EMERGING INFECTIOUS DISEASES
Volume 1, Number 1, January-March 1995

                            Synopsis

Unraveling Mysteries Associated with Cat-Scratch Disease,
Bacillary Angiomatosis, and Related Syndromes

Russell Regnery, Ph.D., and Jordan Tappero, M.D.
National Center for Infectious Diseases, 
Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Abstract
The search for the infectious agents responsible for cat-scratch
disease, bacillary angiomatosis, and related syndromes has a long
and often circuitous history. Recognition of the etiologic agents
and a new understanding of the fundamental features of the
epidemiology and natural history of modern day Bartonella
(formerly Rochalimaea)-associated diseases culminate a
multipartite story that combines clinical medicine, traditional
microbiology, and novel technological approaches to solve a
long-standing enigma.


The quest for the etiologic agent of cat-scratch disease (CSD)
has frequently been described as a mystery (1,2). Indeed, the
search has many qualities of a mystery novel; the pursuit has
spanned several decades and recently taken several unexpected
turns. During this period of important discovery, major microbial
suspects have undergone name changes, novel microbial culprits
have been introduced, new groups of affected patients have been
recognized, and yet significant questions remain to be answered.
Scientific and medical interest has been high; approximately 900
publications have dealt with CSD since the first good clinical
description of the disease in 1950 (3).

Clinical Features of CSD

Throughout the life of this evolving mystery, the clinical
descriptions of "classical" CSD have remained remarkably
consistent (Dalton MJ, et al. Rochalimaea antibody; a new era in
the diagnosis of cat-scratch disease, submitted for publication;
4-6). CSD is typically a benign and self-limited illness lasting
6 to 12 weeks in the absence of antibiotic therapy. Regional
lymphadenopathy (axillary, head and neck, inguinal) is the
predominant clinical feature of CSD; affected nodes are often
tender and occasionally suppurate (4-7). Between 25% and 60% of
patients report a primary cutaneous inoculation lesion (0.5- to
1-cm papule or pustule) at the site of a cat scratch or bite
(5,7). The skin lesions typically develop 3 to 10 days after
injury and precede the onset of lymphadenopathy by 1 to 2 weeks.
Low-grade fever and malaise accompany lymphadenopathy in up to
50% of patients; headache, anorexia, weight loss, nausea and
vomiting, sore throat, and splenomegaly may develop. In addition,
short-lived, non-specific maculopapular eruptions, erythema
nodosum, figurate erythemas, and thrombocytopenic purpura have
been observed (8).

Unusual manifestations of CSD, which occur in up to 14% of
patients, include Perinaud's oculoglandular syndrome (6%),
encephalopathy (2%), hepatic granulomas (0.3%), osteomyelitis
(0.3%), and pulmonary disease (0.2%) (4,5,8). In general, these
complications resolve without sequelae. Perinaud's oculoglandular
syndrome is manifested by conjunctival granuloma, periauricular
lymphadenopathy, and nonsuppurative conjunctivitis.
Encephalopathy, manifested as fever and coma that progress to
convulsions, may last for days to weeks; cerebrospinal fluid is
unremarkable. Optic neuritis with transient blindness may also
occur.

For many years, CSD has been clinically diagnosed when three of
the following four criteria are met in a patient: 1) history of
traumatic cat contact; 2) positive skin-test response to CSD
skin-test antigen; 3) characteristic lymph node lesions; and 4)
negative laboratory investigation for unexplained lymphadenopathy
(8). Although biopsy confirmation of CSD has been rarely required
(especially in lieu of a reliable serologic test--see below), a
constant pathologic hallmark of CSD-affected tissues has been
granuloma formation. With hematoxylin and eosin stains, the
primary inoculation lesion of CSD reveals small areas of frank
necrosis surrounded by concentric layers of histiocytes,
lymphocytes, and nucleated giant cells (9). Affected lymph nodes
are characterized by necrotizing granulomas ringed by lymphocytic
infiltrates and multinucleated giant cells.

