Cat-scratch Disease: Epidemiology, Etiology, and Treabnent

Article
234
0.1 CEC
Cat-scratch Disease: Epidemiology,
Etiology, and Treabnent
Jeffrey J. Windsor
Cat-scratch disease (CSD) is a clinical syndrome
that usually presents as a self-limiting lymphadenopathy associated with a cat scratch or
bite. Commonly affecting children and young
adults, it has a worldwide distribution. In temperate climates, higher rates are reported in the
autumn and winter, which can be attributed to
the seasonal breeding of the domestic cat. The
~rganism responsible was identified in 1983,
having eluded detection for 50 years. Initially,
Afipia felis was thought to be the cause, however, subsequent study failed to confirm a link.
During the 1990s, it was demonstrated conclusively that Rochalimaea hellselae,later reclassified as Bartonella henselae, was the cause of
CSD. B. henselae has been isolated from
bacteremic cats, with transmission among cats
thought to be via the cat flea. Although other
Bartonella species are transmitted by arthropod
vectors, it is unlikely that the cat flea is involved
directly in human infection, but plays a role in
amplifying the reservoir. B. henselae is difficult
to culture, and either serology or the polymerase
chain reaction are considered to be the best
methods of detection. Genetic variation occurs
among B. henselae strains, perhaps explaining
the inconsistency of some diagnostic techniques.
A separate serogroup (Marseilles) has been reported in a seronegative patient with CSD, and
B. clarridgeiae has the potential to cause the
disease. Atypical presentation is seen in up to
25% of cases, and manifests itself as ocular
involvement, encephalopathy, granulomatous
hepatitis, hepatosplenic infection, endocarditis, and osteomyelitis. The majority of CSD
cases resolve spontaneously and do not require
antibiotic treatment. In complicated CSD, treatment with trimethoprim-sulp.hamethoxazole,
ciprofloxacin, or azithromycin is recommended,
wi th gentamicin being reserved for the severely
ill patient.
Jeffrey J. Windsor,
AbenJstwyth Public
Hellltlr La boflltOMJ,
Brollg/nis Hospital,
A bel1jstwy l'h,
Wales
Editor's Note: Reprinted from. the British )o!1Il1n1 of BiomedicoI Science 200];58:101-110. Biomedical EssiJY commissioned by the Editor, British JO l/ rna l of Biomedicnl Scienc~, and based on a structured reading essay submitted
as part of the ISMS Continuing Professional Development Program. Accepted 16 February 2001.
Introduction
Cat-scratch disease (CSD) is characterized
usually as a self-limiting regional lymphadenopathy, associated with a cat scratch or bite. l
Although CSD is normally benign, the causative
organism(s) may cause severe systemic or recurren t disease. l Originally considered rare, it is now
recognized to affect children and young adults
conunonly, and occurs worldwide. Indeed, in
some areas itis the most common cause of chronic
lymphadenopathy in this age group.2 CSD occurs more frequently in certain geographical areas and shows a marked seasonality.3 In the USA,
it is estimated that over 24,000 cases occur annually, with 2,000 patients requiring hospitalization, and a resulting health-care expenditure of
$12 million.4
Despite many clinical descriptions (750 by
the early 1980s)/ the etiological agent remained
elusive. Various organisms have b een implicated
since the early 1900s, including viruses, chlamydia, acid-fast bacilli, and gram-positive bacteria;'I.6 and it was not proven to be a bacterial
infection until 1983.5 However, the isolation and
characterization of the causative organism(s)
would prove to be more difficult. Indeed, it is
only in the past decade, using powerful molecular techniques, that the true etiological picture
has emerged.
Historical overview
CSD was described initially by Debre and
coworkers7 in 1950, although Parinaud is credited with the first report of symptoms consistent
with CSD some 60 years earlier, when he described Pal'maud's oculoglandular syndrome in
1889.8 Debre examin ed his firs t patient, a 10"yearold boy who presented with suppura tive adenitis and severe cat scratches, in 1931.
Although physicians in the USA were aware
of patients with CSD as early as 1932, the first
published American case was not reported until
1951.9 Foshay, a professor of microbiology at the
University ofCincllu1ati, prod uced a crude intradermal skin test in 1947.3•9 TI1e antigen used was
derived from pus obtained from the lymph nodes
of individuals suspected of having the disease.
Professor Mollaret, at the Pasteur Institute, studied CSD independently, and also prepared a skin
antigen test. 3
Many extensive clinical reviews followed,
including Warwick'slO description of 160 cases in
1960, and Carithers'll review of 1,200 cases, published in 1985. Surprisingly, the clinical description of CSD changed litUe over the decades. To
date, over 900 publications have appeared in the
scientific literature, reflecting the high level of
interest shown in this intriguing syndrome. 3,12
Etiology
The etiological agent of CSD eluded detection for 50 years. Although many infectious agents
were suspected,3 it was not until 1983 that Wear
and coworkerss demonstrated that it was a bacterial infection. Using the War thin-Starry silver
stain, they detected small, delicate pleomorphic
bacilli in 34 out of 39 lymph nodes taken from
patients with suspected CSD. Using an
irnmunoperoxidase staining technique, the organisms in sections of lymph node stained intensely when exposed to convalescent sera from
CSD patients, whereas they did not react with
control sera.
These results were supported by the work
ofMargileth and coworkers,13 who used the same
staining methods and detected bacilli in both
biopsies of inoculation papules and the lymph
nodes draining the site of inoculation in CSD
patients.
In 1988, English and coworkers l isolated a
bacterial organism from the lymph nodes of ten
patients with CSD, after extended incubation on
specialized media. After inoculation into a ninebanded armadillo, it caused dermal lesions identical to those seen in humans. The group was able
to reisolate the organism from these lesions,
thereby fulfilling Koch's postulates, and considered it to be the causative agent of CSD.
Initially, it was known simply as the "catscratch disease bacillus./I 14 However, in 1991,
when Brenner and coworkers 15 described the
genus Afipia, it was given the specific name Afipia
felis. Afipia was taken from the Armed Forces
Institute of Pathology, where the original organism was isolated; and feIis referred to the cat as the
probable vector. 3 Subsequent reports failed to
confirm a strong link between A. felis and CSD,
however.16 Indeed, further doubt was cast when
patients with CSD failed to mount either a humoral or cellular response to A. felis antigen. 3 In
addition, other investigators were unable to isolate A. felis from CSD patients; and, despite most
patients reporting exposure to cats, no clear link
could be demonstrated between cats andA.felis.
