus
• Stomach
• Duodenum
• Colon
• Peritoneum
• Diaphragm
• Kidneys
• Adrenal glands
• Pancreas
• Uterine cervix
• Vulva^[8]

Extrinsic compression of the common bile duct by enlarged peripancreatic, celiac, and portohepatic nodes has been reported.

The pathogenesis of bacillary angiomatosis includes early blood-borne dissemination of organisms. Bartonella organisms readily attach to and may enter erythrocytes.^[9] They avoid opsonization and host phagocytosis by unknown mechanisms and become persistent within the intravascular compartment.

An angiogenic factor may be responsible for the vascular proliferation observed in patients with bacillary angiomatosis, because a similar factor mediates vasoproliferation in verruca peruana, the second stage of Bartonella bacilliformis infection. Moreover, deoxyribonucleic acid (DNA) hybridization, 16S ribosomal ribonucleic acid (rRNA) sequence homology, cellular fatty acid profiles, and cytosine and guanine content studies have shown that B henselae and B quintana are closely related to Bartonella bacilliformis.^[10]

Infection sites

The specific Bartonella species, B henselae or B quintana, can affect the location of bacillary angiomatosis, as follows:

• Cutaneous lesions: Result almost equally from B henselae and B quintana infections
• Subcutaneous lesions: Usually caused by B quintana infection
• Osseous lesions: Usually caused by B quintana infection
• Visceral involvement: Almost exclusively caused by B henselae infection
• Neurologic disorders: Associated more frequently with B quintana infection than with B henselae

Disease reservoirs

Domestic cats (Felis domesticus) are the reservoirs of B henselae, which may be transmitted via cat bites or scratches or, potentially, by bites from cat fleas (Ctenocephalides felis). Kittens are more frequently associated with transmission of B henselae than are older cats. Humans appear to be the only reservoir of B quintana; the human body louse, Pediculus humanus, is the transmission vector.

• References

Etiology

Risk factors for bacillary angiomatosis include the following:

• HIV infection^{[11, 12]}
• Chronic lymphocytic leukemia
• Cytotoxic chemotherapy
• Organ transplantations

Additional risk factors for bacillary angiomatosis associated with B henselae infection include the following:

• Cat ownership
• Cat bites
• Cat scratches

Additional risk factors for bacillary angiomatosis associated with B quintana infection include the following:

• Homelessness
• Low socioeconomic status
• Exposure to body and hair lice

Other considerations

Bacillary angiomatosis was reported in a patient who was HIV-seronegative but had idiopathic thrombocytopenic purpura, had undergone splenectomy, and had been administered long-term systemic prednisone.^[13] Although not taken from the same patient, see the image below.

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A 35-year-old retrovirus-negative Mexican immigrant who had undergone recent splenectomy for idiopathic thrombocytopenic purpura, with multiple violac....

Another report described an immunocompetent child with infected facial wound, in the vicinity of which bacillary angiomatosis lesions had developed. Similar lesions also appeared at the donor site of the skin graft, which was grafted on the facial wound.^[14] A case of bacillary angiomatosis presenting as a pyogenic granuloma of the hand in an otherwise apparently healthy man was recently reported from Saudi Arabia.^[15]

Multiple leg ulcers caused by bacillary angiomatosis without a history of direct contact with cats in an adult immunocompetent man has also been reported.^[16]

A case of bacillary angiomatosis in an HIV-negative patient who had chronic hepatitis B but no other immunosuppressive status was reported from Turkey, suggesting that immunologic differences secondary to chronic hepatitis B could have led to an increased risk for the disease.^[17]

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Epidemiology

Occurrence in the United States

The exact incidence of bacillary angiomatosis is not known, but the disease has been reported in almost all states. Reports have been especially high in Florida, Texas, New York, and northern California (San Francisco area), each of which has a high frequency of HIV infection.