Enter Afipia felis

During the past 44 years, a variety of microbial agents,
including herpes viruses and bacteria of the genera Chlamydia and
Pasteurella, have been suspected as the causes of CSD (3). A major
chapter of the CSD saga unfolded with the 1988 announcement by
the Armed Forces Institute of Pathology that a bacterial agent
had been visualized within CSD-involved lymph nodes by using the
Warthin-Starry silver stain (10), and a novel bacterial agent had
been isolated from a CSD patient's lymph node (11). By 1992, this
agent was characterized fully, given the name Afipia felis
(Afipia being a latinized acronym for the source of the original
isolate, the Armed Forces Institute of Pathology, and felis
referring to the presumed vertebrate vector of the human
infection), and proclaimed the agent of CSD (12).
Although A. felis was declared the putative CSD bacillus,
evidence of convincing patient humoral or cellular immune
responses to laboratory cultured A. felis antigen was not
forthcoming. Despite numerous attempts, other laboratories were
unable to recover additional isolates of A. felis from CSD
patients. In addition, although the majority of patients with CSD
reported exposure to a cat(s), no clear link between cats and A.
felis was demonstrated.

Enter New Syndromes

The story of CSD took a significantly divergent path with the
recognition that opportunistic infections were an important
consideration for patients infected with human immunodeficiency
virus (HIV). Bacillary angiomatosis (BA), a newly recognized
disease characterized by cutaneous and subcutaneous vascular
lesions containing bacillary organisms visualized by
Warthin-Starry silver staining, was described predominantly among
HIV-infected patients; however, bacterial isolates were not made
or identified (13-15). Over the ensuing decade, the clinical
spectrum of BA was expanded to include patients with single or
multiple vascular lesions affecting virtually every organ system,
including lymph node, bone, brain, liver (peliosis hepatis), and
spleen (14-17). Independently, an unidentified gram-negative
pathogen was isolated predominantly from HIV-infected patients
with fever and bacteremia, however, these patients lacked
cutaneous or parenchymal vascular lesions and were not recognized
as BA patients (18).

Because silver staining and electron microscopy of both BA and
CSD tissue sections revealed bacillary organisms
indistinguishable from one another, several authors suggested
that BA might represent disseminated CSD in the immunocompromised
host (17,19-21). In addition, several anecdotal reports of BA
described a history of cat contact preceding the onset of disease
(22).

Ultimately, the relationships between possible environmental
exposures and BA or CSD were systematically investigated. The
first case-control study conducted among patients with BA found
traumatic contact with a cat (bite or scratch) to be
significantly associated with BA disease (22). BA patients were
also more likely than controls to have a household kitten (a cat
<1 year of age). A subsequent case-control study of CSD patients
found that these patients were more likely than controls to have
traumatic contact with a cat, to own at least one kitten, and to
have kittens with fleas (7).

Despite the similarities in histochemical staining properties and
epidemiology, serious reservations remained concerning a possible
link between the causative agents of CSD and BA. The pathologic
features of classical CSD (granuloma) and BA (proliferative
vascular lesions without granuloma) were distinctly different,
and the two diseases seemed to respond differently to antibiotic
therapy. Although antimicrobial therapy for BA and CSD have not
been systematically evaluated, the majority of BA patients
evaluated responded quickly to single-agent therapy with either
erythromycin or doxycycline (14,23), whereas the symptoms and
signs of patients with CSD failed to show consistent rapid
resolution following antibiotic therapy (5). In addition,
clinicians' first choices of antibiotics for treating BA and CSD
vary (5,6,14,23).

Enter Rochalimaea henselae

A breakthrough occurred when a novel approach was used to
identify possible prokaryotic ribosomal DNA extracted from BA
skin lesions. When prokaryotic ribosomal gene DNA extracted from
BA lesions and amplified by polymerase chain reaction (PCR) was
compared with sequenced ribosomal genes from other organisms, it
become apparent that the agent associated with BA in this study
was related to, but not necessarily identical to, the agent of
trench fever, Rochalimaea quintana (24).

