MICHAEL GILADI, MOSHE EPHROS, AND DAVID F. WELCH
The bacterial genus Bartonella is named for Dr. A. L. Barton, who described the erythrocyte-adherent Bartonella bacilliformis in 1909. It is the etiologic agent of Oroya fever, an acute bacteremic infection characterized by sepsis and hemolysis, and of verruga peruana, principally a cutaneous nodular vascular eruption representing chronic infection. The previously suspected link between the two conditions was tragically confirmed in 1885 by Daniel Carrión, a medical student who injected himself with bloody material from a verruga and subsequently died of Oroya fever. This form of bartonellosis is thus known as Carrión disease and South American bartonellosis because it is limited to the Andean mountain regions of Peru, Ecuador, and Colombia. It affects the local population and, rarely, travelers to these countries. Bartonellosis garnered little attention outside its endemic zone in recent years until related bacteria, then named Rochalimaea species, were found to be important pathogens, primarily in patients with acquired immunodeficiency syndrome (AIDS).
TAXONOMY
The now supplanted genus Rochalimaea was formerly classified with Bartonella in the order Rickettsiales and consisted of only two species, Rochalimaea (Rickettsia) vinsonii, the “Canadian vole agent,” and Rochalimaea(Rickettsia) quintana, the agent of trench fever. The latter is a debilitating but self-limited human illness so named after it affected many military personnel in World War I. Except for sporadic outbreaks, trench fever had all but disappeared from the clinical scene in recent decades. However, the 1990s saw the reemergence of R. quintana as a pathogen of considerable interest (1–5), coincident with the discovery of two related species that also cause human disease, originally named Rochalimaea henselae and Rochalimaea elizabethae (6–9).
Bartonella species are alphaproteobacteria, which also contains Afipia, Agrobacterium, and Brucella. Unlike members of the order Rickettsiales, Bartonella species have been cultured on cell-free media. Sequencing of 16S ribosomal RNA (rRNA) genes to determine phylogenetic relationships among these organisms revealed high levels of relatedness between B. bacilliformis and the former Rochalimaeaspecies (10) and confirmed that all of them are more closely related to Brucella and Agrobacterium than to members of the rickettsiae. Based on DNA hybridization and 16S rRNA similarity, the former Rochalimaea species were combined with Bartonella in 1993 (11), and the members of the family Bartonellaceae were removed from the order Rickettsiales. A further proposal was made in 1995 to merge into the genus Bartonella a number of species of the genus Grahamella, which are intraerythrocytic pathogens of rodents, birds, fish, and other animals (12). Recently, an increasing number of Bartonellaspecies have been identified and characterized. Currently, the genus Bartonella consists of at least 27 recognized species or subspecies, of which at least 13 have been recognized as confirmed or potential human pathogens. Others have been isolated from nonhuman wild and domestic mammals, including rodents, cervids, and cattle, without associated identifiable human illness (13). Comparison of phylogenetic data, inferred mainly from 16S rDNA, 16S-23S rRNA intergenic spacer, citrate synthase and 60-kd heat shock protein gene sequences have identified six evolutionary clusters within the genus Bartonella (14). Cat-scratch disease (CSD)–causing B. henselae are classified into two serotypes, Houston-1 and Marseille, which correspond to two genotypes based on 16S rRNA gene sequences, genotype I and genotype II. The significance of this and other classifications with respect to pathogenesis and clinical manifestations has not been established (15,16).
EPIDEMIOLOGY
Infections with B. bacilliformis are geographically limited to middle altitudes of the Andes mountains, probably because of the distribution of species of the genus Lutzomyia (formerly Phlebotomus), its sandfly vectors. B. quintanais globally distributed; there have been reports of focal, but widely separated, outbreaks of trench fever, also known as quintan or 5-day fever. Outbreaks commonly have been associated with conditions of poor sanitation and personal hygiene that predispose to exposure to the human body louse Pediculus humanus, the only identified vector of B. quintana. Although B. quintana has also been identified in the human head louse P. humanus capitis, there is no strong evidence that head lice are vectors of this organism between human hosts (17). Nonhuman vertebrate reservoirs have not yet been identified for either B. bacilliformis or B. quintana.
Cats bacteremic with B. henselae constitute the major reservoir of this pathogen. B. henselae has been documented to cause bacteremia (18,19) in seemingly healthy domestic cats, including some that have been specifically associated with bacillary angiomatosis (19) or typical CSD (18) in their human contacts. B. henselae bacteremia has been globally reported among pet, impounded, or stray cats. Rates of bacteremia can vary and may be as high as 89% (18–25). Other animals, particularly dogs, have been implicated as a possible reservoir for B. henselae, but reports are anecdotal and evidence essentially circumstantial. Fleas and ticks are arthropod vectors of B. henselae, based on epidemiologic associations (26,27) and reports of identification of B. henselae by both culture and DNA amplification from cat-associated fleas (18,19). Cat-to-cat transmission by infected fleas has been shown to occur (21), although evidence of cat-to-human transmission by fleas is lacking. Like B. quintana, B. henselae infection is globally endemic. However, regional variations in the prevalence of either B. henselae or B. quintana may occur. Transmission to humans has been linked to cats by serologic and epidemiologic studies (27,28), its recovery from cases of human lymphadenitis consistent with CSD (18,29), and the identification of B. henselae DNA by polymerase chain reaction (PCR) in CSD lymphadenitis and other affected tissues (30–33).
OVERVIEW OF CLINICAL/PATHOLOGIC MANIFESTATIONS
Oroya Fever and Verruga Peruana
Bartonella bacilliformis
Oroya fever, the bacteremic illness of primary B. bacilliformis infection, develops 2 to 14 weeks (mean 3 weeks) after inoculation by the sandfly Lutzomyia verrucarum (34). Bacteria invade blood vessel endothelium, proliferate, and upon reentry into blood vessels replicate and destroy erythrocytes. Microvascular thrombosis results in end-organ ischemia. In its milder form, the febrile illness often remits in a week. When abrupt in onset, high fever, chills, diaphoresis, headache, and mental status changes are associated with a rapidly developing severe hemolytic anemia (35–38). Lymphadenopathy, thrombocytopenia, severe myalgia and arthralgia, and complications such as delirium, coma, dyspnea, and angina can occur during this stage. Without antimicrobial treatment, mortality rates up to 40% to 80% have been reported (39,40); however, a disease milder in severity and with a low (0.7%) case-fatality rate may occur (41). Convalescence is associated with a decline of fever and disappearance of bacteria on blood smears as well as increased susceptibility to intercurrent opportunistic infections such as salmonellosis (42) or toxoplasmosis (43). Usually within months of acute infection, verruga peruana may become evident. This late-stage manifestation of infection is characterized by crops of nodular skin lesions; mucosal and internal lesions can also occur. Their histology typically contains neovascular proliferation with occasional bacteria evident in interstitial spaces. B. bacilliformis invasion of endothelial cells, which was described by Rocha-Lima and believed to be the etiology of cytoplasmic inclusions, is rare (44). Verruga peruana lesions may develop at one site while receding at another. They may persist for months to years and eventually become fibrotic with involution. Asymptomatic persistent bacteremia with B. bacilliformis infection can occur in up to 15% of survivors of acute infection (45) who may serve as the organism’s reservoir.
Bacteremic Illness and Endocarditis
Bartonella quintana, Bartonella henselae, and Other Bartonella Species
The natural course of trench fever includes a spectrum of self-limited clinical patterns (46). Incubation may span days to weeks before the typical sudden onset of fever. The febrile illness may be brief (lasting 4 to 5 days), prolonged (uninterrupted for 2 to 6 weeks), or most commonly, paroxysmal (three to five episodes, each of about 5 days). Fever may be accompanied by other nonspecific symptoms and signs such as headache, vertigo, retroorbital pain, conjunctival injection, nystagmus, myalgia, arthralgia, hepatosplenomegaly, rash, leukocytosis, and albuminuria. B. quintana has reemerged as a cause of bacteremic illness (designated also as urban trench fever) in human immunodeficiency virus (HIV)–uninfected homeless patients with chronic alcoholism (5,47,48). B. quintana was also identified in body lice from these patients. Clinical characteristics include headache, sweats, severe leg pain, and low platelet counts. Many bacteremic patients were afebrile and some were asymptomatic. Chronic bacteremia, as indicated by positive blood cultures up to 78 weeks, and intermittent bacteremia were found to occur.
B. quintana or B. henselae bacteremia in HIV-infected persons is often characterized by insidious development of fatigue, malaise, body aches, weight loss, progressively higher and longer recurring fevers, and sometimes headache. Hepatomegaly may occur. Although there is evidence implicating Bartonella species in some cases of HIV-associated encephalopathy, meningoencephalitis, and neuropsychiatric disease, lumbar puncture during acute bacteremia in HIV-infected persons can be unrevealing (6,9). Rarely, fever without localizing symptoms or signs in association with B. henselae bacteremia has been reported in immunocompetent patients (6,9). Aseptic meningitis concurrent with bacteremia has been documented in an immunocompetent host (26). B. henselae bacteremia can evolve into long-term asymptomatic persistence (26).