International occurrence

Bacillary angiomatosis is reported less commonly in Europe than in North America, which may imply that either diagnoses are missed or that Europe has a minimal reservoir of bacilli. Cases have also been reported in Africa, Peru, Argentina, Brazil,^{[18, 19]} Turkey,^[17] Saudi Arabia,^[15] and Australia.^[20] In 2008, Thailand reported its first case of bacillary angiomatosis associated with B henselae.^[21]

Race-, sex-, and age-related demographics

Approximately 40% of US patients with bacillary angiomatosis are white, 40% are black, and 20% are of Hispanic origin.

Approximately 90% of US patients with bacillary angiomatosis are men, probably because a disproportionate number of patients infected with HIV are also men.

A wide age range exists among patients with bacillary angiomatosis, from infancy to old age. The age range was 26-52 years in one early series of patients with acquired immunodeficiency syndrome (AIDS). Although bacillary angiomatosis is extremely rare in children, it was reported in a boy aged 12 years with acute leukemia who was undergoing chemotherapy and in a 6-year-old immunocompetent girl.

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Prognosis

The prognosis of bacillary angiomatosis is excellent; antibiotics are curative in most patients, with lesions resolving completely after treatment. Hyperpigmentation or slight induration at the site of a lesion may persist indefinitely. Relapses can occur after cessation of therapy and are common in immunocompromised hosts.

Overall prognosis depends on early detection and treatment and on the degree of immunosuppression. Treatment may be more difficult and requires a longer duration of therapy if the diagnosis is delayed. Untreated bacillary angiomatosis may be progressive and life threatening.

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Complications

Bacillary angiomatosis may cause disease of many different organs, including the heart, brain, liver, and spleen, if not treated promptly. Complications include the following:

• Disfigurement
• Biliary obstruction and jaundice
• Gastrointestinal bleeding
• Encephalopathy
• Laryngeal obstruction and asphyxiation

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History

Patients with bacillary angiomatosis commonly have a history of HIV infection, organ transplantation, leukemia, or chemotherapy.^[1] However, it has also been reported in immunocompetent individuals.^[22] Inoculation bartonellosis may be evident in immunocompetent individuals as a pyogenic granuloma–like nodule at the site of a cat scratch.^{[2, 3]}

Most patients with bacillary angiomatosis are infected with HIV and have CD4⁺ cell counts of less than 200/µL (although bacillary angiomatosis can develop prior to HIV seroconversion in some patients). The duration of symptoms before diagnosis is usually several months.

In some cases, bacillary angiomatosis becomes evident or recurs during immune restoration following initiation of highly active antiretroviral therapy (HAART).^{[23, 24]}

Features of skin, subcutaneous, mucosal, and osseous lesions caused by bacillary angiomatosis include the following:

• Raised red or purple lesions in the skin that bleed when traumatized
• Similar lesions in the oral mucosa, tongue, palate, oropharynx, nose, penis, and anus
• Bone pain, frequently in the forearms, hands, or legs^{[25, 26]}
• Facial tumor and multiple abscesses^[27]

Bartonella-related pseudomembranous angiomatous papillomatosis of the oral cavity, seen as vegetating papillomatosis exclusively on the oral mucosa, has been described.^{[28, 29]} Oral lesions may occur without concomitant cutaneous lesions. Oronasal fistula formation has been reported.^[30]

Visceral involvement associated with bacillary angiomatosis may be asymptomatic or may cause the following symptoms:

• Fever, chills, malaise, night sweats, anorexia, and weight loss
• Symptoms of peliosis hepatis: Abdominal pain, nausea, and vomiting
• Jaundice secondary to biliary obstruction caused by external compression of periportal lymph nodes
• Intra-abdominal mass and gastrointestinal bleeding
• Symptoms of colonic bacillary angiomatosis: Abdominal cramps, tenesmus, and bloody diarrhea
• Symptoms of CNS bacillary angiomatosis: Psychiatric symptoms, such as exacerbation of depression or new-onset psychosis; personality changes, including anxiety and irritability; headache; trigeminal neuralgia; seizures; and back pain
• Difficulty breathing secondary to laryngeal obstruction

