CHAPTER 69: BARTONELLA INFECTIONS, INCLUDING CAT-SCRATCH DISEASE

Bartonella species are fastidious, facultative intracellular, slow-growing, gram-negative bacteria that cause a broad spectrum of diseases in humans. This genus includes more than 30 distinct species or subspecies, of which at least 16 have been recognized as confirmed or potential human pathogens; Bartonella bacilliformis, Bartonella quintana, and Bartonella henselae are most commonly identified (Table 69-1). Most Bartonella species have successfully adapted to survival in specific domestic or wild mammals. Prolonged intraerythrocytic infection in these animals creates a niche where the bacteria are protected from both innate and adaptive immunity and which serves as a reservoir for human infections. Bartonella characteristically evades the host immune system by modification of its virulence factors (e.g., lipopolysaccharides or flagella) and by attenuation of the immune response. B. bacilliformis and B. quintana, which are not zoonotic, are exceptions. Arthropod vectors are often involved. Isolation and characterization of Bartonella species are difficult and require special techniques. Clinical presentation generally depends on both the infecting Bartonella species and the immune status of the infected individual. Bartonella species are susceptible to many antibiotics in vitro; however, clinical responses to therapy and studies in animal models suggest that the minimal inhibitory concentrations of many antimicrobial agents correlate poorly with the drugs’ in vivo efficacies in patients with Bartonella infections.

DEFINITION AND ETIOLOGY

Usually a self-limited illness, cat-scratch disease (CSD) has two general clinical presentations. Typical CSD, the more common, is characterized by subacute regional lymphadenopathy; atypical CSD is the collective designation for numerous extranodal manifestations involving various organs. B. henselae is the principal etiologic agent of CSD. Rare cases have been associated with Afipia felis and other Bartonella species.

EPIDEMIOLOGY

CSD occurs worldwide, favoring warm and humid climates. In temperate climates, incidence peaks during fall and winter; in the tropics, disease occurs year-round. Adults are affected nearly as frequently as children. Intrafamilial clustering is rare, and person-to-person transmission does not occur. Apparently healthy cats constitute the major reservoir of B. henselae, and cat fleas (Ctenocephalides felis) may be responsible for cat-to-cat transmission. CSD usually follows contact with cats (especially kittens), but other animals (e.g., dogs) have been implicated as possible reservoirs in rare instances. In the United States, the estimated disease incidence is ~10 cases per 100,000 population. About 10% of patients are hospitalized.

PATHOGENESIS

Inoculation of B. henselae, possibly via contaminated flea feces, usually results from a cat scratch or bite. Infection of mucous membranes or conjunctivae via droplets or licking may occur as well. With lymphatic drainage to one or more regional lymph nodes in immunocompetent hosts, a T_H1 response can result in necrotizing granulomatous lymphadenitis. Dendritic cells, along with their associated chemokines, play a role in the host inflammatory response and granuloma formation.

CLINICAL MANIFESTATIONS AND PROGNOSIS

Of patients with CSD, 85–90% have typical disease. The primary lesion, a small (0.3- to 1-cm) painless erythematous papule or pustule, develops at the inoculation site (usually the site of a scratch or a bite) within days to 2 weeks in about one-third to two-thirds of patients (Fig. 69–1A, B). Lymphadenopathy develops 1–3 weeks or longer after cat contact. The affected lymph node(s) are enlarged and usually painful, sometimes have overlying erythema, and suppurate in 10–15% of cases (Fig. 69–1C, D, and E). Axillary/epitrochlear nodes are most commonly involved; next in frequency are head/neck nodes and then inguinal/femoral nodes. Approximately 50% of patients have fever, malaise, and anorexia. A smaller proportion experience weight loss and night sweats mimicking the presentation of lymphoma. Fever is usually low-grade but infrequently rises to ≥39°C. Resolution is slow, requiring weeks (for fever, pain, and accompanying signs and symptoms) to months (for node shrinkage).

