Bacillary Angiomatosis

Etiology

Bacillary angiomatosis is caused by two species of the Bartonella genus, namely Bartonella henselae and Bartonella quintana. The clinical spectrum of bacillary angiomatosis caused by these species differs. While both species cause cutaneous lesions, subcutaneous and osseous lesions are more frequent with B quintana, and Bartonella henselae causes peliosis of the liver and spleen.

B henselae is an aerobic, oxidase-negative, fastidious gram-negative rod, which is slightly curved. The temperature for optimal growth is 37 C. Under the microscope, the colonies appear like cauliflower. On average, B henselae measures about 2 microns in length. B henselae has a circular genome of 1.9 Mbp, which is slightly larger than the genome of B quintana (1.5 Mbp).[2] B quintana is a Gram-negative bacterium that is slow-growing, and the morphology resembles short rods. It measures about 0.4 mm wide and 1.5 mm long.[3]

Primary isolations of B quintana may take 12 to 14 days and sometimes as long as 45 days. Both B henselae and B quintana do not have flagella, as opposed to other related bacteria such as Bartonella bacilliformis. A twitching motion occurs due to fimbriae in both B henselae and B quintana.

Epidemiology

There is very little published information regarding the epidemiology of bacillary angiomatosis. Bacillary angiomatosis was first identified in patients who were infected with HIV and had low CD4 counts. During the pre-HAART era, the incidence of bacillary angiomatosis was 1.2 per1000 patients. The most frequent site of involvement is the skin, followed by bones and liver.[4] Bacillary angiomatosis is rare amongst patients with HIV due to antiretroviral therapy (ART). Bacillary angiomatosis in patients with HIV can occur in the setting of noncompliance with ART or late diagnosis of HIV infection. A search in PubMed using terms bacillary angiomatosis and HIV results in 17 items after 2000. A careful analysis of these publications shows that 5 cases had low CD4 counts (less than 100), one case had CD4 over 500, one case was nonadherent to the ART regimen, in one case there was worsening of the bacillary angiomatosis in immune reconstitution phase, one case was on second-line regime based on lopinavir/ritonavir (Alluvia) and in one patient, bacillary angiomatosis was the presenting feature of AIDS. Thus, while bacillary angiomatosis is rare in the post-ART era, it can occur at any point in the natural history of the disease.[5]

Bacillary angiomatosis can occur in patients with HIV, such as those with a transplant, who have chronic hepatitis B, patients with leukemia, and those on chemotherapy, particularly when the CD4 T-helper cell counts are suppressed. Bacillary angiomatosis in immunocompetent patients may occur at the burn site or at the site of cat scratch, masquerading as a pyogenic granuloma.[6] Therefore, bacillary angiomatosis must be in the differential diagnosis regardless of the immune status of the patient.

The most common organ is the skin. Although most cutaneous bacillary angiomatosis is treatable, the involvement of the internal organs can lead to fatal disease in some. There are 2 types of B henselae. Type 1 causes peliosis, and type 2 is more likely to cause skin and lymph node lesions. Peliosis lesions are not seen in the lymph nodes.

The incidence of bacillary angiomatosis in the United States is not known, but bacillary angiomatosis has been reported in all states. States with a higher HIV population such as California, New York, and Florida have reported more cases. Compared with North America, fewer cases are reported in Europe. Bacillary angiomatosis has also been reported from Africa, Southeast Asia, the Middle East, Australia, and South America. In the United States, about 40% of patients are White, 40% are Black, and 20% are Hispanic. Ninety percent of cases of bacillary angiomatosis have been men. Bacillary angiomatosis is extremely rare in the pediatric age group, but cases have been reported from infancy to old age. Therefore, there is no age predilection. About half of patients with bacillary angiomatosis are infected with B henselae, and the remaining infections are caused by B quintana. The infection occurs equally in men and women.

Pathophysiology

In nature, cats are the reservoir of B henselae. Cats may have episodes of asymptomatic bacteremia, during which the bacteria have adapted to life within erythrocytes. Cats acquire infection via cat fleas (Ctenocephalides felis) when they carry B henselae or B quintana.[7] Transmission of the organisms to humans by cats occurs when they scratch humans. The body louse Pediculus humanus transmits B quintana to humans. Transmission to humans via cat fleas has been hypothesized but not documented. Transmission to humans via ticks has been reported. B henselae has been isolated from both cat-scratch disease and lesions in bacillary angiomatosis.