• References

Physical Examination

Skin and subcutaneous lesions

Cutaneous lesions due to bacillary angiomatosis may take one of the following forms:

• Solitary or multiple red, purple, flesh-colored, or colorless papules (hemangiomalike lesions) varying in size from 1 mm to several centimeters
• Nodules, often covered with a fine, tightly adherent scale
• Large, friable, pedunculated, or polypoid exophytic masses
• Hyperpigmented, hyperkeratotic, indurated plaques, typically on the extremities and often overlying osseous defects

The number of lesions may vary from 1 to more than 1000, and they are often multiple. Multiple lesions often demonstrate more than 1 morphologic appearance. Black patients, in particular, may bear the plaque form. (See the image below.)

View Image

A 40-year-old HIV-positive homosexual man with lichenoid cutaneous plaques on his upper extremities.

Cutaneous lesions may develop ulceration, discharge, and crusting and are often tender. Smaller lesions tend to be covered with an attenuated epidermis, while larger lesions tend to erode and bleed. Most lesions are rubbery and firm upon palpation and are usually freely mobile. They may be associated with regional lymphadenopathy. In rare cases, lesions may regress spontaneously.

Subcutaneous nodules may erode through the surface and become friable and superinfected. Deep lesions are usually uncolored and either mobile or fixed to the underlying tissues. They are often tender. The overlying skin may appear normal.

Because extensive visceral bacillary angiomatosis may occur with only cutaneous disease evident, regard skin bacillary angiomatosis as a marker of possible internal involvement.

Mucosal lesions

Mucosal lesions are similar to other lesions and may involve oral, conjunctival, nasal, anal, or penile mucosal surfaces.

Ocular involvement

Ocular involvement in bacillary angiomatosis has been reported in immunocompetent and immunocompromised patients. It can range from eyelid involvement to papillitis, hyalitis, and retrobulbar neuritis.^{[31, 32]}

Visceral involvement

Visceral involvement may lead to fever, abdominal distention, hepatomegaly, and splenomegaly. This involvement may eventually progress to bacteremia and sepsis syndrome. Neurologic deficits may accompany intracranial mass lesions.

Visceral involvement may occur in the absence of cutaneous lesions. In this case, the diagnosis is often delayed, because the manifestations of visceral involvement are nonspecific.

A retrospective analysis of 37 speciated bacillary angiomatosis cases demonstrated that fever was present in two thirds of the patients and weight loss in one third of the patients, including patients without extracutaneous involvement.^[33]

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Approach Considerations

Bacillary angiomatosis in patients who are also infected with HIV most commonly causes anemia, leukopenia, and CD4⁺ cell counts of less than 0.2 X 10⁹/L. In a series of 42 patients with bacillary angiomatosis, the average CD4⁺ cell count was 0.021 X 10⁹/L. A rapid drop in hemoglobin level in the absence of bleeding or hemolysis has been reported in a patient with peliosis and was thought to be secondary to the sequestration of blood into pools in a liver or spleen that was massively enlarged. Thrombocytopenia with coagulopathy may also occur with peliosis.

Elevation of alkaline phosphatase, gamma-glutamyltransferase, and transaminase levels may indicate hepatic involvement. Alkaline phosphatase levels are more markedly elevated (5 times normal on average) than transaminase levels, which are usually mildly to moderately elevated or normal.

Well-circumscribed cortical or periosteal osteolytic lesions, mainly affecting the long bones, can be seen in radiographs in patients with bone involvement.^{[26, 30]}

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Procedures

Biopsy

Biopsy specimens of skin, subcutaneous or mucosal lesions, or, in cases of peliosis hepatis, the liver are diagnostic.

Endoscopy

With gastrointestinal involvement, endoscopic studies may reveal ulcerated nodules of the mucosa of the stomach, small intestine, or large intestine.

Bronchoscopy

With lung involvement, bronchoscopy may reveal polypoid lesions.

