Bartonella, Coxiella , and Tropheryma Infections

Cat Scratch Disease

Bartonella henselae is the most commonly encountered pathogenic Bartonella species, and infection with this agent manifests most frequently as cat scratch disease (CSD). Domesticated cats are the primary reservoir of B. henselae, and the pathogen is transmitted among felines by cat fleas (Ctenocephalides felis). Human infections result from inoculation of infectious flea feces into a cutaneous wound created from a cat scratch or occasionally by direct inoculation onto the conjunctiva. The close association of humans with domesticated cats creates an enormous pool of reservoir hosts, and cat ownership, particularly ownership of a young cat or a kitten, is a significant risk factor for cat scratch disease. Most cases occur in children; indeed, cat scratch disease is the most common cause of unilateral regional lymphadenitis in children other than obvious cutaneous infection. Most cases are reported during the fall and winter months, which is believed related to the feline reproductive cycles and flea activity.

In classical cat scratch disease, a small (2 to 5 mm) erythematous papule forms within 3 to 10 days at the inoculation site. Approximately 33% to 60% of patients develop a transient low-grade fever. Ipsilateral lymphadenitis develops at the site of one or more draining lymph nodes within 1 to 7 weeks after inoculation, most commonly in the axillary, epitrochlear, cervical, submandibular, or inguinal regions. The involved nodes are typically enlarged and tender and the overlying skin is often erythematous. The adenopathy consists of a single or several enlarged nodes in one region in approximately two thirds of patients. A minority will have enlarged nodes in multiple anatomic sites, suggesting multiple inoculations. Suppurative changes occur in approximately 10% to 15%. Lymphadenopathy generally persists for 2 to 4 months but may last considerably longer.

Hepatosplenic Disease

Approximately 1% of patients infected with B. henselae develop a systemic illness characterized by malaise, abdominal pain, and persistent fever lasting several weeks to months. In these patients, granulomas form in the liver, spleen, or both organs, accompanied frequently by enlarged lymph nodes in the hilum of the spleen or liver or around the pancreas or aorta. Some patients also exhibit peripheral lymphadenopathy at sites associated with classical cat scratch disease, including the axillary and inguinal regions. Splenomegaly occurs more commonly than hepatomegaly, but the involved organs may also be normal in size. When imaged by using ultrasonography or computed tomography, the visceral granulomas appear as hypoechoic or low attenuation lesions. Collectively, these findings are sometimes mistaken for malignant neoplasms but typically resolve within 2 to10 months and leave no sequelae other than a small calcified focus. Spontaneous splenic rupture attributed to infection with B. henselae has been reported. Hepatosplenic disease is identified more frequently in children than in adults.

Endocarditis

At least eight Bartonella species are recognized causes of infective endocarditis. In several series, Bartonella species have been associated with approximately 2% to 4% of all patients with infective endocarditis and as many as 10% to 35% of all cases of blood culture–negative infective endocarditis. At least seven species or subspecies are known to cause endocarditis, including B. henselae, B. quintana, B. elizabethae, B. vinsonii berkhoffii, B. vinsonii arupensis, B. kohlerae, and B. alsatica; however, the great majority of reported cases of Bartonella endocarditis in the United States have been associated with B. henselae . In France, most described cases are caused by B. quintana and occur most commonly among homeless alcoholic patients infested with body lice. A preexisting valvulopathy is recognized in approximately 40% of endocarditis patients infected with B. quintana and as many as 90% of those infected with B. henselae . Infection of the aortic valve alone occurs in approximately 65% of cases of Bartonella endocarditis, followed by the mitral valve alone in 19%, and simultaneous infection of the mitral and aortic valves in 12%. The tricuspid and pulmonic valves are almost never involved. Embolic phenomena occur in approximately 35% of patients. Vegetations are recognizable by echocardiography in > 90% of patients. Bartonella endocarditis is a life-threatening disease, and a series of 48 patients reported a case-fatality rate of 8% despite surgical and antibiotic interventions.

