Bartonella, Including Cat-Scratch Disease

Bartonella bacilliformis Epidemiology

Natural transmission of B. bacilliformis infection is mainly confined to the Andes mountain range in Peru, Ecuador, and Colombia at altitudes between 500 and 3200 m. This is presumed due to the limited regional distribution of the sand fly vectors (genus Lutzomyia [formerly Phlebotomus ]) of B. bacilliformis . Even in the modern antibiotic era, focal outbreaks continue, and new geographic areas of B. bacilliformis infection have been reported recently. In addition to outbreaks in new geographic areas, outbreaks in areas of endemicity continue to occur; for instance, 191 cases were reported from 2003 in a community with endemic disease in Peru. Cases of B. bacilliformis infection, one possibly from vertical transmission and the other after blood transfusion, have been reported. No nonhuman vertebrate reservoirs have been identified for B. bacilliformis.

Bartonella quintana Epidemiology

B. quintana is globally distributed, and the only identified vector of B. quintana is Pediculus humanus, the human body louse. Outbreaks of trench fever (also known as Wolhynia fever, Meuse fever, His-Werner disease, shin bone fever, shank fever, and quintan or 5-day fever) have been focal and widely separated. Clusters of trench fever cases usually are associated with conditions of poor sanitation and personal hygiene and are significantly associated with exposure to body lice. A survey of published reports of zoonotic and vector-borne infections, as assessed by seroprevalence in the homeless and very poor in the United States and Europe from 1990–2014, identified B. quintana as the most commonly reported vector-borne infection in the homeless. The prevalence of B. quintana in body lice can be high: B. quintana was detected in 33.3% of body lice pools removed from infested homeless persons in San Francisco. B. quintana has been isolated from captive nonhuman primates in China and the United States and, more recently, from wild-caught Japanese macaques, suggesting that nonhuman primates may serve as a natural reservoir for B. quintana .

Bartonella henselae Epidemiology

B. henselae is globally endemic and has been detected in 800-year-old French cats ; serologic studies indicate that infection of domestic cats occurs worldwide, with the prevalence of antibodies in cats being higher in warm, humid climates, where fleas are more prevalent. Prevalence of bacteremia in cats varies but tends to be higher among feral animals in any particular locale. The B. henselae colony-forming units (CFU)/mL of blood in infected cats can reach extremely high levels of ≥10 ⁶ ; yet these cats are usually asymptomatic. Free-ranging and captive wild felids in California also have a substantial prevalence of antibodies reactive with B. henselae , and B. henselae has been isolated from the blood of free-ranging mountain lions (Puma concolor) and bobcats (Lynx rufus) in California.

B. henselae bacteremia in pet cats is significantly associated with development of bacillary angiomatosis (BA) or typical cat-scratch disease (CSD) in their human contacts ; transmission of B. henselae to humans also is linked to domestic cats by serologic and epidemiologic studies. A recent review of cases of CSD in the United States from 2005–13 suggests an incidence of 4.5 outpatient diagnoses and 0.19 inpatient admissions per 100,000 population, with a higher incidence among children (age 5–9 years) and women, and in southern regions ( Fig. 234.1 ). For epidemiologic studies, diagnosis of human B. henselae infection has been confirmed by detection of anti- Bartonella antibodies, culture recovery of B. henselae from lymph nodes with the pathologic findings of CSD lymphadenitis, and by detection of B. henselae DNA by polymerase chain reaction (PCR) in tissue from cases of CSD lymphadenitis, CSD skin test antigen, and BA lesions. For B. henselae , one potential case of human-to-human transmission has been reported: donor-derived B. henselae infection in the recipient of an orthotopic liver transplant. The major arthropod vector of B. henselae is the cat flea, Ctenocephalides felis, as demonstrated by epidemiologic associations, identification of B. henselae by culture and DNA amplification from cat fleas, and transmission of B. henselae to cats by infected fleas under controlled experimental conditions. Cat fleas appear to serve as efficient vectors for cat-to-cat transmission ; their contribution to human infection likely occurs after inoculation of B. henselae –infected flea feces into the human during a cat scratch. Additional Bartonella spp. also have been identified in cat fleas. Other types of fleas, as well as ixodid and Dermacentor ticks, have been found to harbor various Bartonella spp., but transmission to humans via ticks has not yet been demonstrated.