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Laboratory Studies

The diagnosis of cutaneous bacillary angiomatosis and extracutaneous disease is most often based on clinical features coupled with biopsies of lesions and appropriate tissue staining. Detection of Bartonella DNA in tissue specimens via polymerase chain reaction (PCR) assay or of Bartonella antigens targeting the 16S-23S ribosomal RNA gene intergenic transcribed spacer via immunohistochemical methods is diagnostic.^[4] . Note that a negative result suggests the absence of detectable DNA but does not rule out Bartonella infection. The PCR assay does not differentiate between Bartonella henselae and Bartonella quintana.

Indirect immunofluorescent antibody studies

When indirect immunofluorescent antibody testing is used to detect immunoglobulin (Ig) antibodies to B henselae, IgG titers of higher than 1:64 against B henselae suggest the presence of bacillary angiomatosis.

Enzyme immunoassays

An enzyme immunoassay for the detection of IgG antibodies to B henselae is now available and is reported to be 5-10 times more sensitive than the indirect fluorescent antibody test.

In addition, an immunoglobulin M–specific enzyme-linked immunosorbent assay for the detection of an early antibody response to B henselae has been developed that discriminates between B henselae– positive and B henselae –negative patient samples with impressive sensitivity and specificity values, reported as 100% and 97.1%, respectively.^[35]

Blood cultures

Blood cultures may yield organisms in bacillary angiomatosis if they are grown at 35°C in 5% carbon dioxide for 3 weeks using a lysis centrifugation technique. B henselae colonies are rough, cauliflowerlike, and usually deeply embedded in the agar. B quintana colonies are smooth, flat, and shiny and do not pit the agar. Whole-cell fatty acid gas chromatography has been used to identify the organisms once they have been grown in culture. Culture of Bartonella from solid tissue is more difficult but possible.

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Radiography

Radiographs of the bones overlying the skin lesions in patients with bacillary angiomatosis may demonstrate simple cortical erosions, osteolytic lesions, extensive cortical destruction, or a periosteal reaction. Typical lytic bone lesions, which usually manifest as focal bone pain, are sometimes localized only to the area where a subcutaneous lesion is present and can be asymptomatic.

Chest radiography may reveal pulmonary parenchymal nodules, which may have either well-defined or poorly defined borders, with no region of the lung consistently favored.

Bone scan findings are always positive at the site of osseus lesions and may help to identify the additional areas of involvement not revealed by conventional radiography.

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CT Scanning and MRI

In peliosis hepatis, a computed tomography (CT) scan of the liver may demonstrate hypodense, ringlike lesions that enhance with contrast.^[36] The absence of mass effect on adjacent vasculature is characteristic. On magnetic resonance imaging (MRI), the lesions appear bright on T2-weighted images and dark on T1-weighted images. Enhancement patterns of one published MRI case study suggested centripetal enhancement similar to hemangioma, but another MRI case study suggested centrifugal enhancement.^[37]

Although authors disagree on the characteristic radiologic appearance of peliosis hepatis associated with bacillary angiomatosis, the most common presentation on CT scans consists of low-density lesions, some with peripheral enhancement. Homogeneous hypervascularity and nodular peripheral enhancement are not characteristic and would suggest an alternative pathology.^[36]

CT scanning of the chest and abdomen may reveal mediastinal, retroperitoneal, or mesenteric lymph node enlargement.

In intracerebral bacillary angiomatosis, CT scanning of the brain reveals a contrast-enhancing mass lesion.

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Histologic Findings

Some bacillary angiomatosis lesions have 2 distinct regions of vascular proliferation, a superficial one resembling a pyogenic granuloma or a papular angiokeratoma and a deeper one similar to a histiocytoid hemangioma, with a proliferation of small blood vessels lined by protuberant endothelial cells closely adherent to one another in an epithelioid pattern. The presence of neutrophils adjacent to the blood vessels is noteworthy and may be an important diagnostic clue.

