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13.1 Introduction

Bartonella species cause a wide range of clinical syndromes which vary substantially depending on the infecting species and immune status of the infected. Well known as a cause of trench fever and bartonellosis (a febrile illness endemic in the high valleys of the Andes mountains [1]), their recognition as human pathogens in the United States was virtually forgotten until the early 1990s when new diagnostic tests linked this genus to cat scratch disease. Today, the use of such tests has significantly broadened the clinical spectrum of cat scratch disease and also confirmed the role of Bartonella as the cause of bacillary angiomatosis (BA) , an entity seen mainly among the immunocompromised .

13.2 Making the Link Between Bartonella and Cat Scratch Disease

Cat scratch disease (CSD) was first described in a French boy seen in 1931 [2], but >  50 years elapsed before evidence of its bacterial cause emerged. In 1983, Warthin-Starry staining revealed small bacilli among 34 of 39 lymph node samples from patients with CSD and in subcutaneous nodules from a patient with AIDS with unusual neovascular lesions subsequently recognized as BA [3, 4]. In 1988, it was proposed that CSD and BA may result from infection by the same organism based on the similarity of the morphologic and staining characteristics of these bacilli and that a history of cat scratches was often present in these patients. Importantly, antiserum raised against the “CSD bacillus” reacted with organisms in tissue samples from BA patients [5].

In 1990, molecular probe techniques (polymerase chain reaction (PCR)) suggested that BA was caused by a bacterium similar to Bartonella quintana [6]. Other reports described morphologically similar-appearing organisms from patients with a vascular abnormality of the liver known as peliosis hepatitis [7] and febrile bacteremia [8], subsequently noted to be caused by both B. quintana and B. henselae [9–12] . Soon thereafter, a newly developed immunofluorescent antibody serologic test developed for BA was positive in 36 of 41 (88 %) serum samples from persons with suspected CSD, compared with only 6 % among healthy controls [13]; findings soon corroborated in a field trial among CSD patients in Connecticut, USA [14]. During this time, it was reported that CSD skin test antigen contained Bartonella nucleic acid sequences [15]. These observations confirmed the etiologic link between Bartonella and CSD and BA. Subsequently, organisms have been visualized microscopically or detected using PCR at the site of skin inoculation, lymph nodes, bone, eye, liver, and spleen in patients with CSD [16–21] and in nearly every organ, including the brain, among those with BA [22]. Regardless, the organism is only infrequently successfully cultured from clinical specimens among patients with either of these conditions.

13.3 Pathogenesis

Bartonella are facultative , intracellular Gram-negative bacilli with relatively fastidious growth characteristics. To maximize growth, tissue samples ideally should be directly plated onto solid media supplemented with hemin and incubated in a hypercapneic atmosphere. Most standard protocols for detection of such fastidious bacteria will allow for growth of Bartonella, but only after at least 7–10 days of incubation [23]. Currently at least 22 species have been described, 12 are known to cause disease in humans and the complete genome is available for 10 separate species.

In general, Bartonella establish infection within the reservoir host and eventually establish persistence within the erythrocyte. Several observations suggest that Bartonella may persist intracellularly: (1) persistent bacteremia has been noted in humans and a variety of mammals, (2) isolation is enhanced by lysis centrifugation (which disrupts cellular membranes), (3) BA and trench fever patients may experience clinical relapse, and (4) better clinical response has been noted with antimicrobial agents that penetrate intracellularly. The defining pathogenic characteristics of human infection vary substantially with the infecting Bartonella species and also with immune status of the host. Transmission to humans can occur directly via an arthropod vector (e.g. sandflies and bartonellosis) or indirectly via inoculation (perhaps from infected flea feces) through intact skin via a cat scratch or other mucous membrane contact (CSD and BA). Many virulence factors involved in human infection have been identified that contribute to cellular invasion , erythrocyte persistence, pathologic angiogenesis, and evasion from host immune responses. A comprehensive review of Bartonella pathogenetic mechanisms has been recently published [24].

These primary clinical histopathologic manifestations range from focal granulomatous changes (CSD), multifocal angioproliferative changes (BA), endovascular multiplication (endocarditis), and an (proposed) exaggerated inflammatory response without evidence of bacterial invasion (meningoencephalitis). In CSD specifically, the lymph node histology reveals patchy, necrotic, granulomatous change with stellate abscesses and variable infiltration of leukocytes. This is in contrast to BA which typically reveals proliferation of small blood vessels with large, “plump” cuboidal endothelial cells with intermixed leukocyte infiltration and focal necrosis without granulomas, similar to that seen with bartonellosis.

