EMERGING INFECTIOUS DISEASES 0891-5520/98 $8.00 + .

OO

BARTONELLA-ASSOCIATED
INFECTIONS
David H. Spach, MD, and Jane E. Koehler, MD

Although descriptions of infections caused by Bartonella (formerly Rochali-

rnaea), such as Oroya fever, trench fever, and cat-scratch disease (CSD), have
existed for more than 50 years, much of the current understanding of Bartonella-
associated infections has resulted from the AIDS epidemic. In 1983, Stoler et a194
provided the first report of a Bartonella-associated infection in an HIV-infected
individual. This report described an AIDS patient from New York who devel-
oped multiple subcutaneous vascular nodules that contained numerous bacillary
organisms visualized by electron microscopy. Additional reports in the late
1980s described patients with similar cutaneous lesions, and these vascular
proliferative lesions became known as bacillary angiomatosis (BA).52During this
time, however, investigators could not cultivate an organism from these lesions,
and the cause remained unidentified.
In a December 1990 issue of the New England Journal of Medicine, separate
groups of investigabrs respectively described three key new findings: (1) the
close relationship of a DNA sequence from the bacillus in BA tissue to the agent
of trench fever, Rochalirnaea quintana; (2) the isolation of a small, fastidious, gram-
negative rod from patients with relapsing bacteremia; and (3) the association of
a small bacillus with the unusual histopathologic entity of peliosis hepatis in the
livers of HIV-infected 88 These three research groups soon realized
that their separate findings involved the same organism. This newly-recognized
bacillary organism, which was subsequently named Rochalirnaea henselae,79j lo*
was initially presumed to be the sole agent of BA. In 1992, however, Kcehler et

This project was supported by funds from the NIH R29 A136075 and the University-
wide AIDS Research Program. Jane E. Koehler, MD, is a Pew Scholar for the Biomedical
Sciences.

From the Division of Infectious Diseases, University of Washington, Seattle, Washington

(DHS); Division of Infectious Diseases, University of California-San Francisco, San
Francisco, California (JEK)

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA

-
VOLUME 12 NUh4BER 1 * MARCH 1998 137
138 SPACH & KOEHLER

a147became the first group to isolate organisms from BA lesions, and in this
process demonstrated that either R. quintana or R. henselae can cause BA.
The four species belonging to the genus of Rockalimaea were moved to the
genus of Bartonella in 1993 after genetic studies showed the close relationship
between the Rochalimaea species and B. bacilliformis, the original member of the
genus Bart~nella.'~ More recently, the genus of Grahamella was merged with the
genus of Bartonella, and at present, nine cultivated species belong to the genus
Bartonella." Four of these species, B. bacilliformis, B. kenselae, B. quintana, and B.
elizabetkae, have been documented to be pathogenic in humans. Four species, B.
vinsonii, B. grahamii, B. taylorii, and B. doskiae, were isolated from small wild
mammals, and B. clarridgeiae was isolated from a domestic cat.3,lo, 26, 51 In addi-
tion, one group recently isolated a subspecies of B. vinsonii from a dog with
end~carditis.'~
The spectrum of diseases caused by Bartonella has rapidly expanded to
include BA,47,B1 bacillary peliosis,76,Ioz relapsing ba~teremia?~, 88 endocarditis,28,
33,
90,91 and "urban trench fever."92Moreover, in 1992, Regnery et alsodemonstrated

antibodies to Bartonella species in a panel of banked sera from immunocompetent

patients with a clinical diagnosis of CSD, thus contradicting the initial belief
that Afipia felis was the causative agent of CSD. Subsequently, B. henselae was
isolated from the lymph nodes of two patients with apparent CSD and B.
henselae DNA was detected by polymerase chain reaction (PCR) in specimens
from patients with CSD.', 31 In addition, the domestic cat was identified as the
major reservoir for B. h e n ~ e l a e Taken
. ~ ~ together, these data from 1992 to 1994
convincingly identified B. henselae, not A. felis, as the predominant causative
organism of CSD.
Bartonella species represent a fascinating group of emerging pathogens. This
article presents a summary of the manifestations of human Bartonella infections
identified at present in North America and in Europe, but will not discuss B.
bacilliformis, an infection predominantly limited to South America. Although
considerable knowledge of Bartonella-associated infections has been gained,
much data remain to be gdthered to better define disease spectrum, prevalence,
maintenance, and mode of transmission.

CLINICAL MANIFESTATIONS

lmmunocompromised Host

Bacillary Angiomatosis
The manifestations of Bartonella infection in the immunocompromised host
are diverse and often nonspecific, frequently resulting in failure to diagnose
these infections. The vascular proliferative lesions associated with B. henselae
and B. quintana infection occur almost exclusively in HIV-infected and other
immunocompromised individuals (although BA has been identified in seven
apparently immunocompetent patients).75, 89, 95 BA is usually a late-developing
manifestation during the course of HIV infection, occurring after the CD4 count
has decreased to less than 100 ~ e l l s / m m ~68. In
~ , one study of 42 immunocom-
promised patients with BA, the median CD4 count at the time of presentation
was 21 ~ e l l s / m m BA~ . ~has
~ also been reported in immunosuppressed cardiac
and renal transplantation 86 in addition to patients receiving
~hemotherapy~~, 98 for hematologic malignancy.
The histopathologic changes of BA associated with Bartonella infection have
 BARTONELLA-ASSOCIATEDINFECTIONS 139