Both B. quintana and B. henselae are considered important pathogens of endocarditis, accounting for approximately 3% of all patients with infective endocarditis, and a much larger proportion, up to 28%, of patients with culture-negative endocarditis (1,4,49–51). B. elizabethae, B. vinsonii subspecies berkhoffii, B. alsatica, and B. koehlerae have rarely been isolated from patients with endocarditis (8,52–54). Patients with B. quintana endocarditis often have been homeless and alcoholic, whereas patients with B. henselae endocarditis have commonly reported being in contact with a cat. The typical clinical presentation is that of subacute bacterial endocarditis, including neurologic manifestations such as stroke. In a retrospective study of 101 patients with Bartonella endocarditis, embolic phenomena were reported in 43% of patients. A significant number of patients were afebrile at presentation, 12 of the 101 patients died, 2 relapsed, and 76 underwent valvular surgery (55).
Bacillary Angiomatosis and Peliosis
Bartonella quintana and Bartonella henselae
Bacillary angiomatosis (BA), also termed epithelioid angiomatosis or bacillary epithelioid angiomatosis, is a disorder of neovascular proliferation originally described involving skin and regional lymph nodes of HIV-infected persons (56–58). It has since been demonstrated to involve a variety of internal organs (59–61), including the brain (62), and to occur in other immunocompromised (59,63) and immunocompetent hosts (64–66). B. quintanainfections have a predilection for causing subcutaneous and deep soft tissue disease and lytic bone lesions, whereas B. henselae infections are associated with lymph node disease and parenchymal peliosis of the liver and/or spleen. B. henselae and B. quintana (2,9,67) equally cause BA of the skin, the most common manifestation of this illness. Risk factors for B. quintana infection are low income, homelessness, and body louse infestation, whereas B. henselaeinfection is associated with cat or cat fleas contact (67).
Skin lesions often arise in crops, but their timing and gross appearance can vary. They can be remarkably similar to the lesions of verruga peruana. However, most cases of BA have been identified outside the region of endemic B. bacilliformis. Thus, the most important differential diagnoses are Kaposi sarcoma and pyogenic granuloma. Studies addressing the potential association between pyogenic granuloma and Bartonella infection have resulted in conflicting results (68,69). The histologic distinction of BA from other neovascular tumors has been clearly described (70,71).
Bacillary peliosis (BP), originally described involving the liver and sometimes spleen in HIV-infected persons (72), has since been identified in other immunosuppressed persons and found to involve lymph nodes as well (59,73). Involved organs contain numerous blood-filled, partially endothelial cell–lined cystic structures and surrounding clumps of bacilli (identified by Warthin-Starry silver staining) in the midst of inflammatory cells.
Cat-Scratch Disease
Bartonella henselae (Possibly Bartonella clarridgeiae, Bartonella quintana, and Afipia felis)
B. henselae is the major etiologic agent of CSD (18,19,28–32). B. clarridgeiae, B. quintana, and Afipia felis have rarely been associated with CSD in humans (74–76). The various manifestations that comprise CSD have been recognized over the past 100 years, but the syndrome per se was not really defined until 1950 (77).
In typical CSD (about 90% of cases), a cutaneous papule or pustule usually develops within a week after an animal contact (more commonly a kitten) at a site of inoculation (usually a scratch or bite) (78–80). Regional adenopathy (mostly involving head, neck, or upper extremity) develops in 1 to 7 weeks (Fig. 26.1). About one third to one half of patients have fever, and about one sixth develop lymph node suppuration. The histopathology of nodes includes a mixture of nonspecific inflammatory reactions including granulomas and stellate necrosis. Bacilli may be demonstrable by Warthin-Starry staining. Atypical CSD (about 10%) occurs as extranodal or complicated disease in the absence or presence of lymphadenopathy and includes Parinaud oculoglandular syndrome, encephalopathy, neuroretinitis and other neurologic syndromes, fever of unknown origin, hepatic and splenic abscesses, granulomatous hepatitis, debilitating myalgia, arthritis or arthralgia (affecting mostly females older than age 20 years), osteomyelitis and other musculoskeletal manifestations, and erythema nodosum (79,81–84). Other manifestations and syndromes (e.g., pneumonitis, myocarditis, and thrombocytopenia) have also been associated with CSD (85–88).
In most cases, whether typical or atypical, spontaneous resolution occurs in 2 to 4 months. The prolonged course of CSD lymphadenopathy, which is often accompanied by fever, night sweats, weight loss, and liver or spleen involvement, may resemble lymphoma or other malignant processes. Consequently, this may lead to unnecessary, extensive, costly, and sometimes invasive diagnostic procedures (89–91).
NEUROLOGIC MANIFESTATIONS OF BARTONELLA INFECTIONS
Associated with Oroya Fever
Acute B. bacilliformis infection (Oroya fever) has long been recognized to have associated neurologic manifestations (34). Acute onset of severe headache is usually coincident with onset of fever and development of hemolysis. Characteristics of the meningoencephalitis that occurs in about 1 in 10 cases include diffuse neurologic impairment that may result in seizures, hallucinations, delirium, and/or reduced consciousness, which can progress to obtundation and coma. Diminished level of consciousness is associated with a poorer prognosis. Meningeal findings without encephalitis also can occur and vice versa. Less commonly, localized findings in the form of cranial or spinal nerve palsies occur, with the latter sometimes causing a meningomyelitis with flaccid or spastic paralysis. Cerebrospinal fluid (CSF) protein elevation and mild mononuclear leukocytosis can occur, and bacteria may be identified within these leukocytes. Peripheral nerve palsies that occur during the later eruptive verruga stage are usually due to granulomatous inflammatory lesions within peripheral nerves; such impediments are usually chronic but associated with gradual resolution.
The often fatal course of Oroya fever has allowed histopathologic correlation with clinically evident neurologic manifestations (92,93). Most of the neurologic manifestations appear to be the result of the vascular endothelial cell damage that develops. In the leptomeninges, capillary and venous congestion and thrombosis are common, associated with microhemorrhages, adventitial proliferation, perivascular edema, and rarely, formation of new microvasculature. As a consequence of profound hemolytic anemia (hemoglobin concentration ≤4 g/L has been reported in Oroya fever) and microvascular thrombosis, resulting in ischemia, there can be subacute neuronal degeneration. Reactive glial proliferation is usually diffuse but in some cases may be nodular. Occasionally, granuloma-like nodules composed of microglial cells and histiocytes, named verrucomas, are found in the choroid plexus, ependyma, and brain parenchyma. Ultimately, the meningoencephalitis associated with Carrión disease appears to be more a consequence of the damage done to the host’s microvasculature, complicated by the associated profound anemia, than the result of a primary neurotropic affinity on the part of B. bacilliformis.
Associated with Trench Fever and Other Manifestations of Bartonella quintana Infection
Although trench fever is often associated with headache, specific neurologic manifestations of this form of B. quintana infection are uncommon. Few cases of B. quintana infection with distinct central nervous system (CNS) pathology have been described. A 19-year-old HIV-uninfected patient with hypogammaglobulinemia presented with fever, left hemiparesis, slurred speech, urinary incontinence, blurred vision, and behavioral changes, which developed over 2 months due to a necrotizing granulomatous process involving the right thalamus and surrounding tissues. B. quintana was identified in brain tissue, bone marrow, and serum specimens from this patient by PCR and nucleotide sequencing. B. quintana DNA was also amplified from the CSF of an 8-year-old immunocompetent child with encephalitis and axillary adenitis (94). A previously healthy 16-month-old girl was admitted to the intensive care unit with encephalopathy complicated by Guillain-Barré syndrome and hydrocephalus, which necessitated placement of a ventriculoperitoneal shunt. She had serologic and molecular evidence of central nervous system infection by B. quintana (95).
Associated with Cat-Scratch Disease
The most commonly recognized neurologic manifestations associated with B. henselae infection are those of CSD, predominantly encephalopathy and neuroretinitis. Isolated cranial and peripheral neuropathies (e.g., facial palsy), polyneuropathy, transverse myelitis, and other manifestations uncommonly occur (96–145). CSD vertebral osteomyelitis may rarely present with neurologic complications, including intraspinal extension (146–150). Encephalopathy probably occurs in 2% to 4% of all recognized CSD cases, although estimates range from 1% to 7% (115). Extrapolating from an estimated U.S. CSD case rate of 9.3 per year per 100,000 population, 2% to 4% would represent between 500 and 1,000 annual CSD encephalopathy cases in the United States. The California Encephalitis Project reported Bartonella species as the causative agent in 7 (2%) of 334 patients with encephalitis, making it the most common bacteria associated with encephalitis (151). In contrast, Bartonella cases were found neither among 203 patients with encephalitis in a multicenter prospective study from England nor among 253 patients in a national prospective study conducted in France (152,153). However, the diagnosis of Bartonella encephalitis in the latter study may have been underrepresented because the authors excluded survivors hospitalized for more than 5 days because these patients were assumed to have aseptic meningitis rather than encephalitis. Patients with encephalitis due to Bartonella species may have a fulminant presentation but often recover fully within several days after onset and thus could have been excluded from the study (154). Such diagnoses can easily be overlooked if the clinician fails to obtain an adequate history. With domestic cats representing the single largest category of companion animals in the United States, the importance of an accurate history regarding animal exposure cannot be overemphasized when evaluating a patient with findings consistent with one of these syndromes. A common pitfall in history taking is to inquire about a cat scratch or a cat bite rather than cat contact, as a significant proportion of CSD patients report cat contact without injury. Though less established, one must also keep an open mind to the possibility of transmission of B. henselae from other animals such as dogs.