Atypical CSD occurs in 10–15% of patients as extranodal or complicated disease in the absence or presence of lymphadenopathy. Atypical disease includes Parinaud’s oculoglandular syndrome (granulomatous conjunctivitis with ipsilateral preauricular lymphadenitis; Fig. 197–1E), granulomatous hepatitis/splenitis, neuroretinitis (often presenting as unilateral deterioration of vision; Fig. 69–1F), and other ophthalmologic manifestations. In addition, neurologic involvement (encephalopathy, seizures, myelitis, radiculitis, cerebellitis, facial and other cranial or peripheral palsies), fever of unknown origin, debilitating myalgia, arthritis or arthralgia (affecting mostly women >20 years old), osteomyelitis (including multifocal disease), tendinitis, neuralgia, and dermatologic manifestations (including erythema nodosum [see Fig. 14-40], sometimes accompanying arthropathy) occur. Other manifestations and syndromes (pneumonitis, pleural effusion, idiopathic thrombocytopenic purpura, Henoch-Schönlein purpura, erythema multiforme [see Fig. 14-25], hypercalcemia, glomerulonephritis, myocarditis) have also been associated with CSD. In elderly patients (>60 years old), lymphadenopathy is more often absent but encephalitis and fever of unknown origin are more common than in younger patients. In immunocompetent individuals, CSD—whether typical or atypical—usually resolves without treatment and without sequelae. Lifelong immunity is the rule.

DIAGNOSIS

Routine laboratory tests usually yield normal or nonspecific results. Histopathology initially shows lymphoid hyperplasia and later demonstrates stellate granulomata with necrosis, coalescing microabscesses, and occasional multinucleated giant cells—findings that, although nonspecific, may narrow the differential diagnosis. Serologic testing (immunofluorescence or enzyme immunoassay) is the most commonly used laboratory diagnostic approach, with variable sensitivity and specificity. Seroconversion may take a few weeks. Other tests are of low sensitivity (culture, Warthin-Starry silver staining), of low specificity (cytology, histopathology), or of limited availability in routine diagnostic laboratories (polymerase chain reaction [PCR], immunohistochemistry). PCR of lymph node tissue, pus, or the primary inoculation lesion is highly sensitive and specific and is particularly useful for definitive and rapid diagnosis in seronegative patients.

APPROACH TO PATIENT

TREATMENT

PREVENTION

Avoiding cats (especially kittens) and instituting flea control are options for immunocompromised patients and for patients with valvular heart disease.

DEFINITION AND ETIOLOGY

Trench fever, also known as 5-day fever or quintan fever, is a febrile illness caused by B. quintana. It was first described as an epidemic in the trenches of World War I and recently reemerged as chronic bacteremia seen most often in homeless people (also referred to in the latter setting as urban or contemporary trench fever).

EPIDEMIOLOGY

In addition to epidemics during World Wars I and II, sporadic outbreaks of trench fever have been reported in many regions of the world. The human body louse has been identified as the vector and humans as the only known reservoir. After a hiatus of several decades during which trench fever was almost forgotten, small clusters of cases of B. quintana chronic bacteremia were reported sporadically, primarily from the United States and France, in HIV-uninfected homeless people. Alcoholism and louse infestation were identified as risk factors.

CLINICAL MANIFESTATIONS

The typical incubation period is 15–25 days (range, 3–38 days). “Classical” trench fever, as described in 1919, ranges from a mild febrile illness to a recurrent or protracted and debilitating disease. Onset may be abrupt or preceded by a prodrome of several days. Fever is often periodic, lasting 4–5 days with 5-day (range, 3- to 8-day) intervals between episodes. Other symptoms and signs include headache, back and limb pain, profuse sweating, shivering, myalgia, arthralgia, splenomegaly, a maculopapular rash in occasional cases, and nuchal rigidity in some cases. Untreated, the disease usually lasts 4–6 weeks. Death is rare. The clinical spectrum of B. quintana bacteremia in homeless people ranges from asymptomatic infection to a febrile illness with headache, severe leg pain, and thrombocytopenia. Endocarditis sometimes develops.

DIAGNOSIS

Definitive diagnosis requires isolation of B. quintana by blood culture. Some patients have positive blood cultures for several weeks. Patients with acute trench fever typically develop significant titers of antibody to Bartonella, whereas those with chronic B. quintana bacteremia may be seronegative. Patients with high titers of IgG antibodies should be evaluated for endocarditis. In epidemics, trench fever should be differentiated from epidemic louse-borne typhus and relapsing fever, which occur under similar conditions and share many features.

TREATMENT

DEFINITION AND ETIOLOGY

Coxiella burnetii (Chap. 83) and Bartonella species are the most common pathogens in culture-negative endocarditis (Chap. 24). In France, for example, Bartonella species were identified as the etiologic agents in 28% of 348 cases of culture-negative endocarditis. Prevalence, however, varies by geographic location and epidemiologic setting. In addition to B. quintana and B. henselae (the most common Bartonella species implicated in endocarditis, the former more commonly than the latter), other Bartonella species have reportedly caused rare cases (Table 69-1).