Humans were considered the only reservoir for B quintana. However, Japanese macaques (Macaca fuscata) have recently been found to be another reservoir of B quintana. B quintana has been implicated in bacillary angiomatosis but has never been associated with cat-scratch disease. The body louse transmits B quintana in homeless, low socioeconomic, and impoverished populations.[8]

Once Bartonella species are inoculated by blood-sucking arthropods or penetrate the skin after exposure to a cat, the gram-negative bacteria attach themselves to a variety of host cells, which include erythrocytes, monocytes, macrophages, and dendritic cells. The endothelial cell is an important target for B quintana but not so much for B henselae. 

Several mechanisms are employed by Bartonella species to enter host cells and result from complex interactions at the cell surface between bacterial and host cell proteins. Therefore, Bartonella species are highly host-specific. First, adhesion of the bacteria to the host cell membrane is followed by uptake of groups of Bartonella in a vacuole by the host cell. In a second mechanism, bacteria accumulate on the host cell surface and induce self-phagocytosis. This process results in a phagosome, where Bartonella species must survive the harsh environment, resisting enzymes of oxidative stress. Both are well-equipped to deal with intracellular oxidative stress and produce heat shock proteins. A third mechanism is specific for entry into the erythrocytes, which involves secretion of a protein called deformin. Deformin causes invaginations of the erythrocyte membrane, providing entry points for these bacteria, which are adept at rearranging the cell cytoskeleton once they are attached to the cell surface. These bacteria are the carpenters of the bacterial world.[9]

Bartonella is the only genus known to release factors that stimulate endothelial cells to produce angiopoietin-2 and epidermal production of vascular endothelial growth factor. BadA protein on the cell surface of B henselae is responsible for adhesion to endothelial cells and fibronectin. BadA protein is responsible for promoting angiogenesis in B. henselae infections. BadA protein is also known to promote angiogenesis via inducible hypoxia factor-1 (IHF-1). Expression of outer membrane proteins (Vomp) is responsible for promoting vascular growth in the case of B quintana.

The ability to enter the erythrocytes protects these species from the host’s adaptive and innate immune response. CD4 T-helper cells produce interferon gamma and TNF-α, which are responsible for eliminating the bacteria. The Bartonella species are capable of attenuating the host immune response, thereby establishing a chronic asymptomatic carrier state. An asymptomatic carrier state caused by B quintana exemplifies this in patients experiencing homelessness

History and Physical

The most common clinical presentation is a papule that develops into a reddish-to-purple nodule that appears vascular.[10] The nodules can be as small as a pinhead or as large as 10 cm in diameter. As a nodule enlarges, there is central ulceration and bleeding from this nodule. The usual site is the upper extremities. A patient may have multiple papules and nodules as the lesions often arise in crops.[11][12] The differential diagnosis of a nodule is extensive; however, confusion is most likely to occur with Kaposi sarcoma in patients with HIV and pyogenic granuloma in immunocompetent patients. The histology of bacillary angiomatosis is identical to that of pyogenic granuloma; therefore, it cannot be differentiated based on pathology alone. Multiple lymph nodes along the arm may resemble sporotrichosis. Lymphadenopathy is infrequent in bacillary angiomatosis.

While most patients have an immunosuppressed state, rarely a nodule in an otherwise healthy person may be due to bacillary angiomatosis. Therefore, bacillary angiomatosis should be in the differential diagnosis of any nodule of unknown etiology. No diagnostic feature on gross morphology suggests cutaneous bacillary angiomatosis; hence, a high index of suspicion is required.

Similar lesions occur in the oral mucosa, tongue, oropharynx, nose, penis, and anus. The pathogenesis of these lesions is not defined. The lesions in the gastrointestinal mucosa can cause bleeding. Neuropsychiatric symptoms, endocarditis, weight loss, and abdominal pain are other symptoms of visceral bacillary angiomatosis. Neurological involvement is very rare and has been reported in a case report showing intracerebral bacillary angiomatosis that preceded the development of the cutaneous lesions.[13]

Bacillary angiomatosis can also be an invasive disease. B henselae or B quintana can invade and create infection in the heart, brain, liver, spleen, larynx, lymph nodes, and gastrointestinal tract. A history of exposure to cats is not always present. When there are no associated cutaneous lesions, the diagnosis of invasive bacillary angiomatosis is likely to be delayed. The features associated with hepatic and splenic bacillary peliosis are nonspecific, such as fever, lymphadenopathy, visceromegaly, anemia, and elevated alkaline phosphatase. Often bacillary angiomatosis can present as fever of unknown origin. While most frequently hepatic and splenic peliosis lesions are asymptomatic, there are reports of spontaneous hemorrhage and hemoperitoneum at presentation. Patients may also report other symptoms of systemic involvement such as fever, chills, weight loss, and anorexia.