been identified in many different tissues, including skin, brain, bone, lymph
nodes, gastrointestinal tract, respiratory tract, and bone marrow. Cutaneous BA
is the most frequently recognized manifestation, but can appear as diverse
angiomatous lesions, including verrucous, papular, or pedunculated forms.44
Although these lesions most often have an erythematous base and a vascular
appearance, they are occasionally dry, scaly, hyperkeratotic, or plaquelike. The
lesions may occur singly or number in the hundreds, covering the entire body,
usually enlarging if they remain untreated. Patients with BA can also present
with subcutaneous nodules, with or without overlying tenderness and erythema,
or with deep soft-tissue masses. Doppler ultrasonography often demonstrates
the highly vascular characteristics of these deep soft-tissue lesions.
The angiomatous cutaneous lesions of BA can be indistinguishable clinically
from those of Kaposi's sarcoma (KS), particularly the verrucous form of KS. In
addition, KS and BA can coexist in the same patient, further complicating the
diagnosis of BA.7 Other entities to be considered in the differential diagnosis of
cutaneous BA include pyogenic granuloma, verruga peruana (the cutaneous
eruption associated with B. bacilliformis infection and seen only in the Andes of
South America), and several types of subcutaneous tumors.5z
Focal BA affecting bone is usually extremely painful and manifests radio-
graphically as a lytic l e ~ i o nThe
. ~ lytic lesions may occur singly, most commonly
involving the radius, fibula, or tibia, and are easily identified by y9mtechnetium
methylene diphosphonate scanning5 A cellulitic, tender, erythematous plaque
overlying the osseous lesion has been identified in several Many
patients with osseous BA were diagnosed presumptively from biopsy of concom-
itant cutaneous BA lesions and by resolution of radiographically visualized bone
lesions following appropriate antimicrobial therapy.44
Lymphadenopathy frequently accompanies BA lesions, but the involved
nodes rarely suppurate or drain.&BA lesions of the gastrointestinal and respira-
tory tract can be visualized during endoscopy or bronchoscopy, re~pectively.4~. ni
Oral, anal, and peritoneal BA lesions have also been reportedz4;in one of these
patients a large angioma of the larynx enlarged and caused asphyxiati~n.~~ Other
infrequently encountered manifestations of focal Bartonella infection include BA
of the bone marrow, brain parenchyma, intra-abdominal cavity, and cervix and
v~lva.4~f58, 67, 93 Bartonella infection of the central nervous system has also been
proposed as a cause of meningitis and neuropsychiatric, deterioration in HIV-
infected patients with Bartonella antibodies in the cerebrospinal fluid (CSF)
and serum.84

Bacillary Peliosis and Splenitis

In 1990, Perkocha et a176first described bacillary peliosis hepatis. Peliotic
changes of the liver (formation of venous lakes within the liver parenchyma)
had been previously described in patients with terminal malignancy or after
treatment with anabolic steroids; however, when the histopathologic changes of
peliosis hepatis were observed at autopsy in a patient with cutaneous BA lesions,
Warthin-Starry staining and electron microscopy were performed to look for
bacilli in the liver tissue. Small bacilli were observed in the liver parenchyma
adjacent to the peliotic spaces in this patient and then in seven additional HIV-
infected patients.76These eight patients had hepatomegaly; six had splenomegaly
and two had cutaneous BA lesions. Other immunosuppressed patients have
developed bacillary peliosis, including a patient who received chemotherapy for
ovarian cancer.6y
By abdominal computed tomography, the peliotic spaces in liver and spleen
140 SPACH & KOEHLER

appear as hypodense lesions scattered throughout the organ parenchyma. Unfor-

tunately, many infectious and malignant conditions, such as hepatic KS, lym-
phoma, Mycobacterium avium complex infection, and extrapulmonary pneumo-
cystosis, can cause similar radiographic abnormalities.
Studies of the serum hepatic enzyme levels revealed that the alkaline phos-
phatase was the test most consistently elevated, by an average of 5-fold above
the normal level and by as much as 10-fold in one patient.76Aminotransferase
levels were less dramatically elevated (average, two times normal). In this report,
two of the patients with splenomegaly developed progressive pan~ytopenia.~~
Other groups have reported thrombocytopenia or pancytopenia in association
83 Thus, the differential diagnosis of immu-
with peliosis hepatis and ~plenitis.6~.
nocompromised patients with hepatosplenomegalyand either thrombocytopenia
or pancytopenia should include Bartonella infection.

Bacteremia and Endocarditis

HIV-infected individuals with BA or bacillary peliosis can present with
concomitant Bartonella ba~teremia.~~, 65, 86 Bartonella bacteremia can also occur in

the immunocompromised patient in the absence of focal bacillary infection.79,88

Slater et alsSdescribed three immunocompromised patients (two infected with
HIV and a third with pharmacologic immunosuppression following bone mar-
row transplantation) who developed B. henselae bacteremia. Prolonged and
sometimes relapsing fever accompanied by weight loss and other constitutional
symptoms were noted in these patients. Finally, endocarditis may complicate
Bartonella infection in immunosuppressed patients, with development of valvu-
lar vegetations and a clinical course characteristic of subacute bacterial endocar-
d i t i ~In ~ first reported case of BartoneZla species endocarditis, Spach et a190
. ~the
described an HIV-infected patient who presented with fatigue, night sweats,
and weight loss. This patient had a holosystolic murmur, splenomegaly, mild
renal insufficiency, and anemia. Echocardiography identified vegetations and
regurgitant flow of both mitral and aortic valves. Bartonella quintana was isolated
from blood cultures and the patient recovered after prolonged antimicrobial
therapy.