1990, ReIman and coworkers 17 using a
m
novel method for identifying uncultured pathogens, identified the causative agent of bacillary
angiomatosis (BA). This is an infectious disease
that causes cutaneous lesions, and primarily affects human immunodeficiency virus (HIV)-positive patients. IS The organism was visualized previously in infected tissue stained using the
Warthin-Starry method, and looked similar to
that associated with CSD.
Using the polymerase chain reaction (PCR),
this group17 amplified prokaryotic 16S ribosomal
RNA (rRNA) gene products directly from tissue
samples. The primers used were common to all
bacteria, and the amplified DNA was sequenced
and found to be related to Rochalimaea quintana.
At the same time, in Oklahoma, Slater and
coworkers 19 isolated Rochalimaea -like organisms
from the blood of two HIV-positive patients presenting with persistent fever. Similar organisms
were isolated subsequently from blood and
lymph;2D.2l and, after genetic analysis, were named
as a new species, R. 11ellselae. 19 ,2D,22 Then, Koehler
and coworkers ls succeeded in isolating R. he/1seJae
from the cutaneous lesions of patients with SA.
Recently, the genus Rochalimaeawas united
with Bartonella, and Rocltalimaea henselae is now
reclassified as Bartonella he/1selae.23
An indirect fluorescence antibody (lFA)
technique was developed to detect B. henselae
antibodies. 24 Used initially on serum samples
from both HIV-infected BA patients and HIVinfected controls, several BA patients showed
high-titre antibodies, but only one HIV-infected
control gave a strong reaction, Perhaps it was
fortuitous that this patient had CSD.
Subsequently, Regnery and coworkers 25
used this IFA test on 41 patients suspected of
having CSD, and 36 (88%) had serum titres to B.
henseiae antigen of >1 in 64, Furthermore, there
was only a low prevalence (3%) of significant
tit res in healthy controls. Interestingly, when the
sera was tested against A. felis, very few samples
gave significant titres.
Anderson and coworkers 26 confirmed the
association between B, 11enseiae and CSD by PCR
amplification of B.lzenselae DNA from the antigen
used for skin testing. Bergmans and coworkers 27
compared PCR detection of B. henselae andA.Jelis
DNA with serology and skin tests. They could
not detect A. felis DNA in clinical samples, and
concluded that CSD is caused by bartonellae.
Given the body of evidence, it would appear that B. llenselae is the primary cause of CSD,
rather thanA.felis. However, Alkan and coworkers amplified th~ 16S rRNA gene from lymph
node sections in 12 patients with histological
features of CSD, and detected B, llenselae in five,
A.felis in three, and both organisms in two. Giladi
and coworkers 29 c™orrunented on the rare role of
A. felis in CSD, after isolating the organism from
a lymph node of a patient with CSD. Although
they were unable to detect A.felis DNA from 32 B.
henselae DNA-positive patients with CSD, they
felt that A. felis might playa role in its pathogenesis. La Scola and Raoult3'l isolated A. felis from a
hospital water supply, and suggested thatprevious isolation of A. felis from lymph nodes may
have been due to contamination.
In 1997, a newly described organism, B.
clarridgeiae, was recognized as causing CSD in a
veterinarian. 6 A Bartonella-like organism was
isolated from the patient's cat, and the patient's
sera did not react against B. henselae, B. quintana,
or B. elizabetlwe, but did react (titre: 1 in 24) against
the cat isolate. The following year, Margileth and
Baehren31 described another adult patient with a
chest-wall abscess due to CSD, and antibodies to
B. clarridgeiae.
Animal reservoir
Although the association of CSD with cats
is an obvious one, given the name of the syndrome, it was only proven conclusively in the
19905. In 1992, Regnery and coworker?32 isolated
B. hel1selae from an asymptomatic cat on two
occasions, and suggested that the domestic cat
(Felis domesticus) may be a reservoir for human
Bartonella disease.
Zangwill and coworkers33 compared CSD
patients with age-matched, cat-owning subjects,
and found that CSD patients were more likely to
own a kitten, been scratched or bitten by a kitten,
and to have at least one kitten infested with fleas.
Furthermore, serological tests demonstrated that
39 of 48 (81%) patients' cats had antibodies to B.
henselae, compared with 11 of 29 (38%) control
cats.
Sander and coworkers31 investigated blood
cultures from 100 household cats, and isolated B.
henselae from 13%. They found that positive cultures were more likely to be found in young
female cats «24 months) than in male and older
cats.
Koehler and coworkers 35 studied cats in the
San Francisco area and confirmed the domestic
cat to be a large asymptomatic reservoir for human B. henselae infection. The organism was cultured from 25 of 61 (41%) pet and impounded
cats, and was found in seven cats belonging to
four patients with BA. In addition, B. henselae
DNA was detected by PCR in a single flea, and
was isolated from Ctenocephalides felis infesting a
culture-positive cat. Interestingly, B. henselaecould
not be isolated from the fleas of a culture-negative
cat.
It has been suggested that contamination of
cat nails with B. henselae may occur following
excoriation of skin during scratching; or periodontal disease may result in saliva becoming
contaminated. 35 As arthropod vectors are responsible for transmitting other members of the genus
(i.e., B. qttintana by the human body louse, and 8.
bacilli/armis by the sandfly), it would seem plausible that they may be involved in the transmission of B. he11selae .36
Chomel and coworkers 37 provided experimental evidence that cat fleas can transmit B.
henselae from one animal to another. Fleas removed from cats that were bacteremic with B.
henselae transmitted the organism to five specificpathogen-free kittens in two separate experiments, and all developed B. 17enselae bacteremia.
As the cat flea consumes an average amount of
13.6 ilL blood a day, which may contain millions
of B. henselae organisms per mL, they considered
the potential for ingesting large numbers of or:
ganisms to be substantial.
Some fleas can infect mammalian hosts
with Bartonella spp. via infected feces. As large
amounts of potentially infective flea feces are
present in the fur of infested cats, direct inoculation during scratching may lead to feline infection, and be passed directly to humans via claws
contaminated with flea feces. 37 They concluded
that the cat flea plays a substantial indirect role in
human disease by amplifying the size of the cat
reservoir. Although epidemiological data do not
support transmission from cat to human via the
cat flea, the potential exists.