CSD encephalopathy remains predominantly a clinical diagnosis, now subject to laboratory confirmation by techniques described later in this chapter (predominantly antibody testing). Adolescents and adults may represent a greater proportion of cases of CSD encephalopathy than they do of CSD overall (81). Encephalitis was also reported to be more common in elderly patients (older than 60 years of age) with CSD than in younger patients (155). The pathogenesis of CSD encephalopathy and other CNS manifestations associated with CSD remains unclear. Whether these rare complications are attributable to direct invasion of the CNS by B. henselae or to other mechanisms such as vasculitis or immune response is unknown. B. henselae has been shown to infect feline microglial cells in vitro and survive intracellularly for up to 4 weeks; however, no ultrastructural abnormalities were identified within infected brain cells by electron microscopy (156).
In most patients, encephalopathy usually follows lymphadenopathy, by a period of days up to 2 months, although it has also been reported to precede lymph node involvement or to occur in its absence. Persistent generalized headache is a common part of the history, but fever is an inconsistent finding. Patients may become restless and combative. Nearly half of patients develop seizures, which may range from focal to generalized and from brief and self-limited to status epilepticus. Short-term anticonvulsant therapy may be required, as may be supportive therapy in the face of obtundation or coma. Nuchal rigidity, pathologic reflexes, or pupillary dilation may be present transiently. Neurologic deficits such as aphasia, cranial nerve palsy, paresis, hemiplegia, and ataxia are usually self-limited, although time to resolution may span weeks to months to as long as a year. Persistence of intellectual impairment, ataxia, and seizures have been reported (81,112,118,125,128), as well as rare cases of death due to CSD meningoencephalitis in two previously healthy children, aged 4 and 6 years (157,158).
Laboratory studies in the setting of CSD encephalopathy do not add specific positive diagnostic findings to the clinical picture, but they serve to exclude other processes. CSF measurements fit no consistent pattern, except that hypoglycorrhachia is rare. Elevation of CSF protein concentration and pleocytosis with lymphocytic predominance occur in only about one third of patients (but not necessarily in the same patients) (151). Peripheral blood leukocytosis occurs as well in only about one third of patients. CSF cultures have been consistently negative.
Studies of the brain with computed tomography (CT) and/or magnetic resonance imaging (MRI) usually show no abnormalities. Transient nonspecific abnormalities are occasionally identified, but a few cases of persistent structural abnormalities have been reported (128,159). Electroencephalography during the acute phase of CSD encephalopathy commonly reveals diffuse slowing, yet another nonspecific feature that resolves with clinical recovery. Brain biopsy is usually not indicated because of the self-limited nature of CSD encephalopathy, and thus little is known about the histologic correlates of the clinical manifestations. At autopsy of a fatality due to CSD encephalomeningitis, there was marked cerebral edema with no gross evidence of acute meningitis. Microscopic examination revealed multiple granulomatous lesions, meningitis, and encephalitis. Warthin-Starry silver stain of the brain and liver revealed pleomorphic rod-shaped bacilli consistent with B. henselae infection. Analysis of brain tissue with PCR confirmed the presence of B. henselae DNA (157). Histologic examination of the second fatality showed extensive diffuse perivascular lymphocytic infiltrates with microglial nodules scattered throughout the frontal, parietal, and occipital lobes and the pons. In some foci, the nodules appeared vaguely granulomatous (158). Biopsy of concurrent lymphadenopathy, when done, reveals features typical of CSD.
The neuroretinitis associated with CSD (96,108,116,117, 120,121,124,129,133,160–164) has been confirmed by serology and culture to be related to B. henselae infection. Neuroretinitis in association with B. henselae bacteremia (96), aseptic meningitis (165), and encephalopathy (166) have been reported in patients with CSD. Chorioretinitis and multiple hypodense areas within the spleen and liver parenchyma have been described in a 10-year-old previously healthy boy several weeks after a cat scratch (167). Although long-term prognosis is usually good, some individuals may develop mild postinfectious optic neuropathy, and few may develop permanent visual disturbances. Vitrectomy is only rarely indicated. With the refinement of techniques for identification of Bartonella infection, diagnostic accuracy has improved, broadening the spectrum of CSD-associated retinal manifestations and identifying new Bartonella species as possible pathogens in neuroretinitis. B. grahamii was identified by PCR amplification and sequence analysis in the intraocular fluid of an HIV-seronegative patient with bilateral neuroretinitis and behavioral changes, and B. elizabethae infection was diagnosed serologically in another patient with neuroretinitis (168,169).
The typical clinical scenario of CSD neuroretinitis, a process first described as Leber idiopathic stellate retinopathy (116,170), is that of painless, fairly sudden loss of visual acuity, usually unilaterally, and sometimes preceded by an influenza-like syndrome or development of regional lymphadenopathy. Neuroretinitis is characterized by papilledema often associated with macular exudates in a star formation (Fig. 26.2). In a retrospective study among 24 patients with CSD with 35 affected eyes, isolated foci of retinitis or choroiditis were the most common ocular manifestation identified in 83% of eyes and 83% of patients. Optic disk swelling was the second most common finding (46% of eyes, 63% of patients), followed by a macular star (43% of eyes, 63% of patients) and vascular-occlusive events (14% of eyes, 21% of patients). Final visual acuity was 20/25 or better in 26 (74%) of 35 eyes and was similar in both treated and untreated patients (161). Optic disk edema associated with peripapillary serous retinal detachment has been described as an early sign of ocular CSD. The typical macular star may or may not follow these early manifestations (171). Other types of ocular CSD manifestations include optic neuritis, anterior uveitis, panuveitis, vitreitis, pars planitis, focal retinal vasculitis, retinal white spot syndrome, branch retinal arteriolar or venular occlusions, central retinal artery and vein occlusion, focal choroiditis, vitreous and retinal hemorrhages, and a process associated with peripapillary angiomatosis (172–181). The pathophysiology of neuroretinitis is thought to be leakage of lipid-containing exudate from capillaries in the optic head with subsequent extension into the subretinal space and macular region. This type of process has been recognized as a secondary phenomenon in most circumstances, occurring in association with traumatic injuries of the eye or brain, ocular vascular disturbances, toxins, autoimmune states (e.g., Behçet syndrome), or a variety of infections (e.g., influenza-like syndromes, syphilis, leptospirosis, tularemia, tuberculosis, psittacosis, endemic mycoses, and parasites). Thus, although this process can be considered characteristic of CSD neuroretinitis, it is not pathognomonic and many other causes must be included in the differential diagnosis.
Associated with HIV Infection
Intracerebral bacillary angiomatosis was first recognized in 1990 (62) in a man with AIDS. In 1994, antibody and DNA amplification evidence of Bartonella infection was reported in the setting of neurologic manifestations complicating HIV infection (182), and epidemiologic studies have confirmed an association between the presence of serum anti-Bartonella antibodies and increased risk of development of neuropsychologic decline or dementia over 5 years. An estimated 4% of new cases of HIV-associated dementia or neuropsychologic decline might be ascribed to Bartonella infections and therefore are potentially treatable with antibiotics. Subsequent small numbers of case reports have added anecdotal evidence suggesting the potential utility of antimicrobial therapy in reversing Bartonella-associated neuropsychiatric abnormalities.
Chronic Neurologic and Neurocognitive Manifestations
A few recent studies, originating mostly from one group of investigators, reported the detection of various Bartonella species, including B. henselae, B. vinsonii subsp. berkhoffii, B. koehlerae, Candidatus B. melophagi, or coinfection with more than one Bartonella spp. in blood samples, using a novel enrichment blood culture technique, followed by PCR and DNA sequencing. Patients were apparently immunocompetent individuals who presented with various chronic neurologic or neurocognitive syndromes, including seizures, ataxia, memory loss, tremors, fatigue, insomnia, headache, arthralgia, myalgia, hallucinations, and other symptoms. Many individuals had extensive arthropod and animal exposure. It has been suggested that because the duration of illness in these patients ranged from months to many years, these Bartonella species may induce a chronic intravascular, persistent, or relapsing infection. More studies are needed to evaluate the role of these pathogens in patients with chronic neurologic and neurocognitive dysfunction (183–188).
Infections Caused by Other Species
B. vinsonii subsp. arupensis was isolated from the blood of a 62-year-old cattle rancher who was admitted to a hospital with acute onset of confusion, emotional liability, difficulty in walking, facial numbness, slurred speech, diplopia, headache, and myalgias. He was discharged 7 days later with a significant improvement in neurologic symptoms (189).
A case of meningitis attributed to Bartonella washoensis, isolated from a patient’s blood using routine blood culture system, was described in a 47-year-old previously healthy woman with exposure to pet and farm animals. Oropsylla montana fleas were implicated as the vector for disease transmission in this case (190).