Epidemiology of Other Bartonella Species Associated With Human Infection

In addition to B. henselae , Bartonella clarridgeiae and Bartonella koehlerae also cause asymptomatic, persistent bloodstream infection in cats. Although B. koehlerae is infrequently isolated from domestic cats, B. clarridgeiae is quite prevalent, especially in European domestic cats. Of 50 Bartonella isolates recovered from 94 stray cats in France, Heller and colleagues found that 34% were B. henselae genotype I, 36% were B. henselae genotype II, and 30% were B. clarridgeiae. Of interest, despite the high prevalence of B. clarridgeiae in cats, this species has neither been isolated from, nor DNA amplified from, lymph nodes of an immunocompromised or immunocompetent human with CSD. B. koehlerae is occasionally transmitted to humans and represents an uncommon cause of endocarditis. Because Bartonella elizabethae has been isolated only once from a human, little is known of its epidemiology, except that it has been cultured from the blood of rodents, and its DNA has been amplified from the blood of rodents, fleas from rodents, and dogs. Recently, a new species, Bartonella ancashensis , was isolated from the blood of two patients with verruga peruana in Ancash, Peru. The patients, age 3 and 12 years, had clinical features typical of verruga peruana (multiple chronic skin nodules). Sequencing of this blood isolate revealed a Bartonella spp. that was phylogenetically related to, but distinct from, B. bacilliformis . Another recently described human pathogen, Candidatus Bartonella tamiae, was isolated from three patients during a study of people presenting with febrile illness in Thailand; it has been proposed as a new Bartonella spp. but is not yet formally recognized. To date the definitive mammalian reservoir for Candidatus Bartonella tamiae has not been identified, although rodents and bats have been implicated. Bartonella rochalimae was isolated from the blood of a patient with a febrile illness after travel to Peru; subsequently, this organism was isolated from gray foxes (Urocyon cinereoargenteus) in northern California and detected by PCR in fleas (Pulex irritans) from dogs in Peru, implicating a canid reservoir. Bartonella vinsonii is generally not considered a human pathogen, although B. vinsonii subsp. arupensis and B. vinsonii subsp. berkhoffii have been associated with isolated cases of endocarditis in humans by serology and DNA amplification; these Bartonella subspp. have not yet been directly isolated from a human with endocarditis. B. vinsonii subsp. arupensis was isolated from the blood of an otherwise healthy rancher from the western United States who had fever without endocarditis, and this strain was implicated as the cause of endocarditis in another patient. B. vinsonii subsp. berkhoffii also can cause bacteremia and endocarditis in dogs. Bartonella alsatica has been associated with endocarditis in humans, and wild rabbits (a known reservoir of B. alsatica ) were a possible source of infection in these two patients.

Bartonella Bacilliformis Clinical Manifestations: Oroya Fever and Verruga Peruana

The long-suspected link between Oroya fever and verruga peruana was confirmed tragically in 1885 by Daniel Carrión, a medical student who injected himself with blood from a verruga peruana lesion and subsequently died of Oroya fever. The eponym “Carrión disease” has since denoted the full spectrum of B. bacilliformis infection. Oroya fever, an acute hematologic disease resulting from primary B. bacilliformis bacteremia and erythrocyte invasion, develops 3 to 12 weeks after cutaneous inoculation with infected sand fly feces. In its mildest insidiously developing form, a febrile illness can last less than a week and go unrecognized, giving rise to subsequent cutaneous manifestations that are the first-recognized clinical findings. When illness onset is abrupt, high fever, chills, diaphoresis, anorexia, prostration, headache, and mental status changes are associated with rapidly developing, profound anemia resulting from bacterial invasion and destruction of erythrocytes. Intense myalgias and arthralgias, abdominal pain and emesis, jaundice, lymphadenopathy, thrombocytopenia, and complications such as seizures, delirium, meningoencephalitis, obtundation, dyspnea, hepatic/gastrointestinal dysfunction, and angina pectoris can occur during this stage, believed to be a consequence of the anemia and microvascular thrombosis, with subsequent end-organ ischemia.