13.4 Ecology

Various reservoirs for Bartonella species have been identified including feline, bovine, canine, cetacean, and rodent species. Most individual species, however, are relatively restricted in their distribution. Epidemiologic studies of patients with CSD and BA have shown that contact with cats, particularly kittens in the case of CSD, is associated with disease [14, 25]. Cats from households of such patients are more likely to have antibody against B. henselae than are control cats, seroprevalence of anti-Bartonella antibody among community cats can be very high (depending on the region) and overt feline bacteremia among community cats may exceed 50 % persisting for up to a year [14, 26–29]. Younger cats and stray cats are more likely to be infected with Bartonella than are older or domesticated cats [30].

It appears that each pathogenic Bartonella species may be transmitted by an arthropod vector, with variation by species. These vectors include flies, fleas, keds, lice, sandflies, and ticks, but most infections appear to be accidental in animal and human hosts. B. quintana and B. bacilliformis are transmitted by the human body louse and the sandfly, respectively. For B. henselae , the cat flea (Ctenocephalides felis) has been confirmed as a vector for CSD and/or BA through epidemiologic [14, 25] and experimental [14, 27, 31, 32] evidence. These data show that cat fleas can harbor Bartonella as detected by culture and PCR, cats bacteremic with B. henselae are more likely than nonbacteremic cats to be infested with fleas, and fleas can successfully transmit to Bartonella cats in a laboratory setting.

13.5 Cat Scratch Disease

Although definitive evidence is not available, it appears that the majority of infections caused by Bartonella species result in CSD, usually due to B. henselae . Large case series and systematic evaluations have defined the epidemiology of CSD. United States population-based surveillance data indicate that the incidence over all age groups is 3–4 per 100,000 population. Approximately 60 % of cases occur in persons <  18 years of age with children 5–10 years of age at greatest risk (~ 10 per 100,000 population) [14, 33]. Familial and geographic clusters have been reported and incidence peaks in the winter months, with some geographic variability. Hospitalization for this illness occurs most commonly for surgical drainage or excision of affected lymph nodes with an annual incidence of ~ 0.6/100,000 children <  18 years of age in the United States [34]. A case-control evaluation noted that owning a kitten and being scratched, bitten, or licked by a kitten with fleas are the most important risk factors for disease [14]. Nearly 25 % of persons with CSD, however, do not report intimate contact with cats, though person-to-person transmission has not been documented.

Uncomplicated CSD is usually a self-limited illness characterized by lymphadenopathy that occurs after contact with a cat. A few days after a cat-scratch or bite, a papule or wheal frequently develops at the site which is followed by development of regional lymphadenopathy 1–2 weeks later . Concomitant constitutional symptoms occur in up to 60 % of cases including malaise, fever, sore throat, and/or headache (Table 13.1). Children <  15 years of age are more likely to develop lymphadenopathy in the neck, whereas older persons are more likely to have enlarged nodes in the groin or axilla [33]. Up to one-third of patients will report lymphadenopathy at more than one site. Nodes generally are not tender, yet suppuration occurs in 15–30 % of cases with even deep neck space disease reported [35]. Prolonged bacteremia and even widespread dissemination involving multiple organ systems has been reported as well [36, 37]. In most cases of CSD, the clinical illness resolves spontaneously but lymphadenopathy may persist for weeks to months [38] .

Table 13.1 Cat scratch disease: classic manifestations. (Data from [14, 38, 46, 66]
Full size table