LABORATORY CONFIRMATION OF CLINICAL DIAGNOSIS
The laboratory diagnosis of Bartonella-associated diseases can be achieved through modified conventional bacteriologic culture methods, co-culture with endothelial cells, immunoserologic or immunocytochemical means, or DNA amplification. These approaches are described in current diagnostic microbiology references (191). Serologic testing has become the mainstay of diagnosis, particularly when the involved tissue is less accessible for biopsy sampling such as CSD patients with CNS infection. Early lymph node biopsy or fine-needle aspiration (before spontaneous resolution of lymphadenitis occurs) for histopathology, PCR, and culture should be encouraged in patients with serious complications such as encephalitis or neuroretinitis, when CSD is a likely diagnosis and B. henselae serology is negative or equivocal.
Detection and Identification of the Agent
Bartonella species usually do not grow under the conditions used for standard bacteriologic cultures. If culture is attempted, freshly prepared media provide optimal recovery. Heart infusion agar with 5% to 10% defibrinated rabbit or horse blood supports better growth of most strains than chocolate or 5% sheep blood agars. Plates sealed after 24 hours of incubation to preserve moisture content usually can be incubated up to 30 days without notable deterioration. Even when these techniques are strictly applied, recovery of B. henselae from lymph nodes and other specimens of patients with CSD is extremely rare. Moderate success in the recovery of isolates has been achieved using alternate techniques (192,193). The combination of enrichment culture and PCR amplification may optimally detect Bartonella species with respect to sensitivity and a clinically relevant time frame, although this approach is generally not available in the majority of clinical laboratories.
Colonies of Bartonella species are sticky, autoadherent, and of two morphologic types: (a) irregular, raised, whitish, rough, and dry appearing or (b) smaller, circular, tan, and moist appearing. Both types are often present in the same culture. The degree of colonial heterogeneity varies by species, with B. henselae typically having a greater proportion of rough colonies than B. quintana. Repeated subcultures cause most strains of B. henselae to revert to smooth cultures. Gram stain of a colony reveals small, gram-negative, slightly curved rods (which may mimic Haemophilus, Campylobacter, or Helicobacter), and a wet mount usually demonstrates twitching motility. B. bacilliformis and B. clarridgeiae possess flagella, whereas B. henselae, B. elizabethae, and to lesser extent, B. quintana have twitching motility believed due to pili. Presumptive identification of B. henselae or B. quintana can be made on the basis of these features, plus a lengthy (>7-day) period of incubation before appearance, negative catalase and oxidase reactions, and absence of acid production from carbohydrates.
Confirmatory identification is usually by referral to a laboratory experienced with Bartonella species. Newer methods have been applied to identification of Bartonella species including mass spectrometry (194), in addition to PCR-based and DNA hybridization techniques that can be used to distinguish species and for direct detection in clinical material (30,31,90,195–199). DNA fragments of B. henselae can be amplified from various clinical specimens including fresh lymph nodes and other tissues (including brain), CSF, freshly aspirated pus, minute amounts of tissue obtained from lymph node fine-needle aspiration, and paraffin-embedded material. Molecular subtyping of strains can be performed using PCR-based sequence analysis (15) or restriction fragment length polymorphism, and repetitive extragenic palindromic PCR.
Serology
Because culture of Bartonella species remains technically difficult with a low success rate, alternative means of diagnosis are important. Serology is the most commonly used test for diagnosis, replacing the skin test that was poorly standardized and carried a potential risk for transmission of infectious agents. An immunofluorescence assay (IFA) and several enzyme immunoassays (EIAs) have been described for B. henselae and B. quintana detection. They have been used primarily to demonstrate anti-Bartonella antibodies in persons with CSD (28,129,200) and in some cases of HIV-associated aseptic meningitis, encephalopathy, or neuropsychiatric disease (96,182). The IFA described by Regnery et al. (28) in 1992 generally performs well, but it was not designed for detecting immunoglobulin M (IgM) antibodies. In studies in which this assay was performed at the U.S. Centers for Disease Control and Prevention, with reciprocal titers of more than 64 as the cutoff value, both sensitivity (84% to 95%) and specificity (94% to 98%) were high. It has been less consistent in studies performed in Europe (201). A high seroprevalence of anti–B. henselae immunoglobulin G (IgG) in Europe due to exposure to non–B. henselae species may result in inferior performance of the IFA compared with the United States. EIA studies in some HIV-infected persons with encephalopathy or neuropsychiatric findings have demonstrated antibodies reactive with a formalin-fixed whole bacterial cell antigen preparation of B. henselae but have not satisfactorily demonstrated B. henselae specificity (182). An EIA using N-lauroyl-sarcosine–insoluble outer membrane antigen from agar-grown B. henselae to test sera from 84 patients with CSD defined by PCR (82 patients) or skin test (6 patients) determined the EIA sensitivity to be 75% for anti–B. henselae IgG alone, 48% for IgM alone, and 85% overall when positive IgG, IgM, or both were accepted as diagnostic. EIA specificity was 98% (200). The same EIA was used to study antibody kinetics in patients with CSD. Anti–B. henselae IgM remained positive for 3 months or less and its presence indicated acute disease. IgG titers also declined over time but may last for longer than 2 years.
Serologic cross reactivity is among the limitations of both IFA and EIA. Neither adequately discriminates between anti–B. henselae and anti–B. quintana antibodies. Cross reactivity has also been demonstrated between Bartonellaand others including Coxiella burnetii and Chlamydia species. Data regarding the clinical significance of such cross reactivity are limited, and this represents a potential concern because all of these microorganisms are causative agents of endocarditis and may have similar clinical presentations.
Treatment of Bartonella-Related Neurologic Manifestations
Antibiotic regimens for Bartonella infections have been determined empirically, based on clinical experience, as well as published case reports and clinical studies, which are mostly uncontrolled with limited follow-up (202). One of the most intriguing aspects of non–B. bacilliformis infections is the clinical observation that antimicrobial therapy seems to have a much greater impact on immunocompromised patients with systemic disease (e.g., patients with AIDS with bacteremia and BA) than on immunocompetent patients with localized disease (e.g., patients with CSD with regional lymphadenitis). This perhaps reflects the different pathologic processes involved. The recommended therapy for acute B. bacilliformis infection, Oroya fever, is either chloramphenicol (0.5 g PO/IV four times a day for 2 weeks) plus another antibiotic, (preferably a β-lactam), or ciprofloxacin 0.5 g twice a day for 10 days. CNS involvement with impaired consciousness necessitates parenteral therapy. Because of ease of administration, low cost, and observed clinical effectiveness, the initial therapy of choice for uncomplicated bacteremia and BA caused by B. henselae or B. quintana in immunocompromised patients is oral erythromycin (e.g., 0.5 g four times a day as stearate). Other macrolides, doxycycline (100 mg twice daily), or other tetracyclines may serve as alternatives (67,202,203).
The role of antimicrobial therapy for CSD-associated neuroretinitis is controversial. In a small retrospective case series, doxycycline and rifampin appeared to shorten the course of disease and hasten visual recovery in seven patients with CSD neuroretinitis compared to historic cases. The demonstration of B. henselae bacteremia associated with neuroretinitis adds weight to the argument for treatment with antibiotics (96,160). There is no definite evidence of the utility of antibiotic therapy in shortening or altering the course of CSD encephalopathy. However, because of anecdotal reports of apparent efficacy of antimicrobials in the treatment of other manifestations of CSD, and because of the severe clinical manifestations of this complication, antimicrobial therapy is prudent. Doxycycline with or without addition of rifampin seems to be a reasonable choice in these cases (203). Dramatic clinical improvement following treatment with high-dose steroids has been described in a 4-year-old previously healthy child with CSD encephalopathy. Another 12-year-old child with CSD and brainstem encephalopathy with basal ganglia impairment who was admitted with profound coma recovered after treatment with high-dose methylprednisolone and antibiotics; however, because of the self-limited nature of this complication, the role of steroids in this setting is difficult to evaluate (204,205).
References
1. Drancourt M, Mainardi JL, Brouqui P, et al. Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med. 1995;332:419–423.
2. Koehler JE, Quinn FD, Berger TG, et al. Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis. N Engl J Med. 1992;327:1625–1631.
3. Larson AM, Dougherty MJ, Nowowiejski DJ, et al. Detection of Bartonella (Rochalimaea) quintana by routine acridine orange staining of broth blood cultures. J Clin Microbiol. 1994;32:1492–496.
4. Spach DH, Callis KP, Paauw DS, et al. Endocarditis caused by Rochalimaea quintana in a patient infected with human immunodeficiency virus. J Clin Microbiol. 1993;31:692–694.
5. Spach DH, Kanter AS, Dougherty MJ, et al. Bartonella (Rochalimaea) quintana bacteremia in inner-city patients with chronic alcoholism. N Engl J Med. 1995;332:424–428.
6. Slater LN, Welch DF, Hensel D, et al. A newly recognized fastidious gram-negative pathogen as a cause of fever and bacteremia. N Engl J Med. 1990;323:1587–1593.