At nearly the same time in Oklahoma, Rochalimaea-like organisms
were being isolated on blood agar from bacteremic patients (18).
Independently in Houston, Texas, fastidious, slow-growing
Rochalimaea-like isolates were recovered on several occasions
from the blood of an HIV-infected patient with relapsing fever of
unknown origin; like the isolates from the Oklahoma patients, the
Houston isolate was recovered from a patient in the absence of BA
or CSD lesions (25). The Houston isolate (Houston-1) was
identified as the prototype isolate of a novel species of
Rochalimaea by using traditional as well as genotypic methods,
including ribosomal RNA gene analysis similar to that used to
identify the nucleic acid found in BA patients' lesions (25).
Almost simultaneously, the group from Oklahoma had come to a
similar conclusion by using DNA relatedness data (26); most of
their isolates also consisted of the novel species, R. henselae.
The new species designation, first officially used to describe
the Houston-1 isolate, was coined in recognition of the
contribution of Diane Hensel, a microbiologist who had isolated
several of the initial organisms in Oklahoma (18,25,26).
Subsequently, Koehler et al. isolated bacilli directly from
cutaneous lesions of persons with BA (27); surprisingly, either
R. henselae or R. quintana was isolated from BA lesions from
different HIV-infected patients.

At this juncture, R. henselae infections had been described
predominantly among immunocompromised patients with either BA or
fever with bacteremia. The availability of isolates made it
possible to develop a test for serologic evidence of Rochalimaea
infection and to refine PCR methods for identification of
Rochalimaea organisms in tissues and other samples. These
methods, together with new techniques for recovering Rochalimaea
species isolates, were crucial to obtaining a more detailed
account not only of BA but also of CSD.

The Cat-scratch Connection: A Synthesis
A Rochalimaea genus-specific, indirect fluorescence antibody
(IFA) test using irradiated whole cell antigen from the Houston-1
isolate of R. henselae was developed by the Centers for Disease
Control and Prevention (CDC) to help identify risk factors for
Rochalimaea-associated disease. Several blinded serum samples
from both HIV-infected BA patients and HIV-infected controls
residing in San Francisco were sent to CDC for serologic testing.
High-titered antibodies were identified in serum samples from
several of the BA patients (28). Similar high-titered antibodies
were not detected for any of non-BA control patients with one
exception; a serum sample from an HIV-infected patient with CSD
also demonstrated strong serologic reactivity to R. henselae
antigen.

Shortly thereafter, single sera collected from patients with
suspected CSD to look for A. felis antibodies were evaluated with
the new R. henselae serologic test; 36 (88%) of 41 sera were
positive (29). None of the sera had significantly elevated titers
to A. felis antigen. The same set of sera were coded and
resubmitted along with sera taken from other well-characterized
bacterial and viral diseases and tested again in a blinded
manner. The IFA test accurately identified sera of case-patients
with suspected CSD. In addition, 6 (6%) of 107 sera from
ostensibly healthy persons, obtained from a commercial vendor,
showed antibody by IFA testing (29). These serologic data were
the first laboratory evidence suggesting that R. henselae was
associated with CSD.

Data further substantiating the role of R. henselae in the
etiology of CSD soon followed. The newly developed serologic test
was used to help investigate a possible cluster of CSD cases in
Connecticut; 38 (84%) of 45 suspected CSD cases had elevated
Rochalimaea antibody titers, whereas 4 (3.6%) of 112 age-matched
controls had detectable antibody titers (7). In another
investigation, serum samples obtained from 600 prospectively
evaluated patients with well-characterized CSD (i.e., persons
with history of cat scratch, papule at site of inoculation, and
enlarged regional lymph node) had a 95% correlation with positive
Rochalimaea serology.

In 1993, R. henselae was isolated directly from the lymph nodes
of two CSD patients and was identified by genotypic means; both
patients had strong serologic responses to Rochalimaea antigen
(30). Evidence of R. henselae-specific nucleic acid sequences
were found in 21 (84%) of 25 CSD lymph node tissues submitted to
CDC for evaluation (31).