Bacillary Angiomatosis

In persons with severe immune-suppressing conditions, particularly advanced human immunodeficiency virus (HIV) disease, transplantation, and malignancy, infections with B. henselae and B. quintana can cause vasoproliferative lesions in various tissues and organs including skin, central nervous system, bone and bone marrow, cardiac and skeletal muscle, conjunctiva, and the mucosal surfaces of the gastrointestinal and respiratory tracts. Cutaneous bacillary angiomatosis is the most frequently reported manifestation; however, involvement of other organ systems and deep tissues may occur in the absence of skin lesions. Most cases of bacillary angiomatosis are reported from patients with acquired immune deficiency syndrome with CD4 lymphocyte counts < 100 cells/mL. This condition has also been identified in patients receiving cytotoxic and immune-suppressing chemotherapy and very rarely in immune-competent persons. In bacillary peliosis, these lesions form in the liver, spleen, or both organs, generally in the context of hepatomegaly and splenomegaly. Although B. henselae and B. quintana are equally likely to cause cutaneous bacillary angiomatosis, clinical comparisons suggest that B. henselae is more likely to involve the lymph nodes, spleen, and liver, whereas B. quintana infections are more likely to cause lytic bone lesions or deep soft tissue disease ( Table 18-2 ). Bacillary angiomatosis resolves rapidly in response to antimicrobial therapy; however, the infection can be fatal if not treated appropriately.

Carrión Disease

Carrión disease, or bartonellosis, is a biphasic illness caused by infection with Bartonella bacilliformis . This disease, initially described during the pre–Colombian era, is endemic to certain river valleys on the western slope of the Andes Mountains in Peru, Colombia, and Ecuador, where as many as 5% to 10% of apparently healthy persons have persistent infections. Humans represent the only known reservoir of B. bacilliformis, which is transmitted among susceptible persons by various species of phlebotomine sandflies, including Lutzomyia verrucarum . Carrión disease is represented by two distinct clinical syndromes: an acute and potentially life-threatening phase known as Oroya fever and a subsequent and less severe eruptive stage termed verruga peruana that is characterized by vasoproliferative skin lesions that resemble the cutaneous lesions of bacillary angiomatosis. Oroya fever is characterized by extensive intraerythrocytic infection, often involving > 90% of red cells, that causes severe and sometimes fatal hemolytic anemia. Some historical outbreaks were associated with thousands of deaths, but contemporary case fatality rates are < 10%. Verruga peruana may develop weeks to months after Oroya fever, and the lesions can persist for months to years. In addition to the skin lesions, verrugae may occur occasionally on the conjunctivas and oral and nasal mucosae. Early investigators described involvement of various other internal organs and tissues, including the mucous membranes of the gastrointestinal and genitourinary tracts, central nervous system, lungs, liver, pancreas, kidneys, and spleen; however, contemporary descriptions of similarly distributed verrugae are lacking.

Miscellaneous Presentations

Bartonella species, particularly B. henselae, may cause other tissue-associated infections, including osteomyelitis and neuroretinitis, although surgical pathologists seldom encounter specimens from these sources. Osteomyelitis is a rare manifestation of cat scratch disease that most frequently involves bones of the vertebral column or pelvic girdle of children. Fever and concomitant lymphadenopathy are seen in approximately 75% of these patients. Sampled lesions may show granulomatous inflammation and stellate microabscesses but more often reveal small foci of neutrophilic infiltrates.

Gross Findings

In classical cat scratch disease, the involved lymph nodes are generally 1 to 5 cm in greatest dimension but may be as large as 12 cm. There is often prominent nodularity and the nodes may be matted and adherent to the adjacent soft tissues. Ocular inoculation occurs in approximately 5% to 10% of cases and manifests as a nonsuppurative conjunctivitis, an ocular granuloma, or both ( Figure 18-1 ). In hepatosplenic disease, multiple gray-white nodules, measuring 0.2 to 1.5 cm, are scattered throughout the parenchyma and may bulge onto the surface of the liver or spleen when these are in situated subcapsular locations. The macroscopic appearance of cardiac valves infected with Bartonella species generally reveals small, compact vegetations that may be associated with one or more ruptured chordae or leaflet perforations.

Cutaneous bacillary angiomatosis occurs singly or as multiple lesions, and the number of lesions is generally directly proportionate to the degree of immune suppression of the host. Most lesions appear as pink to deep red or violaceous papules and nodules that range from 0.2 to 2 cm and may become ulcerated or hyperkeratotic ( Figure 18-2 ). Peliotic lesions in the liver and spleen are generally small (0.1 to 0.2 cm) and are occasionally interspersed among larger foci of parenchymal necrosis.

Three types of cutaneous eruptions are seen with verruga peruana. The most frequently identified are miliary lesions, observed in approximately 70% of patients. These are represented by multiple, 0.1- to 0.4-cm bright red to violaceous papules, occurring superficially on the face and extremities ( Figure 18-3 ). Nodular-type lesions are generally larger and may reach several centimeters in size. These verrugae are typically fewer in number but extend deeply into the subcutaneous tissue and are prone to hyperkeratosis and ulceration. Mular lesions are the least frequently observed and the largest of the eruptive types, ranging from 0.5 to 5.0 cm. These generally appear as single painful lesions and often become pedunculated or eroded.