lmmunocompetent Host

CSD
Although most immunocompetent patients with CSD manifest with regional
lymphadenopathy, an array of clinical abnormalities can develop, including
Parinaud’s oculoglandular syndrome, encephalopathy, myelitis, peripheral neu-
ropathy, neuroretinitis, granulomatous hepatitis, granulomatous splenitis, ery-
thema nodosum, and osteolytic bone lesions.6,l7 The initial clinical manifestation
of CSD, the primary inoculation lesion, arises in more than 90% of patients,
typically 3 to 10 days after the cutaneous inoculation of the organism by a cat
scratch or bite.17The primary inoculation lesion usually evolves through vesicu-
lar, erythematous, and papular (often with a covering crust) stages. In general,
the primary inoculation lesion persists for about 1 to 3 weeks.
Approximately 2 weeks (range, 3 to 50 days) after inoculation, patients
develop adenopathy, the hallmark finding of CSD. Thus, when most patients
present with regional lymphadenopathy, the primary inoculation lesion can still
be observed, typically appearing at this stage as a crusted, erythematous papule
 BARTONELLA-ASSOCIATED INFECTIONS 141

2 to 6 mm in diameter.62More than 90% of patients with CSD present with

regional lymphadenopathy, with the location of the adenopathy dependent on
the site of the cat scratch or bite. Most commonly, the adenopathy develops in
the axilla, cervical, or submandibular regions.17Less commonly, the adenopathy
may develop at epitrochlear, inguinal, femoral, or supraclavicular sites. Initially,
the nodes are generally firm, tender, and 1 to 5 cm in diameter; overlying
erythema may develop. About 85% of patients will have solitary lymphadenopa-
thy, but some patients will have several abnormally swollen nodes in the
same region.17 Less than 2% of patients will develop noncontiguous bilateral
1ymphaden0pathy.l~Although generalized lymphadenopathy has been reported
in a patient with CSD,’Wthis finding did not appear in a review of more than
1200 patients with CSD,I7and thus probably rarely occurs.
Although most patients have gradual resolution of their lymphadenopathy
within several months, up to 20% experience prolonged adenopathy lasting
longer than 6 months, even for as long as 12 to 24 months in some instances.I7
Various series have reported widely variable rates of lymph node suppuration
(depending on the severity of the lymph node enlargement), ranging from 12%
to 48v0.’~,29 At the time patients present with lymphadenopathy, approximately
one third will have a history of fever greater than 38.3” C, with the fever
generally lasting at least 1 to 2 weeks. Similarly, approximately one third of
patients complain of fatigue, but this often persists for longer periods.
About 2%to 3% of patients with CSD will develop Parinaud’s oculoglandu-
lar syndrome, a disorder characterized by unilateral conjunctivitis and regional
lymphadenitis. In 1985, Wear et allo1 identified the CSD bacillus from
conjunctival lesions in 9 of 24 patients with Parinaud’s oculoglandular syn-
drome, thus adding the CSD bacillus to the list of other infectious agents known
to cause this disorder.lolIn patients with Parinaud’s oculoglandular syndrome,
the organism is inoculated on either the conjunctiva or eyelid via a scratch, lick,
or bite; often the patient introduces the organisms into the eye by their own
hand. Within several weeks after inoculation the patient develops preauricular
adenopathy associated with either a nonpurulent conjunctivitis, a soft ocular
granuloma, or both.19Most patients do not appear seriously ill, and the abnormal
ocular findings resolve within several months without residual ocular damage.
CSD-associated neurologic involvement probably occurs in at least 2% of
patients with CSD, and can manifest as encephalitis, seizures, myelitis, periph-
eral neuropathy, or retinitis.63,7z
In 1986, Lewis and Tucker reviewed the findings
from 38 patients with CSD and neurologic Among these 38
patients, 34 had encephalopathy and 4 had predominantly myelopathic involve-
ment. Patients with encephalopathy developed headache and mental status
changes, typically 2 to 3 weeks after the onset of CSD; most (27 of the 34) had
seizures at some point in their neurologic illness. Two of the 34 patients with
encephalopathy had residual neurologic sequelae, 1 with a residual right hemi-
paresis and 1 with a complex partial seizure disorder that required chronic
anticonvulsant drug therapy; both of these patients had focal abnormalities on
computed tomographic scan at the time of their initial presentation. The four
patients with myelitis had spinal cord or root involvement and presented with
findings that included extremity weakness, sensory loss, reflex changes, and
sphincter dysfunction; two of these four patients had a significant residual
neurologic deficit.
In a more recent review published in 1991, Carithers and Margileth reported
their findings in 61 patients with encephalopathy-the largest series of CSD-
associated encephalopathy.20The patients typically had an abrupt onset of neuro-
logic symptoms approximately 1 to 6 weeks (range, 2 days to 2 months) after
142 SPACH & KOEHLER