7. Regnery RL, Anderson BE, Clarridge JE III, et al. Characterization of a novel Rochalimaea species, R. henselae sp. nov., isolated from blood of a febrile, human immunodeficiency virus-positive patient. J Clin Microbiol. 1992;30:265–274.
8. Daly JS, Worthington MG, Brenner DJ, et al. Rochalimaea elizabethae sp. nov. isolated from a patient with endocarditis. J Clin Microbiol. 1993;31:872–881.
9. Welch DF, Pickett DA, Slater LN, et al. Rochalimaea henselae sp. nov., a cause of septicemia, bacillary angiomatosis, and parenchymal bacillary peliosis. J Clin Microbiol. 1992;30:275–280.
10. Relman DA, Lepp PW, Sadler KN, et al. Phylogenetic relationships among the agent of bacillary angiomatosis, Bartonella bacilliformis, and other alpha-proteobacteria. Mol Microbiol. 1992;6:1801–1807.
11. Brenner DJ, O’Connor SP, Winkler HH, et al. Proposals to unify the genera Bartonella and Rochalimaea, with descriptions of Bartonella quintana comb. nov., Bartonella vinsonii comb. nov., Bartonella henselae comb. nov., and Bartonella elizabethae comb. nov., and to remove the family Bartonellaceae from the order Rickettsiales. Int J Syst Bacteriol. 1993;43:777–786.
12. Birtles RJ, Harrison TG, Saunders NA, et al. Proposals to unify the genera Grahamella and Bartonella, with descriptions of Bartonella talpae comb. nov., Bartonella peromysci comb. nov., and three new species, Bartonella grahamii sp. nov., Bartonella taylorii sp. nov., and Bartonella doshiae sp. nov. Int J Syst Bacteriol. 1995;45:1–8.
13. Breitschwerdt EB, Kordick DL. Bartonella infection in animals: carriership, reservoir potential, pathogenicity, and zoonotic potential for human infection. Clin Microbiol Rev. 2000;13:428–438.
14. Houpikian P, Raoult D. Molecular phylogeny of the genus Bartonella: what is the current knowledge? FEMS Microbiol Lett. 2001;200:1–7.
15. Zeaiter Z, Fournier PE, Raoult D. Genomic variation of Bartonella henselae strains detected in lymph nodes of patients with cat scratch disease. J Clin Microbiol. 2002;40:1023–1030.
16. Arvand M, Feil EJ, Giladi M, et al. Multi-locus sequence typing of Bartonella henselae isolates from three continents reveals hypervirulent and feline-associated clones. PloS One. 2007;2:e1346.
17. Bonilla DL, Kabeya H, Henn J, et al. Bartonella quintana in body lice and head lice from homeless persons, San Francisco, California, USA. Emerg Infect Dis. 2009;15:912–915.
18. Demers DM, Bass JW, Vincent JM, et al. Cat-scratch disease in Hawaii: etiology and seroepidemiology. J Pediatr. 1995;127:23–26.
19. Koehler JE, Glaser CA, Tappero JW. Rochalimaea henselae infection. A new zoonosis with the domestic cat as reservoir. JAMA. 1994;271: 531–535.
20. Chomel BB, Abbott RC, Kasten RW, et al. Bartonella henselae prevalence in domestic cats in California: risk factors and association between bacteremia and antibody titers. J Clin Microbiol. 1995;33:2445–2450.
21. Chomel BB, Kasten RW, Floyd-Hawkins K, et al. Experimental transmission of Bartonella henselae by the cat flea. J Clin Microbiol. 1996;34: 1952–1956.
22. Brunetti E, Fabbi M, Ferraioli G, et al. Cat-scratch disease in Northern Italy: atypical clinical manifestations in humans and prevalence of Bartonella infection in cats. Eur J Clin Microbiol Infect Dis. 2013;32:531–534.
23. Azzag N, Haddad N, Durand B, et al. Population structure of Bartonella henselae in Algerian urban stray cats. PloS One. 2012;7:e43621.
24. Rolain JM, Locatelli C, Chabanne L, et al. Prevalence of Bartonella clarridgeiae and Bartonella henselae in domestic cats from France and detection of the organisms in erythrocytes by immunofluorescence. Clin Diagn Lab Immunol. 2004;11:423–425.
25. Gurfield AN, Boulouis HJ, Chomel BB, et al. Epidemiology of Bartonella infection in domestic cats in France. Vet Microbiol. 2001;80:185–198.
26. Lucey D, Dolan MJ, Moss CW, et al. Relapsing illness due to Rochalimaea henselae in immunocompetent hosts: implication for therapy and new epidemiological associations. Clin Infect Dis. 1992;14:683–688.
27. Tappero JW, Mohle-Boetani J, Koehler JE, et al. The epidemiology of bacillary angiomatosis and bacillary peliosis. JAMA. 1993;269:770–775.
28. Regnery RL, Olson JG, Perkins BA, et al. Serological response to “Rochalimaea henselae” antigen in suspected cat-scratch disease. Lancet. 1992;339:1443–1445.
29. Dolan MJ, Wong MT, Regnery RL, et al. Syndrome of Rochalimaea henselae adenitis suggesting cat scratch disease. Ann Intern Med. 1993;118: 331–336.
30. Waldvogel K, Regnery RL, Anderson BE, et al. Disseminated cat-scratch disease: detection of Rochalimaea henselae in affected tissue. Eur J Pediatr. 1994;153:23–27.
31. Anderson B, Sims K, Regnery R, et al. Detection of Rochalimaea henselae DNA in specimens from cat scratch disease patients by PCR. J Clin Microbiol. 1994;32:942–948.
32. Goral S, Anderson B, Hager C, et al. Detection of Rochalimaea henselae DNA by polymerase chain reaction from suppurative nodes of children with cat-scratch disease. Pediatr Infect Dis J. 1994;13:994–997.
33. Le HH, Palay DA, Anderson B, et al. Conjunctival swab to diagnose ocular cat scratch disease. Am J Ophthalmol. 1994;118:249–250.
34. Ricketts WE. Carrión’s disease: a study of the incubation period in thirteen cases. Am J Trop Med. 1947;27:657–659.
35. Strong RP, Tyzzer EE, Brues CT, et al. Report of the First Expedition to South America, 1913. Cambridge, MA: Harvard University Press; 1915.
36. Ricketts WE. Bartonella bacilliformis anemia (Oroya fever); a study of 30 cases. Blood. 1948;3:1025–1049.
37. Reynafarje C, Ramos J. The hemolytic anemia of human bartonellosis. Blood. 1961;17:562–578.
38. Maguina C, Garcia PJ, Gotuzzo E, et al. Bartonellosis (Carrion’s disease) in the modern era. Clin Infect Dis. 2001;33:772–779.
39. Schultz MG. A history of bartonellosis (Carrion’s disease). Am J Trop Med Hyg. 1968;17:503–515.
40. Ricketts WE. Clinical manifestations of Carrion’s disease. Arch Intern Med (Chic). 1949;84:751–781.
41. Kosek M, Lavarello R, Gilman RH, et al. Natural history of infection with Bartonella bacilliformis in a nonendemic population. J Infect Dis. 2000;182:865–872.
42. Cuadra M. Salmonellosis complication in human bartonellosis. Tex Rep Biol Med. 1956;14:97–113.
43. Pinkerton H, Weinman D. Toxoplasma infection in man. Arch Pathol. 1940;30:374–392.
44. Arias-Stella J, Lieberman PH, Erlandson RA, et al. Histology, immunohistochemistry, and ultrastructure of the verruga in Carrion’s disease. Am J Surg Pathol. 1986;10:595–610.
45. Dooley JR. Bartonellosis In: Binford CH, Connor DH, eds. Pathology of Tropical and Extraordinary Diseases. Washington, DC: Armed Forces Institute of Pathology; 1976:190–193.
46. McNee JW, Renshaw A. “Trench fever”: a relapsing fever occurring with the British forces in France. Br Med J. 1916;1:225–234.
47. Brouqui P, Lascola B, Roux V, et al. Chronic Bartonella quintana bacteremia in homeless patients. N Engl J Med. 1999;340:184–189.
48. Foucault C, Barrau K, Brouqui P, et al. Bartonella quintana bacteremia among homeless People. Clin Infect Dis. 2002;35:684–689.
49. Raoult D, Fournier PE, Drancourt M, et al. Diagnosis of 22 new cases of Bartonella endocarditis. Ann Intern Med. 1996;125:646–652.
50. Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference center: etiologic diagnosis of 348 cases. Medicine (Baltimore). 2005;84: 162–173.
51. Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis. 2010;51:131–140.
52. Roux V, Eykyn SJ, Wyllie S, et al. Bartonella vinsonii subsp. berkhoffii as an agent of afebrile blood culture-negative endocarditis in a human. J Clin Microbiol. 2000;38:1698–1700.
53. Avidor B, Graidy M, Efrat G, et al. Bartonella koehlerae, a new cat-associated agent of culture-negative human endocarditis. J Clin Microbiol. 2004;42:3462–468.
54. Raoult D, Roblot F, Rolain JM, et al. First isolation of Bartonella alsatica from a valve of a patient with endocarditis. J Clin Microbiol. 2006;44:278–279.