EPIDEMIOLOGY

Bartonella endocarditis has been reported worldwide. Most patients are adults; more are male than female. Risk factors associated with B. quintana endocarditis include homelessness, alcoholism, and body louse infestation; however, individuals with no risk factors have had Bartonella endocarditis diagnosed as well. B. henselae endocarditis is associated with exposure to cats. Most cases involve native rather than prosthetic valves; the aortic valve accounts for ~60% of cases. Patients with B. henselae endocarditis usually have preexisting valvulopathy, whereas B. quintana often infects normal valves.

CLINICAL MANIFESTATIONS

Clinical manifestations are usually characteristic of subacute endocarditis of any etiology. However, a substantial number of patients have a prolonged, minimally febrile or even afebrile indolent illness, with mild nonspecific symptoms lasting weeks or months before the diagnosis is made. Initial echocardiography may not show vegetations. Acute, aggressive disease is rare.

DIAGNOSIS

Blood cultures, even with use of special techniques (lysis centrifugation or EDTA-containing tubes), are positive in only ~25% of cases—mostly those caused by B. quintana and only rarely those caused by B. henselae. Prolonged incubation of cultures (up to 6 weeks) is required. Serologic tests—either immunofluorescence or enzyme immunoassay—usually demonstrate high-titer IgG antibodies to Bartonella. Because of cross-antigenicity, serology does not distinguish between B. quintana and B. henselae and may also be low-titer cross-reactive with other pathogens, such as C. burnetii and Chlamydia species. Identification of Bartonella to the species level is usually accomplished by application of PCR-based methods to valve tissue.

TREATMENT

DEFINITION AND ETIOLOGY

Bacillary angiomatosis (sometimes called bacillary epithelioid angiomatosis or epithelioid angiomatosis) is a disease of severely immunocompromised patients, is caused by B. henselae or B. quintana, and is characterized by neovascular proliferative lesions involving the skin and other organs. Both species cause cutaneous lesions; hepatosplenic lesions are caused only by B. henselae, whereas subcutaneous and lytic bone lesions are more frequently associated with B. quintana. Bacillary peliosis is a closely related angioproliferative disorder caused by B. henselae and involving primarily the liver (peliosis hepatis) but also the spleen and lymph nodes. Bacillary peliosis is characterized by blood-filled cystic structures whose size ranges from microscopic to several millimeters.

EPIDEMIOLOGY

Bacillary angiomatosis and bacillary peliosis occur primarily in HIV-infected persons (Chap. 97) with CD4+ T cell counts <100/μL but also affect other immunosuppressed patients and, in rare instances, immunocompetent patients. The previously reported incidence of ~1 case per 1000 HIV-infected persons is now lower; the decrease is most likely attributable to effective antiretroviral therapy and the routine use of rifabutin and macrolides to prevent Mycobacterium avium complex infection in AIDS patients. Contact with cats or cat fleas increases the risk of B. henselae infection. Risk factors for B. quintana infection are low income, homelessness, and body louse infestation.

CLINICAL MANIFESTATIONS

Bacillary angiomatosis presents most commonly as one or more cutaneous lesions that are not painful and that may be tan, red, or purple in color. Subcutaneous masses or nodules, superficial ulcerated plaques (Fig. 69-2), and verrucous growths are also seen. Nodular forms resemble those seen in fungal or mycobacterial infections. Subcutaneous nodules are often tender. Painful osseous lesions, most often involving long bones, may underlie cutaneous lesions and occasionally develop in their absence. In rare cases, other organs are involved in bacillary angiomatosis. Patients usually have constitutional symptoms, including fever, chills, malaise, headache, anorexia, weight loss, and night sweats. In osseous disease, lytic lesions are generally seen on radiography, and technetium scan shows focal uptake. The differential diagnosis of cutaneous bacillary angiomatosis includes Kaposi’s sarcoma, pyogenic granuloma, subcutaneous tumors, and verruga peruana. In bacillary peliosis, hypodense hepatic areas are usually evident on imaging. In patients with advanced immunodeficiency, B. henselae and B. quintana are important causes of fever of unknown origin. Intermittent bacteremia with positive blood cultures can occur with or without endocarditis.