Granular material resembling fibrin may be beside the neutrophils. This is the bacterium, observed best with either Warthin-Starry silver or Grocott-silver methenamine stain. A similar histologic pattern may be evident in affected the oral mucosa, lymph nodes, liver, spleen, bone marrow, larynx, gastrointestinal tract, peritoneum, diaphragm, and bronchial mucosa.^{[38, 39]} (See the images below.)

View Image

Many blood vessels of varying dimensions lined by swollen endothelial cells that contain bacilli. An infiltrate of acute and chronic inflammatory cell....

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Lesion showing large masses of blood vessels of markedly varying dimensions lined by swollen endothelial cells. The tissue is friable with evident fra....

Some lesions have only a few solitary neutrophils and moderate numbers of bacteria, whereas others have clusters of neutrophils and numerous nearby bacteria, in some cases to the extent of mimicking a frank abscess.

Some bacillary angiomatosis nodules may histologically resemble those of histiocytoid (epithelioid) hemangioma, Kaposi sarcoma, and verruga peruana. A proliferation of both endothelial cells and factor XIIIa–positive dermal dendrocytes is observed in bacillary angiomatosis, verruga peruana, granuloma pyogenicum, and Kaposi sarcoma .

Skin

The overlying epidermis may demonstrate atrophy, ulceration, or, at times, pseudoepitheliomatous hyperplasia.^[40] An epithelial collarette may be observed, particularly in those bacillary angiomatosis nodules that clinically resemble pyogenic granuloma. The dermis shows a vascular proliferation with small vessels arranged in clusters around ectatic vessels that may be markedly dilated. A lobular pattern may be observed, with varying amounts of edema and mucinous or fibrotic change between the lobules.

Histologic examination of skin lesions reveals vascular proliferation involving small blood vessels that contain plump cuboidal epithelial cells interspersed with polymorphonuclear inflammatory cell infiltrates and clumps of granular purple material. Coincidental endothelial cell necrosis and cytologic atypia may lead to a misdiagnosis of angiosarcoma. Solid areas of spindle cells may also be present; in some cases, these mimic Kaposi sarcoma or other sarcomas.

Liver

Histologic examination of liver sections in peliosis hepatis reveals dilated, blood-filled spaces in the fibromyxoid stroma that contain inflammatory cells, dilated capillaries, and clumps of granular purple material.

Lymph nodes

Histologic examination of lymph nodes reveals coalescing nodules of proliferated small blood vessels, some with prominent endothelial cells, in the cortical and paracortical areas. The uninvolved parenchyma may show follicular hyperplasia, plasmacytosis, or sinus histiocytosis.

Bacillary angiomatosis lesions of the lymph nodes, bone, and brain may demonstrate a less lobular pattern than cutaneous lesions do and have a less prominent neutrophilic infiltrate.

Bone

Histologic examination of the bone reveals a lobular proliferation of small blood vessels with prominent endothelial cells. Neutrophils may be sparse, and their lobular nature may not be apparent in some bone biopsy findings.

Pseudoepitheliomatous hyperplasia

Pseudoepitheliomatous hyperplasia, a histologic reaction pattern characterized by epithelial proliferation in response to various stimuli, including mycobacterial, fungal, and bacterial infections, has been described in an immunocompromised patient with AIDS and bacillary angiomatosis.^[40] Histologic examination of a finger lesion from this patient demonstrated capillary proliferation with neutrophilic debris and characteristic amorphous granular deposits. Warthin-Starry and Giemsa staining revealed clumps of coccobacilli. PCR assay using cervical lymph node tissue also revealed Bartonella organisms.

Staining techniques

The granular purple material in tissue sections stained with hematoxylin and eosin consists of masses of bacteria, which can be demonstrated by modified silver staining (Warthin-Starry silver stain) or electron microscopy.^{[38, 39]} However, the major drawback of Warthin-Starry silver stain is lack of specificity.