their initial manifestation of CSD (usually regional lymphadenopathy). Existing

data, however, do not suggest that patients with regional adenopathy in the
neck region more frequently develop neurologic complications. Among the 61
patients described by Carithers and Margileth," 46% had convulsions, 40% had
combative behavior, 50% had a temperature greater than 38.2" C, and 26% had
a temperature greater than 39" C. Laboratory studies, including CSF analysis
and computed tomography of the brain, produced inconsistent and nondiagnos-
tic results. Within 1 year, all 61 patients recovered, and most recovered within
the first 12 weeks; none had permanent neurologic sequelae.
Carithers and MargilethZ0also described 15 patients with neurologic abnor-
malities other than encephalopathy. These abnormalities included transient facial
nerve paresis (Bell's palsy) and transient peripheral neuropathy. In addition,
they described 10 patients with neuroretinitis, each of whom suddenly devel-
oped unilateral blindness associated with regional lymphadenopathy and a cat
scratch. These patients had gradual recovery of their vision during a 4- to 12-
month period, with a return to normal (20/20) or almost normal vision (20/50).
Wong et a P 3 describe a woman who developed culture-proven bacteremia with
B. henseZae and acute loss of vision due to stellate neuroretinitis 2 months after
acquiring a kitten. Her husband experienced similar symptoms and positive
blood cultures 1 week later. Bartonella henselae also was isolated from the blood
of the couple's kitten.Io3
Several reports have described patients with CSD who had involvement of
visceral organs.30,54, 66 These reports describe patients with a 1- to 3-week history
of fever with or without peripheral adenopathy. Dunn and colleagues recently
described seven children with hepatosplenic CSD who presented with marked
abdominal pain.34The involvement of abdominal visceral organs is usually first
suspected when either an abdominal ultrasound or computed tomography scan
shows multiple defects in the liver (and sometimes the spleen). The lesions
appear as round, oval, or irregular, typically ranging in size from 3 mm to 3
cm.6 On noncontrast computed tomography scan, the lesions appear hypodense
compared with normal parenchyma, but with contrast they may change to
isodense or even slightly enhance. After several months, the lesions calcify
or resolve. Patients with visceral organ involvement often have a self-limited
clinical course.
In the Carithers review of 1200 patients, 5 patients with CSD developed
erythema nodosum; these patients developed fever and subcutaneous nodules
(on their shins) 1 to 6 weeks after the onset of regional lymphadenopathy, and
all nodules resolved without ~eque1ae.I~ Several reports have also described a
few CSD patients with osteolytic lesions.17, 73 From the limited available data,
it appears that these patients have an absence of several findings typically
associated with osteomyelitis, namely fever and leukocytosis. One patient pre-
sented with a soft-tissue mass suggestive of a soft-tissue sarcoma."

Trench Fever
Most of the clinical descriptions of trench fever have been generated from
the epidemics in World War I and World War II.57Based on clinical observations,
the incubation period appears to range from 3 to 38 d a ~ s . In
5 ~controlled studies,
however, a more narrow range of 5 to 20 days was observed in human volun-
teers inoculated with B. quintana-infected louse fe~es.9~Four major fever patterns
have been described with classic trench fever: (1) a single febrile episode with
no subsequent fever; (2) a single febrile period lasting 4 to 5 days; (3) three to
eight recurrent febrile episodes, each lasting 4 to 5 days; and (4)persistent fever
 BARTONELLA-ASSOCIATEDINFECTIONS 143

lasting 2 to 6 ~ e e k s . 599~Among
. these four fever patterns, the episodic pattern
occurs most frequently. On rare occasions, patients may develop infection with-
out fever. Clinical signs and symptoms associated with these febrile episodes
have varied and include malaise, myalgias, arthralgias, headache, conjunctivitis,
retro-orbital pain, bone pain (particularly the shins), splenomegaly, and a tran-
sient macular rash.99

Bacteremia and Endocarditis

Among the 10 patients involved in the cluster of B. quintana bacteremia
from Seattle, 3 had weight loss that exceeded 20 lb, 7 had a temperature greater
than 38.5" C, 1 had hypothermia (35.5" C), and two had splen~megaly.~~ One
patient initially presented with fever, anemia, cardiomegaly, a 3/6 systolic
murmur, and a 3/6 diastolic murmur; echocardiography showed an aortic
valve vegetation, and the patient subsequently underwent cardiac surgery with
replacement of his aortic valve.91A second patient developed signs and symp-
toms suggestive of endocarditis 9 months after his initial B. quintana bacteremia.
Although echocardiography showed evidence of endocarditis and a computed
tomography showed multiple splenic lesions, B. quintana was not isolated at this
later time. One of the 10 patients died, but of causes probably unrelated to the
B. quintana bacteremia.
In a report from France, three patients with B. quintana bacteremia devel-
oped end~carditis.~~ All three patients presented with fever and two of three
had significant weight loss (12 and 15 kg, respectively). Routine laboratory
findings included thrombocytopenia (two patients), elevated erythrocyte sedi-
mentation rate (two patients), and abnormal liver function tests (one patient).
Cardiac valvular abnormalities involved the mitral valve (one patient), aortic
valve (one patient), and both mitral and aortic valve (one patient); in all cases,
the patient underwent cardiac surgery and had valve replacement.
A multicenter international study from France, England, Canada, and South
Africa evaluated patients with blood culture-negative endocarditis and found 22
patients with Bartonella endocarditis, including 5 with B. quintana infection, 4
with B. henselae, and 13 with an undetermined Bartonella species.77Among these
22 patients, 19 required valvular surgery and 6 died. Several other recent reports
have described Bartonella endocarditis in immunocompetent 37, 40