55. Raoult D, Fournier PE, Vandenesch F, et al. Outcome and treatment of Bartonella endocarditis. Arch Intern Med. 2003;163:226–230.
56. Stoler MH, Bonfiglio TA, Steigbigel RT, et al. An atypical subcutaneous infection associated with acquired immune deficiency syndrome. Am J Clin Pathol. 1983;80:714–718.
57. Cockerell CJ, Whitlow MA, Webster GF, et al. Epithelioid angiomatosis: a distinct vascular disorder in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Lancet. 1987;2:654–656.
58. LeBoit PE, Berger TG, Egbert BM, et al. Epithelioid haemangioma-like vascular proliferation in AIDS: manifestation of cat scratch disease bacillus infection? Lancet. 1988;1:960–963.
59. Slater LN, Welch DF, Min KW. Rochalimaea henselae causes bacillary angiomatosis and peliosis hepatis. Arch Intern Med. 1992;152:602–606.
60. Koehler JE, LeBoit PE, Egbert BM, et al. Cutaneous vascular lesions and disseminated cat-scratch disease in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med. 1988;109:449–455.
61. Kemper CA, Lombard CM, Deresinski SC, et al. Visceral bacillary epithelioid angiomatosis: possible manifestations of disseminated cat scratch disease in the immunocompromised host: a report of two cases. Am J Med. 1990;89:216–222.
62. Spach DH, Panther LA, Thorning DR, et al. Intracerebral bacillary angiomatosis in a patient infected with human immunodeficiency virus. Ann Intern Med. 1992;116:740–742.
63. Relman DA, Loutit JS, Schmidt TM, et al. The agent of bacillary angiomatosis. an approach to the identification of uncultured pathogens. N Engl J Med. 1990;323:1573–1580.
64. Cockerell CJ, Bergstresser PR, Myrie-Williams C, et al. Bacillary epithelioid angiomatosis occurring in an immunocompetent individual. Arch Dermatol. 1990;126:787–790.
65. Tappero JW, Koehler JE, Berger TG, et al. Bacillary angiomatosis and bacillary splenitis in immunocompetent adults. Ann Intern Med. 1993;118: 363–365.
66. Zarraga M, Rosen L, Herschthal D. Bacillary angiomatosis in an immunocompetent child: a case report and review of the literature. Am J Dermatopathol. 2011;33:513–515.
67. Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of Bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med. 1997;337:1876–1883.
68. Lee J, Lynde C. Pyogenic granuloma: pyogenic again? Association between pyogenic granuloma and Bartonella. J Cutan Med Surg. 2001;5:467–470.
69. Levy I, Rolain JM, Lepidi H, et al. Is pyogenic granuloma associated with Bartonella infection? J Am Acad Dermatol. 2005;53:1065–1066.
70. Cockerell CJ, LeBoit PE. Bacillary angiomatosis: a newly characterized, pseudoneoplastic, infectious, cutaneous vascular disorder. J Am Acad Dermatol. 1990;22:501–512.
71. LeBoit PE, Berger TG, Egbert BM, et al. Bacillary angiomatosis. The histopathology and differential diagnosis of a pseudoneoplastic infection in patients with human immunodeficiency virus disease. Am J Surg Pathol. 1989;13:909–920.
72. Perkocha LA, Geaghan SM, Yen TS, et al. Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection. N Engl J Med. 1990;323:1581–1586.
73. Leong SS, Cazen RA, Yu GS, et al. Abdominal visceral peliosis associated with bacillary angiomatosis. Ultrastructural evidence of endothelial destruction by bacilli. Arch Pathol Lab Med. 1992;116:866–871.
74. Kordick DL, Hilyard EJ, Hadfield TL, et al. Bartonella clarridgeiae, a newly recognized zoonotic pathogen causing inoculation papules, fever, and lymphadenopathy (cat scratch disease). J Clin Microbiol. 1997;35:1813–1818.
75. Margileth AM, Baehren DF. Chest-wall abscess due to cat-scratch disease (CSD) in an adult with antibodies to Bartonella clarridgeiae: case report and review of the thoracopulmonary manifestations of CSD. Clin Infect Dis. 1998;27:353–357.
76. Giladi M, Avidor B, Kletter Y, et al. Cat scratch disease: the rare role of Afipia felis. J Clin Microbiol. 1998;36:2499–2502.
77. Debre R, Lamy M, Jammet ML, et al. La maladie des griffes de chat. Sem Hop. 1950;26:1895–1904.
78. Moriarty RA, Margileth AM. Cat scratch disease. Infect Dis Clin North Am. 1987;1:575–590.
79. Carithers HA. Cat-scratch disease. An overview based on a study of 1,200 patients. Am J Dis Child. 1985;139:1124–1133.
80. Margileth AM. Cat scratch disease. Adv Pediatr Infect Dis. 1993;8:1–21.
81. Carithers HA, Margileth AM. Cat-scratch disease. Acute encephalopathy and other neurologic manifestations. Am J Dis Child. 1991;145:98–101.
82. Anderson BE, Neuman MA. Bartonella spp. as emerging human pathogens. Clin Microbiol Rev. 1997;10:203–219.
83. Giladi M, Maman E, Paran D, et al. Cat-scratch disease-associated arthropathy. Arthritis Rheum. 2005;52:3611–3617.
84. Maman E, Bickels J, Ephros M, et al. Musculoskeletal manifestations of cat scratch disease. Clin Infect Dis. 2007;45:1535–1540.
85. Abbasi S, Chesney PJ. Pulmonary manifestations of cat-scratch disease; a case report and review of the literature. Pediatr Infect Dis J. 1995;14:547–548.
86. Wesslen L, Ehrenborg C, Holmberg M, et al. Subacute Bartonella infection in Swedish orienteers succumbing to sudden unexpected cardiac death or having malignant arrhythmias. Scand J Infect Dis. 2001;33:429–438.
87. Meininger GR, Nadasdy T, Hruban RH, et al. Chronic active myocarditis following acute Bartonella henselae infection (cat scratch disease). Am J Surg Pathol. 2001;25:1211–1214.
88. Borker A, Gardner R. Severe thrombocytopenic purpura as a complication of cat scratch disease. Clin Pediatr (Phila). 2002;41:117–118.
89. Ghez D, Bernard L, Bayou E, et al. Bartonella henselae infection mimicking a splenic lymphoma. Scand J Infect Dis. 2001;33:935–936.
90. Gilad J, Wolak A, Borer A, et al. Isolated splenic cat scratch disease in an immunocompetent adult woman. Clin Infect Dis. 2003;36:e10–e13.
91. Markaki S, Sotiropoulou M, Papaspirou P, et al. Cat-scratch disease presenting as a solitary tumour in the breast: report of three cases. Eur J Obstet Gynecol Reprod Biol. 2003;106:175–178.
92. Trelles JO, Palomino L, Trelles L. Neurologic form of Carrion’s disease. Clinical-anatomical study of 9 cases [in Spanish]. Rev Neuropsiquiatr. 1969;32:245–306.
93. Trelles JO. Neurological disorders in Peru. In: Spillane JD, ed. Tropical Neurology. New York: Oxford University Press; 1973:387–396.
94. Parrott JH, Dure L, Sullender W, et al. Central nervous system infection associated with Bartonella quintana: a report of two cases. Pediatrics. 1997;100:403–408.
95. Mantadakis E, Spanaki AM, Psaroulaki A, et al. Encephalopathy complicated by Guillain-Barre syndrome and hydrocephalus and associated with acute Bartonella quintana infection. Pediatr Infect Dis J. 2007;26: 860–862.
96. Wong MT, Dolan MJ, Lattuada CP Jr, et al. Neuroretinitis, aseptic meningitis, and lymphadenitis associated with Bartonella (Rochalimaea) henselae infection in immunocompetent patients and patients infected with human immunodeficiency virus type 1. Clin Infect. 1995;21:352–360.
97. Stevens H. Cat-scratch fever encephalitis. AMA Am J Dis Child. 1952;84:218–222.
98. Debre R, Van Bogaert L, Thieffry S, et al. Accidents nerveux de la maladie des griffes du chat. Bull Acad Natl Med. 1952;136:454–459.
99. Jambor J, Emura E. Benign inoculation lymphoreticulosis (cat-scratch disease); report of two cases with positive skin tests. AMA Arch Derm Syphilol. 1953;67:439–442.
100. Thompson TE Jr, Miller KF. Cat scratch encephalitis. Ann Intern Med. 1953;39:146–151.
101. Weinstein L, Meade RH 3rd. The neurological manifestations of cat scratch disease. Am J Med Sci. 1955;229:500–505.
102. Paxson EM, McKay RJ Jr. Neurologic symptoms associated with cat scratch disease. Pediatrics. 1957;20:13–22.
103. Gair DR, Walls WL. Encephalitis in cat scratch disease; report of two cases. J Fla Med Assoc. 1957;44:491–492.
104. Smith RE, Darling RM. Encephalopathy of cat-scratch disease. AMA J Dis Child. 1960;99:107–108.
105. Steiner MM, Vuckovitch D, Hadawi SA. Cat-scratch disease with encephalopathy. Case report and review of the literature. J Pediatr. 1963;62: 514–520.