Whether or not other animals can act as a
reservoir for B. henselae is unknown. However,
two cases of CSD associated with a dog scratch
have been described; one in a nine-year-old boy
presenting with osteomyelitis,38 the other in a tenyear-old boy with bilateral cervicallymphadenopathy.39 In both cases, the only animal contact
was with a dog; however, in the second case,
Bartonella DNA was found in the gingiva and
buccal membrane of the puppy. Tsukahara and
coworkers,39 using IFA, detected significant B.
henselae antibody titres in four out of 52 dogs
(three titres were 1 in 64, and one was 1 in 128).
Epidemiology
CSD has a worldwide distribution, having
been reported in the United States,2.Z.~·211·3J..j(}-~2 Europe (Germany,43-16 The Netherlands,27.47-so Switzerland,51.52 France,53,54 Spain,55 ItalyS6 and the
UK57,5S), Japan,39 Israel29.3s.s9 and Australia. 60- 62 In
the UK, very few cases were reported after the
late 1970s, and this can be attributed directly to
the withdrawal of the skin antigen test because of
concerns about its safety. However, Harrison
and Doshis8 measured Bartonella antibodies, and
found that infection is common in the UK, with
serological evidence present in 20% of their probable CSD group.
In temperate climates, a higher rate of CSD
cases has been reported in the autumn and winter
months. 3,16,36,63 Some authors suggest that this
may be explained by the seasonal breeding of the
domestic cat, which governs when kittens are
available to new owners. 3,16
Bass and coworkers9considered many variables that might affect the prevalence of CSD,
including geographical location, climate and season, and cat-associated variables such as density,
age, exposure, and degree of flea infestation.
Serological studies in the USA found an increase
in B. henselae antibodies in both humans and cats
in warm, humid areas, compared with those in
the rest of the country.9
Jackson and coworkers 4 analyzed three
national databases in the USA, and found CSD to
be an important cause of morbidity, especially in
children, where it accounted for more than 15%
of lymph-node biopsies performed. CSD was the
diagnosis in 0.77--0.86 per 100,000 hospital discharges, and the incidence in ambulatory patients was higher, at 9.3 per 100,000 population.
There are an estimated 57 million pet cats in the
USA; therefore, the B. henselae reservoir is large
and the potential for human infection immense.33
Clinical presentation
Typically, a non-tender papule 0.5-1 cm in
diameter develops in the scratch line, three to ten
days after exposure;3.9.60 usually healing without
scarring in 2 to 3 weeks. Regionallymphadenopathy follows in more than 80% of cases, but
resolves usually within 2 to 3 months. In about
10% of cases, the lymph nodes may suppurate
and become fluctuant. 60,64 In uncomplicated CSD,
patients usually remain afebrile and do not appear to be ill.
Nowadays, atypical CSD symptoms are
seen in up to 25% of cases, which is considerably
more than reported previously; however, this
increase probably is associated with increased
clinical awareness/ and it is suggested that these
atypical presentations are manifestations of Bartonella infection rather than CSD.9 Nevertheless,
many authors continue to refer to such infection
as atypical CSD, presumably because of an association with a scratch or bite. 3,16.64
One of the most common atypical manifestations of CSD is ocular involvement, either via
direct inoculation or after rubbing the eye following contact with a cat. Parinaud's oculoglandular
syndrome is a type of conjunctivitis described in
up to 6% of patients with CSD.62 Other ophthalmic manifestations include retinitis,
panuveitis, subacute orbital abscess, chorioditis,
optic nerve masses, branch retinal artery occlusion, and peripapillary angioma. 1W,50.6S-<i7 Most
ocular symptoms resolve with or without treatmentwithin 4 months, but severe and permanent
vision loss has been reported. 67
Neurological involvement occurs in a small
proportion (1-7%) of cases, usually characterized
by encephalopathy.3,6B It presents often as the
sudden onset of a seizure or coma that may last
for several days, but usually resolves with rapid
recovery. However, Noyola and coworkers69 described a CSD patient with recurrent encephalopathy who had two distinct episodes of seizures. Carithers and Margileth70 reported a clinical account of 76 patients with neurological complications (encephalopathy: 61; convulsions: 35).
Armengol and Hendley 68 described six children
who presented with sudden onset of status
epilepticus (seizures >30 minutes duration) that
were diagnosed with CSD, based on clinical criteria and elevated B. henselae titres. As CSD encephalopathy is usually self-limiting without
neurological sequelae, they recommended supportive care rather than specific antimicrobial
treatment.
Other reported atypical manifestations include granulomatous hepatitis,71 hepatosplenic
infection/s,n endocarditis,73.74 paronychia,75 and
osteomyelitis. 38•49.60 CSD may be difficult to diagnose and has been mistaken clinically for lymphogranuloma venereum,s7lymphopharyngeal
cancer with lymph-node metasteses,4< and tuberculous lymphaderutis. 61 Systemic CSD has been
reported in both immunocompetent patients,S1.76
and those infected with HIV.77 The clinical presentation may differ greatly in immunocompromised
patients and may become life-threatening.
Clinical diagnosis
Until fairly recently, the diagnosis of CSD
relied on meeting at least three of four criteria: 1)
animal contact (usually a cat or kitten), with a
scratch or eye lesion; 2) a positive CSD skin test;
3) regional lymphadenopathy that develops 2
weeks after contact; and 4) typical histopathological changes in a lymph node biopsy.3.27 However, the skin test antigen is not available commercially and is prepared from a pool of tissue
from CSD patients. Consequently, it carries an
inherent safety risk and may be capable of trans. mitting pathogens.78 In addition, it has been reported to be less sensitive and less specific than
other diagnostic methods, and, as such, is no
longer recommended by some workers. 9.27
Laboratory diagnosis
B. l1enselae can be seen in stained sections of
lymph node (i.e., using Warthin-Starry silver
stain or Brown Hopp's Grain stain5,33). As biopsy
of the lymph node is an invasive procedure, it
should not be used in routine cases but reserved
for atypical CSD.3 The organisms are best observed early in the illness, and may be very
difficult to see once the lymph node suppurates.