EPIDEMIOLOGY AND PREVENTION

lmmunocompromised Host

Limited data exist regarding the incidence of Bartonella infections in immu-

nocompromised patients, in part because systematic reporting of BA and bacil-
lary peliosis hepatis does not occur. Moreover, these disorders are probably
underrecognized and underdiagnosed. Nevertheless, based on available reports
it appears that Bartonella infections in immunocompromised patients are uncom-
mon, but not rare.
Many of the initial BA reports noted prior cat contact among these patients.
Subsequently, risk factors for developing BA were evaluated carefully in a case
control study of 48 patients with BA or bacillary peliosis he pa ti^.^^ Exposure to
a cat and, more specifically, receiving a cat scratch or bite, were significantly
associated with the development of BA or bacillary p e l i ~ s i sTo
.~~further investi-
gate this association between traumatic cat exposure and development of BA in
144 SPACH & KOEHLER

the pet owner, Koehler et ar5 identified four BA patients who still had the cats
with which they had contact at the time they developed BA. Biopsy specimens
were available for three of the patients, and the species causing BA was found
to be B. henselae, not B. quintana, for each patient. Surprisingly, blood cultures of
all seven of the cats that belonged to these four patients grew B. henselae, some
with more than 1000 colony-forming units per milliliter of bl00d.4~Pet and
pound cats in the San Francisco Bay area were then cultured, and 25 (41%) of
61 of the cats had B. henselae bacteremia. Most likely, a large number of cats are
infected in other regions of the United States similar to the San Francisco Bay
area. Childs et alZ1found that 89 (15%) of 592 banked cat sera from Baltimore
had antibodies to B. henselae, with the highest seroprevalence (44%) in feral
catsz1 In addition, Koehler et a145isolated B. henselae from some of the fleas
combed from bacteremic cats, implicating the cat flea as a potential vector for
B. henselae transmission (from cat to cat or from cat to
Preventing B. henselae infection is important for immunocompromised pa-
tients, many of whom are dependent on their pet cats as an important source of
companionship. Screening cats by culture or for antibodies is not currently
recommended because culture is difficult and cats can be intermittently bacter-
emic with B. h e n s e l ~ eOne
. ~ ~ recent study found that absence of antibodies to B.
henselae may be useful in predicting the absence of bacteremia in cats, but
conversely, the presence of antibodies was not predictive of bacteremia.= The
very small potential risk of contracting Bartonella infection appears to be out-
weighed substantially by the benefit of cat owner~hip.’~ It is therefore not
recommended that immunocompromised individuals give up their pet cats, but
that they make their medical caregivers aware that they own a cat, especially if
they develop fever or cutaneous lesions.78Immunocompromised individuals can
reduce their exposure to feline-associated B. henselae by avoiding rough play
that is likely to result in scratches, washing scratches and bites immediately
with soap and water, and controlling cat flea infe~tation.~~ Because younger cats
are more likely to be bacteremi~~~, 74 and to scratch, an immunocompromised

person acquiring a pet cat should consider choosing an adult cat rather than a
kitten. If an economical and reliable serologic test becomes available in the
future, HIV-infected patients should consider choosing a seronegative cat.74
One third of the patients in the epidemiologic study by Tapper0 et a196had
no cat contact, and because B. henselae or B. quintana can cause BA, the reservoir
and vector may be different for these two species. Although it appears that cats
do not transmit B. quintana to humans, the source of BA caused by B. quintana
remains unknown, and at present, the only recommendation for preventing
infection with this species is to avoid contact with lice, a known vector of B.
quint~na.5~,99

lmmunocompetent Host

Using a national database, Jackson and colleagues38estimated an incidence

of approximately 10 cases of CSD (hospitalized and ambulatory) per 100,000
persons per year in the United States, with a disproportionate percentage of
males Although most early studies suggested that CSD predominantly
involved children, two recent large studies have shown that about 40% of CSD
cases occur in persons older than 20 years of age?6,77 The disease appears to
peak in the fall and early winter, perhaps related to the breeding patterns of
cats and Io4 Available data suggest that CSD occurs across a broad
geographic distribution, including most of North America. Zangwill and col-
 BARTONELLA-ASSOCIATED INFECTIONS 145

leagues performed a detailed epidemiologic study in Connecticut and identified

three risk factors among patients with CSD: (1) ownership of a pet kitten 12
months old or younger; (2) a scratch or bite from a kitten; and (3) ownership of
at least one kitten with fleas.'" As noted previously, Koehler's study provided
further evidence that cat fleas may play a significant role in the transmission of
B. hen~elae.4~ Moreover, a subsequent study has shown that cat fleas readily
transmit B. henselae to catsz3
Given the enormous number of North American households with cats
or kittens, preventing CSD is an onerous task. Nevertheless, similar to the
recommendations listed, cat owners should attempt to minimize the likelihood
of B. henselae transmission by avoiding activities that may lead to a bite or
scratch. Based on available data, cat owners should make a special effort to
avoid bites or scratches from kittens.
Historically, trench fever has typically occurred in the setting of crowded,
unsanitary conditions, such as in the trenches of the Western front during World
War I and World War II?7 In the two recent reports of modern day B. quintana
bacteremia that involved patients from Seattle and France, homelessness and
alcoholism were identified as the major risk factors associated with B. quintana
infecti0n.3~.
92 Presumably, these conditions may have led to poor sanitary condi-
tions that favored infestation with a vector, such as lice. Close person-to-person
contact among individuals infested with a competent vector best explains these
clusters of infections, but a clearly identified vector was not implicated in either
of these retrospective studies. Although lice are the only known vector for B.
quintana, other possible vectors, such as fleas, scabies, or ticks, could theoretically
transmit B. quintana. Because the vector for modern day trench fever has not
been established, no clear recommendations can be made regarding prevention
of this infection in immunocompetent hosts. Identifying the vectors would take
on increased importance if more cases of modern day trench fever are reported.
As a follow-up to the Seattle outbreak, patients seen at a downtown Seattle
indigent clinic underwent serologic testing; 20% of patients had B. quintana
antibody titers of at least 1:64 compared with only 2% of blood donors.39
Similarly, Brouqui and co-workers16performed a serologic study in France and
found 16% of hospitalized homeless patients had positive antibodies to B.
quintana whereas none of 250 serum samples from blood donors tested positive.I6
Last, Comer and colleaguesz5conducted a serologic study that involved 630
inner-city individuals from Baltimore and found more than 37% showed reactiv-
ity to Bartonella antigensz5The investigators used three Bartonella antigens for
testing: B. elizabethae, €3. henselae, and B. quintana. Reactive antibodies were
associated with injection drug use and H N seronegative status.