106. Brooksaler F. Cat scratch disease with encephalopathy. Am J Dis Child. 1964;107:185–187.
107. Pollen RH. Cat-scratch encephalitis. Neurology. 1968;18:1031–1033.
108. Sweeney VP, Drance SM. Optic neuritis and compressive neuropathy associated with cat scratch disease. Can Med Assoc J. 1970;103:1380–1381.
109. Lyon LW. Neurologic manifestations of cat-scratch disease. Report of a case and review of the literature. Arch Neurol. 1971;25:23–27.
110. Torres JR, Sanders CV, Strub RL, et al. Cat-scratch disease causing reversible encephalopathy. JAMA. 1978;240:1628–1629.
111. Gadoth N, Oren A, Keynan A, et al. Cat-scratch disease presenting as status epilepticus. A case report. Isr J Med Sci. 1979;15:162–164.
112. Selby G, Walker GL. Cerebral arteritis in cat-scratch disease. Neurology. 1979;29:1413–1418.
113. Miller P, Bell WE. Cat-scratch disease with encephalopathy. Clin Pediatr (Phila). 1980;19:233–234.
114. Pickerill RG, Milder JE. Transverse myelitis associated with cat-scratch disease in an adult. JAMA. 1981;246:2840–2841.
115. Pampe D, Holt RM. Cat scratch disease with reversible encephalopathy. Tex Med. 1984;80:38–39.
116. Dreyer RF, Hopen G, Gass JD, et al. Leber’s idiopathic stellate neuroretinitis. Arch Ophthalmol. 1984;102:1140–1145.
117. Brazis PW, Stokes HR, Ervin FR. Optic neuritis in cat scratch disease. J Clin Neuroophthalmol. 1986;6:172–174.
118. Lewis DW, Tucker SH. Central nervous system involvement in cat scratch disease. Pediatrics. 1986;77:714–721.
119. Melis K, Bochner A, Vandenberghe P, et al. Cat-scratch disease with reversible encephalopathy. Eur J Pediatr. 1989;149:24–25.
120. Bar S, Segal M, Shapira R, et al. Neuroretinitis associated with cat scratch disease. Am J Ophthalmol. 1990;110:703–705.
121. Chrousos GA, Drack AV, Young M, et al. Neuroretinitis in cat scratch disease. J Clin Neuroophthalmol. 1990;10:92–94.
122. Yagupsky P, Sofer S. Cat-scratch encephalopathy presenting as status epilepticus and lymphadenitis. Pediatr Emerg Care. 1990;6:43–45.
123. Harvey RA, Misselbeck WJ, Uphold RE. Cat-scratch disease: an unusual cause of combative behavior. Am J Emerg Med. 1991;9:52–53.
124. Ulrich GG, Waecker NJ Jr, Meister SJ, et al. Cat scratch disease associated with neuroretinitis in a 6-year-old girl. Ophthalmology. 1992;99: 246–249.
125. Revol A, Vighetto A, Jouvet A, et al. Encephalitis in cat scratch disease with persistent dementia. J Neurol Neurosurg Psychiatry. 1992;55:133–135.
126. Slota MC, O’Connor K. Recognizing and treating cat scratch disease with encephalopathy in children. Crit Care Nurse. 1992;12:39–42.
127. Xu DL, Wang Z, Song YJ. Cat-scratch disease encephalopathy. Chin Med J (Engl). 1994;107:104–106.
128. Hahn JS, Sum JM, Lee KP. Unusual MRI findings after status epilepticus due to cat-scratch disease. Pediatr Neurol. 1994;10:255–258.
129. Golnik KC, Marotto ME, Fanous MM, et al. Ophthalmic manifestations of Rochalimaea species. Am J Ophthalmol. 1994;118:145–151.
130. Centers for Disease Control and Prevention. Encephalitis associated with cat scratch disease—Broward and Palm Beach Counties, Florida, 1994. MMWR Morb Mortal Wkly Rep. 1994;43:909, 915–916.
131. Hadley S, Albrecht MA, Tarsy D. Cat-scratch encephalopathy: a cause of status epilepticus and coma in a healthy young adult. Neurology. 1995;45:196.
132. Salgado CD, Weisse ME. Transverse myelitis associated with probable cat-scratch disease in a previously healthy pediatric patient. Clin Infect. 2000;31:609–611.
133. Thompson PK, Vaphiades MS, Saccente M. Cat-scratch disease presenting as neuroretinitis and peripheral facial palsy. J Neuroophthalmol. 1999;19:240–241.
134. Walter RS, Eppes SC. Cat scratch disease presenting with peripheral facial nerve paralysis. Pediatrics. 1998;101:E13.
135. Puligheddu M, Giagheddu A, Genugu F, et al. Epilepsia partialis continua in cat scratch disease. Seizure. 2004;13:191–195.
136. Rondet B, Sarret C, Lacombe P, et al. Neurological symptoms with Bartonella henselae infection: report on 2 pediatric cases [in French]. Arch Pediatr. 2012;19:823–826.
137. Marienfeld CB, Dicapua DB, Sze GK, et al. Expressive aphasia as a presentation of encephalitis with Bartonella henselae infection in an immunocompetent adult. Yale J Biol Med. 2010;83:67–71.
138. Cherinet Y, Tomlinson R. Cat scratch disease presenting as acute encephalopathy. Emerg Med J. 2008;25:703–704.
139. Brenneis C, Scherfler C, Engelhardt K, et al. Encephalitis lethargica following Bartonella henselae infection. J Neurol. 2007;254:546–547.
140. Baylor P, Garoufi A, Karpathios T, et al. Transverse myelitis in 2 patients with Bartonella henselae infection (cat scratch disease). Clin Infect Dis. 2007;45:e42–e45.
141. Stockmeyer B, Schoerner C, Frangou P, et al. Chronic vasculitis and polyneuropathy due to infection with Bartonella henselae. Infection. 2007;35:107–109.
142. Massei F, Gori L, Taddeucci G, et al. Bartonella henselae infection associated with Guillain-Barre syndrome. Pediatr Infect Dis J. 2006;25:90–91.
143. Dyachenko P, Ziv M, Raz R, et al. Cat scratch disease encephalopathy in an immunocompetent patient. Eur J Intern Med. 2005;16:610–611.
144. Angibaud G, Balague JP, Lafontan JF. Bartonella hensalae encephalopathy [in French]. Presse Med. 2005;34:297–298.
145. Rocha JL, Pellegrino LN, Riella LV, et al. Acute hemiplegia associated with cat-scratch disease. Braz J Infect Dis. 2004;8:263–266.
146. Abdel-Haq N, Abuhammour W, Al-Tatari H, et al. Disseminated cat scratch disease with vertebral osteomyelitis and epidural abscess. South Med J. 2005;98:1142–1145.
147. Vermeulen MJ, Rutten GJ, Verhagen I, et al. Transient paresis associated with cat-scratch disease: case report and literature review of vertebral osteomyelitis caused by Bartonella henselae. Pediatr Infect Dis J. 2006;25: 1177–1181.
148. Hussain S, Rathore MH. Cat scratch disease with epidural extension while on antimicrobial treatment. Pediatr Neurosurg. 2007;43:164–166.
149. Tasher D, Armarnik E, Mizrahi A, et al. Cat scratch disease with cervical vertebral osteomyelitis and spinal epidural abscess. Pediatr Infect Dis J. 2009;28:848–850.
150. Al-Rahawan MM, Gray BM, Mitchell CS, et al. Thoracic vertebral osteomyelitis with paraspinous mass and intraspinal extension: an atypical presentation of cat-scratch disease. Pediatr Radiol. 2012;42:116–119.
151. Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: diagnostic challenges in the California Encephalitis Project, 1998–2000. Clin Infect Dis. 2003;36:731–742.
152. Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis. 2010;10:835–844.
153. Mailles A, Stahl JP, Steering Committee and Investigators Group. Infectious encephalitis in France in 2007: a national prospective study. Clin Infect Dis. 2009;49:1838–1847.
154. Glaser C, Bloch KC. Encephalitis: why we need to keep pushing the envelope. Clin Infect Dis. 2009;49:1848–1850.
155. Ben-Ami R, Ephros M, Avidor B, et al. Cat-scratch disease in elderly patients. Clin Infect Dis. 2005;41:969–974.
156. Munana KR, Vitek SM, Hegarty BC, et al. Infection of fetal feline brain cells in culture with Bartonella henselae. Infect Immun. 2001;69: 564–569.
157. Gerber JE, Johnson JE, Scott MA, et al. Fatal meningitis and encephalitis due to Bartonella henselae bacteria. J Forensic Sci. 2002;47:640–644.
158. Fouch B, Coventry S. A case of fatal disseminated Bartonella henselae infection (cat-scratch disease) with encephalitis. Arch Pathol Lab Med. 2007;131:1591–1594.
159. Singhal AB, Newstein MC, Budzik R, et al. Diffusion-weighted magnetic resonance imaging abnormalities in Bartonella encephalopathy. J Neuroimaging. 2003;13:79–82.
160. Reed JB, Scales DK, Wong MT, et al. Bartonella henselae neuroretinitis in cat scratch disease. Diagnosis, management, and sequelae. Ophthalmology. 1998;105:459–466.