Additional supporting evidence for a Rochalimaea as the cause of
CSD came from archival sources. Skin-test antigen, used rather
extensively in the past to help diagnose examples of CSD (4,8),
consisted of pasteurized exudate collected from suppurative CSD
lymph nodes. Among a cohort of CSD patients who were skin-test
positive, 52 (93%) of 56 had positive IFA antibody titers to the
defined Rochalimaea reagents (32). Furthermore, various lots of
skin-test antigen were shown by PCR analysis to contain
Rochalimaea nucleic acid sequences (33), and R. henselae
sequences in particular (34). No A. felis DNA sequences could be
detected by PCR. These data strongly indicated that
microbiologically undefined skin-test reagents, which had been
used for many years for the diagnosis and clinical
characterization of CSD, were in fact R. henselae reagents.

Collectively, these data supported a Rochalimaea species etiology
for both CSD and BA. Despite numerous attempts, recent efforts to
implicate A. felis as a cause of either of these two clinical
entities have repeatedly failed.

Felis domesticus: A Reservoir for Rochalimaea henselae

In addition to epidemiologic data, serologic evidence also
implicated domestic cats with Rochalimaea-associated disease.
Rochalimaea-specific IFA antibodies were demonstrated in 6 (46%)
of 13 pet cats not associated with human disease and among 39
(81%) of 48 cats living in households reporting human CSD in
Connecticut (7). Microbiologic evidence for the domestic cat as a
reservoir for R. henselae soon followed. R. henselae was isolated
over a 3-week period from the blood of a single cat not linked to
human illness (35). Investigations by Koehler et al. established
the cat as a reservoir for R. henselae infection (36). R.
henselae was established as the cause of cutaneous BA in three or
four patients with the disease. R. henselae was isolated from the
blood of all seven asymptomatic pet cats with which these four BA
patients had prolonged contact. The prevalence of infection among
cats in the greater San Francisco Bay region was also studied; 25
(41%) of 61 pet or impounded cats had asymptomatic R. henselae
bacteremia (36). R. henselae was also detected by both direct
culture and PCR from several cat fleas combed from these
bacteremic cats (36).

The human body louse (Pediculus humanus) was established as a
vector for human-to-human trench fever R. quintana transmission
during the First World War (37). Likewise, B. bacilliformis, a
closely related organism (see below) found in the mountains of
South America, can be transmitted by another arthropod, the
Phlebotomus sand fly (38). The observation that related microbes
are vectored between humans by arthropods adds credence to the
proposed role of arthropod vectors of CSD. Despite several
suggestions that fleas or possibly ticks (7,36,39) are associated
with R. henselae disease, no experimental data exist to clearly
demonstrate that arthropods act as direct vectors.

Changes in Nomenclature: Rochalimaea becomes Bartonella

Genotypic evaluation of members of the genus Rochalimaea has led
to the conclusion that members of the genus are closely related
to Bartonella bacilliformis, the agent of Carrin disease, Oroya
fever, and verruga peruana (40). Because of historical
precedence, the genus designation Bartonella is now applied to
all species of the old genus Rochalimaea and replaces the
Rochalimaea designation (species names remain unchanged).

Physicians and researchers need to exercise care in using the
term "bartonellosis." This term has classically been used to
describe the frequently fatal syndromes caused by B.
bacilliformis. To date, B. bacilliformis and its associated
syndrome (bartonellosis) have been identified exclusively in
South America (38,41).

Remaining Questions for Ongoing and Future Research

Although B. henselae is now regarded as the etiologic agent of
CSD, as well as a cause of BA, endocarditis (42), and fever with
bacteremia, many questions remain unanswered. For example, why
did it take so long to isolate and identify B. henselae? Part of
the answer probably stems from the requirements necessary for
growth in vitro, including enriched, non-selective blood agar
incubated over a prolonged period in a CO2 atmosphere. Most
hospital laboratories discard their bacteriological plates before
primary isolates of B. henselae would be expected to appear (9-40
days). Extreme sensitivity to a wide variety of antibiotics, at
least in vitro, suggests that residual levels of antibiotics in
patients' blood or other tissues (such as lymph node biopsy)
might inhibit Bartonella growth during primary isolation attempts
in vitro. Selective medium has yet to be developed. Novel
genotypic methods were crucial for identification of B. henselae;
thus, isolates may well have been made in the past but remained
unidentified.