Although B. henselae is fastidious and difficult to grow routinely, it has been isolated successfully from human lymph node tissue,21 cutaneous BA lesions,18 and from blood. 2O,22,53,79-S2 This
is unlikely to be undertaken in a routine diagnostic laboratory, and has only been performed in a
handful of laboratories worldwide. Growth is
slow, especially on blood agar, and isolates require 5 to 15 days incubation in CO/2Colonies of
B. lzenselae are firm, adherent, often embedded in
the agar, and have been described as "cauliflower-like."20 B. henselae are small, curved gramnegative bacilli, with morphology similar to
Camptjlobacter Spp.22
Isolation from human blood may be difficult because B. henselae does not produce detectable CO2, in some blood culture systems.83 Tierno
and coworkers81 isolated B. henselae from the
blood of five febrile immunocompromised patients, using the automated BacT / Alert™ system
(Organon Teknika, Durham, NC);however, they
found it more difficult to isolate from CSD patients.
Gram staining of blood culture specimens
often fails to detect Bartonella spp; therefore, it is
recommended that acridine orange be used to
stain blood cultures before discarding them as
negative. 83 Brenner and coworkers79 examined
the effect of different methods of blood collection
and handling on the isolation of B. henselae. Using
blood specimens from B. henselae-infected cats,
they found that freezing and thawing the sample
yielded the largest number of colonies, and concluded that cell lysis, disruption of cell membranes, and dispersal of bacterial aggregates improved the sensitivity of B. henselae culture from
blood.
B. henselae are catalase- and oxidase-negative, and display twitching motility; they are nonreactive in routine biochemical tests, and are
neither hemolytic nor acid-fast. 82 Cellular fatty
acid analysis reveals the major fatty acids to be
octadecanoic acid eCI!!;). 56%); octadecanoic acid
(C i8 ,O, 25%), and hexadecanoic acid (C;6:O' 13%).80
Such specialized methodology is beyond th.escope
of most clinicalmicl'obiology laboratories; however, Welch and coworkergEO compared the.ability of six comme.rcial identification systems to
distinguish B. henselae and B. quintana, and found
that the MicroScan Rapid Anaerobe Pan:el'l'M
(Baxter Diagnostics, Deerfield, IL) could separate
the two, and identify B. lzenselae successfully.
The most common laboratory method used
to diagnose CSD is serological detection of B.
henselae antibodies. In 1992, Regnery and coworkers25 developed the IFA testfor the detection
of B. l1enselae antibodies in humans. The antigen
was prepared from B.l1enselae co-cultivated with
vero cells to reduce the autoadherent nature of
the organism. Other workers used an enzyme
immunoassay (EIA) to detect IgG, IgM and IgA
antibodies in patients with suspected CSD.s4 Barka
and coworkers84 found the EIA method to be
highly specific and more sensitive (95%) than the
IFAmethod.
Bergrnans and coworkers 48 evaluated both
methods of detecting B. henselae antibodies. Setting the specificity of the assays at ~95% by analyzing serum from blood donors, they found the
sensitivities of the IgG assays to be very low.
However, by increasing the significant titre to
ensure that 95% of healthy donors were negative,
they may have introduced some bias. For example, Zbinden and coworkersS5 studied 120
blood donors who were positive for B. henselne,
and found 11 (9.2%) to have antibody titres >1 in
256.
The presence of B. lzenselae antibodies in
healthy individuals may depend on many variables, but it appears to be higher in Europe than
in the USA.46 Bergmans and coworkers 46 found
the IgMEIA tohavethehighestsensitivity (71.4%)
in patients fulfilling two or more criteria for CSD,
and 80.6% in patients with a positive Bartonella
PCRresult. Furthermore, they recommended that
if only IgG IFA is performed, two-point serology
is necessary to detect a developing B. henselae
infection.
Drancourt and coworkers86 described genotypic variation among B. henselae strains and
described a separate serogroup (Marseille). Given
the-inconsistency of serological results in CSD,
they suggest that this antigenic variability is partly
to blame. Mainardi and coworkersS-l reported
CSD due to B. henselae serotype Marseille in a
seronegative patient, emphasizing the need to
incorporate this serotype into future immunofluorescence assays.
Anderson and coworkers87 characterized a
17-kDa B.ltenselae antigen that provoked a strong
antibodyresponsein CSD patients. Using recombinant DNA techniques, they isolated clones that
expressed tI1is antigen, and this may prove useful
in the development of a simpler serological test.
In addition, if the antigen elicits a protective
inunlUle response, it may be useful in the development of a suitable vaccine.
PCR techniques have been used to detect B.
l1enselae. Bartonella spp. are very similar, both
Treatment
The majority of CSD cases resolve spontaneously within a month or two and do not require
antibiotic treatment. Zangwill36 conunented on
the lack of controlled studies performed to date
and regarded much of the information on CSD
treatment to be anecdotal. He reconunended
therapy only in patients with unresolved lymphadenopathy, where lymphadenopathy is associated with significant morbidity, severe systemic disease, or an underlying medical disorder
complicated by severe CSD.
Margileth3 retrospectively reviewed antibiotic therapy for CSD and described 202 patients, in whom 18 different antimicrobial agents
were used, 'only four of which (rifampicin [87%
effective], ciprofloxacin [84%], gentamicin [73%],
and trimethoprim-sulphamethoxazole [58%])
proved effective. Ciprofloxacin has been used
successfully to treatfive adult patients with CSD,
but is contraindicated in both children and pregnant women. 92
azithromycin, clarithromycin, amoxycillin,
cefotaxime, ceftriaxone and rifampicin. 93 However, these antibiotics are less effective when
used clinically, as treatment failure and relapse
are conunon, B, henselae is intracellular and therefore MIC testing should be performed in a tissue
culture system, where antibiotics have to penetrate the cells.
Musso and coworkers 94 used a cell-line assay to test B. hense/ae against various antimicrobial agents, and found that only aminoglycosides
were bactericidal. Ives and coworkers95 also used
a cell-line assay (vero) to evaluate in vitro susceptibilities of B. henselae against macrolide antibiotics. They measured the ability of the antibiotics to
inhibit rather than eliminate B. henselae, and concluded that clarithromycin, roxithromycin and
aZithromycin may be useful in the treatment of
CSD.
Margileth and Baehren31 considered the
treatment of a healthy patient with typical CSD to
be supportive. In patients with thoracic or pulmonary disease associated with prolonged symptoms
and/ or severe multisystem disease, they recommended oral trimethoprim-sulphamethoxazole,
ciprofioxacin, orazithromycin. Rifampicin was suggested as an alternative, with gentamicin reserved
for the severely ill patient.