Microscopic Findings

The histologic features of cat scratch evolve over the course of the infection. Initially, small cortical abscesses appear beneath the subcapsular sinus, followed by mixtures of neutrophilic and granulomatous inflammation and non-necrotizing granulomas with multinucleated giant cells in the cortex and medulla ( Figure 18-4 ). Eventually, the centers of some granulomas become irregularly contoured collections of neutrophils and necrotic debris surrounded by a rim of palisading macrophages. These so-called stellate microabscesses are considered the pathologic hallmark of cat scratch ( Figure 18-5 ). Other histologic features include capsular thickening and fibrosis, follicular hyperplasia, and vascular proliferation in the paracortical and subcapsular regions. Bartonella henselae bacilli are best detected using Warthin-Starry, Steiner, or Dieterle silver techniques and appear as minute (1 to 3 μm), delicate, pleomorphic rods that form branching chains or small clusters ( Figure 18-6 ). The bacilli are generally sparse and distributed sporadically, concentrated predominantly in small clusters in microabscesses that occur early during the progression of the disease. Intact bacilli may be absent from more advanced lesions. Bartonella alsatica and B. quintana have also been reported to cause granulomatous lymphadenitis with histologic findings identical to those of classical cat scratch disease. Biopsy specimens of conjunctival inoculation sites show ulcerated epithelium with mixed inflammatory infiltrates accompanied by focal hemorrhages, necrosis, and vascular proliferation. These lesions generally become granulomatous, and bacilli can be detected in the conjunctiva and in enlarged ipsilateral preauricular lymph nodes that often accompany the conjunctival lesion.

The histopathologic appearance of hepatosplenic disease includes a spectrum of granulomatous inflammation that ranges from small aggregates of macrophages with occasional multinucleated giant cells ( Figure 18-7 ) to large stellate microabscesses surrounded by an inner zone of palisaded histiocytes and an outer layer of lymphocytes. Hepatic lesions are distinguished by a peripheral rim of variably developed fibrosis and granulation tissue that is not identified in lymphoid or splenic lesions ( Figure 18-8 ). Enlarged intra-abdominal nodes may also show necrotizing granulomas with stellate microabscesses. Bacteria are occasionally identified in the center of the microabscesses.

In Bartonella endocarditis, the involved valves are frequently mineralized and associated with prominent fibrosis and granulation tissue ( Figure 18-9 ). Inflammatory infiltrates are most frequently mononuclear but may also include some neutrophils, macrophages, and multinucleated giant cells ( Figure 18-10 ). Bartonellae appear most frequently as dense clusters of tiny, extracellular, rod-shaped bacteria enmeshed in fibrin along the valve margin, often in the absence of conspicuous inflammatory cell infiltrates ( Figure 18-11 ).

Bacillary angiomatosis is characterized by a well-circumscribed, lobular proliferation of small, rounded vessels lined by plump cuboidal cells with variable atypia ( Figure 18-12 ). A mixed population of proliferating cells, comprising dendrocytes and endothelium, is identified by immunocytochemistry. A fibrotic or mucinous-appearing stroma containing small clusters of intact and fragmented neutrophils separates the vascular spaces. Within the stroma and often situated near neutrophils are hazy purple and somewhat granular aggregates that represent dense clusters of bartonellae ( Figure 18-13 ). The pleomorphic bacteria are best demonstrated by using Dieterle, Steiner, or Warthin-Starry techniques ( Figure 18-14 ). In the liver and spleen, bacillary angiomatosis appears as multiple, small, and irregularly distributed blood-filled spaces, lined by flattened or cuboidal endothelial cells ( Figure 18-15 ). The peliotic spaces are separated by fibromyxoid stroma containing small clusters of neutrophils and bacteria ( Figure 18-16 ).

The cutaneous lesions of verruga peruana, regardless of the macroscopic appearance, are histologically similar to those of bacillary angiomatosis. Verrugae show multinodular and lobulated collections of plump endothelial cells and dermal dendrocytes. The vasoproliferative elements form solid sheets and cords as well as small vessels with patent lumens ( Figure 18-17 ). Some of the endothelial cells may be mitotically active and exhibit mild atypia. Giemsa stain reveals occasional intracytoplasmic conglomerates of rose-colored granules, known as Rocha-Lima inclusions, which represent phagosomes packed with degenerating B. bacilliformis bacteria. Small clumps of extracellular coccoid and ovoid bacteria can also be identified in the edematous stroma, although the number of bacilli are few relative to those seen in bacillary angiomatosis. Mononuclear inflammatory cell infiltrates, comprising predominantly lymphocytes and plasma cells, are generally seen in the interstitium; however, some verrugae contain neutrophilic microabscesses.