The widespread use of a serologic test against Bartonella species has rapidly and significantly expanded the clinical spectrum of this illness to include nearly every organ system. Delays in diagnosis are commonplace and occur most likely due to general lack of awareness with the potential for infection among patients who have a non-classic presentation. Central nervous system disease most commonly presents as encephalopathy with associated seizures in 40–50 % of patients [21]. Status epilepticus, cranial and peripheral nerve paresis, and intracranial masses also have been reported. Onset is usually 1–2 months after the development of lymphadenopathy , and complete and rapid recovery is the rule, but severe disease with sequelae may occur [21, 39, 40]. Cerebrospinal fluid analysis is usually normal, but lymphocytic pleocytosis is noted in approximately one-third of patients. Ophthalmic disease usually presents as Parinaud oculoglandular syndrome (bulbar conjunctivitis, preauricular lymphadenopathy , and conjunctival granuloma), but other manifestations are well-described and neuroretinitis in the form of a “macular star” is particularly distinctive [41, 42]. Hepatitis and/or splenitis is well-described as well, usually accompanied by prolonged fever, abdominal pain, arthralgias, and/or pleomorphic rashes. Back pain is a common presenting symptom in such children [43–45]. In addition, many patients have been reported with musculoskeletal disease (particularly in women >  20 years of age) or osteomyelitis with vertebral disease and contiguous abscess formation being prominent [46, 47]. Pulmonary disease has also been described in which nearly all patients developed pleural effusion [48]. The majority of patients with non-classic disease recover completely, and no deaths have been directly attributable to CSD. Clinical disease appears to provide lifelong protection insofar as recurrent disease has been described very rarely [43].

13.6 Bacillary Angiomatosis

BA is an uncommon manifestation of B. henselae or B. quintana infection seen primarily in adults with acquired immunodeficiency , usually during the late stages of AIDS [22] . The incidence and seasonal distribution of BA is unknown. Being scratched or bitten by a cat has been established as a risk factor for BA, but overall, one-third of patients did not report such contact in one study [25]. The clinical manifestations of BA are quite varied and may involve nearly every organ system but cutaneous, osseous, hepatic (peliosis hepatis), and splenic disease are the most commonly reported [22]. The range of cutaneous disease is broad, usually including superficial, erythematous, highly vascular, exophytic lesions or subcutaneous nodules. Lesions occur singly, or hundreds of lesions may occur in the same patient. Bone disease usually is painful and localized to tubular bones, with osteolysis noted on roentgenogram. Hepatosplenic disease often presents with prolonged fever, abdominal pain, and substantial weight loss. Only a few instances of BA have been reported among children some of whom were immunocompetent [49–51].

13.7 Other Syndromes

In addition to “classic” CSD and BA, Bartonella species have been linked to several other syndromes. B. quintana and B. henselae bacteremia, most commonly seen among the homeless or those infested with scabies or lice, may persist for prolonged periods despite antimicrobial therapy [8, 11, 12, 52]. Endocarditis caused by several Bartonella species has been described and now should be included as a potential cause of “culture-negative” HACEK-type endocarditis, i.e., endocarditis caused by fastidious Gram-negative organisms. Such patients usually have one or more underlying conditions, including infection with HIV, chronic alcoholism, or homelessness [53–56]. The homelessness and infestations associated with Bartonella infection noted above parallel conditions experienced by soldiers with trench fever in which prolonged bacteremia with B. quintana was also reported .

Lastly, Bartonella have been implicated in several different central nervous system syndromes which may represent rare forms of CSD or BA, or unique manifestations of Bartonella infection altogether. These syndromes, most frequently noted in patients with HIV infection, include aseptic meningitis, transient cranial and/or peripheral nerve dysfunction, aphasia, alteration in mood or affect, psychoses, space-occupying lesions, and an acute psychiatric complex [41, 57, 58].

13.8 Diagnosis

The approach to diagnosis of infection with Bartonella varies with the clinical presentation. For classic CSD, particularly in immunocompetent hosts, the diagnosis can usually be confidently made with the subacute emergence of regional lymphadenopathy with or without constitutional symptoms in persons with prior traumatic contact with a cat or kitten distal to the affected node . In such instances, serologic testing, molecular diagnostics , or imaging is usually unnecessary.

Other Bartonella syndromes, however, require the use of serologic testing or clinical specimens for microbiologic and/or molecular evaluations. Currently, serologic testing is the mainstay of diagnosis and is most commonly done using a commercially available enzyme immunoassay or an indirect immunofluorescence assay for Bartonella IgM and IgG antibody levels . The sensitivity of these tests is variable and may be low, but specificity is generally quite high [59, 60]. Among patients with CSD, antibody titers peak at 4–5 months after onset of symptoms and have been shown to persist for up to 3 years [14, 61]. Serologic tests have completely supplanted the use of the CSD skin test, a non-standardized preparation previously available in limited quantities, originally developed in 1946 [2]. Currently available serologic tests are not able, however, to differentiate reliably between species of Bartonella. Molecular techniques are also available in many commercial laboratories, but the methods are not standardized .