In 1998, Bass and coworkers 41 published a
prospective, randomized, double-blind placebocontrolled study of the use of azithromycin in
CSD. They concluded that patients with typical
CSD showed significant clinical benefit after a 5day course, indicated by a decrease in lymphnode volume within the first month of treatment.
However, Zangwill96 was critical of this study
because 10% patients, who had not undergone
serological testing, were excluded from the final
analysis; and considered a combination oftherapeutic restraint and reassurance to be the key with
patients presenting with uncomplicated CSD.
Antibiotic treatment is reconunended in
immunocompromised patients with CSD. Patients with BA, bacillary peliosis hepatis, or relapsing bacteremia should be treated with
macrolides or tetracycline, preferably for 6
weeks. 9.36 Acquired immune deficiency syndrome
(AIDS) patients with BA respond dramatically to
various antibiotics,2.3 and HIV-infected patients
require at least 6 to 8 weeks treatment. In
immunocompromised patients who relapse,
treatment should be continued for 4 to 6 months,
and repeated relapses should be treated indefinitely.9
B. henselae is sensitive to many antibiotics
when tested on agar, with minimum inhibitory
concentration (MIC) <0.125 mg/L for gentamicin, tetracycline, doxycycline, minocycline,
Conclusions
Cat-scratchdiseaseisafairlyconunonclinical syndrome that has puzzled microbiologists
genotypically and phenotypically, and molecular techniques are powerful tools for definitive
species identificationY In addition, these techniques have been used to good effect in elucidating the etiology of CSD. For example, Bergmans
and coworkers 27 used PCR to detect B. l1e11selae
DNA in pus and lymph node specimens from
CSD patients, but failed to detect A. felis DNA.
Many different molecular techniques have
been employed successfully, including amplification ofBartonella DNA and dot-blothybridization with a specific B. henselae probe,4O and amplification of B. henselae genes encoding for citrate
synthase or a 60 kDaheat-shock protein. 59,68 Sander
and coworkers B9 reconunended at least two different primer pairs for higher sensitivity, as falsenegative reactions are likely when performing
PCR for B. henselae on fixed and paraffin-waxembedded tissue.
Molecular methods proved invaluable
when typing strains of B. henselae, with many authors reporting at least two genotypes.34,43,63,89-91 It
would appear that some B. herzseiae genotypes are
more prevalent in different geographical locations. Furthermore, different genotypes were
found in cats and humans, which may be related
to pathogenicity.B9 Sander and coworkers 43 compared different DNA fingerprinting methods for
molecular typing of B. henselae and found that
genetic heterogeneity was high. This may prove
useful in future epidemiological studies.
for many years. There is now little doubt that B.
henselae causes CSD, and is transmitted to man
via infected cats; however, in some CSD patients
the organism cannot be detected, even by sensitive molecular techniques. This raises the possibility that more than one causative agent is involved.
A. fe/is has been isolated from the lymph
nodes of CSD patients, and could be responsible
for a small number of cases; however, the lack of
a serological response to this organism in humans, and its absence from cats, would seem to
argue against this hypothesis.
Genotypic variation among B. henselae isolates may result in negative diagnostic tests in
CSD patients, especially as the Marseilles
serogroup is not screened for routinely. In addition, other Bartonella spp, such as B. clarridgeiae,
also may be associated with CSD.
At the beginning of the 21 ,I century we have
a much better understanding of the etiology and
epidemiology of CSD; however, there is much
still to discover, and the vexing question of how
the organism is transmitted from the blood of an
asymptomatic cat to man largely remains unanswered.
Acknowledgments
The authorwouldlike to thank Dr. T. C. Harrison,
Respiratory and Systemic Infection Laboratory,
PHLS Central Public Health Laboratory, UK, for
help and guidance.
References
1. EngUsh CK, Wear DJ, M<!rgileth AM, et al: Cat scratch
disease: Isolationand culture ofthe bacterial agent. JAMA
19B8;259:1347-1352.
2. MargilelhAM: An tibiot ic therapy fOl'cal-scratchdisease:
Clinical stud.y of therapeutic outcome in 268 patients and
a review of the Iiteratme. Pedinlr infect Dis J 1992;11 :474478.
3. Midani S, Ayoub EM, Anderson B: Cat-scratch disease.
Adll Paedintr 1996;43:397-423.
4. Jackson LA, Peikins BA, Wenger JD: Cat scratch disease
in the United States. Am JPublic HeaItlI1993;83:1707-171l.
5. Wear DJ, Margileth AM, Hadfield TL, et al: Cat scratch
disease: A bacterial infection. Science 1983:221 :1403-1405.
6. Kordick DL, Hiliard EJ, Hadfield TL, et al: Bartonella
clarridgeiae, a newly recognized zoonotic pathogen causing inoculation papules, fever, and lymphadenopathy
(cat scratch disease). J CIIIl MicrobioI1997;35:1813-1818.
7. Debre R, Lary M, Jemmet ML, et al: La maladie des griffes
du chat. Sem Hop Paris 1950;26:1B95-1904.
8. Parinaud H: ConJunctivite infectieuse transmise par les
animaux. A lin d'Oculistiql.lf! 1B89;101:252-253.
9.13ass]W, Vincent 1M, Person DA; The expanding spectrum of Bartonella jJ,fection. II. Cat-scratch disease. Piled/lllr
Infect Dis J 1997;16:163-179.
10. Warwick W]: The cat scratch syndromes, many diseases
or one disease? Prog Med ViroI1967:9:256--301.
11. Carithers HA: Cat scratch disease. An overview based on
a study of 1,200 patients. Am J Dis Child 19B5;139:11241131.
12. Regnery R, Tappero J; Unr,weling mysteries associated
with cat-scratch disease, bacillary angiomatosis, and related syndromes. Ewerg bifecl D;sl995;1:16-21.
13. Margileth AM, Wear OJ, Hadfield TL, et al: Cat-scratch
disease: Bacteria in skin at the primary inoculation site.
JAMA 1984:252:938-942.
14. Solley WA, Martin DF, Newman NJ, at ai. Cat scratch
disease: Posterior segment manifestations. Opiltllnlmol-
ogy 1999;106:1546--1553.
15. Brenner OJ, Ho llis DG, Moss CW, et al. Propos,11or Aftl.lin
gen. nov " WiUl AJ/pia felis sp. nov. (formerly the cat
scratch disease bacillus), lifipin c/l!!letflJ1riclIs is sp. nov.