PATHOLOGY

Bacillary angiomatosis consists of lobular proliferations of small blood vessels lined by enlarged endothelial cells interspersed with mixed infiltrates of neutrophils and lymphocytes, with predominance of the former. Histologic examination of organs with bacillary peliosis reveals small blood-filled cystic lesions partially lined by endothelial cells that can be several millimeters in size. Peliotic lesions are surrounded by fibromyxoid stroma containing inflammatory cells, dilated capillaries, and clumps of granular material. Warthin-Starry silver staining of bacillary angiomatosis and peliosis lesions reveals clusters of bacilli. Cultures are usually negative.

DIAGNOSIS

Bacillary angiomatosis and bacillary peliosis are diagnosed on histologic grounds. Blood cultures may be positive.

TREATMENT

PREVENTION

Control of cat-flea infestation and avoidance of cat scratches (for prevention of B. henselae) and avoidance and treatment of body louse infestation (for prevention of B. quintana) are reasonable strategies for HIV-infected persons. Primary prophylaxis is not recommended, but suppressive therapy with a macrolide or doxycycline is indicated in HIV-infected patients with bacillary angiomatosis or bacillary peliosis until CD4+ T cell counts are >200/μL. Relapse may necessitate lifelong suppressive therapy in individual cases.

DEFINITION AND ETIOLOGY

Carrión’s disease is a biphasic disease caused by B. bacilliformis. Oroya fever is the initial, bacteremic, systemic form, and verruga peruana is its late-onset, eruptive manifestation.

EPIDEMIOLOGY AND PREVENTION

Infection is endemic to the geographically restricted Andes valleys of Peru, Ecuador, and Colombia (~500–3200 m above sea level). Sporadic epidemics occur. The disease is transmitted by the phlebotomine sandfly Lutzomyia verrucarum. Humans are the only known reservoir of B. bacilliformis. Sandfly control measures (e.g., insecticides) and personal protection measures (e.g., repellents, screening, bed nets) may decrease the risk of infection.

PATHOGENESIS

After inoculation by the sandfly, bacteria invade the blood vessel endothelium and proliferate; the reticuloendothelial system and various organs may also be involved. Upon reentry into blood vessels, B. bacilliformis invades, replicates, and ultimately destroys erythrocytes, with consequent massive hemolysis and sudden, severe anemia. Microvascular thrombosis results in end-organ ischemia. Survivors sometimes develop cutaneous hemangiomatous lesions characterized by various inflammatory cells, endothelial proliferation, and the presence of B. bacilliformis.

CLINICAL MANIFESTATIONS

The incubation period is 3 weeks (range, 2–14 weeks). Oroya fever may present as a nonspecific bacteremic febrile illness without anemia or as an acute, severe hemolytic anemia with hepatomegaly and jaundice of rapid onset leading to vascular collapse and clouded sensorium. Myalgia, arthralgia, lymphadenopathy, and abdominal pain may develop. Temperature is elevated but not extremely so; high fever may suggest intercurrent infection. Subclinical asymptomatic infection also occurs. In verruga peruana, red, hemangioma-like, cutaneous vascular lesions of various sizes appear either weeks to months after systemic illness or with no previous suggestive history. These lesions persist for months up to 1 year. Mucosal and internal lesions may also develop.

DIAGNOSIS AND APPROACH TO THE PATIENT

Systemic illness (with or without anemia) or the development of cutaneous lesions in a person who has been to an endemic area raises the possibility of B. bacilliformis infection. Severe anemia with exuberant reticulocytosis—and sometimes thrombocytopenia—can occur. In systemic illness, Giemsa-stained blood films show typical intraerythrocytic bacilli, and blood and bone marrow cultures are positive. Serologic assays may be helpful. Biopsy may be required to confirm the diagnosis of verruga peruana. Differential diagnosis includes the spectrum of coendemic systemic febrile illnesses (e.g., typhoid fever, malaria, brucellosis) as well as diseases producing cutaneous vascular lesions (e.g., hemangiomata, bacillary angiomatosis, Kaposi’s sarcoma).

TREATMENT

COMPLICATIONS AND PROGNOSIS

Mortality rates associated with Oroya fever have been reported to be as high as 40% without treatment but are considerably lower (~10%) with treatment. Complications such as bacterial superinfection and neurologic and cardiac manifestations occur frequently. Generalized massive edema (anasarca) and petechiae are associated with poor outcome. Permanent immunity usually develops.