DIAGNOSTIC TESTS

Histopathology

To distinguish between BA and KS, all immunocompromised patients with

new vascular-appearing cutaneous lesions should have a lesion biopsied. Ih a
patient with biopsy-proven KS, a new vascular proliferative lesion that has a
different appearance compared with the patient's other KS lesions also should
be biopsied. The biopsy specimen should be examined by hematoxylin and
eosin staining, which differentiates BA from KS, and by Warthin-Starry staining,
a stain that identifies the bacillary organisms in BA lesions.5zBacillary angio-
matosis of skin and other organs is characterized by a lobular proliferation of
146 SPACH & KOEHLER

small capillaries, each of which is lined with endothelial cells. The endothelial
cells in BA lesions are protuberant, unlike the endothelial cells of KS that usually
appear spindle-shaped and form slit-like spaces." The Bartonella bacilli are
usually located in the extracellular matrix adjacent to the proliferating endothe-
lial cells, and are rarely intracellular.The inflammatory infiltrate usually includes
both lymphocytes and neutrophils, with focal areas of
Microscopic examination of the lesions of bacillary peliosis hepatis reveals
histopathologic characteristics distinct from those of BA. Lesions of bacillary
peliosis show dilated capillaries and larger, even macroscopically visualized
cystic, blood-filled spaces scattered throughout the hepatic or splenic paren-
chyma. The lining of these cystic spaces is often thin and devoid of the protu-
berant endothelial cells observed in BA lesions.76Clumps of bacilli are seen
adjacent to the peliotic spaces, best visualized with Warthin-Starry silver deposi-
tion staining as with BA lesions.
Findings on lymph node biopsy specimens from immunocompetent patients
with CSD depend on the stage of the infection6 Early in the course, specimens
show lymphoid hyperplasia, arteriolar proliferation, and reticulum cell hyper-
plasia. Subsequently, granulomas appear, often with central necrosis; at this
stage, multinucleate giant cells may become evident. Late in the disease, the
specimen characteristically shows multiple stellate microabscesses. Similar to
BA, routinely stained specimens generally do not show microorganisms. War-
thin-Starry stains, however, show clumps of pleomorphic bacilli, primarily in
the walls of blood vessels, in macrophages lining the sinuses, and in microabs-
cesses. Biopsy samples from either liver or spleen typically show multiple
granulomas and stellate abscesses49;in some instances, organisms have been
observed with Warthin-Starry staining.

Culture from Clinical Specimens

Species of the Bartonella genus are small, gram-negative rods that are ex-
tremely fastidious and require special culture conditions for isolation.a The
isolation from blood of 45 and humansss is optimally accomplished by use
of pediatric or adult Isolator tubes (Wampole, Cranbury, NJ) or EDTA blood
tubes. Recovery of Bartonella species can be achieved by plating samples onto
either heart infusion agar supplemented with 5% rabbit blood or chocolate agar,
but without added antimicrobial^?^, s8 The agar plates must be fresh, and after
inoculation, should be incubated for at least 21 days in 5% CO, at 35 to 37" C.
In addition, acridine orange staining, when performed 8 days after incubation,
has been used to identify growth of B. quintana in BACTEC bottles (Becton
Dickinson Diagnostic Instrument Systems, Sparks, MD), with the organisms
appearing as pale orange amorphous clumps.5oOnce identified, the organisms
can then be recovered by subculturing onto chocolate agar. The sensitivity of
the acridine orange staining technique decreases in patients who have received
recent or concurrent antimicrobial therapy.
Recovery of Bartonella species from BA and CSD lesions remains very
difficult. B. henselae and B. quintana have been isolated from cutaneous BA
lesions by direct plating of tissue homogenate onto agar and by cocultivation
with a bovine endothelial cell mon01ayer.~~ Dolan et al3I isolated B. henselae from
CSD lymph nodes of two patients using direct plating of tissue homogenate
onto both chocolate agar and CDC anaerobic blood agar; colonies were detected
after 13 days for one patient and 33 days for the other.
 BARTONELLA-ASSOCIATEDINFECTIONS 147