(fonnerly the Cleveland Clinic Foundatloll sh'ai n), Afipin
braomellc sp. nov ., il nd three unnamed genospecies.J Clill
MicrobioI1991;29:24SQ-02460.
16. Anderson BE, Neuman MA: Bflrtonella spp. as emerging
human pathogens. Clill Microbiol Rell1997;10:203-219.
17. Reiman DA, Loutit JS, Schmidt TM, et al: The ngent of
bacillary angiomatosis: An approach to the identification
of uncultured pathogens. N Engl J Med 1990;323:15731580.
18. Koehler jE, Quinn FD, Berger TG, et ai: Isolation of
Roc!ralimaen species from cutaneous and osseous lesions
of bacillary angioimatosis. N Engl JMet! 1992;327:16251631.
19. Slaterl.N, Welch DF, Hensel D, et al: A newly recognized
pa thogen as a cause of fever and bacteremia. N Engl JMed
1990;323: l.587-1593.
20 ..Regnery RE, AndersQIl BE, Clarridge fE III, et al: Characterization of a novel Rodmli/llflea species, R. iIense/ne sp.
nov" isolated from blood of a febrile, human immunodeficiencyvirus-positive patient. JClill Microbio/1992;30:265274.
21. Dolan Mj, Wong MT, Regnery RL, et ili: Syndrome of
Roc/rnlillrnea Ilen.clne adenitis suggesting cat-scratch disease. AmI Intel'll Mcd 1993;1l8:331 -~36.
22. WeJchDF,PickettDA,SlaterLN,etal:Roc/w/i/llneaiIcnselne
sp. nov., a cause of septicaemia, bacillary angiomatosis,
and parenchymal bacillary peliosis. J Clin Microbiol
1992;30:275-2BO.
23. Brenner DJ, O'COImor SP, Winkler HH, et al: Proposals to
unify the genera Bartonella and Rochalimaea, with descriptions of Bartonella quintana comb. nov., Bartonelln
vinsonii comb. nov., Bartonella he/lselae comb. nov., and
Bar1oncJlneliznbetlwecomb.nov., and to remove the family
Bartonellaceae from the order Rickettsiaies. ll'lt J Syst
BncterioI1993;43:777-7B6.
24. Tappero J, Regnery R, Koehler j, et al: Detection of serologic response to RoclJIIlilllaea /tellseine i1\ patients with
bacilliny angiomatosis (BA) by immunofiuorescental1tibody (rEA) testing. 32nd lutcrscimceCDllferellC(!OII Alltilllic]'cbinl Agel1ls Ilmi C!te/llQllzempy, Anah eim. CA. Octnber
10-14, 1992. Abstract no. 674.
25. Regnery RL, Olson JG, Perkins BA, et al: Serological
response to 'RodlllllllllJen Ilel1se1ne' antigen insuspected cat
scratch d ise<tse. ulIlcet 1992:339:1443-1445.
26. Anderson B, Kelly R, Threlkei R, et al: Detection of
Rocllalimaea henselne in cat-scratch disease skin test antigens. JInfec Dis 1993;168:1034-1036.
27. Bergmans AMC, Groothedde J-W, Schellekens JFP, et ai:
Aetiology o( cal scratch disease: comparison of polymerase chain reaction detection of Bartonella (formerly
Rochalimaea) and Afipin fells DNA with serology and
skin tests. JlIz/ect D,s 1995;171 :916-923.
28. AlkanS, MorganMB,SandinRL, et al: Duni role for Afipia
felis and Rod1ll1imaea lIenselne in cat-scratch disease. La"cct
1995;345:385.
29. Giiadi M, Avidor B, Kletter Y, et al: Cat scratch disease:
The rare role of Afipiafe1is. JClin MicrobioI1998;36:24992502.
30. La Scola B, Raoult D: Afipiafelis in hospital water suppiy
in association with free-living amoeba. Lancet
1999;353:1330.
31. Margileth A, Baehren DF: Chest-wall abscess due to cat
scratch disease (CSD) in an adult with antibodies to
Bartollella dnn'idgeiae: Case report and review of the
thoracopulmonary manifestations of CSD. Clin Infect Dis
1998;27:353-357.
32.Regnery R, Martin M, Olson J: Naturally occurring
Rodwlimnen lIenselae i.nfection in domestic cats. Lancet
1992;340:557-558.
33. Zangwill KM, Hamilton DEL, Perkins BA, et al: Cat
scratch disease in Connecticut. Epidemiology, risk factors, and evaluation of a new diagnostic test. N Eng/ JMed
1993;329:8-13.
34. Sander A, Buhler C, Pelz K, et al: Detection and identification of two Bartonella hense/ae variants in domestic cats
in Germany. J Clin Microbio/1997:35:584-587.
35. Koehler JE, Glaser CA, Tappero JW: Rocha/imaea hense/ne
infection. A new zoonosis with the domestic cat as reservoir. JAMA 1994;271:531-535.
36. Zangwill KM: Bartonella infections. Sem Paediatr Infect
Dis 1997;8:57-{i3
37. Chomel BB, Kasten RW, Floyd-Hawkins K, et al: Experimental transmission of Bartonella hense/ae by the cat flea.
J Clin Microbio/1996;34:1952-1956.
38. Keret D, Giladi M, Kletter Y, et al: Cat-scratch disease
osteomyelitis from a dog scratch. J Bone Joint SHrg
1998;80:766-767.
39. Tsukahara M, Tsuneoka H, Lino H, et al: Bartonella henselae
infection from a dog. Lancet 1998;352:1682.
40. Anderson B, Sims K, Regnery R, et al: Detection of
Roclmlimaea hense/ae DNA in specimens from cat scratch
disease patients by PCR. JClinMicrobio/1994;32:942-948.
41. Bass ]W, Freitas BC, Freitas AD, et al: Prospective randomized double-blind placebo-controlled evaluation of
azithromycin for treatment of ca t-scratchdisease. Paediatr
Infect Dis 1998;17:447-452.
42. Golnik KC, Marotto ME, Fanous MM, et al: Ophthalmic
manifestations of Rocllnlimaea species. Am J Ophtllll/mol
1994;118:145-151.
43. Sander A, Ruess M, Bereswill S, et al: Comparison of
different DNA fingerprinting techniques for molecular
typing of Bartonella henseille isolates. J Clin Microbiol
1998;36:2973-2981.