Without antimicrobial therapy, the fatality rate is high for the severe, abrupt form of bacteremic illness, Oroya fever. With appropriate treatment in the modern era, mortality is reported to be less than 10%. For survivors, convalescence is associated with a decline of fever and disappearance of bacteria on blood smears, but also a temporarily increased susceptibility to subsequent (opportunistic) infections, such as salmonellosis or toxoplasmosis. Asymptomatic persistent bacteremia with B. bacilliformis infection can occur in up to 15% of survivors of acute infection. It has been suggested that initial infection may be asymptomatic, or only mildly symptomatic, more often than was previously thought. Both the Oroya fever survivors and asymptomatically bacteremic individuals are suspected to serve as the reservoir for B. bacilliformis.

Verruga peruana lesions, the eruptive phase of B. bacilliformis infection, usually become evident within weeks to months after resolution of untreated acute infection. This late-stage manifestation is characterized by crops of skin lesions marked by an evolution of stages : miliary, then nodular ( Fig. 234.2 ), and subsequently what are called mulaire lesions ( Fig. 234.3 ). Of the eruptive manifestations, mulaire lesions are the most superficial and obviously vascular: often bulbous, engorged with blood, and prone to ulceration and bleeding. Mucosal and internal lesions also can occur. The nodules may develop at one site while receding at another. Healing at a particular skin site is often punctuated by recurrences and usually takes place over several weeks to 3 or 4 months. Subsequently, fibrosis of mulaire lesions can occur. Histology of active lesions demonstrates vascular proliferation with occasional bacteria evident in interstitial spaces. Bacterial invasion of/replication within endothelial cells (long believed to be the cause of cytoplasmic inclusions first described by Rocha Lima) is actually rare.

Bartonella henselae and Bartonella quintana : Clinical Manifestations Depend on the Infecting Bartonella Species and Immune Status of Host

The clinical manifestations of infection with these two Bartonella spp. depend on a combination of species-specific microbiologic and host-specific immunologic factors ( Fig. 234.4 ). Species-specific epidemiologic risk factors, such as exposure to cats and cat fleas for B. henselae , and homelessness and exposure to lice for B. quintana , are applicable to both immunocompetent and immunocompromised hosts. In immunocompetent hosts, infection with B. henselae typically manifests as CSD: regional, granulomatous lymphadenitis ( Fig. 234.5A ). Both B. henselae and B. quintana can present as fever of unknown origin (FUO). Endocarditis, usually due to B. quintana, most commonly occurs in immunocompetent hosts, often in the absence of a history of valvular abnormalities. B. henselae endocarditis is a less frequent cause of endocarditis and most often occurs in patients with underlying valvular pathology or congenital heart disease (CHD). Immunocompromised solid-organ transplant (SOT) recipients and persons living with human immunodeficiency virus (HIV; CD ₄ ⁺ cell count <100/mm ³ ) who are infected with either B. henselae or B. quintana can develop BA (see Fig. 234.5B–D ) but also can present with other clinical manifestations, for instance, bacillary peliosis (BP) hepatis ( B. henselae ), bacteremia ( B. quintana or B. henselae ), endocarditis ( B. quintana or B. henselae ), and/or FUO ( B. quintana or B. henselae ). Additional host/immunologic risk factors for more severe Bartonella infection, such as the use of biologic disease-modifying antirheumatic drugs, have been reported, although a clear association between the use of these agents and a particular clinical manifestation of Bartonella infection is not clearly defined.