Other organisms that stain positive with Warthin-Starry silver stain include the following:

• Legionella species (Legionnaires pneumonia)
• Nocardia species (nocardiosis)
• Trophermyma whippleii (Whipple disease)
• Afipia felis (catscratch disease)
• Treponema pallidum (syphilis)
• Borrelia burgdorferi (Lyme disease)
• Helicobacter pylori (chronic active gastritis)

However, bacillary angiomatosis is clinically distinguishable from infections caused by these organisms, except for those caused by Nocardia brasiliensis.

Transmission electron microscopy

Transmission electron microscopy reveals clumps of pleomorphic bacilli measuring 0.2-0.5 µm by 1-3 µm that have a trilaminar structure to the cell walls, which is typical of vegetative forms of gram-negative bacilli.

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Approach Considerations

Bacillary angiomatosis can be cured in most patients with antibiotics, so recognition of the disease is critical. Treatment recommendations are based on retrospective studies or clinical observations. A systematic review found that current clinical practice for the treatment of bartonellosis, including bacillary angiomatosis, relies mostly on expert opinion and antimicrobial susceptibility data.^[41] No antibiotics have been studied prospectively or in randomized controlled trials. Corticosteroid, cytotoxic, and radiation therapy are not effective.^[41] Jarisch-Herxheimer reaction shortly after doxycycline initiation was reported in a 2017 study.^[24]

The reader is referred to the 2014 guidelines published by the Infectious Diseases Society of America (IDSA) for the treatment of bacillary angiomatosis (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).^[5]

Surgical care

Cryotherapy, electrodesiccation and curettage, and surgical excision of solitary cutaneous lesions can be useful as adjunctive therapy. However, antibiotic therapy provides treatment for possible occult dissemination of bacteria, in addition to regression of the lesions.

Consultations

Consultations can include the following:

• Infectious diseases specialist
• Dermatologist

Long-term monitoring

For cutaneous lesions, the number and size of the lesions should be monitored to determine the efficacy of treatment.

For visceral involvement, imaging study findings, hepatic transaminase levels, organomegaly, and/or lymph node enlargement should be monitored to determine response to therapy.

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Antibiotic Therapy

Clinical experience strongly favors the use of erythromycin or a tetracycline derivative in the treatment of bacillary angiomatosis. Erythromycin remains the drug of choice because it yields an excellent clinical response in almost all patients. (An antiangiogenic effect by erythromycin has been postulated and tested with in vitro models of B quintana infection.^[42] )

Tetracyclines are the first alternative in patients who cannot tolerate erythromycin. A combination of doxycycline (100 mg PO/IV q12h) plus rifampin (300 mg PO bid) may be used in immunocompromised patients with severe disease.

Other antibiotics display in vitro activity but are not effective against bacillary angiomatosis in vivo. Penicillins and cephalosporins have no activity against Bartonella species despite in vitro susceptibilities. The following antibiotics have produced good clinical responses when combined with either doxycycline or ciprofloxacin:

• Clarithromycin
• Azithromycin
• Chloramphenicol
• Ciprofloxacin
• Trimethoprim-sulfamethoxazole
• Rifampin
• Isoniazid
• Gentamicin

These antibiotics have been used successfully in limited numbers of patients. However, treatment failures with ciprofloxacin, trimethoprim-sulfamethoxazole, isoniazid, and rifampin have been reported.^{[43, 20]} Doxycycline is contraindicated in pregnancy.

A reaction resembling the Jarisch-Herxheimer reaction has been described upon the initiation of appropriate antibiotic therapy. The reaction is characterized by fever, myalgias, and constitutional symptoms.

The optimal duration of therapy is not known. Recommendations are based on clinical experience rather than scientific data. Usually, recommendations indicate that skin lesions be treated for 8-12 weeks and osseous and liver lesions for at least 3 months, although these treatment periods have not been studied in prospective, randomized trials. Patients with HIV infection may require life-long therapy if relapses occur.

The cutaneous lesions resolve substantially after approximately 4-7 days of therapy, and they usually resolve completely after 1 month.