44. Ridder GJ, Richter B, Laszig R, et al: A farmer witha lump
in his throat. Lancet 1998;351:954.
45. Arvand M, Wendt C, Regna th T, et al: Characterization of
Bartonella henselae isolated from bacillary angiomatosis
lesions in a human immunodeficiency virus infected
patient in Germany. Clin Infect Dis 1998;26:1296-1299.
46. Sander A, Posselt M, Oberle K, et al: Seroprevalence of
antibodies to Bllttfmella helT.elnein patients with cat scratch
disease and in hea lthy controls: Evaluation and comparison of two commercial serological tests. Clin Diagn Lnb
Inl1lHtI1oI1998;5:486-490.
47. Rothova A, Kerkhofff, Hooft HI, et al: Bartonella serology
for patients with intraocular inflammatory disease. Retina
1998;18:348-355.
48. Bergmans AMC, Peeters MF, Schellekens JFP, et al: Pitfalls and fallacies of cat scratch disease serology: Evaluation of Bartonella !tenselne-based indirect fluorescence assay and enzyme-linked immunoassay. J c/in Microbiol
1997;35:1931-1937.
49. Hulzebos CV, Koetse HA, Kimpen JLL, et al: Vertebral
osteomyelitis associated with cat-scratch disease. Clin
Infect Dis 1999;28:1310-1312.
50. Kerkhoff FT, Ossewaarde JM, de Loos WS, et al: Presumed ocular bartonellosis. Br JOphtha/mo/1999;83:270275.
51. Waldvogel K, Regnery RL, Anderson BE, et al: Disseminated cat-scratch disease: Detectionof RoclJalil1laea !renselae
in affected tissue. Eur JPediatr 1994;153:23-27.
52. ZbindenR: Bartonella hense/ae-based indirect fluorescence
assays are useful for diagnosis of cat scratch disease. JClill
MicrobioI1998;36:3741-3742.
53. La Scola BL, Raoult 0 : Culture of Bar/oncllll quintana and
Bartonella hellse!ae from human samples: A 5-year experience (1993 to 1998). JClill M1crobioI1999;37:1899-1905.
54. MainardiJ-L, Figliolini C, GoldsteinFW, et al. Cat scratch
disease due to Bartonella henselaeserotype Marseille (Swiss
cat) in a seronegative patient. JClin Microbio/1998;36:2800.
55. Fortuno a, Uriel JA, Lomba E, et al: Hepatosplenic cat
scratch disease diagnosed by serology. Eur J Pediatr
1999;158:432
56. Not T, Canciani M, Buratti E, et al: Serologic response to
Bartonella henselae in patients with cat scratch disease and
in sick and healthy children. Acta Pediatr 1999;88:284-289.
57. Hagley M, Came CA, Gorgees N: A case of cat scratch
disease masquerading as lymphogranuloma venereum.
Int J STD AIDS 1999;10:334-335.
58. Harrison TG, Doshi N: Serological evidence of Bartonella
spp. infection in the UK. Epidemiol Infect 1999;123:233240.
59. Avidor B, Kletter Y, Abulatia S, et al: Molecular diagnosis
of cat scratch disease: A two-step approach., CUn Microbio/
1997;35:1924-1930.
60. Robson JMB, Harte GJ, Osborne DRS, et al: Cat scratch
disease with paravertebral mass and osteomyelitis. Ciill
Infect Dis 1999;28:274-278
61. Gottlieb T, Atkins BL, Robson JMB: Cat scratch disease
diagnosed by polymerase chain reaction in a pa tien t with
suspected tuberculous lymphadenitis. Med J Allst
1999;170:168-170.
62. Grando O,Sullivan LJ, FlexmanjP, et al: Bar/onella !rense/ae
associated with Parinaud's oculoglandular syndrome.
CUn Infect Dis 1999;28:1156-1158
63. Sander A, Ruess M, Deichrnalill K, et al: Two different
serotypes of Bnrtonella !rense/ae in children with ca t-scratch
disease and their pet cats. Scand J Infect Dis 1998:30:387391.
64. Seals JE, Oken HA: Cat scratch encephalopathy. Md Med
J 1999;48:176-178.
65. Gaebler jW, Burgett RA, Caldermeyer KS: Subacute orbital abscess in a four-year-old girl with a new kitten.
Paediatr Infect Dis J 1998:17:844-846.
66. Kerrison JB, Bennett MD, Newman NJ, et al: Atypical
mass lesions associated with cat-scratch disease. Clill
Infect Dis 1999;29:221-223.
67. Gray AV, Reed jB, Wendel RT, et al: Bartonella hellselne
infection associated with peripapillary angioma, branch
retinal artery occlusion, and severe vision loss. Am J
OplJt!lIlllloI1999;127:223-224.
68. Armengol CE, Hendley 10: Cat-scratch disease encephalopathy: A cause of status epileplicus in school-aged
children. J Pediatr 1999;134:635--{;38.
69. Noyola DE, Holder or, Fishman MA, et al: Recurrent
encephalopathy in cat-scratch disease. Pediatr Infect Dis J
199;8:567-568.
70. Carithers HA, Margileth AM: Cat-scratch disease: Acute
encephalopathy and other neurologic manifestations.
Am J Dis Gild 1991;145:98-101.
71. Lenoir AA, Storch GA, Deschryver-Kecskemeti K, et al:
Granulomatous hepatitis associated with cat scratch disease. Lnncet 1988;1:1132-1136.
72. Tan TQ, Wagner .ML. Kaplan SL: Bartonella (Roc1l1lli",nen)
lreJlselaehepatospleniciniectionoccurringsimultaneously
in two Siblings. Clin Infect Dis 1996;22:721-722.
73. Baorto E, Payne M, Slater LN, et al: Culture-negative
endocarditis caused by Bartonella !rense/ae. J Paediatr
1998;132:1051-1054.
74. Holmes AH, Greenough TC, Balady G], et al: Bartonella
Irenselaeendocarditis in an immunocompetent adult. Clil1
Infect Dis 1995:21:1004-1007.
75. Sander A, Frank B: Paronychia caused by Bartonella
hense/ae. Lnncet 1997;350:1078.