Bartonella henselae and Bartonella quintana: Bacteremic Illness

Acute mortality resulting from bacteremia with non- bacilliformis Bartonella spp., even when persistent, is uncommon in immunocompetent hosts in the absence of endocarditis. In recent years, B. quintana bacteremic infection in immunocompetent individuals (“trench fever”) has been identified sporadically and in small clusters, predominantly in homeless people in North America and Europe. Trench fever is characterized by a self-limited fever, often with a 5-day periodicity (quintan pattern). The incubation period may span 3 to 38 days before the usually sudden onset of chills and fevers. In the most limited form of trench fever, a single bout of fever lasts 4 or 5 days. In the more typical periodic form, there are three to five, and sometimes up to eight, febrile paroxysms, each approximately 5 days apart. Patients are often asymptomatic between febrile paroxysms. The continuous form is manifested by 2 or 3 weeks, and up to 6 weeks, of uninterrupted fever. Afebrile infection with Bartonella is very common; one study found 8 of 10 homeless individuals with active B. quintana bacteremia were afebrile. Other nonspecific symptoms and signs, such as headache, retro-orbital pain, conjunctival injection, myalgias, arthralgias, bone pain, hepatosplenomegaly, rash, leukocytosis, and albuminuria can accompany B. quintana bacteremia. B. quintana bacteremia has the potential to evolve into long-term persistence if not treated appropriately. B. henselae bacteremia in immunocompetent hosts is rare, and localizing symptoms or physical findings are unusual. However, B. henselae bacteremia can present with abrupt onset of isolated fever or, rarely, accompany CSD lymphadenitis. Aseptic meningitis concurrent with B. henselae bacteremia also has been documented. B. henselae bacteremia is much less likely to persist or become relapsing than B. quintana in immunocompetent people.

HIV-infected patients with advanced immunosuppression (CD ₄ ⁺ cell count <100/mm ³ ) are more likely to develop severe and prolonged bacteremia with B. quintana or B. henselae. In these patients Bartonella bacteremia has been associated with cutaneous BA ( B. henselae or B. quintana ), hepatic and splenic BP (B. henselae), granulomatous hepatitis (B. henselae), infiltration of the bone marrow (B. henselae), FUO ( B. quintana and B. henselae ), and occasionally endocarditis ( B. quintana much more frequently than B. henselae ). In one area of high HIV prevalence, evidence of B. henselae or B. quintana infection was found in 18% of people evaluated for acute or persistent unexplained fever, 97% of whom were HIV infected and had a median CD ₄ ⁺ cell count of 35 per mm ³ and no antiretroviral exposure. In a study of 49 patients with documented BA/BP (92% had HIV infection), 50% of patients sampled had bacteremia with either B. quintana or B. henselae. The clinical presentation of Bartonella bacteremia often is characterized by insidious development of malaise, body aches, fatigue, weight loss, progressively higher and longer recurring fevers, and sometimes headache. Hepatosplenomegaly and/or splenomegaly may occur, but localizing symptoms or physical findings can be lacking. Secondary hemophagocytic lymphohistiocytosis has been associated with B. henselae in both HIV-infected and transplant hosts, heralded by hepatosplenomegaly and cytopenias.

Bartonella henselae and Bartonella quintana: Endocarditis

Bartonella spp. are recognized as one of the most important causes of blood culture-negative endocarditis. Two large European studies of patients with blood culture-negative endocarditis found Bartonella spp. to be the second most frequently identifiable cause, after Coxiella burnetii . In the United States, where Coxiella endocarditis is less common than in Europe, Bartonella spp. are quite likely the most common cause of culture-negative endocarditis. Patients with B. quintana endocarditis are usually homeless, often substance abusers, and have exposure to body lice, whereas people with B. henselae endocarditis more commonly have cat exposure and preexisting valvular heart disease. B. henselae endocarditis is infrequent in humans; despite the frequency of CSD in the pediatric population, B. henselae endocarditis has been recognized only rarely. The reports of pediatric endocarditis usually involve patients with CHD. The more common cause of human endocarditis, B. quintana, is extremely rare in pediatric practice because of the less frequent exposure of children to risk factors associated with B. quintana: homelessness and body lice.

Patients with Bartonella endocarditis typically present with a prolonged (weeks to months) history of nonspecific symptoms, such as fever, fatigue, and weight loss. In a retrospective study of 101 patients with Bartonella endocarditis, ≈83% were febrile and 43% had evidence of embolic phenomena at the time of presentation. Fifty-eight patients (57%) had previously known valvular heart disease, 58 (57%) had involvement of the aortic valve, and 18 (18%) had involvement of multiple valves. Irrespective of antimicrobial therapy, 76 patients had severe valvular damage and required valvular surgery. Twelve patients ultimately died; two were cured only after treatment for a relapse, and the remaining 87% were cured with the initial therapy.