In patients who are not severely immunosuppressed, there may be inflammatory nodules involving the internal organs without angiomatosis. This appears to be on a spectrum of infections caused by B henselae and intermediate between bacillary angiomatosis and cat-scratch disease. B quintana infections can cause cutaneous bacillary angiomatosis as well as involvement of the subcutaneous tissues and bone but do not cause peliosis in the liver and spleen.[14]

Evaluation

When a cutaneous nodule is present, a biopsy is ideal to diagnose bacillary angiomatosis. A workup to exclude peliosis of the liver and spleen should be done. Further evaluation can be guided by the associated symptoms and physical exam. Some prominent differential diagnoses to consider are Kaposi sarcoma, pyoderma gangranosum, and benign hemangioma. In endemic regions, the lesions may be confused with verruga peruana due to B bacilliformis. Histological evaluation is used to differentiate bacillary angiomatosis from neovascular tumors.

In routine clinical practice, histological methods are used to confirm the diagnosis of bacillary angiomatosis. The hematoxylin and eosin stain demonstrates endothelial-lined peliosis spaces. Warthin-Starry stain shows clumps of bacteria. The histological methods cannot make a diagnosis to the species level.

Serology at the initial presentation followed by a fourfold rise during convalescence is useful and more sensitive than culture methods. Immunofluorescence assays detecting IgG and immune enzyme assays have been developed.[15][16] The reported sensitivity of serological tests developed by the Centers for Disease Control and Prevention (CDC) is between 85% and 94%. However, there is cross-reactivity between B henselae and B quintana as well as Coxiella and Chlamydia species.

Polymerase chain reaction-based testing performed on whole blood, serum samples, or plasma can identify and differentiate between the different species of Bartonella.[17] Culture methods are insensitive. In patients with endocarditis, the sensitivity of shell vial culture was 28% in one study. The sensitivity of culture on agar plates was only 5% in the same study. Therefore, culture methods are not employed in clinical practice.

Treatment / Management

The drug of choice is macrolide erythromycin or doxycycline. In patients who cannot tolerate erythromycin or doxycycline, azithromycin or clarithromycin may be used.[18] Mild cutaneous bacillary angiomatosis can be treated for 12 weeks. The response is seen by 3 to 4 weeks. The nodule size and the number may be followed to determine the response to therapy. If the response is not satisfactory, the duration of therapy can be extended. Antibiotic therapy can cure most cutaneous lesions. Even peliosis responds to antibiotic therapy. The duration of therapy has not been determined and is most likely longer in cases with invasive disease. Infectious disease consultations should be obtained. In patients who are immunosuppressed, therapy should be continued till the CD4 T-helper cell count normalizes. In patients with HIV, antiretroviral therapy is essential; however, a case of immune reconstitution inflammatory syndrome has been reported.[19] Therapy in patients with HIV should be continued until the CD4 count remains above 200 cells/µL for over 6 months.(B3)

Cryotherapy, electrodesiccation with curettage, and surgical excision of solitary cutaneous lesions can be useful as adjunctive therapy after treatment with antibiotics to prevent occult bacteremia during the procedure. In vitro susceptibility does not correlate with clinical response. Bactrim, β-lactams, and fluoroquinolones do not interfere with the recovery of the organisms in culture. Tetracyclines, macrolides, and rifampin dramatically reduce the recovery of the organisms in cultures. 

Since the cat carries the bacillus only for a short period of time, disposal of the cat is not routinely recommended. Declawing of the cat makes no difference in the transmission rates from cats to humans. Strict flea-control measures are recommended and should be performed on a regular basis and are the only effective preventive measure.[20](B3)

Differential Diagnosis

Clinically, the physical appearance of the cutaneous lesions may be indistinguishable from those of Kaposi sarcoma, pyogenic granuloma, and epitheliod hemangioma. In endemic regions, the lesions may be confused with verruga peruana due to B bacilliformis. Multiple lymph nodes along the arm may also resemble sporotrichosis.

Prognosis

Bacillary angiomatosis resolves rapidly when antimicrobial therapy is instituted early. Relapses are common in immunocompromised patients and can occur after cessation of therapy. However, if the infection is not treated appropriately it can be fatal. 

Complications

Bacillary angiomatosis may affect the heart, brain, liver, spleen, larynx, lymph nodes and gastrointestinal tract. Complications include gastrointestinal bleeding, encephalopathy, endocarditis, laryngeal obstruction and disfigurement due to the extensive lesions.[21][22]