76. Rosenburg A: Systemic cat scratch disease: A brief case
report and review of the literature. Conn Med 1998;62:205-
208
77. Wong MT, Dolan MJ, Lattuada CP, et al: Neuroretinitis,
aseptic meningitis, and lymphadenitis associated with
Bnrtonella (Rochlllimaea) hense/ae infection in immunocompetent patients and patients infected with human
immunodeficiency virus type 1. Ciin Infect Dis 1995;21:352360.
78. Arvand M, Mielke MEA, Sterry K, et al: Detection of
specific cellular immtUle response to Bartonella henselae in
a patient with cal' scratch disease. C/il1 Illfect Dis
1998;27:1533-1534.
79. BrennerSA, Rooney JA, Manzewitsch P, et al: Isolation of
Bartonella (Roc1Ullimaea) hense/ae: Effects of methods of
blood collection and handling. JCIiI1Microbio/1997;35:544547.
80. Welch OF, Hensel DM,Pickett DA, etal: Bacteraemia clue
to Roc/mUll/ilea Ilellselae in a child: practical identification
of isolates In the clinical laboratory. J Clin Microbiol
1993;31:2381-2386.
81. Tierno PM, Inglima K, Parisi MT: Detection of Bartonella
(Roc/llllimaea) henselae bacteremia using BacT/Alert blood
culture system. Am JCIin PatllOl 1995;104: 530-536
82. Lucey D, Dolan MJ, Moss CW, et al:.Relapsing i1lnes-5due
to Roclmlilllllea IlIlI/ selae jn immunocompetent hosts: Implications for therapy and new epidemiological association. CUI/II/feet Dis 1992;14:683-638.
83. Larson AM, Dougherty MJ, Nowowiej'ski DI, eta!. Detection of Bnrtollelln (Rochalillmea) qlli/l/ll1m by routine acridine staining of broth blood cultures. J eli" Microbial
1994;32:1492-1496.
84. Barka NE, Hadfield T, Patnail M, et al: EIA for detection
of Rochnlill/llen !tell seine-reactive IgG, IgM, and IgA antibodies in patients with suspected cat-scratch disease. I
Infect Dis 1993;167:1503-1504.
85. Zbinden R, Michael N, Sekulovki M, et al: Evaluation of
cOmmercial slide for detection of immunoglobulin G
against Bllrlonella lumselne by indirect immunofluorescence. ElIr JClin Micr.obioJ II/fect Dis 1997;16:648-651
86. Drancourt M, Birlles R, Chammentin G, et al: New serotype of Bartonella henselae in endocarditis and cat-scratch
disease. lAncet 1996;347:441-443.
87. Anderson l3, Lu E, Jones D, et al: Characterization of a 17kilodalton antigen of Bartonella henselae reactive with the
sera from patients with catscratch disease. I Clin Microbial
1995;33:2358-2365.
88. Norman AF, Regnery R,Jameson P, eta.l: Differentiation
of Bartonella-llke isolates at the species level by PCRrestri tion fragment length polymorphism in the citrate
Article
234
0.1 CEC
synthase gene. I c/in Microbio/1995;33:1797-1803.
89. Sander A, Posselt M, B6hm N, etal: Detection of Bartollella
henselae DNA by MO different PCR assays and determination of the genotypes of strains involved in histologically deffned cat scrat.ch disease. I Clill Microbiol
1999;37:993-997.
90. Rodriguel.-B~rradas MC, Hamill RJ, Houston ED, et al:
Genomicfingerprinting ofBnrlondla species by repetitive
element PCR for distinguishing species and isolates. J
Clill Microbio/1995;33:1089- 1093.
91.l3ergmans AMC,Schellekens JFP, vanEmbden JDA, et al:
Predominance of MO Bartonella henselae variants in The
Netherlands. J Clin Microbio/1996;34:254-260.
92. Holley HPJr: Successful treatment of cat-scratch disease
with ciprofloxacin. lAMA 1991;265:1563-1565.
93. Maurin M, Raoull D: Antimicrobial susceptibility of
ROc/lIlliI1ll7enqllilllmla, Roc/lalilllaea vinson ii, and the newly
recognized Roclllllillll1en ilel1selae. JAn limic/'obinl CI,e/1/olller
1993;32:587-594.
94. Musso D, Drancourt M, Raoult D: Lack of bactericidal
effect of antibiotics except aminoglycosides on Barlollelln
(Rociwlimaen) Ilenselae. J Antimicrobiol Cllemollrer
1995;36:101-108.
95. IvesIT, Manzewitsch P. j{egnery.RL. et ~l : In vi lro susceptibilities of Bnr/ollella llenselae, B. quilltalla. B. eliznbetlme,
Rit:k~tlsla ric.kellsli. R. conorii, R. IIknti, and R. pI'DwlIZfkii to
macrolJde antibiotics as determined by immunotluorescent-antibody analysis of infecled vl!ro cell m0I101a.yers.
An/illlicrob Agellis Chemot/rer 1997:41:578-582.
96. Zangwill K: Therapeutic options for cat-scratch disease.
Pediatr Infect Dis J 1998;17:1059-1061.
Questions for STEP Participants
\
Answer questions only on the official STEP answer sheet. !fyou do nothav~ the official STEP answer sheet, a year's
supply can be obtained (a t no cost) simply by writing to: STEP Program Answer Sheets, American Medical
Technologists, 710 Higgins Road, Park Ridge, IL 60068-5765.
In addition to marking your answers, be sure to include all the required information on the answer sheet
and a processing fee of $2.00 per article. In the following, choose the one best answer for each question.
1
2
3
6
The most common laboratory method used to
diagnose CSD is serological detection of B.
henselae antibodies. (True or false.)
The etiological agent for CSD eluded
detection until 1983. (True or false.)
7
The disorder is so named because it is
associated with a cat bite or scratch. (True or
false.)
One of the criteria for diagnosis of CSD is
regional lymphadenopathy, which develops 3
days after contact. (True or false.)
8
The majority of CSD cases:
A. resolve spontaneously
B. require intensive treatment
C. require antibiotic therapy
D. are in temperate climates
9
Because there are over 57 million cats in the
United States, there is an immense reservoir
for potential infections. (True or false.)
Cat scratch disease (CSD) was first described
in 1864. (True or false.)
4
Nearly 25% of the 24,000 cases annually
require hospitalization. (True or false.)
5
Typically a papule develops in the scratch
line in about:
A. 3 to 5 days
B. 3 to 7 days
C. 3 to 10 days
D. 3 to 15 days
10
CSD in immunocompromised patients may
be life-threatening. (True or false.)