It is important to be aware of the rapidly increasing number of reports of vasculitis associated with Bartonella endocarditis. Patients with B. henselae and B. quintana endocarditis can present with clinical features of a systemic, small vessel vasculitis associated with a positive cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA), anti–proteinase 3 antibodies (anti-PR3), and/or kidney injury with glomerulonephritis. In these patients, detection of Bartonella infection is critical to avoid exposure to immunosuppressive therapy for vasculitis and to institute timely antimicrobial therapy for Bartonella endocarditis. In c-ANCA–positive patients the c-ANCA titers may be useful for clinical monitoring of endocarditis treatment, and antimicrobial treatment of the underlying endocarditis usually results in resolution of the vasculitis, without steroids.

As noted earlier, in addition to antimicrobial therapy (see “Treatment”) Bartonella endocarditis requires surgical intervention in the majority of cases. Delays in surgical intervention have been associated with morbid complications, such as stroke and acute myocardial infarction.

The diagnosis of culture-negative endocarditis due to Bartonella has been established with serology, amplification of Bartonella DNA from blood or valve tissue, immunohistochemistry, or a combination of these modalities. A series of 106 cases from a single center in France revealed the sensitivity of two of their diagnostic tests: immunoblotting with patient serum (100%) and PCR of DNA extracted from valvular tissue (92%). Serology testing for Bartonella immunoglobulin G (IgG) antibodies by immunofluorescence was positive (defined as ≥1 : 100) in 91% of Bartonella endocarditis patients; an IgG titer ≥1 : 800 had a positive predictive value of 94% for endocarditis. In a review of Bartonella endocarditis among 13 patients with CHD, serology was positive in 100% of cases, and PCR on DNA extracted from valvular tissue detected Bartonella in all 11 patients who underwent surgery. Evaluation of homeless individuals or SOT recipients with fever and glomerulonephritis, cutaneous small vessel vasculitis, and/or positive c-ANCA or anti-PR3 should prompt a clinical workup for Bartonella endocarditis.

Other Bartonella Species: Endocarditis and Bacteremia

B. elizabethae has been isolated from a single patient with bacteremia and endocarditis. B. vinsonii subsp. arupensis and B. vinsonii subsp. berkhoffii have been associated with a few isolated cases of endocarditis in humans. B. vinsonii subsp. arupensis also was isolated from a US rancher who had bacteremia and fever. In addition, B. koehlerae and B. alsatica have been associated with endocarditis in humans. B. rochalimae caused a febrile bacteremic illness with splenomegaly in an immunocompetent traveler returning from Peru, who had sustained numerous arthropod bites. A novel species, Candidatus Bartonella tamiae, was isolated from the blood of three patients being evaluated for fever in Thailand. It is evident that many Bartonella spp. associated with wild and peridomestic animals can infect humans, albeit rarely, especially patients with abnormal heart valves or CHD.

Bartonella henselae and Bartonella quintana Infections in Immunocompromised Patients: Bacillary Angiomatosis/Bacillary Peliosis

BA (also referred to as bacillary epithelioid angiomatosis) is a manifestation of B. quintana or B. henselae infection involving vascular proliferation in skin and regional lymph nodes, which was initially described in patients with advanced HIV-infection (CD ₄ ⁺ cell count <100/mm ³ ). Subsequently, BA has been identified in a variety of internal organs, including liver, spleen, bone, brain, lung, bowel, and uterine cervix. BA has been increasingly identified in other hosts with compromised immunity (such as SOT and chemotherapy recipients) and, very rarely, immunocompetent hosts. B. henselae and B. quintana have been found to be a cause of BA both by direct culture and by PCR amplification of Bartonella -specific DNA sequences from tissue. Either species can cause cutaneous BA lesions, but subcutaneous and osseous lesions are more often associated with B. quintana and hepatic and splenic BP only with B. henselae. In addition, patients with B. henselae genotype I infection may be more likely to have hepatic and splenic peliosis, whereas patients with B. henselae genotype II are more likely to develop BA lesions involving the skin or lymph node, or both.