Bartonella species are relatively fastidious and recovery is maximized with the use of lysis centrifugation technique and selective media that contain hemin, followed by growth in a hypercapnic atmosphere for at least 10 days. Tissue samples may reveal Bartonella with the use of a range of silver stains and Gram’s stain is generally insensitive for this pathogen.

13.9 Therapy

The majority of mild-to-moderate cases of CSD resolve in 1–2 months without any antimicrobial therapy. Although Bartonella species appear to be susceptible to several antimicrobials when tested in vitro, such results do not predict reliably the clinical response to therapy; use of such tests as a clinical tool should therefore be discouraged.

Only one prospective controlled study of therapy for cat scratch disease has been published [62]. This study reported on 29 patients who were randomized to azithromycin (for 5 days) or placebo after diagnosis was confirmed by serologic testing . The outcome measure was change in the (largest) lymph node size, as determined by ultrasound 30 days after initiation of treatment. No other clinical signs or symptoms were reported and drug compliance was not monitored. The authors note that those in the treatment group had significant improvement in nodal size and suggested that azithromycin be considered for therapy of this condition.

This study, however, was flawed in several important areas rendering its conclusions highly suspect [63]. There were only 14–15 patients per group, >  50 % of whom in each group received at least one antimicrobial before randomization and the details of type and duration of antimicrobial use are not presented. Very little information was presented with regard to clinical resolution of signs and symptoms (aside from the ultrasound data) and interestingly there was little correlation between physical examination and findings on ultrasonography of lymph nodes. As well, the authors report a statistically significant difference in nodal size at 30 d, but this difference was not present by 60 d. The clinical relevance of the ultrasonographic findings, specifically for deciding about the need for antimicrobial therapy in the absence of demonstrable clinical benefit, is unclear. Anecdotal evidence and retrospective series suggest that some clinical response may be achieved for patients with CSD with trimethoprim-sulfamethoxazole, rifampin, gentamicin, and in adults, ciprofloxacin.

A combination of therapeutic restraint, pain control, and reassurance remains the most prudent approach to the great majority of patients with uncomplicated CSD in whom clinical symptoms and signs, as well as lymphadenopathy , will likely spontaneously resolve over several weeks to months. Antimicrobial therapy may be considered for those patients (1) in whom lymphadenopathy does not resolve over a reasonable period, (2) in whom lymphadenopathy is associated with significant morbidity , such as pain or persistence of debilitating constitutional symptoms, (3) with severe systemic disease; i.e., encephalopathy, osteomyelitis, or neuroretinitis, and/or (4) with an underlying medical disorder complicated by severe CSD. Specific recommendations for these circumstances cannot be definitive as controlled data are unable, but an expert panel has published guidelines [64].

Aspiration of inflamed lymph nodes only should be performed to rule out more serious diagnoses or if a treatable superinfection is suspected. In such cases, either a fine-needle aspiration or excisional biopsy should be done; incision and drainage procedures may promote the development of fistulae. No specific measures regarding antimicrobial prophylaxis of close contacts of the implicated cat itself can be recommended. Also, declawing of the cat or its removal from the household is not necessary.

Patients with BA usually respond to macrolides or tetracyclines. Uncomplicated cutaneous disease in HIV-infected patients requires at least 6–8 weeks of therapy, whereas more severe or invasive disease may require months of therapy or perhaps lifetime suppressive therapy. Others have proposed specific treatment regimens for BA, bacteremia, and endocarditis caused by Bartonella that include various combinations of gentamicin, erythromycin, or ceftriaxone [64].

13.10 Opportunities

With the wide availability of serologic and molecular diagnostic tools , new information about Bartonella infections will likely continue to emerge. Important knowledge gaps remain in nearly all domains of this organism as a human pathogen including the dynamics of its ecology and transmission in nature, human pathogenesis , relationship of the host to the pathogen, and differing responses to antimicrobial therapy. Cats remain the most important reservoir for CSD and BA—and over one-third of all U.S. households include at least one cat [65]—perhaps new information will lead to a preventive approach such as vaccination of cats.