As mentioned above, it has become apparent that in addition to B.
henselae, B. quintana can also be another significant cause of BA
disease, at least among immunocompromised patients in San
Francisco (27). Another focus of B. quintana infections ("urban
trench fever") has been identified among homeless alcoholics in
Seattle (43,44). How common are B. quintana infections; are they
louseborne and vectored strictly between humans, as was believed
during World War I (37)? B. quintana-associated disease has no
known link with an alternative vertebrate vector (such as cats).
Bartonella elizabethae is known only from a single isolate from a
man surviving endocarditis following aortic valve-replacement
surgery (45). Is there further public health significance to this
organism? What additional Bartonella species have yet to be
identified and what diseases may they cause?

Members of the genus Bartonella are exquisitely sensitive to
antibiotics in vitro (30,46). Why then do CSD patients not
respond as rapidly and consistently to antibiotic therapy as BA
patients do? One hypothesis is that immunocompetent patients
somehow sequester infectious organisms beyond the reach of
antibiotics, whereas immunocompromised patients do not. An
alternative hypothesis regarding differential antibiotic
responsiveness recognizes that many of the signs of CSD are
immune mediated; antibiotics, even if effective in neutralizing
or killing bacteria, may not immediately alleviate long-duration
immunologic tissue manifestations of antigen stimulation.
Conversely, in the absence of the immunologic capability to react
to bacterial infection by forming granulomas, as in the case of
severely immunocompromised persons with BA, antibiotics are
generally effective in alleviating the symptoms and signs of
infection. Does this suggest that possible non-granulomatous
manifestations of CSD (for example, neuroretinitis and
encephalopathy) should respond well to the appropriate antibiotic
therapy?

Although BA has been described in immunocompetent patients (15),
the vast majority of BA patients are immunocompromised (14). What
are the factors explaining why B. henselae and B. quintana induce
vascular proliferative lesions, such as BA and parenchymal
bacillary peliosis, almost exclusively in severely
immunocompromised patients?

What percentage of the relatively large numbers of undiagnosed
febrile disease among HIV-infected persons is in fact due to
Bartonella species infections? The answer to this important
question may help alleviate significant morbidity among
HIV-infected patients. The potential for selection for
drug-resistance during long-term antimicrobial therapy deserves
scrutiny.

Does the 4%-6% of IFA antibody-positive, ostensibly healthy
"control" study populations suggest a relatively common
undercurrent of undiagnosed, subclinical Bartonella-associated
disease?

Is it possible to immunize cats and thereby interrupt B. henselae
transmission to humans? Preliminary data suggest that
asymptomatic bacteremia in cats can be successfully treated with
antimicrobial therapy (36). Once cleared of bacteremia, are these
cats routinely susceptible to reinfection?

Are the complications occasionally associated with CSD and BA
associated with different strains of Bartonella species or are
the variations in clinical presentation strictly functions of
dose, route of inoculation, and immune status?

And finally, in what role, if any, will A. felis reappear as an
agent of human disease? Is A. felis responsible for the
relatively small number of cases of CSD-like lymphadenopathy that
have no evidence of antibody to B. henselae? Or is there another
explanation for the originally proposed association between A.
felis and CSD that has not yet come to light?

The new recognition of the importance of Bartonella-associated
diseases will continue to spawn a host of unanswered related
questions. Whereas novel subplots will continue to unfold, the
new puzzles are no longer totally shapeless, and answers to
questions of natural history and epidemiology, enhanced diagnosis
and treatment, and methods for disease intervention should now
begin to unfold rapidly.

Address for correspondence: Russell Regnery, Centers for Disease
Control and Prevention, 1600 Clifton Road, MS G13, Atlanta, GA
30333, USA; fax 404-639-1058; e-mail rur1@ciddvd1.em.cdc.gov.

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