Cutaneous BA lesions often arise in crops ( Fig. 234.6D and E ), but both the temporal pattern of development and the gross morphologic characteristics can vary. Of interest, the clinical and histopathological appearance of verruga peruana lesions caused by B. bacilliformis in immunocompetent hosts closely resembles the cutaneous BA lesions caused by B. henselae and B. quintana in immunocompromised hosts. BA lesions also can resemble pyogenic granuloma, but the major clinical differential diagnosis in HIV-infected patients is Kaposi sarcoma. In gross appearance, BA skin lesions can be subcutaneous (see Fig. 234.6F ); form dermal nodules (see Fig. 234.6C ); or form single or multiple papules that are flesh colored, red, or purple (see Fig. 234.6E ). Skin lesions also can display ulceration (see Fig. 234.6D ), serous or bloody drainage, and crusting (see Fig. 234.6B ). Lesions can range in diameter from millimeters to centimeters (see Fig. 234.6C ), number from a few to hundreds (see Fig. 234.6E ), be fixed or freely mobile, be associated with enlargement of regional lymph nodes, involve mucosal surfaces or deeper soft tissues (see Fig. 234.6A ), occur in a variety of distributions, and bleed copiously when incised. Osteomyelitis also can be associated with BA lesions (see Fig. 234.6F ). Visceral BA lesions can be quite dramatic as well, in both their number and heterogeneity of gross appearance.

Although BA can closely resemble other neovascular tumors clinically, BA can be distinguished from other vascular proliferative tumors histologically. BA consists of lobular proliferation of small blood vessels containing plump, cuboidal endothelial cells, interspersed with mixed inflammatory cell infiltrates having a neutrophil predominance ( Fig. 234.7B1 ). Endothelial cell atypia, mitoses, and necrosis may be present. Fibrillar- or granular-appearing amphophilic material is often present in interstitial areas when stained by hematoxylin and eosin (H&E) stain. Warthin-Starry staining or electron microscopy shows this material to be clusters of bacilli (see Fig. 234.7B2 and B3 ).

When cutaneous BA lesions are absent, diagnosis is often delayed because of the nonspecific features associated with hepatic or splenic BP (fever, lymphadenopathy, hepatomegaly, splenomegaly, anemia, pancytopenia, and serum alkaline phosphatase elevation). BP, originally described as a process involving the liver, sometimes occurs in the spleen and occasionally lymph nodes in HIV-infected people and has since been identified in other immunocompromised people. Molecular epidemiologic investigation has revealed that B. henselae (and not B. quintana ) appears to be the only Bartonella spp. eliciting this host response of BP. Involved organs contain numerous blood-filled cystic spaces (peliosis) that can range from microscopic to several millimeters in size. Hepatic and splenic BP appear as multiple hypodense or low-attenuation lesions on ultrasonographic or computed tomographic (CT) abdominal scanning ( Fig. 234.8C ). H&E-stained tissue reveals that the peliotic spaces (see Fig. 234.8F ) are partially lined with endothelial cells and often separated from surrounding parenchymal cells by fibromyxoid stroma containing a mixture of inflammatory cells, dilated capillaries, and clumps of granular material. Such clumps are composed of aggregates of bacilli that stain with Warthin-Starry stain. Presenting clinical features of BP hepatis are often nonspecific, although there is a dramatic report of an HIV-infected patient presenting with fever and abdominal pain, who developed massive hemoperitoneum from hepatic BP.

B. henselae –related inflammatory reactions in immunocompromised hosts, in the absence of associated angiomatosis or peliosis, have been reported in liver (see Fig. 234.8B ), spleen, lymph nodes, heart, lung, and bone marrow. They are characterized by nodular collections of lymphocytes and nonepithelioid histiocytes that can become centrally necrotic, containing aggregates of neutrophils and karyorrhectic debris suggestive of microscopic abscess formation (see Fig. 234.8E ). These may represent a clinical-pathologic link with CSD and are more likely to occur in HIV-infected patients who have less severe immunosuppression or SOT recipients with a later disease presentation (mean, 5.2 years) posttransplantation.

Bartonella henselae : Cat-Scratch Disease