161. Solley WA, Martin DF, Newman NJ, et al. Cat scratch disease: posterior segment manifestations. Ophthalmology. 1999;106:1546–1553.
162. Ullrich K, Saha N, Lake S. Neuroretinitis following bull ant sting. BMJ Case Rep. 2012;2012.
163. Irshad FA, Gordon RA. Bartonella henselae neuroretinitis in a 15-year-old girl with chronic myelogenous leukemia. J AAPOS. 2009;13:602–604.
164. Donnio A, Jean-Charles A, Merle H. Macular hole following Bartonella henselae neuroretinitis. Eur J Ophthalmol. 2008;18:456–458.
165. Pinto VL Jr, Curi AL, Pinto Ada S, et al. Cat scratch disease complicated with aseptic meningitis and neuroretinitis. Braz J Infect Dis. 2008;12: 158–160.
166. Smith RA, Scott B, Beverley DW, et al. Encephalopathy with retinitis due to cat-scratch disease. Dev Med Child Neurol. 2007;49:931–934.
167. Belvisi V, Tieghi T, Grenga PL, et al. Bartonella henselae infection presenting with ocular and hepatosplenic manifestations in an immunocompetent child. Pediatr Infect Dis J. 2012;31:882–883.
168. Kerkhoff FT, Bergmans AM, van Der Zee A, et al. Demonstration of Bartonella grahamii DNA in ocular fluids of a patient with neuroretinitis. J Clin Microbiol. 1999;37:4034–4038.
169. O’Halloran HS, Draud K, Minix M, et al. Leber’s neuroretinitis in a patient with serologic evidence of Bartonella elizabethae. Retina. 1998;18:276–278.
170. Carroll DM, Franklin RM. Leber’s idiopathic stellate retinopathy. Am J Ophthalmol. 1982;93:96–101.
171. Wade NK, Levi L, Jones MR, et al. Optic disk edema associated with peripapillary serous retinal detachment: an early sign of systemic Bartonella henselae infection. Am J Ophthalmol. 2000;130:327–334.
172. Gray AV, Reed JB, Wendel RT, et al. Bartonella henselae infection associated with peripapillary angioma, branch retinal artery occlusion, and severe vision loss. Am J Ophthalmol. 1999;127:223–224.
173. Ormerod LD, Dailey JP. Ocular manifestations of cat-scratch disease. Curr Opin Ophthalmol. 1999;10:209–216.
174. Pinna A, Puglia E, Dore S. Unusual retinal manifestations of cat scratch disease. Int Ophthalmol. 2011;31:125–128.
175. Font RL, Del Valle M, Mitchell BM, et al. Cat-scratch uveitis confirmed by histological, serological, and molecular diagnoses. Cornea. 2011;30: 468–471.
176. Curi AL, Machado D, Heringer G, et al. Cat-scratch disease: ocular manifestations and visual outcome. Int Ophthalmol. 2010;30:553–558.
177. Terrada C, Bodaghi B, Conrath J, et al. Uveitis: an emerging clinical form of Bartonella infection. Clin Microbiol Infect. 2009;15(suppl 2): 132–133.
178. Drancourt M, Berger P, Terrada C, et al. High prevalence of fastidious bacteria in 1520 cases of uveitis of unknown etiology. Medicine (Baltimore). 2008;87:167–176.
179. Martinez-Osorio H, Calonge M, Torres J, et al. Cat-scratch disease (ocular bartonellosis) presenting as bilateral recurrent iridocyclitis. Clin Infect Dis. 2005;40:e43–e45.
180. Khurana RN, Albini T, Green RL, et al. Bartonella henselae infection presenting as a unilateral panuveitis simulating Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol. 2004;138:1063–1065.
181. Gray AV, Michels KS, Lauer AK, et al. Bartonella henselae infection associated with neuroretinitis, central retinal artery and vein occlusion, neovascular glaucoma, and severe vision loss. Am J Ophthalmol. 2004;137: 187–189.
182. Schwartzman WA, Patnaik M, Barka NE, et al. Rochalimaea antibodies in HIV-associated neurologic disease. Neurology. 1994;44:1312–1316.
183. Breitschwerdt EB, Maggi RG, Duncan AW, et al. Bartonella species in blood of immunocompetent persons with animal and arthropod contact. Emerg Infect Dis. 2007;13:938–941.
184. Breitschwerdt EB, Maggi RG, Nicholson WL, et al. Bartonella sp. bacteremia in patients with neurological and neurocognitive dysfunction. J Clin Microbiol. 2008;46:2856–2861.
185. Maggi RG, Kosoy M, Mintzer M, et al. Isolation of Candidatus Bartonella melophagi from human blood. Emerg Infect Dis. 2009;15:66–68.
186. Breitschwerdt EB, Maggi RG, Farmer P, et al. Molecular evidence of perinatal transmission of Bartonella vinsonii subsp. berkhoffii and Bartonella henselae to a child. J Clin Microbiol. 2010;48:2289–2293.
187. Breitschwerdt EB, Maggi RG, Robert Mozayeni B, et al. PCR amplification of Bartonella koehlerae from human blood and enrichment blood cultures. Parasit Vectors. 2010;3:76.
188. Breitschwerdt EB, Mascarelli PE, Schweickert LA, et al. Hallucinations, sensory neuropathy, and peripheral visual deficits in a young woman infected with Bartonella koehlerae. J Clin Microbiol. 2011;49:3415–3417.
189. Welch DF, Carroll KC, Hofmeister EK, et al. Isolation of a new subspecies, Bartonella vinsonii subsp. arupensis, from a cattle rancher: identity with isolates found in conjunction with Borrelia burgdorferi and Babesia microti among naturally infected mice. J Clin Microbiol. 1999;37:2598–2601.
190. Probert W, Louie JK, Tucker JR, et al. Meningitis due to a “Bartonella washoensis”-like human pathogen. J Clin Microbiol. 2009;47:2332–2335.
191. Maggi RG, Kemp VAJ, Chomel BB, et al. Bartonella. In: Versalovic J, Carroll KC, Funke G, et al, eds. Manual of Clinical Microbiology. Washington, DC: ASM Press; 2011:786–798.
192. Fournier PE, Robson J, Zeaiter Z, et al. Improved culture from lymph nodes of patients with cat scratch disease and genotypic characterization of Bartonella henselae isolates in Australia. J Clin Microbiol. 2002;40:3620–3624.
193. Duncan AW, Maggi RG, Breitschwerdt EB. A combined approach for the enhanced detection and isolation of Bartonella species in dog blood samples: pre-enrichment liquid culture followed by PCR and subculture onto agar plates. J Microbiol Methods. 2007;69:273–281.
194. Fournier PE, Couderc C, Buffet S, et al. Rapid and cost-effective identification of Bartonella species using mass spectrometry. J Med Microbiol. 2009;58:1154–1159.
195. Avidor B, Kletter Y, Abulafia S, et al. Molecular diagnosis of cat scratch disease: a two-step approach. J Clin Microbiol. 1997;35:1924–1930.
196. Mouritsen CL, Litwin CM, Maiese RL, et al. Rapid polymerase chain reaction based detection of the causative agent of cat scratch disease (Bartonella henselae) in formalin-fixed, paraffin-embedded samples. Hum Pathol. 1997;28:820–826.
197. George TI, Manley G, Koehler JE, et al. Detection of Bartonella henselae by polymerase chain reaction in brain tissue of an immunocompromised patient with multiple enhancing lesions. Case report and review of the literature. J Neurosurg. 1998;89:640–644.
198. Diederen BMW, Vermeulen MJ, Verbakel H, et al. Evaluation of an internally controlled real-time polymerase chain reaction assay targeting the groEL gene for the detection of Bartonella spp. DNA in patients with suspected cat-scratch disease. Eur J Clin Microbiol. 2007;26:629–633.
199. Diaz MH, Bai Y, Malania L, et al. Development of a novel genus-specific real-time PCR assay for detection and differentiation of Bartonella species and genotypes. J Clin Microbiol. 2012;50:1645–1649.
200. Giladi M, Kletter Y, Avidor B, et al. Enzyme immunoassay for the diagnosis of cat-scratch disease defined by polymerase chain reaction. Clin Infect Dis. 2001;33:1852–1858.
201. Sander A, Posselt M, Oberle K, et al. Seroprevalence of antibodies to Bartonella henselae in patients with cat scratch disease and in healthy controls: evaluation and comparison of two commercial serological tests. Clin Diagn Lab Immunol. 1998;5:486–490.
202. Rolain JM, Brouqui P, Koehler JE, et al. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents and Chemother. 2004;48:1921–1933.
203. Spach DH, Koehler JE. Bartonella-associated infections. Infect Dis Clin North Am. 1998;12:137–155.
204. Weston KD, Tran T, Kimmel KN, et al. Possible role of high-dose corticosteroids in the treatment of cat-scratch disease encephalopathy. J Child Neurol. 2001;16:762–763.
205. Genizi J, Kasis I, Schif A, et al. Effect of high-dose methyl-prednisolone on brainstem encephalopathy and basal ganglia impairment complicating cat scratch disease. Brain Dev. 2007;29:377–379.