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Prevention

Prevention of bacillary angiomatosis associated with B henselae infection includes avoidance of contact with cats and control of flea infestations in cats.

Preventive measures associated with B quintana infection are as follows:

• Delousing procedures, such as the use of permethrin dusting powder (1%, 30-50 g per adult)
• Treatment of clothing and bedding

In addition, macrolides for Mycobacterium avium-intracellulare prophylaxis in patients infected with HIV are protective against bacillary angiomatosis.

A study by Lappin et al indicated that the risk of B henselae infection in cats via contact with the flea Ctenocephalides felis can be reduced with the use of a flea and tick collar containing 10% imidacloprid and 4.5% flumethrin. In the 8-month trial, cats infected with B henselae and exposed to C felis were housed with a group of uninfected cats who wore flea collars during the trial period and another group of uninfected cats who received no preventive treatment.^[44]

The three groups were separated from each other by mesh, preventing the cats from having physical contact with members of the other groups but allowing the fleas to move among the groups and, potentially, transmit B henselae to the uninfected cats. Four out of 7 of the cats who received no treatment tested positive by the end of the study for B henselae, while none of the cats treated with flea collars were positive for the bacterium.

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Medication Summary

Oral erythromycin remains the drug of choice for bacillary angiomatosis, with skin lesions often gradually fading over a period of 4 weeks. If the lesions persist, however, even in diminished form, medication can be changed to tetracycline. If the infection appears to be serious, adding a bactericidal medication, such as a third-generation cephalosporin or an aminoglycoside, may be prudent during the initial 3 weeks of therapy. According to a report from Chile, a patient with HIV infection and bacillary angiomatosis caused by B quintana responded favorably to azithromycin plus ciprofloxacin started together with antiretroviral therapy.^[45]

The Infectious Disease Society 2014 Guidelines suggest erythromycin 500 mg 4 times a day or doxycycline 100 mg twice a day to be used for at least 2 weeks and up to 2 months.^[5]

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Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Tetracycline inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits. Primarily bacteriostatic, it has anti-inflammatory activity and is active against a wide range of gram-positive and gram-negative organisms.

• References

Erythromycin (Ery-Tab, E.E.S., Erythrocin)

• Dosing, Interactions, etc.

Clinical Context:  Erythromycin is a highly bacteriostatic macrolide antibiotic isolated from a Streptomyces strain. Its spectrum is between those of penicillin and tetracyclines. The mechanism of action involves binding to the 50S ribosomal subunit and inhibiting microbial protein synthesis.

• References

Clarithromycin (Biaxin)

• Dosing, Interactions, etc.

Clinical Context:  This agent is a highly bacteriostatic, semisynthetic macrolide. A 6-methoxy erythromycin, clarithromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer RNA (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. It has a spectrum between those of penicillin and tetracyclines.

• References

Azithromycin (Zithromax, Zmax)

• Dosing, Interactions, etc.

Clinical Context:  Azithromycin is a highly bacteriostatic macrolide with a spectrum between those of penicillin and tetracyclines. Its mechanism of action involves binding to the 50S ribosomal subunit and inhibiting microbial protein synthesis.

• References

Doxycycline (Vibramycin, Monodox, Adoxa, Doryx)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is a bacteriostatic antibiotic that inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It is an important form of tetracycline that is effective in twice-daily dosing.

• References

Rifampin (Rifadin)

• Dosing, Interactions, etc.

Clinical Context:  This is a bactericidal antibiotic that inhibits bacterial protein synthesis by inhibiting DNA-dependent RNA polymerase. It is useful in immunocompromised patients with severe disease.

• References

Trimethoprim and sulfamethoxazole (Bactrim, Bactrim DS, Septra DS)

• Dosing, Interactions, etc.

Clinical Context:  This synthetic, antibacterial combination product discourages bacterial growth by inhibiting the synthesis of dihydrofolic acid.

• References

Class Summary

Empiric antimicrobial therapy should cover all likely pathogens in the context of the clinical setting.

• References