Serology

Using an indirect immunofluorescence assay (IFA) developed at the CDC

Tapper0 et a197 found Bartonella antibodies in seven of seven patients with
biopsy-confirmed BA, but in none of seven HIV-infected patients without BA.
Interestingly, banked sera from three of the seven BA patients showed presence
of Bartonella antibodies for up to 7 years before the development of BA.y7
Moreover, the three patients with banked sera had a fourfold rise in Bartonella
antibody titers prior to the appearance of clinically evident lesions, and another
patient had elevated antibody titers that predicted a relapse of infection follow-
ing 4 months of antimicrobial therapy. As noted previously, one study has
shown an increased incidence in serum and CSF Bartonella antibodies among
HIV-infected patients with neuropsychiatric
Using an indirect IFA to detect antibodies to B. kenselae, Regnery et a18"
showed that 36 (88%) of 41 persons with CSD had an antibody titer of at least
1:64. Using the same cut off, only 6 (6%) of 107 healthy controls had a positive
test. False-positive results (antibody titer of at least 1:64) were observed in 2 of
10 patients with brucellosis and in 1 of 3 patients with Lyme disease. Eight
patients with B. kenselae antibody titers of at least 1:64 also had low titers against
B. quintana (less than or equal to 1:32). Subsequently, Dalton and co-workersZ7
reported that among 91 persons who had an illness that met a strict clinical
definition of CSD, 87 (95%) had antibody titers of at least 1:64 to either B.
kenselae or B. quintana. Barka et a14 used an enzyme immunoassay (EIA) method
to detect antibodies to B. kenselae, and found 38 (95%) of 40 patients with
confirmed CSD had elevated (cut off of 12 units [0.250 OD,,,]) antibody titers to
either IgG, IgM, or IgA.4 They did not find positive antibody responses to €3.
kenselae when they tested 92 serum samples from patients who had documented
high antibody titers to other infectious agents, such as Brucella abortus, Rickettsia
typki, Rickettsia rickettsii, A . felis, Borrelia burgdorferi, Yersinia pestis, Francisella
tularensis, Chlamydia trackomatis, cytomegalovirus, and rubella.
In the 1970s, Hdllingdale et a136compared an EIA assay with counterimmu-
noelectrophoresis (CIE) to diagnose trench fever. They found all patients with
primary or relapsed trench fever to have elevated antibody titers (1:20-1:640)
using EIA and positive (one to three precipitin lines) CIE tests. These authors,
however, did observe significant cross-reactivity in patients infected with either
R. tsutsugamuski or R. typki. In the recent report from France that involved three
patients also with B. quintma endocarditis, Drancourt et a133used a microimmu-
nofluorescent test and found all three patients to have elevated B. quintana
antibody titers, but all three patients also had elevated antibody titers to Ckla-
mydia p n e ~ m o n i a e In
. ~ ~a separate study, La Scola and RaoulP showed that more
than 50% of patients with chronic Coxiella burnetii infection (chronic Q fever)
had antibody tests positive for B. k e n ~ e l a e . ~ ~
Given the available serologic data, it appears that most patients with either
BA, CSD, or trench fever will have positive Bartonella antibody titers. These
serologic tests generally show relatively high specificity (to the genus level),
with a few exceptions (as noted previously). Although one group has used IFA,
enzyme immunoassay, and immunoblots in a murine model to distinguish
between B. quintana and B. hen~elae,8~the ability to clearly differentiate one
Bartonella species from another in serologic tests in humans has not been well
established. Although serologic tests may take on an increasingly important role
in the diagnosis of BA, CSD, and trench fever, their role at the present time has
not been clearly defined. In the United States, three commercial laboratories
offer B. kenselae antibody testing: (1)Associated Regional University Pathologists
148 SPACH 81 KOEHLER

(Salt Lake City, Utah), (2) Specialty Laboratories, Inc. (Santa Monica, California),
and (3) Microbiology Reference Laboratory (Cypress, California). The sensitivity
and specificity of these commercial tests have not been compared in a peer-
reviewed publication.

PCR-Based DNA Detection of Bartonella Species

PCR has been a very useful technique in demonstrating Bartonella DNA in

clinical materials, especially because culturing and isolating these fastidious
bacilli have remained extremely difficult. PCR detection techniques remain ex-
perimental, however, and are thus not routinely available. Relman et a P devel-
oped the first PCR primers specific for detection of Bartonella DNA. These
primers amplify a 296 base pair fragment of the 16s ribosomal RNA gene
(rDNA). Within this fragment there are four hypervariable nucleotides that can
be used to distinguish the four Bartonella species that affect humans, but this
technique requires sequencing the entire amplified segment. Koehler et a147
used these 16s rDNA primers to show that the Bartonella species isolated from
cutaneous BA lesions were B. quintana in some cases and B. kenselae in others;
this speciation was subsequently confirmed by a more specific test: DNA-DNA
hybridization.
Bergmans et a18 also used these 16s rDNA primers with blotting and
hybridization to detect Bartonella DNA in 85 (96%) of 89 pus and lymph node
specimens from CSD patients. They also designed PCR primers for A . felis DNA
detection, but were unable to identify A. felis DNA in any of the same 89 clinical
CSD specimens. Different primers were developed by Anderson et alz and used
in conjunction with dot blot hybridization to detect B. kenselae DNA in clinical
specimens from CSD patients. Using this combination of techniques, they were
able to demonstrate B. kenselae.DNA in 21 (84%) of 25 lymph node specimens
from CSD patients. B. quintana DNA was not detected in any of the same
specimens. Amplification of the citrate synthase gene (or a gene fragment), with
subsequent sequencing or restriction fragment length polymorphism analysis,
also has been used to distinguish among Bartonella species?,41, 74 These tests are
not commercially available, but development of a widely available PCR-based
test would facilitate evaluation of patients with suspected CSD or BA.

Skin Tests

Historically, a positive CSD cutaneous antigen test was part of the diagnos-
tic criteria for CSD. The material used for this test is derived from lymph nodes
obtained from patients with CSD. The CSD antigen material (0.1 cc) is injected
intradermally, with a reaction of at least 5 mm of induration at 72 hours
considered a positive test.61Most studies suggest that the CSD antigen is positive
in approximately 90% of patients with CSD. This test, however, may be falsely
negative in patients with an illness less than 4 weeks in duration, and it does
not differentiate present from past infection. In recent years, investigators have
analyzed CSD antigen material and have detected B. kenselue DNA (but not A .
felis DNA).' Given the potential for transmission of infectious pathogens with
this test, most clinicians currently depend on other methods to diagnose CSD.
 BARTONELLA-ASSOCIATEDINFECTIONS 149

THERAPY

lmrnunocompromised Host

Antimicrobial treatment for immunocompromised individuals with Barto-

nella infection is beneficial and clearly indicated. Although treatment of BA and
bacillary peliosis has not been studied systematically, experience with treatment
of approximately 50 patients at San Francisco General Hospital and summarized
from numerous case reports demonstrates that lesions and symptoms respond
rapidly to erythromycin or doxycycline therapy." Other antimicrobials used
to successfully treat BA in immunocompromised patients include tetracycline,
minocycline, and a~ithromycin.~~ Rifampin may have activity against Bartonella
species in vivo, but because efficacy has not been established with this drug
alone, use of rifampin is recommended as a second drug in combination with
either erythromycin or doxycycline for severely ill patients.
A case report details treatment of a pregnant patient with BA using ceftizox-
ime,82but there is inadequate experience with the third-generation cephalospo-
rins, trimethoprim-sulfamethoxazole,or quinolone antimicrobials to recommend
their use at present. Our experience and numerous case reports have clearly
shown that BA lesions do not adequately respond to the penicillins and first-
generation cephalosporins. In addition, the published in vitro susceptibilities@,
70, 88 have not correlated completely with the in vivo response of Bartonella,
particularly with regard to the penicillins and first-generation cephalosporins."
Clinicians should advise immunocompromised patients with BA or bacillary
peliosis that they may develop a Jarisch-Herxheimer reaction after the first
several doses of antimi~robials.4~ Patients with only cutaneous BA should receive
at least 2 months of antimicrobial therapy, and patients with either osteomyelitis
or peliosis hepatis should receive at least 4 months. Numerous published reports
detail relapse of Bartonella infection in immunocompromised patients, in part
because of the shorter duration of treatment used several years ago, but also
probably because of the relapsing nature of Bartonella infections, even in immu-
nocompetent individuals. If relapse occurs, the HIV-infected patient should
receive life-long treatment with erythromycin or doxycycline.

lmmunocompetent Host

In contrast to the excellent responses observed with HIV-infected patients

who have BA, treatment responses of immunocompetent individuals with CSD
have been disappointing. In a 24-month uncontrolled retrospective study, Margi-
lethmanalyzed treatment responses in 202 patients with CSD who took at least
3 days of antimicrobial therapy.60Among 18 antimicrobials used, only four
(rifampin, ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole)ap-
peared to provide any clinical benefit. Two other reports that involved a total
of four patients suggested that intravenous gentamicin may shorten the course
of CSD.12,55 A separate report described five adult patients who had rapid
improvement in symptoms after receiving oral ciprofloxacin. Results of in vitro
susceptibility testing often do not correlate with clinical outcome, and therefore
should generally not be used to guide therapy.
Clear guidelines for the treatment of CSD do not exist, mainly because no
randomized controlled trials have been performed. Given the lack of data
showing a clear benefit of antimicrobial therapy in the treatment of patients
with mild to moderate CSD, most authorities have recommended managing
150 SPACH & KOEHLER

these patients without antimicrobial therapy. Based on the limited available data
(and considering the experience in immunocompromised hosts), if therapy is
given to patients with mild to moderate disease, it would be reasonable to
attempt a 10- to 14-day trial of oral therapy with either doxycycline or erythro-
mycin. For patients with severe disease (including central nervous system dis-
ease), we recommend intravenous doxycycline with or without addition of
rifampin. The reasons for the relatively poor response of patients with CSD
compared with patients who have BA remain unclear, but may relate to differ-
ences in host inflammatory response or organism load.
Published data regarding antimicrobial therapy for trench fever have been
sparse.” In the recent Seattle outbreak, most patients received a p-lactam agent
followed by either erythromycin or azithromycin, generally with satisfactory
results (if given for at least 14 days); in this series of patients, patients did not
receive therapy as part of a trial, and follow-up was limited.9zMost cases of
endocarditis have required valve replacement despite intravenous antimicrobial
therapy.33,91 Because of the sporadic nature of this illness, large controlled
treatment trials will probably not be performed. The lack of clinical data, com-
bined with unreliable in vitro susceptibility testing, make clear treatment guide-
lines unrealistic. Nonetheless, based on limited data and extrapolating from
experience with HIV-infected patients, the authors recommend administering
either erythromycin, azithromycin, doxycycline, or tetracycline for at least 14
days for patients with uncomplicated bacteremia. Patients with endocarditis
should receive prolonged therapy (at least 4 to 6 months), and should be
carefully followed for clinical deterioration that would require valve replace-
ment. In addition, further research is needed to determine whether a bactericidal
agent, such as a third-generation cephalosporin, is necessary for patients with
uncomplicated bacteremia or endocarditis.

CONCLUSIONS AND FUTURE PlRECTlONS FOR

BARTONELLA RESEARCH

The recent years have produced a tremendous advance in the understand-

ing and appreciation of Bartonella-associated infections. It has become clear that
Bartonella can infect immunocompromised and immunocompetent individuals,
but distinct clinical manifestations develop in these two groups. Many questions,
however, remain unanswered. For instance, does Bartonella have an even broader
spectrum of manifestations that have not, as of yet, been appreciated? Why does
antimicrobial therapy have a much greater impact on immunocompromised
persons with Bartonella infections than those who are immunocompetent? Can
large studies define effective antimicrobial therapy for patients with CSD, and
will effective antimicrobial therapy require more than one agent? What is the
vector for B. quintana in the United States? What is the natural history of patients
seropositive for Bartonella? What is the extent of B. quintana infections in areas
outside of Seattle, Baltimore, or France? These and many other questions will
likely surface in the upcoming years and will require well-designed research
studies to answer.

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David H. Spach, MD
Harborview Medical Center, Mailstop 359930
325 9th Ave
Seattle, WA 98104